TABLE OF CONTENTS

Introduction and Forward

Biochemistry
Immunology
Microbiology
General Pathology
General Pharmacology
Biostatistics, Bioethics, and Health Sciences
Cardiovascular
Hematology and Oncology
Respiratory
Gastrointestinal
Renal
Endocrine
Reproductive
Skeletal
Muscular
Skin
CNS
Psychiatry
Introduction
Every study guide is a compromise between competing aims, goals, and philosophies: brevity versus comprehensiveness, explanation versus summary, just
enough versus too much. This document is no exception. In light of the wealth of resources directed at helping students succeed on STEP 1, I thought a brief
word about this addition was merited.

Why another STEP 1 prep document? Every year medical students come to some version of this realization: ‘First Aid is an awesome resource, but there is a lot
of essential information missing from it.’ So they buy their favorite set of fancy pens and write all over their copy of First Aid, a medical school rite of passage
born from necessity. Those same medical students begin their arduous trek (or treks) through UWORLD and most realize, ‘This is an amazing Q-bank packed with
information and amazing diagrams and tables, but it is not set up for systematic review. Their annotations in First Aid are an attempt to meld the two resources.
This, in a word, is what I have attempted here. If First Aid and UWORLD were melded together into one high yield textbook, this would be that textbook.

What is the goal of this study guide? Every quality STEP 1 resource has its own primary goal and usually a secondary goal. Here are some examples:

• First Aid: 1.) Primary Goal: COMPILE, i.e. narrow down all the basic medical science information available into a smaller amount of the highest yield
information, 2.) Secondary Goal: MEMORIZE, mostly through mnemonics, which I do not find to be particularly effective, although some people like
them
• Kaplan/USMLE RX: 1.) Primary Goal: EXPLAIN, 2.) Secondary Goal: COMPILE, although much less so, since they try to be as comprehensive as possible
• Sketchy Medical: 1.) Primary Goal: MEMORIZE, 2.) Secondary Goal: EXPLAIN, especially the more recent additions, as Sketchy Micro is very light on
explanation and those original sketches consist mainly of memory hooks
• Pathoma: 1.) Primary Goal: COMPILE and EXPLAIN, one of the reasons Pathoma is so popular and useful is because it has 2 primary goals and is
incredibly effective at accomplishing both of them
• This Study Guide: 1.) Primary Goal: COMPILE, the main purpose of this guide is to compile all of the information you need to know to do well on STEP 1.
It is not designed to help you MEMORIZE or to really EXPLAIN much, although I do provide explanations throughout, instead, I have attempted to do the
best possible job of COMPILING

Should you still use First Aid? Yes! First Aid is great for quick review. If you are looking for a review book to read in a weekend, then First Aid is what you
want. I recommend reading it straight through before you start studying hardcore and 2-3 days before you take STEP 1. But if you want a guide to review the
systems blocks in a comprehensive way that covers exactly what you need to know for STEP 1, this is it! I estimate this guide would take 8-12 days to read
straight through, and it is designed for reviewing 1-2 chapters/blocks per day.

Where did the information in this book come from? I drew from First Aid, UWORLD, Sketchy Medical, Pathoma, medbullets.com, and several other reliable
sources. I used the 2017 First Aid book as my outline, and I guarantee there is nothing in there that is not in this guide (I even corrected the accepted major
and minor errata reported for the 2017 edition). I have not included the quick review section from First Aid because as I mentioned above, First Aid is what
you should read for quick review.

What have you added? High yield topics appearing in UWORLD or in the other mentioned resources that were not covered in First Aid, a lot of high yield
images, and I have notably beefed up the neuro section, which I believe is very weak in First Aid. I have removed some of the mnemonics I considered dumb
or unhelpful, which I admit is a totally subjective assessment. Overall I left many of the mnemonics in although I rarely use mnemonics.
Is this guide free? Yes. These are my notes that I actually used to prepare for STEP 1. They very obviously draw on a lot of copyrighted material. I have not
received any money or other compensation in return for this guide, and I highly recommend that you make use of the resources I mentioned above (First
Aid, Sketchy Medical, UWORLD, Pathoma, etc.), since as I explained, each of these resources has a different goal and philosophy, and each is useful in its
own way.

Probably the best general study advice I can give you is to find a method that works for you and do it. Talk to other people, get ideas from them, but don’t
worry that your study method isn’t exactly what someone else is doing. Some people use flashcards, some people like to write notes by hand, some people
draw diagrams, some people annotate, some people don’t write many notes at all, some people devour Q-banks – Kaplan, USMLE Rx, UWORLD twice, while
you barely get through UWORLD once, some people read, some people can’t read and instead watch videos all day during their study time. It’s OK! Everyone
is different, and the “right” way truly is the way that works for you.

My final request of you as a medical student is to work selflessly with your classmates and peers. Try to make them look good, try to help them learn, don’t
compete with them. You may get the idea that medicine is “cut-throat” and that you have to compete with your classmates to get top residencies. Without
disclosing too many personal details, I can tell you based on my experience that life doesn’t work this way. You can do all that competitive BS and chip away
small pieces of your soul and at the end of the day what is it for? Everyone seems to get the residency they need. Thus I would implore you: help your
classmates, help them be the best doctors they can be. You’ll still get a great residency, you’ll be a happier person, you’ll have better relationships with
those around you, and in general when doctors work together and help each other succeed, humanity wins. If you learn nothing else from this guide,
remember this paragraph. If you take this advice, I promise it will make you a better and happier person. 
Organization
This guide is set up just like First Aid, with general topics first and organ systems after. Each organ system is also arranged similarly to First Aid, with Embryology
first, then Anatomy, then Pathology, and finally Pharmacology. One idiosyncrasy of this guide is that the only words in bold within paragraphs are names of
drugs. I did this to make them stand out more.

There is also an underlying organization within each microbiology entry and a similar organization within each pathology entry (i.e. within an entry in any section
describing a disease). You don’t really need to know this in order to find the material useful, but it may help you understand why things are where they are
within a paragraph (e.g. if you want to know the prognosis of a condition, it’s always at the end).

Microbiology Annotations

• Basic description with lab findings

• Appearance specifics
• Pathogenesis
• Transmission and reservoir
• Epidemiology and other associations
• Presentation
• Means of diagnosis (excluding already mentioned labs)
• Treatment
• Vaccine
• Prognosis/complications

Pathology Annotations

• Basic description
• Pathogenesis/cause
• Location/gene associations
• Epidemiology including the typical test question patient and other associations, e.g. elderly woman (>60)
• Histological features
• Presentation
• Lab/test results
• Means of diagnosis (excluding already mentioned labs)
• Treatment
• Prognosis/complications/metastatic potential
Biochemistry Homepage
DNA Structure
• Chromatin Structure – DNA exists in condensed, chromatin form in order to fit into the nucleus, negatively-charged DNA loops twice around positively-
charged histone octamer to form nucleosome (“beads on a string”), histones contain 2 sets each of H2A, H2B, H3, H4, rich in Lysine and Arginine, H1
binds nucleosome and linker DNA, stabilizing chromatin fiber, during mitosis DNA condenses to form chromosomes, DNA and histone synthesis occur
during S (“synthesis”) phase

• Heterochromatin – condensed form of chromatin, appears darker on EM, transcriptionally inactive, sterically inaccessible, increased methylation,
decreased acetylation (both epigenetic changes), includes Barr bodies (inactivated X chromosomes in females)
• Euchromatin – less condensed form of chromatin, appears lighter on EM, transcriptionally active, sterically accessible, decreased methylation, increased
acetylation (both epigenetic changes)
• DNA Methylation – template strand Cytosine and Adenine methylated in DNA replication, allows mismatch-repair enzymes to distinguish between old
and new strands in prokaryotes, DNA methylation at CpG islands repress transcription
 • Histone Methylation – epigenetic change (altered expression without altered DNA sequence), usually reversibly represses DNA transcription, but can
activate it in some cases depending on methylation location
• Histone Acetylation – relaxes DNA coiling, allowing for transcription

Nucleotides
• Nucleoside – base + (deoxy)ribose sugar
• Nucleotide – base + (deoxy)ribose sugar + phosphate, can be XMP (1 phosphate), XDP (2 phosphates), XTP (3 phosphates), nucleotides linked by 3’-5’
phosphodiester bonds, 5’ end of incoming nucleotide contains triphosphate energy source for bond, target of 3’ hydroxyl attack)
• Purines – 2 rings, Adenine (deamination makes Hypoxanthine), Guanine (deamination makes Xanthine, “Pure As Gold”), Glycine, Aspartate, Glutamate,
and THF required for purine synthesis
• Pyrimidines – 1 ring, cytosine (deamination makes Uracil), Uracil (RNA only, methylation makes Thymine), Thymine (DNA only, methyl group)
• Heating DNA – G-C bond (3 H bonds) stronger than A-T bond (2 H bonds), increased G-C content increases melting temperature (“C-G bonds are like
Crazy Glue”)
De Novo Pyrimidine and Purine Synthesis
• De Novo Pyrimidine and Purine Synthesis – phosphoribosyl pyrophosphate a key intermediate, used to produce either purines or pyrimidines, various
immunosuppressive, antineoplastic, and antibiotic drugs interfere with nucleotide synthesis
• Disrupts Pyrimidine Synthesis:
o Leflunomide: inhibits dihydroorotate dehydrogenase, which converts carbamoyl phosphate and aspartate to orotic acid
o Methotrexate (MTX) (humans), Trimethoprim (TMP) (bacteria), Pyrimethamine (protozoa): inhibits dihydrofolate reductase, decreasing
deoxythymidine monophosphate (dTMP)
o 5-Fluorouracil (5-FU): antimetabolite, forms 5-F-dUMP, inhibiting thymidylate synthase, decreasing dTMP
• Disrupts Purine Synthesis:
o 6-Mercaptopurine (6-MP) and Azathioprine (prodrug): inhibit de novo purine synthesis
o Mycophenolate and Ribavirin: inhibit inosine monophosphate (IMP) dehydrogenase, preventing conversion of IMP to GMP
• Disrupts Purine and Pyrimidine Synthesis:
o Hydroxyurea: inhibits ribonucleotide reductase, preventing conversion of UDP to dUDP on its way to Thymine
Purine Salvage Deficiencies
• Adenosine Deaminase (ADA) Deficiency – autosomal recessive (when part of SCID), ADA required for degradation of adenosine and deoxyadenosine,
without it dATP increases, producing lymphocyte toxicity, major cause of SCID
• Lesch-Nyhan Syndrome – X-linked recessive, defective purine salvage due to absent hypoxanthine guanine phosphoribosyltransferase (HGPRT), which
converts hypoxanthine to IMP and guanine to GMP, results in excess uric acid production and de novo purine synthesis, presents with intellectual
disability, self-mutilation, aggression, hyperuricemia with orange “sand” (sodium urate crystals) in diaper, gout, dystonia, treat with Allopurinol or
Febuxostat (both xanthine oxidase inhibitors, Febuxostat 2nd line) (HGPRT: “Hyperuricemia, Gout, Pissed off – aggression, self-mutilation, Retardation –
intellectual ability, dysTonia”)
Features of the Genetic Code
• Unambiguous – each codon specifies only 1 amino acid
• Degenerate/Redundant – most amino acids coded for by multiple codons, Exceptions: Methionine (AUG), Tryptophan (UGG), “Wobble Hypothesis”:
codons that differ in 3rd “wobble” position may code for the same tRNA/amino acid (specific base pairing only required in first 2 positions of mRNA
codon for most amino acids)
• Comma-less/Non-overlapping – read from a fixed starting point as continuous sequence of bases, Exceptions: some viruses
• Universal – genetic code conserved throughout evolution, Exceptions: mitochondria (in humans)

DNA Replication
• Introduction to DNA Replication – eukaryotic DNA replication more complex than prokaryotic version, but uses many analogous enzymes, DNA
replication semiconservative in both, involving continuous and discontinuous (Okazaki fragment) synthesis, and occurs in 5’ to 3’ direction
• Origin of Replication – particular consensus sequence of base pairs in a genome where DNA replication begins, single in prokaryotes, multiple in
eukaryotes, AT-rich sequences (e.g. TATA boxes) found in promoters and origins of replication
• Replication Fork – Y-shaped region along DNA template where leading and lagging strands synthesized
• DNA Helicase – unwinds DNA template at replication fork, Bloom Syndrome: rare autosomal recessive disorder caused by mutation in BLM gene, which
encodes DNA helicase, dysfunction results in chromosomal instability and breakage, presents with growth retardation, facial anomalies (e.g.
microcephaly), photosensitive rash, and immunodeficiency (e.g. recurrent infections).
• Single-Stranded Binding Proteins – prevent strands from reannealing
• DNA Topoisomerases – create single- or double-stranded break in helix to add or remove supercoils, various immunosuppressive, antineoplastic, and
antibiotic drugs target these proteins:
o Irinotecan and Topotecan: Eukaryotic topoisomerase 1
o Etoposide and Teniposide: Eukaryotic topoisomerase 2 (“eTWOposide”)
o Fluoroquinolones (Ciprofloxacin, Levofloxacin): Prokaryotic topoisomerase 2 (DNA gyrase) and 4
• Primase – makes RNA primer on which DNA polymerase 3 can initiate replication
• DNA Polymerase 3 – prokaryotes only, elongates leading strand by adding deoxynucleotides to 3’ end (5’ to 3’ synthesis), elongates lagging strand until
it reaches primer of preceding fragment, 3’ to 5’ exonuclease activity (“proofreads” each added nucleotide), drugs blocking DNA replication often have
modified 3’ OH, preventing addition of the next nucleotide (“chain termination”)
• DNA Polymerase 1 – prokaryotes only, degrades RNA primer, replaces it with DNA, same functions as DNA Polymerase 3, also excises RNA primer with 5’
to 3’ exonuclease activity
• DNA Ligase – catalyzes formation of phosphodiester bond within a strand of dsDNA, joins Okazaki fragments
• Telomerase – eukaryotes, RNA-dependent DNA polymerase (reverse transcriptase) that adds DNA to 3’ ends of chromosomes to avoid loss of genetic
material with every duplication, 2 subunits: 1.) TERT: reverse transcriptase, 2.) TERC: “built in” RNA template that is repeatedly read by TERT to add
TTAGGG DNA sequence repeats to telomeres, often dysregulated (downregulated) in cancer, allowing unlimited replication, may be upregulated in
Progeria, stem cells have very long telomeres due to high telomerase activity
DNA Mutations
• Introduction to DNA Mutations – severity of damage: silent << missense < nonsense < frameshift, for point (silent, missense, nonsense) mutations:
o Transition: purine to purine (e.g. A to G) or pyrimidine to pyrimidine (e.g. C to T)
o Transversion: purine to pyrimidine (e.g. A to T) or pyrimidine to purine (e.g. C to G)
• Silent Mutation – nucleotide substitution that codes for the same (synonymous) amino acid, base change usually in 3rd position of codon (tRNA wobble)
• Missense Mutation – nucleotide substitution resulting in changed amino acid (“conservative” if new amino acid chemically similar), Example: SCD
(substitution of Valine for Glutamic Acid at position 6)
• Nonsense Mutation – nucleotide substitution resulting in an early stop codon (UAG, UAA, UGA), usually results in nonfunctional protein (“stop the
nonsense!”), Example: Hemophilia (Factor 8, some forms)
• Frameshift – deletion or insertion of a number of nucleotides not divisible by 3, resulting in misreading of all nucleotides downstream, protein may be
shorter or longer, and its function may be disrupted or altered, Example: Duchenne Muscular Dystrophy, Tay-Sachs Disease, CF is caused by a 3 base pair
deletion which does not cause a frameshift (ΔF508), Tay-Sachs disease caused by 4 nucleotide insertion causing frameshift in gene coding
hexosaminidase A
• Trinucleotide Repeat Expansion – trinucleotide sequence repeated, may occur in coding or noncoding regions, often shows anticipation (more copies in
successive generations with younger onset of symptoms), Example: Huntington Disease (insertion not causing a frameshift in gene for huntingtin),
Fragile X Syndrome, Myotonic Dystrophy, Spinobulbar Muscular Atrophy, Friedreich Ataxia
• Splice Site – mutation at a splice site leads to a retained intron in the mRNA, producing a protein with impaired or altered function, Example: rare cause
of cancers, dementia, epilepsy, some types of β-thalassemia

Lac-Operon
 • Lac-Operon – classic example of a genetic response to environmental change, glucose the preferred metabolic substrate in E. coli, but when glucose
absent and lactose available, lac operon activated to switch to lactose metabolism, 2 mechanisms of regulation: 1.) Low Glucose Activates Operon: low
glucose increases adenylate cyclase activity, increases cAMP, activates catabolite activator protein (CAP), increases transcription, 2.) High Lactose
Disinhibits Operon: high lactose unbinds repressor protein from repressor/operator site, increasing transcription, Note: repressor protein binds to
operator locus, activator (CAP) binds upstream of promotor region

DNA Repair
• Introduction

Disorder Defect
Ataxia-Telangiectasia DNA hypersensitivity to ionizing radiation
Xeroderma Pigmentosum DNA hypersensitivity to UV radiation
Fanconi Anemia DNA hypersensitivity to cross-linking agents
Bloom Syndrome Generalized chromosomal instability
Hereditary Nonpolyposis Colorectal Cancer (PNPCC) Defective DNA mismatch repair enzymes
• Nucleotide Excision Repair – single strand repair, specific endonucleases release oligonucleotides containing damaged bases, DNA polymerase fills gap,
DNA ligase reseals it, repairs bulky, helix-distorting lesions, occurs during G1 of cell cycle, Example of Defect: Xeroderma Pigmentosum (prevents repair
of pyrimidine dimers formed by UV light exposure)
• Base Excision Repair – single strand repair, base specific glycosylase removes altered base and creates AP (apurinic/apyrimidinic) site, one or more
nucleotides removed by AP-Endonuclease, which cleaves 5’ end, Lyase cleaves 3’ end, DNA Polymerase-β fills gap, DNA ligase seals it, occurs throughout
cell cycle, important in repair of spontaneous/toxic deamination

• Mismatch Repair – single strand repair, newly synthesized strand is recognized, mismatched nucleotides removed, gap filled and resealed, occurs
predominantly during G2 phase of cell cycle, Example of Defect: Lynch Syndrome, causing Hereditary Nonpolyposis Colorectal Cancer (HNPCC)
• Nonhomologous End Joining – double strand repair, brings together 2 ends of DNA fragments to repair double-stranded breaks, no requirement for
homology, some DNA may be lost, Example of Defect: Ataxia Telangiectasia, breast/ovarian cancers with BRCA1 mutation, Fanconi Anemia
Start and Stop Codons
• mRNA Start Codons – AUG (rarely GUG), Eukaryotes: codes for Methionine, which may be removed before translation completed, Prokaryotes: codes
for N-formylmethionine (fMet), which stimulates neutrophil chemotaxis
• mRNA Stop Codons – UGA, AAA, UAG, releasing factor recognizes stop codons and terminates protein synthesis

Functional Organization of a Eukaryotic Gene

Regulation of Gene Expression

• Promoter – site where RNA polymerase II and multiple other transcription factors bind to DNA upstream from gene locus (AT-rich upstream sequence
with TATA and CAAT boxes), mutation commonly results in dramatic decrease in level of gene transcription
• Enhancer/Silencer – stretch of DNA that alters gene expression (enhancing or silencing it) by binding transcription factors (e.g. activating proteins), may
be located close to, far from, or even within (in an intron) the gene whose expression it regulates
 • Leucine Zipper – class of eukaryotic transcription factors composed of 2 α-helical monomers that combine to form a dimer, each dimer contains 2
structural subdomains, a DNA binding basic region (contains basic amino acids, e.g. Arginine, Lysine) and a leucine zipper dimerization region,
dimerization occurs due to interactions between Leucine residues at every 7th position in each alpha helix

RNA Polymerases
• Eukaryotes – 1 (rRNA), 2 (mRNA), and 3 (tRNA), numbered in same order that their products are used in protein synthesis, types: 1.) RNA Polymerase 1:
makes rRNA (most numerous, “rampant”), 2.) RNA Polymerase 2: makes mRNA (largest, “massive”), mRNA read 5’ to 3’, opens DNA at promoter site, 3.)
RNA Polymerase 3: makes 5S rRNA and tRNA (smallest, “tiny”), no proofreading function, but can initiate chains
 • Prokaryotes – single RNA polymerase (multisubunit complex) makes all 3 kinds of RNA
• RNA Polymerase Inhibitors
o α-amanitin: found in Amanita phalloides (death cap mushrooms), inhibits RNA Polymerase 2, causes severe hepatotoxicity if ingested
o Actinomycin D: inhibits both eukaryotic and prokaryotic RNA Polymerase
o Rifampin: inhibits DNA-dependent RNA Polymerase in prokaryotes

RNA Processing (Eukaryotes)

• RNA Processing (Eukaryotes) – initial transcript called heterogeneous nuclear RNA (hnRNA), which is then modified into mRNA, process: 7-
methylguanosine cap added to 5’ end, 3’ end polyadenylated (with ~200 A’s), introns spliced out, this capped, tailed, and spliced transcript called mRNA,
mRNA transported out of nucleus into cytosol, where it is translated, mRNA quality control occurs at cytoplasmic processing bodies (P bodies), which
contain exonucleases, decapping enzymes, and microRNAs, mRNAs may be stored in P-bodies for future translation, Poly-A polymerase does not require
a template, AAUAAA = polyadenylation signal

Splicing of Pre-mRNA
• Splicing of Pre-mRNA – steps: 1.) Primary transcript combines with small nuclear ribonucleoproteins (snRNPs) and other proteins to form spliceosome,
2.) Lariat-shaped (looped) intermediate generated, 3.) Lariat released to precisely remove intron and join 2 exons
• Splicing Antibodies:
o Anti-Smith Antibodies: antibodies against spliceosomal snRNPs, highly specific for SLE
o Anti-U1 RNP: highly associated with Mixed Connective Tissue Disease (MCTD)
Introns vs. Exons
• Introns vs. Exons – exons contain actual genetic information coding for protein, introns are intervening noncoding segments of DNA, different exons
frequently combined by alternative splicing to produce larger number of unique proteins than allowed by the number of exons alone if they were always
read in the same sequence, introns stay in the nucleus, exons exit and are expressed, abnormal splicing variants implicated in oncogenesis and many
genetic disorders (e.g. β-thalassemia)
microRNA (miRNA)
• microRNAs (miRNA) – small, conserved, noncoding RNA molecules that posttranscriptionally regulate gene expression by targeting the 3’ untranslated
region of specific mRNAs for degradation or translational repression, abnormal expression of miRNAs contributes to certain malignancies (e.g. by
silencing mRNA from a tumor suppressor gene)
tRNA
• tRNA Structure – 75-90 nucleotides, 2° structure, cloverleaf form, anticodon end is opposite 3’ aminoacyl end, all tRNAs (prokaryotic and eukaryotic)
have CCA at 3’ end along with high percentage of chemically modified bases, amino acid is bound to 3’ end (“CCA Can Carry Amino acids”), components:
1.) T-Arm: contains TΨC (ribothymidine, pseudouridine, cytidine) sequence necessary for tRNA-ribosome binding, (“T-arm Tethers tRNA to ribosome”),
2.) D-Arm: contains dihydrouridine residues necessary for tRNA recognition by correct aminoacyl-tRNA synthetase (“D-arm Detects tRNA by aminoacyl-
tRNA synthetase”), 3.) Acceptor Stem: 5’-CCA-3’ is the amino acid acceptor site
• tRNA Charging – aminoacyl-tRNA synthetase (1 per amino acid, “matchmaker”, uses ATP) scrutinizes amino acid before and after it binds to tRNA, if
incorrect, bond is hydrolyzed, amino acid-tRNA bond has energy for formation of peptide bond, a mischarged tRNA reads correct codon but inserts
wrong amino acid, accuracy of amino acid selection ensured by aminoacyl-tRNA synthetase and binding of proper charged tRNA to codon

Protein Synthesis (Translation)

• Initiation – initiated by GTP hydrolysis, initiation factors (IFs) help assemble the 40S ribosomal subunit with the initiator tRNA and are released when the
mRNA and ribosomal 60S subunit assemble with the complex (ATP used for tRNA Activation, GTP used for tRNA Gripping and Going places, i.e.
translocation), synthesis occurs from N-terminus to C-terminus
• Elongation – steps: 1.) Aminoacyl-tRNA binds to A site (except for initiator methionine), 2.) rRNA (“ribozyme”) catalyzes peptide bond formation,
transfers growing polypeptide to amino acid in A site, 3.) Ribosome advances 3 nucleotides toward 3’ end of mRNA, moving peptidyl tRNA to P site
(translocation), order of progression is APE: A Site: holds incoming Aminoacyl-tRNA, P Site: accommodates growing Peptide, E site: holds Empty tRNA as
it Exits
• Termination – stop codon recognized by release factor, completed polypeptide released from ribosome
• Eukaryotic Ribosome – 40S (small subunit) + 60S (large subunit) = 80S (entire ribosome) (Eukaryotes are Even)
• Prokaryotic Ribosome – 30S (small subunit) + 50S (large subunit) = 70S (entire ribosome) (PrOkaryotes are Odd)
Posttranslational Modifications
• Trimming – removal of N- or C- terminal pro-peptides from zymogen to generate mature protein (e.g. trypsinogen to trypsin)
• Covalent Alterations – phosphorylation, glycosylation, hydroxylation, methylation, acetylation, and ubiquitination

• Chaperone Protein – intracellular protein involved in facilitating and/or maintaining protein folding, Example: in yeast, heat shock proteins (e.g. HSP60)
expressed at high temperatures to prevent protein denaturing/misfolding

Cell Cycle Phases and Cell Types

• Cell Cycle Phases – checkpoints control transitions between phases of the cell cycle, a process regulated by cyclins, cyclin-dependent kinases (CDKs), and
tumor suppressors, Phases: 1.) M Phase: “mitosis” phase, shortest, includes mitosis (prophase, prometaphase, metaphase, anaphase, telophase) and
cytokinesis (division of cytoplasm between daughter cells), 2.) G1 Phase: “growth 1” phase, variable duration, 3.) G0 Phase: “growth 0” phase, mitotically
inactive phase, variable duration, most cells in the body, cells may enter and exit this phase, 4.) G2 Phase: “growth 2” phase, 5.) S Phase: synthesis phase
 • Permanent Cells – remain in G0, regenerate from stem cells, Example: neurons, skeletal and cardiac muscle, RBCs
• Stable (Quiescent Cells) – enter G1 from G0 when stimulated, Example: hepatocytes, lymphocytes
• Labile Cells – never enter G0, rapidly dividing with short G1, most affected by chemotherapy, Example: bone marrow, gut epithelium, skin, hair follicles,
germ cells

Regulation of Cell Cycle

• Cyclin Dependent Kinases (CDKs) – constitutive and inactive
• Cyclins – regulatory proteins that control cell cycle events by activating CDKs, phase specific
• Cyclin-CDK Complexes – phosphorylate other proteins to coordinate cell cycle progression, must be activated and inactivated at appropriate times for
cell cycle to progress
• Tumor Suppressors – p53 induces p21, which inhibits CDKs, leads to hypophosphorylation (activation) of Rb, which inhibits progression from G1 to S
phase, mutations in tumor suppressor genes can result in unrestrained cell division, Example: Li-Fraumeni Syndrome

Cell Components – Excretion and Trafficking

• Rough Endoplasmic Reticulum (RER) – site of synthesis of secretory (exported) proteins and of N-linked oligosaccharide addition to many proteins,
called Nissl bodies in neurons (synthesize neurotransmitters for secretion), free ribosomes unattached to any membrane synthesize cytosolic and
organelle proteins, mucus-secreting goblet cells of the small intestine and antibody secreting plasma cells rich in RER
• Smooth Endoplasmic Reticulum (SER) – site of steroid synthesis and detoxification of drugs and poisons, lacks surface ribosomes, liver hepatocytes and
steroid hormone-producing cells of the adrenal cortex and gonads rich in SER
• Golgi Apparatus – organizer of cell trafficking, distribution center for proteins and lipids from the ER to the vesicles and plasma membrane, modifies N-
oligosaccharides on asparagine, adds O-oligosaccharides onto serine and threonine, adds mannose-6-phosphate to proteins for trafficking to lysosomes
• Endosome – sorting center for material imported from outside cell or from Golgi, sending it to lysosomes for destruction or back to the membrane/Golgi
for further use
• I-Cell Disease (Inclusion Cell Disease/Mucolipidosis Type 2) – inherited lysosomal storage disorder, defect in N-acetylglucosaminyl-1-
phosphotransferase leads to failure of Golgi to phosphorylate mannose residues (decreased mannose-6-phosphate) on glycoproteins, thus proteins are
secreted extracellularly rather than delivered to lysosomes, presents with coarse facial features, gingival hyperplasia, clouded corneas, restricted joint
movement, serum shows high levels of lysosomal enzymes, often fatal in childhood
• Signal Recognition Particle (SRP) – abundant, cytosolic ribonucleoprotein that traffics proteins from ribosome to RER, absent or dysfunctional SRP
results in protein accumulation within cytosol
• Vesicular Trafficking Proteins: types: 1.) COP1: retrograde transport, Golgi to Golgi or cis-Golgi to ER, 2.) COP2: anterograde transport, ER to cis-Golgi
(“two steps forward, one step back”), 3.) Clathrin: endocytosis, trans-Golgi to lysosomes, plasma membrane to endosomes (receptor-mediated
endocytosis), Example: LDL receptor activity
 • Peroxisome – membrane-enclosed organelle involved in catabolism of very-long-chain fatty acids (via β-oxidation), branched-chain fatty acids, amino
acids, and ethanol, peroxisomal disorders commonly lead to neurologic diseases due to deficits in the synthesis of plasmalogens, important
phospholipids in myelin
• Zellweger Syndrome – peroxisomal disease, presents with hypotonia, seizures, hepatomegaly, early death
• Refsum Disease – peroxisomal disease, presents with scaly skin, ataxia, cataracts/night blindness, shortening of the 4th toe, epiphyseal dysplasia,
chlorophyl must be restricted as it contains phytanic acid
• Plasma Membrane – asymmetric lipid bilayer containing cholesterol, phospholipids, sphingolipids, glycolipids, and proteins

Cell Components – Cytoskeleton

• Introduction – network of protein fibers within cytoplasm that supports cell structure, cell and organelle movement, and cell division

Type of Filament Predominant Function Examples

Microfilaments Muscle contraction, cytokinesis Actin, microvilli
Intermediate Filaments Maintenance of cell structure Vimentin, desmin, cytokeratin, lamins, glial fibrillary acid
proteins (GFAP), neurofilaments
Microtubules Movement, cell division Cilia, flagella, mitotic spindle, axonal trafficking, centrioles
• Immunohistochemical Stains for Intermediate Filaments

Stain Cell Type Identifies

Vimentin Mesenchymal tissue (e.g. fibroblasts, endothelial cells, Mesenchymal tumors (e.g. sarcoma), many other tumors
macrophages) also (e.g. endometrial carcinoma, renal cell carcinoma,
meningioma)
Desmin Muscle Muscle tumors (e.g. rhabdomyosarcoma)
Cytokeratin Epithelial cells Epithelia tumors (e.g. SCC)
GFAP Neuroglia (e.g. astrocytes, Schwann cells, Astrocytoma, Glioblastoma
oligodendrocytes)
Neurofilaments Neurons Neuronal tumors (e.g. neuroblastoma)
• Microtubule – cylindrical outer structure composed of helical array of polymerized heterodimers of α- and β-tubulin, each dimer binds 2 GTP,
incorporated into flagella, cilia, mitotic spindles, grows slowly, collapses quickly, involved in slow axoplasmic transport in neurons
• Drugs Acting on Microtubules: (“Microtubules Get Constructed Very Poorly”)
o Mebendazole: antihelminthic
o Griseofulvin: antifungal
o Colchicine: antigout (antineutrophil via non-microtubule mechanism), also used as prophylaxis for post-MI pericarditis
o Vincristine/Vinblastine: antineoplastic
o Paclitaxel: antineoplastic
• Molecular Motor Proteins – transport cellular cargo toward opposite ends of microtubule tracks, types: 1.) Dynein: retrograde (positive to negative),
many viruses, 2.) Kinesin: anterograde (negative to positive), neurotransmitters in neurons (“Negative end Near Nucleus, Positive end Points toward
Periphery”)
• Cilia – 9 doublet + 2 singlet microtubule arrangement, basal body (base of cilium below cell membrane) consists of 9 microtubule triplet with no central
microtubules, axonemal dynein an ATPase that links peripheral 9 doublets and causes bending of cilium by differential sliding of doublets
• Kartagener Syndrome (Primary Ciliary Dyskinesia) – caused by immotile cilia due to dynein arm defect, results in decreased male (immotile sperm) and
female (dysfunctional fallopian tube cilia) fertility, presents with bronchiectasis, recurrent sinusitis, chronic ear infections, conductive hearing loss, situs
inversus, complications include increased risk of ectopic pregnancy
Cell Components – Sodium-Potassium Pump (Na+-K+ ATPase)
• Sodium-Potassium Pump (Na+-K+ ATPase) – located in plasma membrane with ATP on cytosolic side, for each ATP consumed, 3 Na+ exit cell (pump
phosphorylated) and 2 K+ enter cell (pump dephosphorylated)
• Drugs Inhibiting the Sodium-Potassium Pump:
o Ouabain: inhibits by binding to K+ site
o Digoxin/Digitalis: cardiac glycosides, directly inhibits pump, decreases intracellular Na+ concentration, indirectly inhibiting Na+/Ca2+ exchange,
which increases intracellular calcium concentration and thus cardiac contractility
Cell Components – Structural Proteins
• Collagen – most abundant protein in human body, extensively modified posttranslationally, organizes and strengthens extracellular matrix
o Type 1: most common (90%), makes up bone (via osteoblasts), ski, tendons, dentin, fascia, cornea, late wound repair, Example of Deficiency:
Osteogenesis Imperfecta Type 1
o Type 2: makes up cartilage (including hyaline), vitreous body, nucleus pulposus (“carTWOlage”)
o Type 3: reticulin, makes up skin, blood vessels, uterus, fetal tissue, granulation tissue, Example of Deficiency: Ehlers-Danlos Syndrome
o Type 4: makes up basement membranes, basal lamina, lens, Example of Deficiency: Alport Syndrome, targeted in Goodpasture Syndrome
(“Type 4 under the floor”)

• Collagen Synthesis and Structure – steps: 1.) Synthesis: translation of collagen α chains (preprocollagen), usually Gly-X-Y (X and Y are Proline or Lysine),
Glycine content best represents collagen synthesis (collagen is 1/3 Glycine), 2.) Hydroxylation: hydroxylation of specific Proline and Lysine residues,
requires vitamin C, Example of Deficiency: Scurvy, 3.) Glycosylation: glycosylation of pro-α-chain hydroxylysine residues and formation of procollagen via
hydrogen and disulfide bonds (triple helix of 3 collagen α chains), Example of Deficiency: Osteogenesis Imperfecta, 4.) Exocytosis: exocytosis of collagen
into extracellular space, 5.) Proteolytic Processing: cleavage of disulfide-rich terminal regions of procollagen produces insoluble tropocollagen, Example
of Deficiency: Ehlers-Danlos syndrome, 6.) Cross-Linking: reinforcement of many staggered tropocollagen molecules by covalent lysine-hydroxylysine
cross-linkage (by copper-containing lysyl oxidase) makes collagen fibrils, Example of Deficiency: Ehlers-Danlos Syndrome, Menkes Disease, Note: β-
aminopropionitrile (chemical found in certain types of sweat peas) inhibits lysyl oxidase and causes change in aortic elasticity that mimics the
myxomatous degeneration in patients with Marfan Syndrome
• Disorders of Collagen Synthesis

Disorder Impairment Defining Characteristics

Ehlers-Danlos Syndrome (1 and 2) Mutation in Type 5 collagen Joint hypermobility, hyperextensible, fragile skin (most common form of EDS)
Osteogenesis Imperfecta (OI) Mutation in Type 1 collagen Spontaneous fractures, bone and tooth malformation, blue sclerae
Scurvy (Vitamin C deficiency) Impaired collagen hydroxylation Bleeding gums, ecchymoses and petechiae, impaired wound healing
• Elastin – stretchy protein within skin, lungs, large arteries, elastic ligaments, vocal cords, ligamenta flava (connect vertebrae producing relaxed and
stretched conformations), rich in non-hydroxylated Proline, Glycine, and Lysine residues, tropoelastin with fibrillin scaffolding, cross-linking takes place
extracellularly and gives elastin its elastic properties, broken down by elastase, which is normally inhibited by α1-antitrypsin, α1-antitrypsin deficiency
results in excess elastase activity, which causes emphysema, wrinkles of aging (skin rhytides) caused by decreased collagen and elastin production
 • Osteogenesis Imperfecta, Ehlers-Danlos Syndrome, Menkes Disease, Marfan Syndrome – see Bones, Joints, and Soft Tissue Tumors
• α1-Antitrypsin Deficiency – see Respiratory: Emphysema and Gastrointestinal: α1-Antitrypsin Deficiency

Cell Components – Cell Junctions

Type of Cell Junction Proteins Function Associations
Gap Junction Connexins Intercellular communication Initiation of labor
Tight Junction Claudins, occludins Paracellular barrier C. perfringens endotoxin
Adherens Junction Cadherins (anchored to actin) Cellular anchor
Desmosomes Cadherins (e.g. desmogleins, desmoplakin, Cellular anchor Pemphigus Vulgaris
anchored to intermediate filaments)
Hemidesmosomes Integrins Cellular anchor Bullous Pemphigoid, Pemphigoid Gestationis
Laboratory Techniques
• Polymerase Chain Reaction (PCR) – procedure used to amplify a desired fragment of DNA, useful as a diagnostic tool (e.g. neonatal HIV, herpes
encephalitis)
• Introduction to Blots

• Southern Blot – used to analyze DNA, procedure: 1.) DNA sample enzymatically cleaved into smaller pieces, which are separated on a gel by
electrophoresis, then transferred to a filter, 2.) Filter is exposed to radiolabeled DNA probe that recognizes and anneals to its complementary strand, 3.)
Resulting labeled dsDNA piece is visualized when filter is exposed to film
• Northern Blot – used to analyze RNA, procedure similar to Southern Blot, except RNA sample electrophoresed, used to study mRNA levels, which are
reflective of gene expression
• Western Blot – used to analyze proteins, procedure: 1.) Sample protein separated via gel electrophoresis and transferred to a membrane, 2.) Labeled
antibody used to bind to relevant protein, used for old HIV confirmatory test following positive ELISA screening test

• Southwestern Blot – used to analyze DNA-binding proteins (e.g. transcription factors) using labeled oligonucleotide probes
• Dot Blot – used to analyze RNA, DNA, or proteins, the details of the mutation in question must be known, used for a handful of diseases
• Flow Cytometry – technique used to assess size, granularity, and protein expression (immunophenotype) of individual cells in a sample, commonly used
in workup of hematologic abnormalities (e.g. Paroxysmal Nocturnal Hemoglobinuria, fetal RBCs in mother’s blood, and immunodeficiencies, esp. CD4
count in HIV), cells tagged with antibodies specific to surface or intracellular proteins, antibodies then tagged with unique fluorescent dye, sample
analyzed one cell at a time by focusing laser on cell and measuring light scatter and intensity of fluorescence, data plotted as histogram (one measure) or
scatter plot (any two measures), in scatter plot below:
o Cells in LLQ: ⊖ for both CD8 and CD3
o Cells in RLQ: ⊕ for CD8, ⊖ for CD3, RLQ empty because all CD8-expressing cells also express CD3
o Cells in LUQ: ⊕ for CD3, ⊖ for CD8
o Cells in RUG: ⊕ for both CD8 and CD3
• Microarrays – thousands of nucleic acid sequences arranged in a grid on glass or silicon, DNA or RNA probes hybridized to the chip, then a scanner
detects the relative amounts of complementary binding, used to profile gene expression levels of thousands of genes simultaneously to study certain
diseases and treatments, able to detect single nucleotide polymorphisms (SNPs) and copy number variations (CNVs) for a variety of applications
including genotyping, clinical genetic testing, forensic analysis, cancer mutations, and genetic linkage analysis
• Enzyme-Linked Immunosorbent Assay – immunologic test used to detect the presence of either a specific antigen (e.g. HBsAg) or antibody (e.g. anti-
HBs) in a patient’s blood sample, antibody linked to an enzyme, added substrate reacts with enzyme, producing detectable signal, can have high
sensitivity and specificity, but less specific than Western Blot
• Radioimmunoassay – uses specific antibodies and known quantity of radiolabeled antigen to determine amount of antigen present in unknown sample,
specific antibodies against known antigen attached to assay plate, fixed quantity of radiolabeled antigen and varying quantities of unlabeled antigen
added to plate, which is then washed to remove unbound antigens and radioactivity is measured, if test (unlabeled) antigen shares epitopes with
radiolabeled antigen, it competitively competes for its binding spots, displaces it, and thus the concentration of radiolabeled antigen (i.e. the
radioactivity) drops as more test (unlabeled) antigen added, if test (unlabeled) antigen has no epitopes in common with radiolabeled antigen, none of it
binds and the concentration of radiolabeled antigen (i.e. the radioactivity) does not change as more test (unlabeled) antigen is added
• Karyotyping – metaphase chromosomes stained, ordered, and numbered according to morphology, size, arm-length ratio, and banding pattern, can be
performed on a sample of blood, bone marrow, amniotic fluid, or placental tissue, used to diagnose chromosomal imbalances (e.g. autosomal trisomies,
sex chromosome disorders)
 • Fluorescence in Situ Hybridization (FISH) – fluorescent DNA or RNA probe binds to specific gene site of interest on chromosomes, used for specific
visualization of chromosomal abnormalities at the molecular level, findings: 1.) Microdeletion: no fluorescence on a chromosome compared to
fluorescence at the same locus on a second copy of that chromosome, 2.) Translocation: fluorescence signal that corresponds to one chromosome found
on a different chromosome, 3.) Duplication: extra site of fluorescence on one chromosome relative to its homologous chromosome

Cloning and Genetics – Methods

• Cloning Methods – production of recombinant DNA molecule that is self-perpetuating, steps: 1.) Isolate eukaryotic mRNA (post-RNA processing) of
interest, 2.) Expose mRNA to reverse transcriptase to produce cDNA (lacks introns), 3.) Insert cDNA fragments into bacterial plasmids containing
antibiotic resistance genes, 4.) Transform recombinant plasmid into bacteria, 5.) Surviving bacteria on antibiotic medium produce cloned DNA (copies of
cDNA)
• Gene Expression Modifications – transgenic strategies in mice include random gene insertion or targeted insertion (“knock-in”) or deletion (“knock-
out”) of gene through homologous recombination with mouse gene
• Cre-Lox System – can inducibly manipulate genes at specific developmental points (e.g. to study a gene whose deletion causes embryonic death)
• RNA Interference – dsRNA synthesized that is complementary to mRNA sequence of interested, when transfected into human cells, dsRNA separates
and promotes degradation of target mRNA, “knocking down” gene expression
Cloning and Genetics – Terms
• Codominance – both alleles contribute to the phenotype of the heterozygote, Example: blood groups A, B, AB, α1-antitrypsin deficiency (MM, MZ, ZZ)
• Variable Expressivity – patients with same genotype but different phenotype, all individuals have some pathology, Example: 2 patients with NF1 who
have varying disease severity
• Incomplete Penetrance – mostly autosomal dominant, not all individuals with mutant genotype show mutant phenotype (i.e. some have no pathology),
Degree of Penetrance = # of individuals with pathology / # of individuals with defective gene, Example: BRCA1 gene mutations do not always result in
breast or ovarian cancer, also Retinoblastoma, Hemochromatosis (penetrance ~30%), HNPCC (Lynch Syndrome)
• Pleiotropy – one gene contributes to multiple phenotypic effects, Example: untreated PKU manifests with light skin, intellectual disability, and musty
body odor, also Marfan Syndrome, CF
• Anticipation – increased severity or earlier onset of disease in succeeding generations, Example: trinucleotide repeat diseases, e.g. Huntington Disease
• Loss of Heterozygosity – if a patient inherits or develops a mutation in a tumor suppressor gene, the complementary allele must be deleted/mutated
before cancer develops, this is not true of oncogenes, Example: Retinoblastoma and Knudson’s “2-hit hypothesis”, Lynch Syndrome (HNPCC), Li-
Fraumeni Syndrome

• Dominant Negative Mutation – heterozygote produces a nonfunctional altered protein that also prevents the normal gene product from functioning,
usually by competitively binding to the same site, thus exerting a dominant effect, Example: mutation of a transcription factor at an allosteric site,
nonfunctioning mutant can still bind DNA, competitively preventing wild-type transcription factor from binding
• Linkage Disequilibrium – tendency for certain alleles at 2 linked loci to occur together more or less often than expected by chance alone, measured in a
population, not in a family, often varies in different po pulations
• Mosaicism – presence of genetically distinct cell lines in the same individual, types: 1.) Somatic Mosaicism: mutation arises from mitotic errors after
fertilization and propagates through multiple tissues or organs, 2.) Gonadal Mosaicism: mutation only in egg or sperm cells, if parent and relatives do not
have disease, suspect gonadal (or germline) mosaicism, Example: McCune-Albright Syndrome
• McCune-Albright Syndrome – caused by mutation affecting G-protein signaling, presents with unilateral café-au-lait spots with ragged edges,
polyostotic fibrous dysplasia, and at least one endocrinopathy (e.g. precocious puberty), lethal if mutation occurs before fertilization, survivable in
parents with mosaicism, see Skeletal: Fibrous Dysplasia
• Locus Heterogeneity – mutations at different loci that produce a similar phenotype, e.g. in OI Type 2, 2 components of trimeric Type 1 collagen are
coded by Chr 17, 1 is coded by Chr 7, if either is defective, disease results, Example: Albinism, Osteogenesis Imperfecta Type 2
• Allelic Heterogeneity – different mutations at the same locus (i.e. on the same gene) that produce the same phenotype, may show variable expression,
Example: β-Thalassemia, G6PD Deficiency
• Heteroplasmy – presence of both normal and mutated mtDNA, resulting in variable expression in mitochondrially inherited disease
• Lyonization (X Chromosome Inactivation) – female carriers in X-linked disorders variably affected depending on pattern of X chromosome inactivation,
X chromosomes with mutant and normal alleles inactivated randomly in early embryo (~day 16 in ~100 cell blastocyst) via cytosine methylation forming
a Barr body)
• Recurrence Risk – probability that offspring will express a genetic disease (i.e. display the diseased phenotype)
• Uniparental Disomy (UPD) – offspring receives 2 copies of a chromosome from one parent and no copies from the other parent, types: 1.)
Heterodisomy: indicates meiosis 1 error, 2,) Isodisomy: indicates a meiosis 2 error or postzygotic chromosomal duplication of one member of a pair of
chromosomes, and loss of the other member of the original pair, uniparental is euploid (correct number of chromosomes), not aneuploid, most cases
result in normal phenotype, consider in an individual manifesting a recessive disorder when only one parent is a carrier
• Hardy-Weinberg Population Genetics – mostly autosomal recessive, if a population is in Hardy-Weinberg equilibrium with respect to alleles A and a, and
if p and q are frequencies of separate alleles, then p2 + 2pq + q2 = 1 and p + q = 1, which implies that p2 = frequency of homozygosity for allele A, q2 =
frequency of homozygosity for allele a, 2pq = frequency of heterozygosity (carrier frequency, if autosomal recessive disorder), frequency of X-linked
recessive disease = q in males and q2 in females, Hardy-Weinberg law assumes: 1.) no mutation occurring at locus, 2.) natural selection not occurring, 3.)
completely random mating, 4.) no net migration

• Imprinting – at some loci, only one allele is active with the other inactive (imprinted/inactivated by methylation), with one allele inactivated, deletion of
the active allele leads to disease, Example: Prader-Willi and Angelman Syndromes
 • Prader-Willi Syndrome – epigenetic disease (Chr 15) caused by maternal imprinting (maternal gene normally silent, paternal gene is deleted/mutated),
25% of cases due to maternal uniparental disomy (two maternally imprinted genes received with no paternal gene received), presents with hyperphagia,
obesity, intellectual disability, hypogonadism (bifid uterus in females), hypotonia
• Angelman Syndrome – epigenetic disease (Chr 15) caused by paternal imprinting (paternal gene normally silent, maternal gene is deleted/mutated), 5%
of cases due to paternal uniparental disomy (two paternally imprinted genes received with no maternal gene received), presents with inappropriate
laughter (“happy puppet”), seizures, ataxia, severe intellectual disability

Cloning and Genetics – Modes of Inheritance

• Introduction
• Autosomal Dominant – often due to defects in structural genes, many generations, both males and females affected, often pleiotropic (multiple
apparently unrelated effects) and variably expressive (different between individuals), family history crucial to diagnosis, with one affected parent, on
average ½ of children affected
• Autosomal Dominant Diseases – Achondroplasia, Autosomal Dominant Polycystic Kidney Disease, Familial Adenomatous Polyposis, Familial
Hypercholesterolemia (LDL receptor deficiency), Hereditary Hemorrhagic Telangiectasia, Hereditary Spherocytosis, Huntington Disease, Li-Fraumeni
Syndrome, Marfan Syndrome (fibrillin), Multiple Endocrine Neoplasias, NF1 (von Recklinghausen Disease), NF2, Tuberous Sclerosis, von Hippel-Lindau
Disease, Acute Intermittent Porphyria (most porphyrias)
• Autosomal Recessive – often due to enzyme deficiencies, usually seen in only 1 generation, commonly more severe than dominant disorders, patients
often present in childhood, increased risk in consanguineous families, with 2 carrier (heterozygous) parents, on average ¼ of children will be affected
(homozygous recessive), ½ of children will be carriers (heterozygous), and ¼ of children will be neither affected nor carriers (homozygous dominant)
• Autosomal Recessive Diseases – Albinism, Autosomal Recessive Polycystic Kidney Disease (ARPKD), CF, glycogen storage diseases, Hemochromatosis,
Kartagener Syndrome (Primary Ciliary Dyskinesia), mucopolysaccharidoses (except Hunter Syndrome), PKU, SCD, sphingolipidoses (except Fabry
Disease), thalassemias, Wilson Disease, Tay-Sachs Disease (hexosaminidase A deficiency)

• X-linked Recessive – sons of heterozygous mothers have a 50% chance of being affected, no male-to-male transmission, skips generations, commonly
more severe in males, females usually must be homozygous to be affected
• X-linked Recessive Diseases – Ornithine Transcarbamylase (OTC) Deficiency, Fabry Disease, Wiskott-Aldrich Syndrome, Ocular Albinism, G6PD
Deficiency, Hunter Syndrome, Bruton’s Agammaglobulinemia, Hemophilia A (Factor 8) and B (Factor 9), Lesch-Nyhan Syndrome (hypoxanthine-guanine
phosphoribosyltransferase deficiency), Duchenne (and Becker) Muscular Dystrophy (“Oblivious Female Will Often Give Her Boys Her X-lined Disorders”),
also red-green color blindness, Menkes Disease, SCID (IL-receptor-γ-chain deficiency)
• X-linked Dominant – transmitted through both parents, mothers transmit to 50% of daughters and sons, fathers transmit to all daughters, but no sons,
Example: Hypophosphatemic Rickets (formerly Vitamin D-Resistant Rickets) – inherited disorder resulting in increased phosphate wasting at proximal
tubule, presents like Rickets, Fragile X Syndrome, Alport Syndrome
• X-linked Dominant Diseases – Hypophosphatemic Rickets, Fragile X Syndrome

• Mitochondrial Inheritance – transmitted only through mother, all offspring of affected females may show signs of disease, variable expression in a
population or even within a family due to heteroplasmy, mitochondria encode 22 tRNAs and 2 rRNAs, Example: Mitochondrial Myopathies – rare
disorders, often present with myopathy, lactic acidosis, and CNS disease, e.g. MELAS Syndrome (mitochondrial encephalopathy, lactic acidosis, stroke-
like episodes), caused by failure of oxidative phosphorylation, muscle biopsy often shows “ragged red fibers” (accumulation of diseased mitochondria),
see Peripheral Nerves and Skeletal Muscles
 • Mitochondrial Diseases – Leber Hereditary Optic Neuropathy (oxidative phosphorylation defect), Mitochondrial Encephalomyopathy, Lactic Acidosis,
and Stroke-like episodes (MELAS, defect in tRNA for Lysine), Myoclonic Epilepsy with Ragged Red Fibers (MERRF, defect in tRNA for Leusine)
• Muscular Dystrophies – see Peripheral Nerves and Skeletal Muscles
• Polygenic – traits controlled by more than one gene, which may be located on entirely different chromosomes and thus inherited in different fashions
(e.g. mix of autosomal and X-linked inheritance)

• Trinucleotide Repeat Expansion Diseases – Huntington Disease (CAG), Myotonic Dystrophy (CTG), Fragile X Syndrome (CGG), Friedreich Ataxia(GAA),
may show anticipation

Cloning and Genetics – Genetic Diseases of Abnormal Chromosomes

• Restriction Length Polymorphism in Nondisjunctions – nondisjunction indicated in examples below:

Maternal Meiosis I Maternal Meiosis II Paternal Meiosis I Paternal Meiosis II

• Introduction to Trisomies – usually caused by meiotic nondisjunction, Age Mnemonic: Drinking age is 21 = Down Syndrome, Election (Voting) age is 18 =
Edwards Syndrome, Puberty is 13 = Patau Syndrome

• Down Syndrome (Trisomy 21) – causes: 1.) Meiotic Nondisjunction: 95% of cases, increased incidence with maternal age, from 1:1500 in women <20 to
1:25 in women >45, recurrence risk increases with age, 2.) Unbalanced Robertsonian Translocation: 4% of cases, usually between Chr 14 and 21, high
recurrence risk if balanced translocation present in one parent, 3.) Mosaicism: 1% of cases, no association with maternal nondisjunction, postfertilization
mitotic error, most common viable chromosomal disorder, recurrence risk same as general population, most common cause of genetic intellectual
disability (1:700), presents with intellectual disability, flat facies, prominent epicanthal folds, upslanting palpebral fissures, low-set small ears, short neck
with excess skin, single palmar crease, hypoplastic incurved 5th finger, gap between first 2 toes (“sandal deformity”), duodenal atresia, Hirschsprung
Disease, congenital heart disease (e.g. AV septal defect), Brushfield spots in eyes, 1st trimester ultrasound commonly shows increased nuchal
translucency and hypoplastic nasal bone, decreased serum PAPP-A, increased free β-hCG, 2nd trimester quad screen shows decreased α-fetoprotein,
increased β-hCG, decreased estriol, increased inhibin A, complications include early onset Alzheimer’s Disease (chromosome 21 codes for amyloid
precursor protein) and increased risk of ALL and AML
• Edwards Syndrome (Trisomy 18) – 2nd most common autosomal trisomy resulting in live birth (after Downs Syndrome, 1:8,000), 1st trimester ultrasound
shows decreased serum PAPP-A and free β-hCG, decreased estriol, decreased or normal inhibin A, presentation: PRINCE Edward mnemonic: Prominent
occiput, Rocker-bottom feet, Intellectual disability, Nondisjunction, Clenched fists with overlapping fingers, low-set Ears, micrognathia, congenital heart
disease, death usually occurs by age 1
• Patau Syndrome (Trisomy 13) – rarest of the trisomies (1:15,000), presents with severe intellectual disability, rocker-bottom feet, microphthalmia,
microcephaly, cleft lip/palate, holoprosencephaly, polydactyly, cutis aplasia, congenital heart disease, 1st trimester ultrasound shows decreased serum
PAPP-A and free β-hCG, death usually occurs by age 1
• Common Genetic Disorders by Chromosome

Chromosome Common Diseases

3 Von Hippel-Lindau Disease, Renal Cell Carcinoma
4 ADPKD (PKD2), Achondroplasia, Huntington Disease
5 Cri-du-Chat Syndrome, Familial Adenomatous Polyposis
 6 Hemochromatosis (HFE)
7 Williams Syndrome, CF
9 Friedreich Ataxia
11 Wilms Tumor, β-globin gene defects (SCD, β-Thalassemia, MEN1)
13 Patau Syndrome, Wilson Disease, Retinoblastoma (RB1), BRCA2
15 Prader-Willi Syndrome, Angelman Syndrome, Marfan Syndrome
16 ADPKD (PKD1), α-globin gene defects (α-Thalassemia)
17 NF1 (17 letters if you spell it, comes before NF2), BRCA1, p53
18 Edwards Syndrome
21 Down Syndrome
22 NF2, DiGeorge Syndrome (22q11)
X Fragile X Syndrome, X-linked Agammaglobulinemia, Klinefelter Syndrome (XXY)
• Robertsonian Translocation- chromosomal translocation commonly involving pairs 13, 14, 15, 21, and 22, common type of translocation, occurs when
long arms of 2 acrocentric chromosomes (those with centromeres near end) fuse at centromere and short arms are lost, balanced translocations
normally do not cause abnormal phenotype, unbalanced translocations can result in miscarriage, stillbirth, and chromosomal imbalance (e.g. produce
trisomies)
• Cri-du-Chat Syndrome – congenital macrodeletion of short arm of chromosome 5 (46,XX or XY,5p-), presents with microcephaly, moderate-to-severe
intellectual disability, high pitched crying/meowing (cri du chat means “cry of the cat”), epicanthal folds, cardiac abnormalities (VSD)
• Williams Syndrome – congenital microdeletion of long arm of chromosome 7 (deleted region includes elastin gene), presents with distinctive “elfin”
facies, intellectual disability, hypercalcemia (increase vitamin D sensitivity), well-developed verbal skills, extreme friendliness with strangers,
cardiovascular problems
• 22q11 Deletion Syndromes – microdeletion at chromosome 22q11 leading to variable presentations: CATCH-22 mnemonic: Cleft palate, Abnormal facies
(abnormal development of 3rd and 4th branchial pouches), Thymic aplasia (T-cell deficiency), Cardiac defects, and Hypocalcemia due to parathyroid
aplasia, common manifestations: 1.) DiGeorge Syndrome: thymic, parathyroid, and cardiac defects, 2.) Velocardiofacial Syndrome: palate, facial, and
cardiac defects
Nutrition – Vitamins
• Water-Soluble Vitamins – B1 (Thiamine: TPP), B2 (Riboflavin: FAD, FMN), B3 (Niacin: NAD+), B5 (Pantothenic Acid: CoA), B6 (Pyridoxine: PLP), B7 (Biotin), B9
(Folate), B12 (Cobalamin), C (Ascorbic acid), all wash out from the body easily except B12 (stored in liver for ~3-4 years) and B9 (folate, stored in liver for
~3-4 months), B-complex deficiencies often result in dermatitis, glossitis, and diarrhea, may act as coenzymes (e.g. Ascorbic Acid) or precursors to
organic cofactors (e.g. FAD, NAD+)
• Fat-Soluble Vitamins – A, D, E, K, absorption depends on gut and pancreas, toxicity more common than for water-soluble vitamins because fat-soluble
vitamins accumulate in fat, malabsorption syndromes with steatorrhea such as CF and Celiac Disease, or mineral oil intake may cause deficiencies
• Vitamin A (Retinol) – fat-soluble, antioxidant, constituent of visual pigments (retinal), essential for normal differentiation of epithelial cells into
specialized tissue (pancreatic cells, mucus-secreting cells), prevents squamous metaplasia, used to treat measles and Acute Promyelocytic Leukemia
(APL), found in liver and leafy vegetables, oral isotretinoin used to treat cystic acne, all-trans retinoic acid (ATRA) used to treat APL, Deficiency: night
blindness (nyctalopia), dry, scaly skin (xerosis cutis), corneal degeneration (keratomalacia), Bitot spots on conjunctiva, immunosuppression, Excess: acute
toxicity (nausea/vomiting, vertigo, blurred vision), chronic toxicity (alopecia, dry, scaly skin, hepatic toxicity and hepatomegaly, arthralgia, pseudotumor
cerebri), teratogenicity (cleft palate, cardiac abnormalities), negative pregnancy test and 2 forms of contraception required before isotretinoin
prescribed

Vitamin A Toxicity Type Signs/Symptoms

Acute Nausea/vomiting, vertigo, blurred vision, may occur after single dose
Chronic Alopecia, dry skin, hyperlipidemia, hepatotoxicity, hepatosplenomegaly, visual difficulties, occurs after long-term ingestion of
high doses, complications include pseudotumor cerebri (papilledema/elevated ICP)
Teratogenic Microcephaly, cardiac anomalies, fetal death (esp. in 1st trimester)

• Vitamin B1 (Thiamine) – water-soluble, thiamine pyrophosphate (TPP) form a cofactor for several dehydrogenase enzyme reactions: α-ketoglutarate
dehydrogenase (TCA cycle), transketolase (HMP shunt), pyruvate dehydrogenase (links glycolysis to TCA cycle – “ATP” mnemonic), also branched-chain
ketoacid dehydrogenase, Deficiency: impaired glucose breakdown leads to ATP depletion (worsened by glucose infusion), highly aerobic tissues (brain,
heart) affected first, give alcoholics or malnourished patients thiamine before dextrose to reduce risk of precipitating Wernicke Encephalopathy,
diagnose with increased RBC transketolase activity following vitamin B1 administration, presentations: 1.) Wernicke-Korsakoff Syndrome: classic triad of
confusion, ophthalmoplegia, and ataxia, with confabulations, personality changes, permanent memory loss, damage to medial dorsal nucleus of
thalamus and mamillary bodies, 2.) Dry Beriberi: polyneuritis, symmetrical muscle wasting, 3.) Wet Beriberi: high-output cardiac failure (dilated
cardiomyopathy), edema (“Thiamine deficiency is beriberi bad”, “Ber1Ber1”)
• Vitamin B2 (Riboflavin) – water-soluble, component of flavins FAD and FMN, cofactors in redox reactions (e.g. succinate dehydrogenase reaction in TCA
cycle), Deficiency: cheilosis (inflammation of lips, scaling and fissures at corners of mouth), corneal vascularization (“2 C’s of B2)
• Vitamin B3 (Niacin) – water-soluble, constituent of NAD+, NADP+ (used in redox reactions), derived from Tryptophan, synthesis requires vitamins B2 and
B6, used to treat dyslipidemia, lowers VLDL, raises HDL, Deficiency: glossitis, severe deficiency leads to Pellagra, which can be caused by Hartnup Disease,
malignant carcinoid syndrome (increased Tryptophan metabolism), and Isoniazid (decreased vitamin B6), presentations: 1.) Pellagra: Diarrhea, Dementia
(with hallucinations), Dermatitis (C3/C4 dermatome circumferential “broad collar” rash called “Casal necklace”, hyperpigmentation of sun-exposed limbs
– “3 D’s of vitamin B3”), 2.) Hartnup Disease: autosomal recessive, deficiency of neutral amino acid (e.g. Tryptophan) transporters in proximal renal
tubular cells and on enterocytes leads to neutral aminoaciduria and decreased absorption from gut, decreasing available Tryptophan for conversion to
Niacin, produces Pellagra-like symptoms, treat with high-protein diet and nicotinic acid, Excess: facial flushing (induced by prostaglandin, not histamine,
avoid by taking ASA with Niacin), hyperglycemia, hyperuricemia
• Vitamin B5 (Pantothenic Acid) – water-soluble, essential component of coenzyme A (CoA, cofactor for acyl transfers) and fatty acid synthase, Deficiency:
dermatitis, enteritis, alopecia, adrenal insufficiency (“Pentothenic Acid”)
• Vitamin B6 (Pyridoxine) – water-soluble, converted to pyridoxal phosphate (PLP), a cofactor used in transamination (e.g. ALT, AST), decarboxylation
reactions, glycogen phosphorylase, synthesis of cystathionine heme, Niacin, histamine, and neurotransmitters including serotonin, epinephrine,
norepinephrine, dopamine, and GABA, Deficiency: convulsions, hyperirritability, peripheral neuropathy (deficiency inducible by Isoniazid and PO
contraceptives), sideroblastic anemias due to impaired Hb synthesis and iron excess
• Vitamin B7 (Biotin) – water-soluble, cofactor for carboxylation enzymes (add a 1-carbon group): pyruvate carboxylase (converts 3C pyruvate to 4C
oxaloacetate), acetyl-CoA carboxylase (converts 2C acetyl-CoA to 3C malonyl-CoA), propionyl-CoA carboxylase (converts 3C propionyl-CoA to 4C
methylmalonyl-CoA, Deficiency: relatively rare, dermatitis, alopecia, enteritis, caused by antibiotic use or excessive ingestion of raw egg whites (“Avidin
in egg whites avidly binds biotin”)
• Vitamin B9 (Folate) – water-soluble, converted to tetrahydrofolic acid (THF), a coenzyme for 1-carbon transfer/methylation reactions, important for
synthesis of nitrogenous bases for DNA/RNA, found in leafy green vegetables, absorbed in jejunum, small reserve pool stored primarily in liver,
Deficiency: macrocytic, megaloblastic anemia, hypersegmented polymorphonuclear cells (PMNs), glossitis, no neurologic symptoms (contrast vitamin B12
deficiency), serum shows increased homocysteine, normal methylmalonic acid (contrast vitamin B12 deficiency, which leads to increased levels of both),
most common vitamin deficiency in US, seen in alcoholism and pregnancy, deficiency may be caused by several drugs (e.g. Phenytoin, Sulfonamides,
Methotrexate), supplemental maternal folic acid given at least 1 month prior to conception and during early pregnancy to reduce risk of neural tube
defects, see Red Blood Cells and Bleeding Disorders
• Vitamin B12 (Cobalamin) – water-soluble, cofactor for methionine synthase (transfers methyl groups as methylcobalamin) and methylmalonyl-CoA
mutase, important for DNA synthesis, found in animal products, synthesized by microorganisms only, very large reserve pool (several years) stored
primarily in liver, deficiency caused by malabsorption (e.g. sprue, enteritis, Diphyllobothrium latum), lack of intrinsic factor (pernicious anemia, gastric
bypass surgery), absence of terminal ileum (surgical resection, e.g. for Crohn Disease), or insufficient intake (e.g. veganism), anti-intrinsic factor
antibodies diagnostic for pernicious anemia, Deficiency: macrocytic, megaloblastic anemia, hypersegmented PMNs, paresthesias and subacute combined
degeneration (dorsal columns, lateral corticospinal tracts, and cerebellar tracts) due to abnormal myelin, serum shows increased homocysteine and
methylmalonic acid levels (contrast vitamin B9 deficiency, where only homocysteine levels are elevated), secondary folate deficiency, prolonged
deficiency leads to irreversible nerve damage, see Red Blood Cells and Bleeding Disorders
• Vitamin C (Ascorbic Acid) – water-soluble, antioxidant, facilitates iron absorption by reducing it to Fe2+ state, necessary for hydroxylation of Proline and
Lysine in collagen synthesis, and for dopamine β-hydroxylase, which converts dopamine to norepinephrine, found in fruits and vegetables, ancillary
treatment for methemoglobinemia by reducing Fe3+ to Fe2+ (“Absorbic acid”), Deficiency: Scurvy (swollen gums, bruising, petechiae, hemarthrosis,
anemia, poor wound healing, perifollicular and subperiosteal hemorrhages, “corkscrew” hair), weakened immune response, all caused by collagen
synthesis deficiency, Excess: nausea/vomiting, diarrhea, fatigue, calcium oxalate nephrolithiasis, may increase risk of iron toxicity in predisposed
individuals (e.g. those with transfusions or hereditary hemochromatosis), see Bones, Joints, and Soft Tissue Tumors

• Vitamin D – fat-soluble, forms: D2 (ergocalciferol, ingested from plants), D3 (cholecalciferol, consumed in milk, formed in stratum basale of sun-exposed
skin), 25-OH D3 (storage form), 1,25-(OH)2D3 (calcitriol, active form), increases intestinal absorption of calcium and phosphate, increases bone
mineralization and resorption at higher levels, Deficiency: rickets in children (deformity, such as genu varum/“bow legs”), Osteomalacia in adults (bone
pain and muscle weakness), hypocalcemic tetany, breastfed infants should receive oral vitamin D, deficiency exacerbated by low sun exposure,
pigmented skin, prematurity, Excess: hypercalcemia, hypercalciuria, loss of appetite, stupor, seen in CGD (increased activation of vitamin D by epithelioid
macrophages), see Bones, Joints, and Soft Tissue Tumors
• Vitamin E (Tocopherol/Tocotrienol) – fat-soluble, antioxidant (protects RBCs and membranes from free radical damage), high dose supplementation
may alter metabolism of vitamin K leading to enhanced anticoagulant effects of Warfarin, Deficiency: hemolytic anemia, acanthocytosis, muscle
weakness, posterior column and spinocerebellar tract demyelination, neurologic presentation may appear similar to vitamin B12 deficiency, but without
megaloblastic anemia, hypersegmented neutrophils, or increased serum methylmalonic acid levels
• Vitamin K (Phytomenadione, Phylloquinone, Phytonadione) – fat-soluble, activated by epoxide reductase to reduced form, which is a cofactor for γ-
carboxylation of glutamic acid residues on various proteins required for blood clotting, synthesized by intestinal flora, necessary for maturation of
clotting factors 2, 7, 9, 10, and proteins C and S (“K is for Koagulation”, Warfarin inhibits their synthesis), Deficiency: neonatal hemorrhage with
increased PT and aPTT time, but normal bleeding time (neonates have sterile intestines and are unable to synthesize vitamin K), may also occur after
prolonged use of broad-spectrum antibiotics, not in breast milk, neonates given vitamin K injection at birth to prevent Hemorrhagic Disease of the
Newborn
 • Zinc – mineral essential for activity of 100+ enzymes, important in formation of zinc fingers (transcription factor motifs used in binding of steroid
hormones, thyroid hormones, and vitamins A and D), Deficiency: delayed wound healing, hypogonadism, decreased adult hair (axillary, facial, and
pubic), dysgeusia, anosmia, acrodermatitis enteropathica, may predispose to alcoholic cirrhosis

Starvation (Protein-Energy Malnutrition)

• Kwashiorkor – protein malnutrition resulting in skin lesions, edema (low plasma oncotic pressure), liver malfunction (fatty change due to decreased
apolipoprotein synthesis), presents as gaunt child with swollen abdomen (“caused by protein-deficient MEALS: Malnutrition, Edema, Anemia, fatty Liver,
Skin lesions, esp. hyperkeratosis/hypopigmentation”)
 • Marasmus – malnutrition not causing edema, diet deficient in calories, but no nutrients entirely absent (“Marasmus causes Muscle wasting”)

Metabolism – Alcohol Metabolism

• Ethanol Metabolism – metabolized by alcohol dehydrogenase to acetaldehyde (buildup causes hangover symptoms), then by acetaldehyde
dehydrogenase to acetate, which can be excreted, NAD+ the limiting reagent, zero order kinetics (constant amount, not percent, metabolized per hour),
increases NADH/NAD+ ratio in liver, with the following consequences: 1.) Pyruvate Converted to Lactate: lactic acidosis, 2.) Oxaloacetate Converted to
Malate: prevents gluconeogenesis, producing fasting hypoglycemia, 3.) Dihydroxyacetone phosphate Converted to Glycerol-3-Phosphate: combines with
fatty acids to make triglycerides producing hepatosteatosis, end result is clinical picture seen in chronic alcoholism, 4.) Disfavors TCA Production of
NADH: leads to increased utilization of acetyl-CoA for ketogenesis, producing ketoacidosis and lipogenesis (hepatosteatosis)
 • Alcohol Dehydrogenase Inhibitors – Fomepizole, antidote for ethanol/methanol poisoning (“FOMEpizole is antidote For Overdoses of Methanol or
Ethylene glycol”)
• Acetaldehyde Dehydrogenase Inhibitors – Disulfiram, acetaldehyde accumulates, producing rapid hangover effects, discourages drinking, not used

Metabolism – Metabolism Sites

• Mitochondria – fatty acid oxidation (β-oxidation), acetyl-CoA production, TCA cycle, oxidative phosphorylation, ketogenesis
• Cytoplasm – glycolysis, HMP shunt, synthesis of steroids (SER), proteins (ribosomes, RER), fatty acids, cholesterol, nucleotides
• Both – heme synthesis, urea cycle, gluconeogenesis (“HUGs take both”)
Metabolism – Enzyme Terminology
• Kinase – catalyzes transfer of phosphate group from high energy molecule (usually ATP) to substrate, Example: phosphofructokinase
• Phosphorylase – adds inorganic phosphate onto substrate without using ATP, Example: glycogen phosphorylase
• Phosphatase – removes phosphate group from substrate, Example: fructose-1,6-bisphosphatase
• Dehydrogenase – catalyzes oxidation-reduction reactions, Example: pyruvate dehydrogenase
• Hydroxylase – adds hydroxyl group (-OH) onto substrate, Example: tyrosine hydroxylase
• Carboxylase – transfers CO2 groups with using biotin, Example: pyruvate carboxylase
• Mutase – relocates functional group within molecule, Example: vitamin B12-dependent methylmalonyl-CoA mutase
• Synthase/Synthetase – combines 2 molecules into 1 (condensation reaction) either using an energy source (synthetase, Example: glycogen synthase) or
not (synthase, Example: PRPP synthetase)

Metabolism – Rate Determining Enzymes of Metabolic Processes

Process Enzyme Regulators
Glycolysis Phosphofructokinase-1 (PFK-1) ⊕: AMP, fructose-2,6-bisphosphonate
⊖: ATP, citrate
Gluconeogenesis Fructose-1,6-bisphosphatase ⊕: citrate
⊖: AMP, fructose-2,6-bisphosphonate
TCA Cycle Isocitrate dehydrogenase ⊕: ADP
⊖: ATP, NADH
Glycogenesis Glycogen synthase ⊕: glucose-6-phosphate, insulin, cortisol
⊖: epinephrine, glucagon
Glycogenolysis Glycogen phosphorylase ⊕: epinephrine, glucagon, AMP
⊖: glucose-6-phosphate, insulin, ATP
HMP Shunt Glucose-6-phosphate dehydrogenase (G6DP) ⊕: NADP+
⊖: NADPH
De Novo Pyrimidine Synthesis Carbamoyl phosphate synthetase 2 ⊕: ATP, PRPP
⊖: UTP
De Novo Purine Synthesis Glutamine-phosphoribosylpyrophosphate (PRPP) ⊕: AMP, inosine monophosphate (IMP)
aminotransferase ⊖:GMO
Urea Cycle Carbamoyl phosphate synthetase I ⊕: N-acetylglutamate
Fatty Acid Synthesis Acetyl-CoA carboxylase (ACC) ⊕: insulin, citrate
⊖: glucagon, palmitoyl-CoA
Fatty Acid Oxidation Carnitine acyltransferase 1 ⊖: malonyl-CoA
Ketogenesis HMG-CoA synthase
Cholesterol Synthesis HMG-CoA reductase ⊕: insulin, thyroxine
⊖: glucagon, cholesterol
Metabolism – Summary of Pathways
Metabolism – ATP Production
• Summary of ATP Production – production modes: 1.) Aerobic Metabolism of Glucose: produces 32 net ATP via malate-aspartate shuttle (heart and
liver), 30 net ATP via glycerol-3-phosphate shuttle (muscle), 2.) Anaerobic Glycolysis: produces only 2 net ATP per glucose molecule, arsenic causes
glycolysis to produce 0 net ATP, ATP hydrolysis can be coupled to energetically unfavorable reactions

Metabolism – Activated Carriers

• ATP – carries phosphoryl groups
• NADH, NADPH, FADH2 – carries electrons
• CoA, Lipoamide – carries acyl groups
• Biotin – carries CO2
• Tetrahydrofolates – carries 1-carbon units
• S-Adenosylmethionine (SAM) – carries methyl (CH3) groups
• TPP – carries aldehydes

Metabolism – Universal Electron Acceptors

• NAD+, NADP+ – nicotinamide from vitamin B3, used in catabolic processes to carry reducing equivalents away as NADH
• FAD+ – flavin nucleotide from vitamin B2, used in catabolic processes to carry reducing equivalents away as FADH2
• NADPH – nicotinamide from HMP shunt, used in anabolic processes (steroid and fatty acid synthesis) as a supply of reducing equivalents, also used in
respiratory burst, CYT-P450 system, glutathione reductase

Metabolism – Hexokinase vs. Glucokinase

• Introduction – phosphorylation of glucose to glucose-6-phosphate the first step of glycogen synthesis in liver, catalyzed by either hexokinase or
glucokinase, depending on tissue, at low glucose concentrations, hexokinase sequesters glucose in tissue, at high glucose concentrations, excess glucose
stored in liver

Hexokinase Glucokinase
Location Most tissues, except liver and pancreatic β cells Liver and pancreatic β cells
Km Lower (increased affinity) Higher (decreased affinity)
Vmax Lower (decreased capacity) Higher (increased capacity)
Induced by insulin No Yes
Feedback inhibition from G6P Yes No
Metabolism – Glycolysis, TCA Cycle, Electron Transport Chain/Oxidative Phosphorylation, and Gluconeogenesis
• Glycolysis Regulation – net glycolysis (cytoplasm): Glucose + 2Pi + 2ADP + 2NAD+  2 pyruvate + 2ATP + 2NADH + 2H+ + 2H2O, net production of 2 ATP,
equation not balanced chemically, exact balanced equation depends on ionization state of reactants and products, steps impacting ATP: 1.) Require ATP:
conversion of glucose to glucose-6-phosphate by hexokinase (everywhere except liver and pancreatic β cells, negative/product feedback inhibition by
glucose-6-phosphate) or glucokinase (liver and pancreatic β cells, negative/product feedback inhibition by fructose-6-phosphate), conversion of
fructose-6-phosphate to fructose-1,6-bisphosphate by phosphofructokinase-1 (rate-limiting step, stimulated by AMP, fructose-2,6-bisphosphate,
inhibited by ATP, citrate), 2.) Produce ATP: conversion of 1,3-bisphosphoglycerate to 3-phosphoglycerate by phosphoglycerate kinase, conversion of
phosphoenolpyruvate to pyruvate by pyruvate kinase (stimulated by fructose-1,6-bisphosphate, inhibited by ATP, alanine)
• Regulation by Fructose-2,6-Bisphosphate – fructose bisphosphatase-2 (FBPase-2) and phosphofructokinase-2 (PFK-2) are the same bifunctional enzyme
whose function is reversed by phosphorylation by protein kinase A
o Fasting State: glucagon increases cAMP and protein kinase A activity (decreased protein phosphatase activity), producing increased FBPase-2
activity, decreased PFK-2 activity, less glycolysis, and more gluconeogenesis (glucagon increases phosphorylation)
o Fed State: insulin decreases cAMP and protein kinase A activity (increased protein phosphatase activity), producing decreased FBPase-2
activity, increased PFK-2 activity, more glycolysis, less gluconeogenesis (insulin decreases phosphorylation)

• Pyruvate Dehydrogenase Complex – mitochondrial enzyme complex linking glycolysis and the TCA cycle, differentially regulated in fed/fasting states
(active in fed state), complex similar to α-ketoglutarate dehydrogenase complex (same cofactors, similar substrate and action), which converts α-
 ketoglutarate to succinyl-CoA in the TCA cycle, reaction: pyruvate + NAD+ + CoA  acetyl-CoA + CO2 + NADH, complex contains 3 enzymes requiring 5
cofactors: thiamine pyrophosphate (vitamin B1), lipoic acid, CoA (vitamin B5, pantothenic acid), FAD (vitamin B2, riboflavin), NAD+ (vitamin B3, niacin)
(“The Lovely Co-enzyme For Nerds”), activated by increased NAD+/NADH ratio, increased ADP, increased Ca2+, arsenic inhibits lipoic acid (arsenic
poisoning presents with vomiting, rice-water stools, garlic breath, QT prolongation)

• Pyruvate Dehydrogenase Complex Deficiency – X-linked, produces pyruvate buildup that gets shunted to lactate (via lactate dehydrogenase – LDH) and
alanine (alanine transaminase – ALT), presents with neurologic defects, lactic acidosis, serum shows increased alanine starting in infancy, treat with
increased intake of ketogenic nutrients (e.g. high fat diet or increased lysine and leucine)
• Pyruvate Metabolism – functions of different pyruvate metabolic pathways (and their associated cofactors): 1.) Alanine Aminotransferase (ALT):
cofactor vitamin B6, alanine carries amino groups to liver from muscle, 2.) Pyruvate Carboxylase (PC): cofactor biotin, oxaloacetate can replenish TCA
cycle or be used in gluconeogenesis, 3.) Pyruvate Dehydrogenase (PDH): cofactors vitamins B1, B2, B3, B5, lipoic acid, transition from glycolysis to the
TCA cycle, 4.) Lactic Acid/Lactate Dehydrogenase (LDH)): cofactor vitamin B3, end of anaerobic glycolysis (major pathway in RBCs, WBCs, kidney medulla,
lens, testes, and cornea)
• TCA Cycle (Krebs Cycle) – precursor reaction (bridging products of glycolysis): pyruvate  acetyl-CoA + NADH + CO2, TCA cycle produces 3 NADH, 1
FADH2, 2 CO2, 1 GTP per acetyl-CoA = 10-12 ATP per acetyl-CoA (2x everything per glucose since 1 glucose makes 2 acetyl-CoA), reactions occur in
mitochondria, α-ketoglutarate dehydrogenase complex requires same cofactors as pyruvate dehydrogenase complex (“Citrate Is Krebs’ Starting
Substrate For Making Oxaloacetate = Citrate, Isocitrate, α-Ketoglutarate, Succinyl-CoA, Succinate, Fumarate, Malate, Oxaloacetate”)
• Electron Transport Chain – NADH electrons from glycolysis enter mitochondria via malate-aspartate or glycerol-3-phosphate shuttle, FADH2 electrons
transferred to complex 2 (at lower energy level than NADH electrons), passage of electrons results in formation of proton gradient that, coupled to
oxidative phosphorylation, drives ATP production, 1 NADH  2.5 ATP, 1 FADH2  1.5 ATP
• Electron Transport Poisons

Mechanism Mechanism Examples

Electron Transport InhibitorsDirectly inhibits electron transport, decreasing proton Rotenone (complex 1, “rotenONE"), Antimycin A (complex
gradient and blocking ATP synthesis 3, “An-3-mycin”), CO/CN (complex 4, “4 letters”)
ATP Synthase Inhibitors Directly inhibits ATP synthase increasing proton gradient, no Oligomycin
ATP produced due to halted electron transport
Uncoupling Agents Increases membrane permeability, decreasing proton 2,4-Dinitrophenol (used illicitly for wight loss), ASA (fevers
gradient and increasing O2 consumption, ATP synthesis stops, often occur after overdose), thermogenin in brown fat
but electron transport continues (they are “uncoupled” from
each other)
• Gluconeogenesis – Irreversible Enzymes – occurs primarily in liver, maintains euglycemia during fasting, enzymes also found in kidney and intestinal
epithelium, deficiency of key gluconeogenesis enzymes causes hypoglycemia (muscle cannot participate in gluconeogenesis because it lacks glucose-6-
phosphatase), odd chain fatty acids yield 1 molecule of propionyl-CoA during metabolism, which can enter TCA cycle as succinyl-CoA, undergo
gluconeogenesis, and serve as glucose source, even-chain fatty acids cannot produce new glucose since they yield only acetyl-CoA equivalents, enzymes
(“Pathway Produces Fresh Glucose”): 1.) Pyruvate Carboxylase: mitochondria, converts pyruvate to oxaloacetate, requires biotin and ATP, activated by
acetyl-CoA, 2.) Phosphoenolpyruvate Carboxykinase: cytosol, converts oxaloacetate to phosphoenolpyruvate, requires GTP, 3.) Fructose-1,6-
Bisphosphatase: cytosol, converts fructose-1,6-bisphosphate to fructose-6-phosphate, stimulated by citrate, inhibited by AMP, fructose-2,6-
bisphosphate, 4.) Glucose-6-Phosphatase: ER, converts glucose-6-phosphate to glucose
• Triglyceride Metabolism
Metabolism – Hexose Monophosphate (HMP) Shunt
• Hexose Monophosphate Shunt (Pentose Phosphate Pathway)
• Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency – X-linked recessive, most common human enzyme deficiency, more prevalent among AA,
confers malarial resistance, NADPH necessary to keep glutathione reduced, which in turn detoxifies free radicals and peroxides, decreased NAPDH in
RBCs leads to hemolytic anemia due to poor RBC defense against oxidizing agents (e.g. fava beans, Sulfonamides, Primaquine, antituberculosis drugs),
infection (most common cause) may also precipitate hemolysis, inflammatory cells produce free radicals that diffuse into RBCs, causing oxidative
damage, peripheral smear shows Heinz bodies (denatured Hb precipitates in RBCs due to oxidative stress) and bite cells (phagocytic removal of Heinz
bodies by splenic macrophages, “bite into some Heinz ketchup”), see Hematology and Oncology
Disorders of Fructose Metabolism
• Fructose Metabolism – fructose bypasses phosphofructokinase-1, the major regulatory step in glycolysis, allowing it and its metabolite F1P to be
metabolized faster
• Essential Fructosuria – autosomal recessive defect in fructokinase, benign, asymptomatic condition, since fructose not trapped in cells, serum and urine
show fructose (fructosemia, fructosuria), disorders of fructose metabolism generally cause milder symptoms than analogous disorders of galactose
metabolism
• Fructose Intolerance – autosomal recessive aldolase B deficiency, fructose-1-phosphate accumulates decreasing available phosphate, which results in
inhibition of glycogenolysis and gluconeogenesis, symptoms occur following consumption of fruit, juice, or honey, urine dipstick negative (tests for
glucose only), reducing sugar detected in urine (nonspecific test for inborn errors of carbohydrate metabolism), presents with hypoglycemia, jaundice,
cirrhosis, vomiting, treat by decreasing intake of fructose and sucrose (glucose + fructose)
Disorders or Galactose Metabolism
• Galactokinase Deficiency – autosomal recessive galactokinase deficiency, galactitol accumulates if galactose present in diet, may present with failure to
track objects or develop social smile, infant cataracts, serum and urine show galactose (galactosemia, galactosuria), relatively mild
 • Classic Galactosemia – autosomal recessive galactose-1-phosphate uridyltransferase, damage caused by accumulation of toxic substances (including
galactitol, which accumulates in lens of eye), symptoms develop when infant begins feeding (lactose present in breast milk and routine formula),
presents with failure to thrive, jaundice, hepatomegaly, infantile cataracts, intellectual disability, treat by excluding galactose and lactose (glucose +
galactose) from diet, complications include predisposition to E. coli sepsis, more serious defects lead to phosphate depletion

Other Enzyme Deficiencies

• Sorbitol – alternative method of glucose trapping within cells is to convert it to alcohol counterpart sorbitol via aldose reductase, some tissues then
convert sorbitol to fructose via sorbitol dehydrogenase, tissues with insufficient sorbitol dehydrogenase amount/activity at risk for intracellular sorbitol
 accumulation, causing osmotic damage (e.g. cataracts, retinopathy, and peripheral neuropathy seen with chronic hyperglycemia in diabetes), high serum
galactose also results in conversion to osmotically active galactitol via aldose reductase, the body can break down the amount of sorbitol normally
produced in the eye, but a pathologic amount overwhelms this ability and it accumulates producing pathology

• Lactase Deficiency – insufficient lactase enzyme leads to dietary lactose intolerance, lactase functions on brush border to digest lactose (human and cow
milk) into glucose and galactose, types: 1.) Primary: age-dependent decline after childhood (absence of lactase-persistent allele), common in people of
Asian, African, or Native American descent, 2.) Secondary: loss of brush border due to gastroenteritis (e.g. Rotavirus), autoimmune disease, sprue, 3.)
Congenital: rare, caused by defective gene, all types present with bloating, cramps, flatulence (bacteria in gut use excess lactose and produce excess
gas), osmotic diarrhea (lactose in gut osmotically active), stool shows decreased pH, lactose hydrogen breath test shows increased hydrogen, intestinal
biopsy reveals normal mucosa in patients with hereditary lactose intolerance, treat with avoidance of dairy products (or using lactose-free milk), or add
lactase pills to diet

Metabolism – Amino Acids

• Introduction – only L-amino acids found in proteins

Amino Acid R Group Association

Nonpolar, Aliphatic Side Chains
Glycine (Gly)
Alanine (Ala)
Valine (Val) – BCAA
Leucine (Leu) – BCAA
Isoleucine (Ile) – BCAA
Proline (Pro)
-H Collagen, smallest
-CH3 Starvation, major precursor of gluconeogenesis
-CH-(CH3)2 Maple Syrup Urine Disease
-CH2-CH-(CH3)2 Maple Syrup Urine Disease
-CH-(CH3,CH2-CH3) Maple Syrup Urine Disease
-(CH2)3 ring connecting to NH3+ end Collagen (hallmark), HO-Pro via proline hydroxylase (needs vitamin C,
nonfunctional in Ehlers-Danlos, Scurvy)
 Aromatic Side Chains
Phenylalanine (Phe) -Be PKU (with Tyr, nonfunctional phenylalanine hydroxylase, tetrahydrobiopterin a
coenzyme also needed), precursor of catecholamines, melanin, T3 and T4
Tyrosine (Tyr) -Be-OH Precursor of catecholamines, melanin, T3 and T4, target of tyrosine kinases
Tryptophan (Trp) -CH2-C=NH-Be=C- ring Precursor of Serotonin, Niacin
Positively Charged Side Chains
Lysine (Lys) – strongly charged -(CH2)4-NH3+ Histones (with Arg), HO-Lys via lysine hydroxylase, lysyl oxidase requiring Cu
cross-links collagen
Arginine (Arg) – strongly charged -(CH2)3-NH-C(=NH2+,NH2) Histones, urea synthesis, precursor of NO
Histidine (His) – weakly charged -CH2, C-NH-CH=NH+-CH= ring Active site of enzymes, precursor of Histamine
Negatively Charged Side Chains
Aspartate/Aspartic Acid (Asp) -CH2-COO- Urea synthesis
-
Glutamate/Glutamic Acid (Glu) -(CH2)2-COO Precursor of GABA via glutamate decarboxylase
Polar, Uncharged Side Chains
Serine (Ser) -CH2OH Targets of protein kinases A, C, G
Threonine (Thr) -CH(OH, CH3) Targets of protein kinases A, C, G
Cysteine (Cys) -CH2-SH Tertiary structure of proteins, potent reductants (electron donors)
Methionine (Met) -(CH2) 2-S-CH3 Tertiary structure of proteins, SAM donates -CH3 group
Asparagine (Asn) CH2-C(=O, H2N) N-glycosylation in ER
Glutamine (Gln) (CH2) 2-C(=O, H2N) Hyperammonemia, used to remove NH3
• Essential Amino Acids – all must be supplied in diet, “Argh, it’s PVT TIM HALL, he’s not a Pro, but he doesn’t get tyred”: Phenylalanine, Valine,
Tryptophan, Threonine, Isoleucine, Methionine, Histidine, Arginine (only during periods of positive Nitrogen balance, as in a child, need arginine, all cells
growing quickly), Leucine, Lysine, PKU: need supplemental Tyrosine (adult), Tyrosine and Arginine (child/positive N balance)
o Glucogenic: Methionine (Met), Histidine (His), Valine (Val) (“I met his valentine, she is so sweet”)
o Glucogenic/Ketogenic: Isoleucine (Ile), Phenylalanine (Phe), Threonine (Thr), Tryptophan (Trp)
o Ketogenic: Leucine (Leu), Lysine (Lys)
• Acidic Amino Acids – Aspartic Acid (Asp) and Glutamic Acid (Glu), negatively charged at body pH
• Basic Amino Acids – Histidine (His, no charge at body temperature), Lysine (Lys), Arginine (Arg, most basic) (“His Lys are Basic”), Arginine and Histidine
required during periods of growth, Arginine and Lysine increased in histones, which bind negatively charged DNA
• Amino Acid Derivatives

Precursor Amino Acid/s Derived Substance

Arginine Nitric Oxide (NO)
Arginine + Aspartate Urea
Glycine + Succinyl CoA Heme
Glycine + Arginine + SAM Creatine
 Glutamate GABA, Glutathione
Glutamine + Aspartate Pyrimidines
Glutamine + Aspartate + Glycine Purines
Histidine Histamine
Tyrosine Dopamine, Epinephrine, Norepinephrine, Thyroxine, Melanin
Tryptophan Serotonin, Melatonin, Niacin

•
• Catecholamine Synthesis/Tyrosine Catabolism – primary circulating catecholamines are Dopamine, Norepinephrine, and Epinephrine, Norepinephrine
and Dopamine produced in CNS and PNS, Epinephrine predominantly produced in adrenal medulla from Norepinephrine via phenylethanolamine-N-
methyltransferase (PNMT), which is stimulated by cortisol, normally venous flow through adrenal medulla is high and cortisol levels are high, however
following pituitary resection, ACTH levels would drop, cortisol levels would drop, PNMT would drop, and Epinephrine levels would drop
Amino Acid Disorders
• Alkaptonuria – autosomal recessive congenital deficiency of homogentisic acid dioxygenase (metabolizes homogentisic acid to maleylacetoacetate) in
the degradative pathway of tyrosine to fumarate, which leads to pigment-forming homogentisic acid accumulation in connective tissue, presents with
bluish-black connective tissue, ear cartilage, and sclerae (ochronosis), urine turns black on prolonged exposure to air due to oxidization of homogentisic
acid, usually benign, complications include severe, debilitating arthritis (homogentisic acid toxic to cartilage)
• Cystinuria – autosomal recessive, common (1:7,000), hereditary defect of renal PCT and intestinal amino acid transporter that prevents reabsorption of
cystine (made of 2 Cysteines connected by disulfide bond), ornithine, Lysine, and Arginine (“COLA”), excess cystine in urine can lead to recurrent
precipitation of hexagonal stones, diagnose with urinary cyanide-nitroprusside test, treat with urinary alkalinization (e.g. Potassium Citrate,
Acetazolamide) and chelating agents (Penicillamine) to increase solubility of cystine stones, and with good hydration

• Homocystinuria – autosomal recessive, causes: 1.) Cystathionine Synthase Deficiency: treat by decreasing dietary Methionine, increasing Cysteine,
vitamins B6, B12, and folate, 2.) Decreased Affinity of Cystathionine Synthase for Pyridoxal Phosphate: treat with highly increased dietary vitamin B6 and
Cysteine, 3.) Methionine Synthase (Homocysteine Methyltransferase) Deficiency: treat by increasing dietary Methionine, all forms result in excess
homocysteine, presents with osteoporosis, Marfanoid habitus, downward and inward lens subluxation, thrombosis and atherosclerosis leading to stroke
and MI, kyphosis, and intellectual disability, urine shows highly elevated homocysteine
• Maple Syrup Urine Disease – autosomal recessive, caused by blocked degradation of branched chain amino acids (Isoleucine, Leucine, Valine) due to
decreased branched-chain α-ketoacid dehydrogenase (vitamin B1), leads to increased α-ketoacids in blood, esp. those of Leucine, presents with
vomiting, poor feeding, urine that smells like maple syrup/burnt sugar, severe CNS defects, intellectual disability, death, treat with restriction of
Isoleucine, Leucine, and Valine in diet, and with thiamine supplementation (“I Love Vermont maple syrup from maple trees with B1ranches”)
• Methylmalonic Acidemia
• Phenylketonuria – autosomal recessive (incidence 1:10,000), caused by phenylalanine hydroxylase deficiency or tetrahydrobiopterin (BH4) deficiency
(malignant PKU), Tyrosine becomes essential, increased Phenylalanine leads to excess phenyl ketones in urine (phenylacetate, phenyllactate,
phenylpyruvate), presents with intellectual disability, growth retardation, seizures, fair skin, eczema, musty body odor (“disorder or aromatic amino acid
metabolism”), treat by decreasing dietary Phenylalanine and increasing Tyrosine, and with tetrahydrobiopterin (BH4) supplementation, avoidance of
artificial sweetener aspartame, which contains Phenylalanine, also essential, screening occurs 2-3 days after birth (normal at birth due to maternal
enzyme during fetal life), complications include Maternal PKU: lack of proper dietary therapy during pregnancy leads to infant microcephaly, intellectual
disability, growth retardation, and congenital heart defects
Metabolism – Urea and Ammonia
• Urea Cycle – amino acid catabolism results in formation of common metabolites (e.g. pyruvate, acetyl-CoA), which serve as metabolic fuels, excess
nitrogen generated converted to urea and excreted in kidneys (“Ordinarily, Careless Crappers Are Also Frivolous About Urination = ornithine, carbamoyl
phosphate input, citrulline, aspartate, arginosuccinate, fumarate, arginine, urea”), urea cycle disorders treated with protein restriction
• Transport of Ammonia by Alanine
• Hyperammonemia – acquired (e.g. liver disease) or hereditary (e.g. urea cycle enzyme deficiencies), results in excess NH3, which depletes α-
ketoglutarate leading to inhibition of TCA cycle, presents with tremor (asterixis), slurred speech, somnolence, vomiting, cerebral edema, blurred vision,
treat chronically with limited protein in diet, acutely with Lactulose (acidifies GI tract, promotes conversion of NH3 to NH4+, which is then trapped and
excreted), antibiotics (e.g. Rifaximin, decreases colonic ammoniagenic bacteria), Benzoate, Phenylacetate, or Phenylbutyrate (reacts with Glycine or
Glutamine, forming products which can be renally excreted)
 • Arginase Deficiency – presents with spastic diplegia, abnormal movements, and growth delay in the setting of elevated arginine levels, but with mild or
no hyperammonemia (unlike other urea cycle disorders), diagnose based on elevated arginine levels and plasma amino acid testing, treat with low-
protein diet devoid of arginine
• Ornithine Transcarbamylase Deficiency – X-linked recessive, most common urea cycle disorder (contrast others, which are autosomal recessive),
interferes with body’s ability to eliminate ammonia, often evident in first few days of life, but may present later, excess carbamoyl phosphate converted
to orotic acid (pyrimidine synthesis pathway), presents with symptoms of hyperammonemia, serum and urine show increased orotic acid, decreased
BUN, no megaloblastic anemia (contrastOrotic Aciduria)

Metabolism – Glycogen Regulation

• Glycogen Regulation by Insulin and Glucagon/Epinephrine
• Glycogen – branches have α-(1,6) bonds, linkages have α-(1,4) bonds, locations: 1.) Skeletal Muscle: glycogen undergoes glycogenolysis to glucose-1-
phosphate then to glucose-6-phosphate, which is rapidly metabolized during exercise, 2.) Hepatocytes: glycogen stored and undergoes glycogenolysis to
maintain blood sugar at appropriate levels, glycogen phosphorylase liberates glucose-1-phosphate residues off branched glycogen until 4 glucose units
remain on branch, then 4-α-D-glucanotransferase (debranching enzyme) moves 3 molecules of glucose-1-phosphate from branch to linkage, then α-1,6-
glucosidase (debranching enzyme) cleaves off last residue, liberating glucose, “limit dextrin” refers to the 1 to 4 residues remaining on branch after
glycogen phosphorylase has already shortened it, Note: a small amount of glycogen is degraded in lysosomes by α-1,4-glucosidase (acid maltase)
Glycogen Storage Diseases
• Introduction- 12 types, all resulting in abnormal glycogen metabolism and resulting accumulation within cells, Periodic acid-Schiff stain identifies
glycogen and is useful for identification, Types 1, 2, 3, and 5 are autosomal recessive, most clinically relevant (“Very Poor Carbohydrate Metabolism”)
• Von Gierke Disease (Type 1) – autosomal recessive, caused by glucose-6-phosphate deficiency, which results in impaired gluconeogenesis and
glycogenolysis, presents with severe fasting hypoglycemia, greatly increased glycogen in liver, increased serum lactate, triglycerides, and uric acid (gout),
hepatomegaly, treat with frequent oral glucose/cornstarch, avoidance of fructose or galactose
• Pompe Disease (Type 2) – autosomal recessive, caused by lysosomal acid α-1,4-glucosidase deficiency with α-1,6-glucosidase (acid maltase) activity,
presents with cardiomegaly, hypertrophic cardiomyopathy, hypotonia (heart, liver, and muscle problems), exercise intolerance, systemic findings leading
to early death (“PomPe trashes the PumP, 1st and 4th letters)
• Cori Disease (Type 3) – autosomal recessive, caused by α-1,6-glucosidase deficiency (debranching enzyme), gluconeogenesis remains intact, only
glycogenolysis impaired, presents as milder form of von Gierke Disease (Type 1) with normal blood lactate levels, accumulation of limit dextrin-like
structures in cytosol
• McArdle Disease (Type 5) – autosomal recessive, caused by skeletal muscle glycogen phosphorylase (myophosphorylase) deficiency, blood glucose
levels typically unaffected, increased glycogen in muscle which cannot be broken down produces painful muscle cramps, myoglobinuria (red urine) with
strenuous exercise, and arrhythmias from electrolyte abnormalities, second-wind phenomenon noted during exercise due to increased muscular blood
flow (“McArdle = Muscle”)
Lysosomal Storage Diseases
• Introduction – caused by deficiency of one of many lysosomal enzymes resulting in accumulation of abnormal metabolic products, increased incidence
of Tay-Sachs, Niemann-Pick, and some forms of Gaucher Disease in Ashkenazi Jews
• Tay-Sachs Disease – autosomal recessive sphingolipidosis, caused by hexosaminidase A deficiency (enzyme 1 above, “tAy-saX”), GM2 accumulates,
presents with progressive neurodegeneration, developmental delay, “cherry-red” spot on macula, lysosomes with onion skin, no hepatosplenomegaly
(contrast Niemann-Pick)
• Fabry Disease – X-linked recessive sphingolipidosis, caused by α-galactosidase A deficiency (enzyme 2 above), ceramide trihexoside accumulates,
presents early with triad of episodic peripheral neuropathy, angiokeratomas, hypohidrosis, late with progressive renal failure and cardiovascular disease

• Metachromatic Leukodystrophy – autosomal recessive sphingolipidosis, most commonly caused by arylsulfatase A deficiency (enzyme 3 above),
cerebroside sulfate accumulates, leading to impaired production and increased destruction of myelin sheath, presents with central and peripheral
demyelination with ataxia, dementia
• Krabbe Disease – autosomal recessive sphingolipidosis, caused by galactocerebrosidase deficiency (enzyme 4 above), galactocerebroside psychosine
accumulates, destroying myelin sheath, presents with peripheral neuropathy, oligodendrocyte destruction, developmental delay, optic atrophy, globoid
cells
• Gaucher Disease – autosomal recessive sphingolipidosis, most common lysosomal storage disease, caused by glucocerebrosidase (β-glucosidase)
deficiency (enzyme 5 above), glucocerebroside accumulates, presents with hepatosplenomegaly, pancytopenia, osteoporosis, avascular necrosis of
femur, bone crises, Gaucher cells (lipid-laden macrophages resembling crumpled tissue paper), treat with recombinant glucocerebrosidase
• Niemann-Pick Disease – autosomal recessive sphingolipidosis, caused by sphingomyelinase deficiency (enzyme 6 above), sphingomyelin accumulates,
presents with progressive neurodegeneration, hepatosplenomegaly, foam cells (lipid-laden macrophages), “cherry red” spot on macula (“No man picks
his nose with his finger”)
 • Hurler Syndrome – autosomal recessive mucopolysaccharidosis, caused by α-L-iduronidase deficiency, heparan and dermatan sulfate accumulate,
presents with developmental delay, gargoylism, airway obstruction, corneal clouding, hepatosplenomegaly

• Hunter Syndrome – X-linked recessive mucopolysaccharidosis, caused by iduronate sulfatase deficiency, heparan and dermatan sulfate accumulate,
presents with mild Hurler Syndrome with aggressive behavior, but no corneal clouding (“hunters see clearly and aggressively aim for the X”)

Metabolism – Fatty Acid Metabolism

• Introduction – fatty acid synthesis requires transport of citrate from mitochondria to cytosol, predominantly occurs in liver, lactating mammary glands,
and adipose tissue, long-chain fatty acid (LCFA) degradation requires carnitine-dependent transport into mitochondrial matrix (“Sytrate = Synthesis,
Carnitine = Carnage of fatty acids”)
• Systemic Primary Carnitine Deficiency – inherited defect in LCFA transport into mitochondria leading to toxic accumulation, presents with muscle
weakness/hypotonia, cardiomyopathy, hypoketotic hypoglycemia, and elevated muscle triglycerides
• Medium-Chain Acyl-CoA Dehydrogenase Deficiency – decreased ability to break down fatty acids into acetyl-CoA leading to accumulation of fatty acyl
carnitines in the blood with hypoketotic hypoglycemia, presents with vomiting, lethargy, seizures, coma (all signs of hypoglycemia), liver dysfunction,
may lead to sudden death in infants or children, treat by avoiding fasting
Fuel, Fasting, and Starvation
• Ketone Bodies – ketone bodies include acetone, acetoacetate, β-hydroxybutyrate, in the liver, fatty acids and amino acids are metabolized to
acetoacetate and β-hydroxybutyrate (to be used in muscle and brain), in prolonged starvation and diabetic ketoacidosis, oxaloacetate is depleted for
gluconeogenesis, in alcoholism, excess NADH shunts oxaloacetate to malate, both processes lead to acetyl-CoA accumulation, which shunts amino acids
and FFA toward ketone body production, breath in ketotic state has fruity odor (smells like acetone), urine ketones can detect acetoacetate but not β-
hydroxybutyrate
• Metabolic Fuel Use – kcal provided by fuel type (“# of letters = # of kcals”): 1g carb = 4 kcal, 1 g alcohol = 7 kcal, 1 g fatty acid = 9 kcal, 1 g meat (protein)
= 4 kcal

Metabolic Fuel (1 g) Energy Provided (kcal)

Fat 9
Alcohol 7
Protein 4
Carbohydrate 4
• Fasting and Starvation – body prioritizes supplying sufficient glucose to brain and RBCs as well as preserving protein, metabolic states: 1.) Fed State
(After a Meal): glycolysis and aerobic respiration, insulin stimulates storage of lipids, proteins, and glycogen, 2.) Fasting (Between Meals): hepatic
glycogenolysis (major), hepatic gluconeogenesis, adipose release of FFAs (minor), glucagon and epinephrine stimulate use of fuel reserves, 3.) Starvation
Days 1-3: blood glucose levels maintained by hepatic glycogenolysis (lasts 12 hours), adipose release of FFAs, muscle and liver shift fuel use from glucose
to FFAs, hepatic gluconeogenesis from peripheral tissue lactate and Alanine, and from adipose tissue glycerol and propionyl-CoA (from odd-chain FFAs –
the only triacylglycerol components that contribute to gluconeogenesis), RBCs lack mitochondria, cannot use ketones, 4.) Starvation After Day 3: adipose
stores (ketone bodies become main energy source for brain), once they are depleted, vital protein degradation accelerates leading to organ failure and
death, amount of excess stores determines survival time
Lipids and Lipid Transport
• Lipid Transport – Key Enzymes – key enzymes in the degradation of triglycerides (TGs) include pancreatic lipase (small intestine), lipoprotein lipase (LPL,
found on vascular endothelial surface, degrades TGs circulating in chylomicrons and VLDLs), hepatic TG lipase (HL, degrades TGs remaining in IDL),
hormone-sensitive lipase (adipocytes), LCAT (catalyzes esterification of 2/3 of plasma cholesterol), cholesterol ester transfer protein (CETP, mediates
transfer of cholesterol esters to other lipoprotein particles)
 • Major Apolipoproteins

Apolipoprotein Function Chylomicron Chylomicron Remnant VLDL IDL LDL HDL

A-1 Activates LCAT  
B-48 Mediates chylomicron secretion into lymphatics  
B-100 Binds LDL receptor   
C-2 Lipoprotein lipase cofactor that catalyzes cleavage   
E Mediates remnant uptake (everything except LDL)     
• Lipoprotein Functions – composed of varying proportions of cholesterol, TGs, and phospholipids, LDL and HDL carry the most cholesterol
• Cholesterol – needed to maintain cell membrane integrity and synthesize bile acids, steroids, and vitamin D
• Chylomicron – delivers dietary TGs to peripheral tissues and cholesterol to liver in form of chylomicron remnants, which are mostly depleted of their
TGs, secreted by intestinal epithelial cells
• VLDL – delivers hepatic TGs to peripheral tissue, secreted by liver
• IDL – delivers TGs and cholesterol to liver, formed in degradation of VLDL
• LDL – delivers hepatic cholesterol to peripheral tissues, formed by hepatic lipase modification of IDL in liver and peripheral tissue, taken up by target
cells via receptor-mediated endocytosis
• HDL – mediates reverse cholesterol transport from periphery to liver, acts as repository for apolipoproteins C and E (needed for chylomicron and VLDL
metabolism), secreted from both liver and intestine, alcohol increases synthesis

Lipid and Lipid Transport Deficiencies

• Abetalipoproteinemia – autosomal recessive, chylomicrons, VLDL, LDL absent, deficiency in ApoB48, ApoB100, affected infants present early with
severe fat malabsorption, steatorrhea, failure to thrive, later with retinitis pigmentosa, spinocerebellar degeneration due to vitamin E deficiency,
progressive ataxia, acanthocytosis, treat by restricting dietary long-chain fatty acids, with large doses of oral vitamin E

• Introduction to Familial Hyperlipoproteinemias

• Hyperchylomicronemia (Type 1 Familial Dyslipidemia) – autosomal recessive, lipoprotein lipase or apolipoprotein C-2 deficiency, increased
chylomicrons, TG, cholesterol in blood, presents with pancreatitis, hepatosplenomegaly, and eruptive/pruritic xanthomas (no increased risk of
atherosclerosis), creamy layer in supernatant
• Familial Hypercholesterolemia (Type 2 Familial Dyslipidemia) – autosomal dominant, absent or defective LDL receptors, increased LDL, cholesterol (2A,
2B), and VLDL (2B only), heterozygotes (common, 1:500) have cholesterol ≈300 mg/dL, homozygotes (very rare) have cholesterol ≈700+ mg/dL, presents
with accelerated atherosclerosis (may have MI before age 20), tendon xanthomas (cholesterol deposits, esp. in Achilles), and corneal arcus
• Dysbetalipoproteinemia (Type 3 Familial Dyslipidemia) – autosomal recessive, defective ApoE, increased chylomicrons, VLDL, presents with premature
atherosclerosis, tuboeruptive xanthomas, xanthoma striatum palmare

• Hypertriglyceridemia (Type 4 Familial Dyslipidemia) – autosomal dominant, hepatic overproduction of VLDL, increased VLDL, TGs, hypertriglyceridemia
(>1,000 mg/dL), may present with acute pancreatitis
Immunology Homepage
Immune System Organs
• Introduction – classification: 1.) Primary Organs: bone marrow (immune cell production, B-cell maturation), thymus (T-cell maturation), 2.) Secondary
Organs: spleen, lymph nodes, tonsils, Peyer patches, allow immune cells to interact with antigen
• Lymph Node – secondary lymphoid organ with many afferents, 1 or more efferents, encapsulated with trabeculae, performs nonspecific filtration via
macrophages, storage of B- and T-cells, and activation of immune response, components: 1.) Follicle: site of B-cell location, primary follicles dense and
dormant, secondary follicles active with pale central germinal centers, 2.) Medulla: consists of medullary cords (closely packed lymphocytes and plasma
cells) and medullary sinuses, medullary sinuses communicate with efferent lymphatics and contain reticular cells and macrophages, 3.) Paracortex:
houses T-cells, located between follicles and medulla, contains high endothelial venules through which T- and B-cells enter from blood, not well
developed in patients with DiGeorge Syndrome, enlarges in an extreme cellular immune response (e.g. viral infection)
• Lymph Drainage – right lymphatic duct drains everything from right side of body above diaphragm, thoracic duct drains everything else into junction of
left subclavian and internal jugular veins

Lymph Node Cluster Area of Body Drained

Cervical Head and neck
Hilar Lungs
Mediastinal Trachea and esophagus
Axillary Upper limb, breast, skin above umbilicus
Celiac Liver, stomach, spleen, pancreas, upper duodenum (foregut)
Superior Mesenteric Lower duodenum, jejunum, ilium, colon to splenic flexure (midgut)
Inferior Mesenteric Colon from splenic flexure to upper rectum (most of hindgut)
Internal Iliac Lower rectum to anal canal (above pectinate line), bladder, vagina (middle third), cervix, prostate
Para-aortic Testes, ovaries, kidneys, uterus
Superficial Inguinal Anal canal (below pectinate line), skin below umbilicus (except popliteal area), scrotum, vulva
Popliteal Dorsolateral foot, posterior calf

• Spleen – blood filter that also produces antibodies against blood-borne and encapsulated pathogens, located in LUQ of abdomen anterior to left kidney,
protected by ribs 9-11, red pulp contains numerous thin-walled vascular sinusoids (long vascular channels in red pulp with fenestrated “barrel hoop”
basement membrane) separated by splenic cords (“cords of Billroth”), T-cells found in periarteriolar lymphatic sheath (PALS) within white pulp, B-cells
found in follicles within white pulp, marginal zone between red and white pulp contains macrophages and specialized B-cells, location where antigen-
presenting cells (APCs) capture blood-borne antigens for recognition by lymphocytes, splenic macrophages remove encapsulated bacteria, 4 primary
functions: 1.) Phagocytosis of RBCs and Particulate Matter: macrophages in cords consume RBCs with poor membrane flexibility that become trapped,
remove Heinz and Howell-Jolly bodies from RBCs, remove bacteria and other particles from blood, 2.) Antibody Production: dendritic cells in PALS trap
antigens and present them to T-cells, T- and B-cell interaction at edges of white pulp lead to generation of plasma cells which produce antibodies
against encapsulated organisms, 3.) Hematopoiesis: minor site of hematopoiesis during fetal life, subsides by birth, but major site of extramedullary
hematopoiesis in severe chronic anemia, myeloproliferative disorders, CML, and primary myelofibrosis, 4.) Sequestration of Formed Blood Elements:
normally holds 30-40% of platelets, but may hold up to 80-90% producing thrombocytopenia, may trap WBCs and induce leukopenia, splenic
dysfunction (e.g. postsplenectomy, autosplenectomy in SCD) results in decreased IgM leading to decreased compliment activation, decreased C3b
opsonization, and increased susceptibility to encapsulated organs, peripheral smear in postsplenectomy may show Howell-Jolly bodies (nuclear
remnants), target cells, thrombocytosis (loss of sequestration removal) and lymphocytosis (loss of sequestration), patients undergoing splenectomy
vaccinated against encapsulated organisms (Strep pneumoniae, H. influenzae type B, N. meningitidis)
 • Ruptured Spleen – spleen the most common organ injury following trauma that results in significant intraabdominal bleeding (liver injury the most
common cause of bleeding, but is more often clinically insignificant), risk factors include left-sided rib fractures, history of blunt abdominal trauma, EBV
infection leading to splenomegaly, presents with shock (hypotension, tachycardia), rigid abdomen, and referred pain to the left shoulder (Kehr sign) due
to irritation of the diaphragm, diagnose with CT (important for showing extent of splenic injury) and exploratory laparotomy, treat with endovascular
embolization (incomplete rupture) or splenectomy (complete rupture or intractable bleeding, post-splenectomy immunizations to encapsulated
organisms recommended), complications include subphrenic abscess

• Thymus – located in anterosuperior mediastinum, site of T-cell differentiation and maturation, encapsulated, derived from 3rd pharyngeal pouch,
lymphocytes of mesenchymal origin, cortex dense with immature T-cells, medulla pale with mature T-cells and Hassall corpuscles containing epithelial
reticular cells, hypoplastic in DiGeorge Syndrome and Severe Combined Immunodeficiency (SCID) (“T-cells from Thymus, B-cells from Bone Marrow”)

• Thymoma – benign thymic neoplasm, associated with Myasthenia Gravis and Superior Vena Cava Syndrome

Innate vs Adaptive Immunity

• Innate vs. Adaptive Immunity

Innate Immunity Adaptive Immunity

Components Neutrophils, macrophages, monocytes, dendritic cells, T-cells, B-cells, circulating antibodies
natural killer (NK) cells (lymphoid origin), complement
 Mechanism Germline encoded
Resistance Persists through generations (does not change within an
organism’s lifetime)
Response to Pathogens Nonspecific, occurs rapidly (hours to minutes), no memory
response
Physical Barriers Epithelial tight junctions, mucus
Secreted Proteins Lysozyme, complement, C-reactive protein (CRP), defensins
Pathogen Recognition Toll-like receptors (TLRs): pattern recognition receptors
that recognize pathogen-associated molecular patterns
(PAMPs) and damage associated molecular patterns
(DAMPs), PAMPs include LPS (G⊖ bacteria), flagellin
(bacteria), nucleic acids (viruses)
Major Histocompatability Complex I and II
• Introduction – MHC encoded by HLA genes, present antigen fragments to T-cells and bind T-cell receptors (TCRs)
Variation through V(D)J recombination during lymphocyte
development
Microbial resistance not heritable
Highly specific, refined over time, develops over long periods,
memory response faster and more robust
-
Immunoglobulins
Memory Cells: activated B- and T-cells, subsequent exposure to
previously encountered antigen results in stronger, quicker
immune response

MHC 1 MHC 2
Loci HLA-A, HLA-B, HLA-C (MHC 1 loci have 1 letter) HLA-DP, HLA-DQ, HLA-DR (MHC 2 loci have 2 letters)
Binding TCR and CD8 (Cytotoxic T-cells) TCR and CD4 (Helper T-cells)
Structure 1 long chain, 1 short chain 2 equal-length chains
Expression/Location All nucleated cells, APCs, platelets, not on RBCs APCs only
Function Present endogenously synthesized antigens (e.g. viral Present exogenously synthesized antigens (e.g. bacterial
or cytosolic proteins) to CD8⊕ Cytotoxic T-cells proteins) to CD4⊕ Helper T-cells
Antigen Loading Antigen peptides loaded onto MHC 1 in RER after Antigen loaded following release of invariant chain in acidified
delivery via TAP (transporter associated with antigen endosome
processing)
Associated Proteins β2-microglobulin Invariant Chain
Result of Antigen Presentation Apoptosis in presenting cell Stimulation of humoral and cell-mediated immune responses
 MHC 1 MHC 2

HLA Subtypes Associated with Diseases

 • A3 – Hemochromatosis
• B8 – Addison’s Disease, Myasthenia Gravis, Graves’ Disease
• B27 – Psoriatic Arthritis, Ankylosing Spondylitis, IBD-associated Arthritis, Reactive Arthritis (Reiter’s Syndrome) (Seronegative Arthropathies, “PAIR”)
• DQ2/DQ8 – Celiac Disease (“I ate (8) too (2) much gluten at Dairy Queen”)
• DR2 – MS, Hay Fever, SLE, Goodpasture Syndrome
• DR3 – DM Type 1, SLE, Graves’ Disease, Hashimoto Thyroiditis, Addison’s Disease
• DR4 – RA, DM Type 1, Addison’s Disease
• DR5 – Pernicious Anemia leading to vitamin B12 deficiency, Hashimoto Thyroiditis

Immune Cells
• Natural Killer Cells – lymphocyte member of innate immune system, uses perforin and granzymes to induce apoptosis of virally infected cells and tumor
cells (do not directly lyse cells), activated by IFN-γ and IL-12, activity enhanced by IL-2, IL-12, IFN-α, and IFN-β, induced to kill when exposed to
nonspecific activation signal on target cell and/or to absence of MHC 1 on target cell surface (counter to viruses that downregulate MHC 1 in the cells
they infect), also kills via antibody-dependent cell-mediated cytotoxicity (CD16 binds Fc region of bound Ig, activating NK cell)
• Major Functions of B-Cells – functions: 1.) Humoral Immunity: recognizes antigen then undergoes somatic hypermutation to optimize antigen
specificity, 2.) Produces Antibodies: differentiates into plasma cells to secrete specific immunoglobulins, 3.) Maintains Immunologic Memory: memory
B-cells persist and accelerate future response to antigen
• Major Function of T-Cells – functions: 1.) Cell-Mediated Immunity, 2.) CD4⊕ T-Cells: help B-cells make antibodies and produce cytokines to recruit
phagocytes and activate other leukocytes, 3.) CD8⊕ T-Cells: directly kills virus-infected cells, 4.) Delayed Cell-Mediated Hypersensitivity (T4), 5.) Acute
and Chronic Cellular Organ Rejection, Rule of 8: MHC 2 x CD4 = 8 (CD4⊕ Helper T-cells express MHC 2), MHC 1 x CD8 = 8 (CD8⊕ Cytotoxic T-cells
express MHC 1)
• Differentiation of T-Cells – 2 phases: 1.) Positive Selection: thymic cortex, only T-cells expressing TCRs capable of binding self MHC on cortical epithelial
cells survive (ensures mature T-cells will be able to recognize self MHC), 2.) Negative Selection: thymic medulla, T-cells expressing TCRs with high affinity
for self-antigens undergo apoptosis (ensures mature T-cells will not be activated by self-antigens), tissue-restricted self-antigens expressed in thymus
due to action of autoimmune regulator (AIRE), deficiency leads to Autoimmune Polyendocrine Syndrome-1
• Helper T-Cells – macrophage-lymphocyte interaction occurs when dendritic cells, macrophages, and other APCs release IL-12, which stimulates T-cells
to differentiate into TH1 cells, TH1 cells then release IFN-γ to stimulate macrophages, helper T cells have CD4, which binds MHC 2 on APCs

TH1 TH2
Immunity Type Cell-mediated Humoral (antibody-mediated)
Secretes IFN-γ, IL-2, Lymphotoxin β IL-4, IL-5, IL-6, IL-10, IL-13
Function Activates macrophages and cytotoxic T-cells Activates B-cells, promotes class-switching, recruits eosinophils for
parasite defense and promotes IgE production from B-cells
Differentiation Induced by IFN-γ and IL-12 Induced by IL-2 and IL-4
Inhibition Inhibited by IL-4 and IL-10 (from TH2-cell) Inhibited by IFN-γ (from TH1-cell)
Result Cytotoxicity, delayed-type hypersensitivity (T4) Secretion of antibodies
 • Cytotoxic T-Cells – has CD8, which binds MHC 1 on virus infected cells, kills virus-infected, neoplastic, and donor graft cells by inducing apoptosis,
releases cytotoxic granules containing preformed proteins (e.g. perforin, granzyme B)
• Regulatory T-cells (Tregs) – helps maintain specific immune tolerance by suppressing CD4 and CD8 T-cell effector functions, identified by expression of
CD3, CD4, CD25, and FOXP3, activated regulatory T-cells (Tregs) produce anti-inflammatory cytokines (e.g. IL-10, TGF-β)
• IPEX (Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-linked) Syndrome – X-linked genetic deficiency of FOXP3 leading to autoimmunity,
associated with diabetes in male infants, presents with enteropathy, endocrinopathy, nail dystrophy, dermatitis, and/or other autoimmune
dermatologic conditions

T-Cell and B-Cell Activation

• Introduction – APCs include B-cells, dendritic cells, Langerhans cells, macrophages, 2 signals required for T-cell activation, B-cell activation, and class
switching
• T-Cell Activation – steps: 1.) Antigen Presentation: dendritic cell (specialized APC) samples and processes antigen, then migrates to draining lymph
node, 2.) T-cell Activation (signal 1): antigen presented on MHC 2 and recognized by TCR on Helper T-cell, endogenous or cross-presented antigen
presented on MHC 1 to Cytotoxic T-cell, 3.) Proliferation and Survival (Signal 2): costimulatory signal given via interaction of B7 protein on dendritic cell
(CD80/86) and CD28 on naïve T-cell, 4.) Full Activation: Helper T-cell activates and produces cytokines, Cytotoxic T-cell activates and is able to recognize
and kill virus-infected cell

• B-Cell Activation and Class Switching – steps: 1.) Helper T-cell Activation: as described above, 2.) B-cell Receptor-Mediated Endocytosis: foreign antigen
presented on MHC 2 and recognized by TCR on Helper T-cell, 3.) Costimulation: CD40 receptor on B-cell binds CD40 ligand (CD40L) on Helper T-cell, 4.)
Full Activation: Helper T-cell secretes cytokines that determine B-cell class switching, once activated, B-cell undergoes class switching, affinity
maturation, and antibody production, vaccines that do not generate a T-cell response (killed or recombinant) can only induce IgM production due to
role of Helper T-cells in inducing B-cell class switching
Antibody Structure and Function
• Antibody Structure and Function – made of Fab and Fc regions, Fc region of IgM and IgG fixes complement, heavy chain contributes to Fc and Fab
regions, light chain contributes only to Fab region, components: 1.) Fab Region: “fragment, antigen binding”, contains variable/hypervariable regions
consisting of light (L) and heavy (H) chains, recognize antigens, determines idiotype, contains unique antigen-binding pocket, only 1 antigenic specificity
expressed per B-cell, 2.) Fc Region: constant, contains carboxy terminal and carbohydrate side chains, binds complement, determines isotype (IgM, IgD,
etc.)
• Generation of Antibody Diversity – antigen-independent process that occurs during B-cell maturation in bone marrow via random recombination of VJ
(light-chain) or V(D)J (heavy-chain) genes, by random addition of nucleotides to DNA during recombination by terminal deoxynucleotidyl transferase
(TdT), and by random combination of heavy chains with light chains
• Generation of Antibody Specificity – antigen-dependent process that occurs following activation via somatic hypermutation and affinity maturation
(variable region) and by isotype switching (constant region)
Immunoglobulin Isotypes, Antigen Type and Memory
• Immunoglobulin Isotypes – all isotypes can exist as monomers, mature naïve B-cells express IgM and IgD on their surfaces prior to activation, may
differentiate in germinal centers of lymph nodes by isotype switching (gene rearrangement mediated by cytokines and CD40L) into plasma cells that
secrete IgA, IgE, or IgG
• IgG – main antibody in secondary (delayed) response to antigen, most abundant serum isotype, fixes complement, crosses placenta (provides infants
with passive immunity), opsonizes bacteria, neutralizes bacterial toxins and viruses

• IgA – prevents attachment of bacteria and viruses to mucous membranes, does not fix complement, monomer in circulation, dimer with J chain when
secreted, crosses epithelial cells by transcytosis, produced in GI tract (e.g. by Peyer patches), protects against gut infections (e.g. Giardia), most
produced antibody overall, but lower serum concentrations, released into secretion (tears, saliva, mucus) and breast milk, picks up secretory
component from epithelial cells, which protects Fc portion from luminal proteases
• IgM – produced in primary (immediate) response to antigen, fixes complement, but does not cross placenta, antigen receptor on B-cell surface ,
monomer on B-cell, pentamer with J chain when secreted, pentamer enables avid binding to antigen while humoral response evolves
• IgD – unclear function, found on surface of many B-cells and in serum
• IgE – binds mast cells and basophils, cross-links when exposed to allergen, mediating immediate hypersensitivity (T1) through release of inflammatory
mediators such as histamine, contributes to immunity against helminths by activating eosinophils, lowest concentration in serum
• Thymus-Independent Antigens – antigens lacking a peptide component (e.g. lipopolysaccharides from G⊖ bacteria), cannot be presented by MHC to T-
cells, weakly immunogenic, vaccines often require boosters and adjuvants (e.g. pneumococcal polysaccharide vaccine)
• Thymus-Dependent Antigens – antigens containing protein component (e.g. diphtheria vaccine), direct contact between B-cells and Helper T-cells
allows class switching and immunologic memory
• Mucosal IgA Transcytosis
Acute-Phase Reactants
• Introduction – factors whose serum concentrations change significantly in response to inflammation, produced by liver in both acute and chronic
inflammatory states, notably induced by IL-6

Reactant Function
Positive (Upregulated)
C-Reactive Protein Opsonin, fixes complement and facilitates phagocytosis, measured clinically as nonspecific sign of ongoing inflammation
Ferritin Binds and sequesters iron to inhibit microbial iron scavenging
Fibrinogen Coagulation factor, promotes endothelial repair, correlates with ESR
Hepcidin Decreases iron absorption (by degrading ferroportin) and decreases iron release (from macrophages), leads to anemia of
chronic disease
Serum Amyloid A Prolonged elevation can lead to amyloidosis
Negative (Downregulated)
Albumin Reduction conserves amino acids for positive reactants
Transferrin Internalized by macrophages to sequester iron
Complement Physiology
• Introduction – system of hepatically-synthesized plasma proteins that play a role in innate immunity and inflammation, membrane attack complex
(MAC) defends against G⊖ bacteria, 3 activation pathways: 1.) Classical: uses antibodies (IgG or IgM), 2.) Alternative: uses opsonins (microbe surface
molecules), 3.) Lectin: uses microbe surface directly (mannose and other sugars on microbe surface, “GM makes classic cars”), components include C3b
(opsonization), C3a, C4a, C5a (anaphylaxis), C5a (neutrophil chemotaxis), C5b-C9 (cytolysis by MAC), C3b and IgG the primary opsonins in bacterial
defense, enhancing phagocytosis, C3b also helps clear immune complexes, decay accelerating factor (DAF, aka CD55) and Cl esterase inhibitor prevent
complement activation on self cells (e.g. RBCs)
Complement Disorders
Complement Deficiency
Protein Deficiency
C3 Deficiency
C5-9 Deficiencies
Regulatory Protein Deficiency
C1 Esterase Inhibitor
CD55 Deficiency
Cytokines
Cytokine
Secreted by Macrophages
Interleukin-1 (IL-1)
Interleukin-6 (IL-6)
Interleukin-8 (IL-8)
Interleukin-12 (IL-12)
Tumor Necrosis Factor-α (TNF-α)
Secreted by all T-cells
Interleukin-2 (IL-2)
Interleukin-3 (IL-3)
Secreted by TH1-cells
Interferon-γ (IFN-γ)
Secreted by TH2-cells
Interleukin-4 (IL-4)
Interleukin-5 (IL-5)
Interleukin-10 (IL-10)
Consequence
Increases risk of severe, recurrent pyogenic sinus and respiratory tract infections, increases susceptibility to T3
hypersensitivity reactions
Terminal complement deficiency, increases susceptibility to recurrent Neisseria infections
Causes hereditary angioedema due to unregulated activation of kallikrein leading to increased bradykinin, characterized
by decreased C4 levels, ACE inhibitors contraindicated
Also called decay-accelerating factor (DAF) deficiency, causes complement-mediated lysis of RBCs and paroxysmal
nocturnal hemoglobinuria
Function
Causes fever, acute inflammation, activates endothelium to express adhesion molecules, induces chemokine secretion
to recruit WBCs, “Hot T-bone stEAK: IL-1: fever (hot), IL-2: T-cells, IL-3: bone marrow, IL-4: IgE, IL-5: IgA, IL-6: aKute-
phase protein production”
Causes fever and stimulates production of acute-phase proteins
Major chemotactic factor for neutrophils (“cleanup on aisle 8: neutrophils recruited by IL-8 to clean up infections”)
Induces differentiation of T-cells into TH1-cells, activates NK-cells
Activates endothelium, recruits WBCs, causes vascular leak, cachexia in malignancy, maintains granulomas in TB, IL-1,
IL-6, and TNF-α can mediate sepsis
Stimulates growth of Helper, Cytotoxic, and Regulatory T-cells, NK-cells
Supports growth and differentiation of bone marrow stem cells, functions like GM-CSF
Secreted by NK-cells and T-cells in response to antigen or IL-12 from macrophages, stimulates macrophages to kill
phagocytosed pathogens, inhibits differentiation of T-cells into TH2 cells
Induces differentiation of T-cells into TH2 cells, promotes growth of B-cells, enhances class switching to IgE and IgG
Promotes growth and differentiation of B-cells, enhances class switching to IgA, stimulates growth and differentiation
of eosinophils
Attenuates inflammatory response (TGF-β and IL-10 both attenuate the immune response), decreases expression of
MHC 2 and TH1 cytokines, inhibits activated macrophages and dendritic cells, also secreted by Regulatory T-cells
Respiratory Burst (Oxidative Burst) and Interferons
• Respiratory Burst (Oxidative Burst) – activation of phagocyte NADPH oxidase complex (e.g. in neutrophils and monocytes), which utilizes O2 substrate,
leads to rapid release of reactive oxygen species (ROS), NADPH responsible for both creation and neutralization of ROS, myeloperoxidase a blue-green
heme-containing pigment that gives sputum its color, phagocytes of patients with CGD can utilize H2O2 generated by invading organisms and convert it
to ROS, catalase ⊕ species (S. aureus, Aspergillus) capable of neutralizing their own H2O2, leaving phagocytes without ROS for fighting infections, thus
increasing risk of infection by these species in CGD patients, Pyocyanin of P. aeruginosa generates ROS to kill competing microbes, lactoferrin inhibits
microbial growth via iron chelation, found in secretory fluids and neutrophils, Note: glutathione reductase does not require selenium as shown below
• Interferon-α and -β – component of innate host defense against both RNA and DNA viruses, glycoproteins synthesized by virus-infected cells act locally
on uninfected cells, priming them for viral defense by promoting degradation of viral nucleic acid and protein
Cell Surface proteins, Anergy, Bacterial Toxins, and Antigenic Variation
• Cell Surface Proteins

Cell Type Surface Protein

All Nucleated Cells MHC 1 (not on mature RBCs)
All T-cells TCR (binds antigen-MHC complex), CD3 (associates with TCR for signal transduction), CD28 (binds B7 on APCs), CXCR4/CCR5
(co-receptors for HIV)
Helper T-cells CD4, CD40L
Cytotoxic T-cells CD8, CXCR4/CCR5
Regulatory T-cells CD4, CD25
B-cells Ig (binds antigen), CD19, CD20, CD21 (receptor for EBV, “you can drink a beer at the bar when you’re 21”), CCD40, MHC 2, B7
Macrophages CD14 (receptor for PAMPs, e.g. LPS), CD40, CCR5, MHC 2, B7 (CD80/86), Fc and C3b receptors (enhances phagocytosis)
NK-cells CD56 (suggestive marker for NK-cells)
Hematopoietic Stem Cells CD34
• Anergy – state during which cell cannot become activate by exposure to its antigen, T- and B-cells become anergic when exposed to antigen without
costimulatory signal (signal 2), mechanism of self-tolerance
• Bacterial Superantigen Toxins – notable examples: 1.) Superantigens: S. aureus, S. pyogenes, cross-link β region of T-cell receptor to MHC 2 on APCs,
can activate any CD4⊕ T-cell leading to massive cytokine release, 2.) Endotoxins (LPS): G⊖ bacteria, directly stimulate macrophages by binding to
endotoxin receptor TLR4/CD14, Helper T-cells not involved
• Antigenic Variation – mechanisms for variation include DNA rearrangement and RNA segment reassortment (e.g. Influenza major genetic shift) or
protein mutations (Influenza minor genetic drift), classic examples: 1.) Bacteria: Salmonella (2 flagellar variants), Borrelia recurrentis (relapsing fever), N.
gonorrhoea (pilus protein), 2.) Viruses: Influenza, HIV, HCV, 3.) Parasites: trypanosomes

Passive vs. Active Immunity

• Passive vs. Active Immunity

Passive Immunity Active Immunity

Means of Acquisition Receiving preformed antibodies Exposure to foreign antigens
Onset Rapid Slow
Duration Sport span of antibodies (half-life = 3 weeks) Long-lasting protection via memory
Examples IgA in breast milk, maternal IgG crossing placenta, antitoxin, Natural infection, vaccines, toxoid
humanized monoclonal antibody
Notes Patients given preformed (passive) antibodies after exposure to Combined passive and active immunizations can be given for
Tetanus toxin, Botulinum toxin, HBV, Varicella, Rabies Virus, or HBV or Rabies exposure
Diphtheria antitoxin “To Be Healed Very Rapidly”
Hypersensitivities
• Overview of Hypersensitivities – 4 types: 1.) Anaphylactic and Atopic: T1, 2.) Cytotoxic: T2, antibody-mediated, 3.) Immune Complex: T3, 4.) Delayed:
T4, cell-mediated, T1-T3 antibody-mediated

Type Humoral Components Cellular Components Examples

Type 1 (Immediate) IgE
Type 2 (Cytotoxic) IgG and IgM autoantibodies,
complement activation
Type 3 (Immune Complex) Antigen-antibody complex
deposition, complement activation
Type 4 (Delayed) None
Basophils, mast cells Anaphylaxis, allergies
NK cells, eosinophils, neutrophils, Autoimmune hemolytic anemia, Goodpasture
macrophages Syndrome
Neutrophils Serum sickness, PSGN, SLE nephritis
T-cells, macrophages Contact dermatitis, tuberculin skin test

• Type 1 Hypersensitivity (T1) – anaphylactic and atopic, free antigen cross-links IgE on presensitized mast cells and basophils, triggering immediate
release of vasoactive amines that act at postcapillary venules (i.e. Histamine), reaction develops rapidly after antigen exposure due to preformed
antibody, delayed phase results from mast cells and basophils releasing cytokines that induce cellular inflammation, Test: skin test or blood test (ELISA)
for allergen-specific IgE, Example: anaphylaxis (e.g. food, drug, bee sting allergies)
• Type 2 Hypersensitivity (T2) – antibodies bind to cell-surface antigens leading to cellular destruction, inflammation, and cellular dysfunction,
components: 1.) Cellular Destruction: cell opsonized by antibodies leading to either phagocytosis and/or activation of complement system, or NK-cell
killing (antibody-dependent cellular cytotoxicity), Examples: autoimmune hemolytic anemia, immune thrombocytopenic purpura, transfusion reactions,
Hemolytic Disease of the Newborn, 2.) Inflammation: antibody binding to cell surfaces produces activation of complement system and Fc receptor-
mediated inflammation, Examples: Goodpasture Syndrome, RF, hyperacute transplant rejection, 3.) Cellular Dysfunction: antibodies bind to cell surface
receptors producing abnormal blockade or activation of downstream process, Example: Myasthenia Gravis, Graves’ Disease, Test: 1.) Direct Coombs
Test: detects antibodies bound to RBC surface, 2.) Indirect Coombs Test: detects unbound antibodies in serum, patient’s plasma mixed with RBCs from
another patient
• Type 3 Hypersensitivity (T3) – antigen-antibody (IgG) immune complexes activate complement, which attracts neutrophils that release lysosomal
enzymes, may be associated with vasculitis and systemic manifestations, Example: SLE, Polyarteritis Nodosa, PSGN, Serum Sickness, Arthus Reaction
• Type 4 Hypersensitivity (T4) – response does not involve antibodies (contrast T1-T3), 2 mechanisms, each involving T-cells: 1.) Direct Cell Cytotoxicity:
CD8⊕ Cytotoxic T-cells kill targeted cells, Example: Type 1 Diabetes Mellitus (possibly T2), 2.) Delayed-Type Hypersensitivity: sensitized CD4⊕ Helper T-
cells encounter antigen and release cytokines, producing inflammation and macrophage activation, Example: Contact Dermatitis (e.g. poison ivy, nickel
allergy), Graft-versus-Host Disease, Test: PPD, patch test (“4 T’s: T-cells, Transplant rejections, TB skin test, Touching – contact dermatitis)

• Arthus Reaction – local subacute antibody-mediated hypersensitivity reaction (T3), intradermal injection of antigen into presensitized individual
(circulating IgG) leads to immune complex formation in skin, presents with edema, necrosis, and complement activation,
• Serum Sickness – immune complex disease (T3) in which antibodies to foreign proteins are produced (takes 5 days), complexes form and are deposited
in membranes, where they fix complement and produce tissue damage, more common than Arthus Reaction, now most often caused by drugs acting as
haptens (not actual serum), presents with fever, urticaria, arthralgia, proteinuria, lymphadenopathy 5-10 days after antigen exposure
 • Systemic Mastocytosis – clonal mast cell proliferation in bone marrow, skin, and other organs, often caused by mutations in KIT receptor tyrosine
kinase, producing cells with prominent expression of mast cell tryptase, most symptoms caused by excessive histamine release from mast cell
degranulation, presents with syncope, flushing, hypotension, pruritus, and urticaria, histamine may also induce gastric acid secretion, leading to gastric
ulceration, excess acid also inactivates pancreatic and intestinal enzymes, producing diarrhea, nausea/vomiting, and abdominal cramps

Blood Transfusion Reactions

Type Onset Pathogenesis Presentation
Allergic/Anaphylactic Within minutes T1 reaction against plasma proteins in transfused Urticaria, pruritus, fever, wheezing, hypotension,
to 2-3 hours blood, IgA-deficient individuals must receive respiratory arrest, shock
blood products without IgA
Febrile Nonhemolytic Within 1-6 hours T2 reaction, host antibodies against donor HLA Fever, headache, chills, flushing
antigens and WBCs
Acute Hemolytic Within 1 hour T2 reaction, intravascular hemolysis (ABO blood Fever, hypotension, tachypnea, tachycardia, flank pain,
group incompatibility) or extravascular hemolysis hemoglobinuria (intravascular hemolysis), jaundice
(host antibody reaction against foreign antigen (extravascular hemolysis)
on donor RBCs)
Transfusion-Related Within 6 hours Donor anti-leukocyte antibodies against recipient Respiratory distress and noncardiogenic pulmonary
Acute Lung Injury neutrophils and pulmonary endothelial cells edema
Autoantibodies
Autoantibody Associated Disorder
Anti-ACh receptor Myasthenia Gravis
Anti-glomerular basement membrane (α3 chain of type 4 collagen) Goodpasture Syndrome
Anti-β2 glycoprotein Antiphospholipid Syndrome
Anticardiolipin, Lupus coagulant SLE, Antiphospholipid Syndrome
Anticentromere Limited Scleroderma (CREST Syndrome)
Anti-desmoglein (anti-desmosome) Pemphigus Vulgaris
 Anti-glutamic acid decarboxylase, islet cell cytoplasmic antibodies Type 1 Diabetes Mellitus
Anti-hemidesmosome Bullous Pemphigoid
Antisynthetase (e.g. anti-Jo), anti-SRP, anti-helicase (anti-Mi-2) Polymyositis, Dermatomyositis
Antimicrosomal, antithyroglobulin, anti-thyroid peroxidase Hashimoto Thyroiditis
Antimitochondrial Primary Biliary Cirrhosis
Antiparietal cell, anti-intrinsic factor Pernicious Anemia
Anti-phospholipase A2 receptor Primary Membranous Nephropathy
Anti-Scl-70 (anti-DNA topoisomerase 1) Scleroderma (diffuse)
Anti-smooth muscle Autoimmune Hepatitis Type 1
Anti-SSA, anti-SSB (anti-Ro, anti-La) Sjögren Syndrome
Anti-TSH receptor Graves’ Disease
Anti-presynaptic voltage-gated calcium channel Lambert-Eaton Myasthenic Syndrome
IgA anti-endomysial, IgA anti-tissue transglutaminase Celiac Disease
MPO-ANCA/p-ANCA Microscopic Polyangiitis, Eosinophilic Granulomatosis with Polyangiitis (Churg-
Strauss Syndrome), Ulcerative Colitis
PR3-ANCA/c-ANCA Granulomatosis with Polyangiitis (Wegener Granulomatosis)
Rheumatoid factor (IgM antibody against IgG Fc region), anti-CCP Rheumatoid Arthritis (RA)
(more specific)
Antinuclear (ANA) Nonspecific screening antibody, often associated with SLE
Anti-dsDNA, anti-Smith SLE
Anti-histone Drug induced lupus
Anti-U1 RNP (ribonucleoprotein) Mixed Connective Tissue Disease
Immunodeficiencies
• Introduction
• X-Linked (Bruton) Agammaglobulinemia – X-linked recessive B-cell disorder (mostly in boys), caused by defective BTK (tyrosine kinase gene), resulting
in no B-cell maturation, presents with recurrent bacterial and enteroviral infections after 6 months (once maternal IgG levels drop), serum shows absent
B-cells, decreased Ig of all classes, lymph nodes and tonsils absent/scanty, live vaccines contraindicated
• Selective IgA Deficiency – B-cell disorder of unknown cause, most common primary immunodeficiency, majority are asymptomatic, if symptoms,
presents with airway and GI infections, atopy, anaphylaxis to IgA-containing products, serum shows decreased IgA with normal IgM and IgG levels,
increased susceptibility to giardiasis

• Common Variable Immunodeficiency – disorder due to defective B-cell differentiation, many causes, usually presents after age 2 and may be
considerably delayed, increased risk of autoimmune disease, presents with bronchiectasis, lymphoma, sinopulmonary infections, serum shows
decreased plasma cells and Ig
• Thymic Aplasia (DiGeorge Syndrome) – T-cell disorder caused by 22q11 deletion, failure of 3rd and 4th pharyngeal pouches leads to absent thymus and
parathyroids, presents with tetany (hypocalcemia), recurrent viral/fungal infections (T-cell deficiency), conotruncal abnormalities (e.g. Tetralogy of
Fallot, Truncus Arteriosus), CXR shows absent thymic shadow, serum shows decreased T-cells, low PTH, hypocalcemia
• IL-12 Receptor Deficiency – autosomal recessive T-cell disorder, caused by decreased TH1 response, presents with disseminated mycobacterial and
fungal infections, may present after administration of BCG vaccine, serum shows decreased IFN-γ
• Autosomal Dominant Hyper-IgE Syndrome (Job Syndrome) – T-cell disorder caused by deficiency of TH17 cells due to STAT3 mutation, leading to
impaired recruitment of neutrophils to site of infection, presents with coarse Facies, cold (noninflamed) staphylococcal Abscesses, retained primary
Teeth, increased IgE, Dermatologic problems (eczema) (“FATED”), bone fractures from minor trauma, serum shows increased IgE and eosinophils,
decreased IFN-γ
• Chronic Mucocutaneous Candidiasis – T-cell disorder, many causes, presents with noninvasive Candida infections of skin and mucous membranes,
absent in vitro T-cell proliferation in response to Candida antigens and absent cutaneous reaction to Candida antigens
• Severe Combined Immunodeficiency – B- and T-cell disorder, several types, including defective IL-2R gamma chain (X-linked, most common) and
adenosine deaminase deficiency (autosomal recessive), characterized by recurrent viral, bacterial, fungal, and protozoal infections, presents with failure
to thrive, chronic diarrhea, thrush, decreased T-cell receptor excision circles (TRECs), CXR shows absence of thymic shadow, lymph node biopsy shows
absence of germinal centers, flow cytometry shows absence of T-cells, treat by avoiding vaccines, with antimicrobial prophylaxis and IVIG, bone marrow
transplant curative (no concern for rejection)

• Ataxia-Telangiectasia – defects in ATM gene lead to failure to repair DNA double strand breaks, producing cell cycle arrest, presents with triad of
cerebellar defects (Ataxia due to cerebellar atrophy), spider Angiomas (telangiectasia) and IgA deficiency (“3 A’s”), serum shows elevated AFP,
decreased IgA, IgG, and IgE, lymphopenia, increased risk of lymphoma and leukemia
• Hyper-IgM Syndrome – X-linked recessive B- and T-cell disorder, most commonly due to defective CD40L on Helper T-cells, leading to a class switching
defect, presents with severe pyogenic infections early in life, opportunistic infection with Pneumocystis, Cryptosporidium, CMV, serum shows normal or
increased IgM, very low IgG, IgA, and IgE, lymph node biopsy shows failure to produce germinal centers

• Wiskott-Aldrich Syndrome – X-linked recessive B- and T-cell disorder, caused by mutation in WASp gene, leukocytes and platelets unable to reorganize
actin cytoskeleton, leading to defective antigen presentation, presents with thrombocytopenia, eczema, recurrent pyogenic infections, increased risk of
autoimmune disease and malignancy (“WATER: Wiskott-Aldrich, Thrombocytopenia, Eczema, Recurrent infections), serum shows normal or decreased
IgG and IgM, increased IgE and IgA, fewer and smaller platelets
• Leukocyte Adhesion Deficiency – autosomal recessive disorder of phagocyte dysfunction, types: 1.) LAD 1: caused by defect in LFA-1 integrin (CD18)
protein on phagocytes, 2.) LAD 2: impaired fucosylation of sialylated carbohydrate ligands prevents selectin binding, 3.) LAD 3: impaired cytokine
signaling prevents integrin activation, all types lead to impaired migration and chemotaxis, presents with recurrent skin and mucosal bacterial
infections, absent pus, impaired wound healing, delayed (>30 days) separation of umbilical cord, serum shows increased neutrophils, overall absence of
neutrophils at infection sites
• Chédiak-Higashi Syndrome – autosomal recessive disorder of phagocyte dysfunction, caused by defect in lysosomal trafficking regulator gene (LYST),
producing microtubule dysfunction in phagosome-lysosome fusion, presents with recurrent pyogenic infections by Staphylococci and Streptococci,
partial albinism, peripheral neuropathy, progressive neurodegeneration, infiltrative lymphohistiocytosis, mild coagulation defects, serum shows
pancytopenia, peripheral smear shows giant granules in granulocytes and platelets

• Chronic Granulomatous Disease (CGD) – X-linked recessive (most common form) disorder of phagocyte dysfunction, caused by defect of NADH oxidase
leading to decreased production of reactive oxygen species (ROS, e.g. superoxide), and decreased respiratory burst in neutrophils, presents with
increased susceptibility to catalase⊕ organisms (Staph aureus, Burkholderia cepacia, Serratia marcescens, Nocardia, Aspergillus), abnormal
dihydrorhodamine (flow cytometry) test (decreased green fluorescence), nitroblue tetrazolium dye reduction test (obsolete) fails to turn blue
Autoimmune Diseases
• Antiphospholipid Syndrome – primary or secondary (most commonly part of SLE) disorder, diagnose based on clinical criteria including history of
thrombosis (arterial or venous) or spontaneous abortion along with laboratory findings of lupus anticoagulant, anticardiolipin, anti-β2 glycoprotein
antibodies, anticardiolipin antibodies may cause false ⊕ RPR/VDRL test for Syphilis, lupus anticoagulant may prolong PTT (not corrected by addition of
normal platelet-free plasma), treat with systemic anticoagulation

• Mixed Connective Tissue Disease (MCTD) – autoimmune disease with symptoms that resemble SLE, Systemic Sclerosis, and Polymyositis, highly variable
presentation with symptoms that occur sequentially over years, presents with Raynaud’s Phenomenon, non-specific constitutional symptoms (fever,
 fatigue, headache), arthralgia and myalgia, esophageal dysmotility leading to dysphagia and acid reflux, Pulmonary Arterial Hypertension (PAH) a serious
complication (main cause of death), serum shows anti-U1-ribonucleoprotein (anti-U1-RNP) antibodies, elevated titer of speckled pattern ANA (could be
initial disease indication), no universally accepted diagnostic criteria, routine echocardiography recommended for early diagnosis of PAH, treat with
Corticosteroids (very responsive), Nifedipine (CCB), IV Prostacyclin or Epoprostenol, prolonged Corticosteroid use, ACE Inhibitors for PAH
• Sarcoidosis – disorder characterized by immune-mediated, widespread noncaseating granulomas, more common in AA females, associated with
restrictive lung disease (interstitial fibrosis), Erythema Nodosum, lupus pernio (skin lesions on face resembling lupus), Bell’s Palsy, histology: epithelioid
granulomas containing microscopic Schaumann and asteroid bodies, often asymptomatic except for enlarged lymph nodes, may also present with
uveitis, CXR shows bilateral adenopathy and coarse reticular opacities, chest CT better demonstrates extensive hilar and mediastinal adenopathy, serum
shows hypercalcemia (due to increased 1α-hydroxylase-mediated activation of vitamin D in macrophages), elevated ACE, elevated CD4⊕/CD8⊕ ratio in
bronchoalveolar lavage (BAL) fluid, treat with Corticosteroids if symptomatic, see also Respiratory: Sarcoidosis

• Sjögren Syndrome – autoimmune destruction of exocrine glands (esp. lacrimal and salivary) by lymphocytic infiltrates, commonly primary or secondary
to other autoimmune disorders (e.g. RA, SLE, Systemic Sclerosis), middle aged to elderly female (40-60), associated with HLA-DR3, presents with classic
triad of dry eyes (keratoconjunctivitis sicca, decreased tear production and subsequent corneal damage), dry mouth (xerostomia, decreased saliva
production), and arthritis/inflammatory joint pain (less severe than in RA), also nasal and vaginal dryness, chronic bronchitis, reflux esophagitis, bilateral
parotid enlargement, serum shows ANA⊕, anti-Ro (SS-A)⊕, anti-La (SS-B)⊕ (both ribonucleoproteins), RF⊕ (70%, even in absence of RA), lip biopsy
shows lymphoid infiltrate with destruction of salivary glands, diagnose with labial salivary gland biopsy, treat with Corticosteroids, artificial tears,
Cevimeline (muscarinic agonist, increases saliva production), complications include dental caries (decreased saliva results in increased bacterial activity),
increased risk (40x) of mucosa-associated lymphoid tissue lymphoma (MALToma)
• Systemic Lupus Erythematosus (SLE) – multisystem autoimmune disorder, immune system disturbance leads to polyclonal B-cell activation with
production of autoantibodies against DNA, symptoms caused by antibody-mediated cellular attack, deposition of antibody-antigen complexes,
associated with HLA haplotypes, STAT4 allele associated with increased risk of SLE, disease triggered by sunlight, estrogen, drugs (“HIP: Hydralazine,
Isoniazid, Procainamide”, symptoms resolve with drug removal), female of childbearing age (20-30), prevalent among AA, presentations: 1.) Arthritis:
very common (>90% of patients over disease course), nonerosive, involves >2 peripheral, predominantly small joints, arthralgia, myalgia, symmetric
morning stiffness and swelling of MCP and PIP joints of the hand, 2.) Malar Rash: fixed erythema over malar eminences with sparing of nasolabial folds,
caused by immune complex deposition along BM, 3.) Discoid Rash: erythematous raised patches with adherent keratotic scaling and follicular plugging,
4.) Photosensitivity, 5.) Neurologic Changes: psychosis, seizures, personality changes in the absence of offending drugs or metabolic derangements (e.g.
uremia, ketoacidosis), 6.) Lupus Nephritis: glomerular deposition of anti-DNA immune complexes that can be nephritic or nephrotic (presents with
hematuria or proteinuria), most common type is diffuse proliferative glomerulonephritis, 7.) Serositis: pericarditis and/or pleuritis common (effusion is
an exudate – any unexplained pleural effusion in a young woman is SLE until proven otherwise), Libman-Sacks Endocarditis (nonbacterial, verrucous
thrombi usually on mitral or aortic valve that can be present on either surface of valve, but usually on undersurface, mnemonic SLE = LSE), 8.) Oral
Aphthous Ulcers: usually painless, 9.) Hematologic Disorders: cytopenias (hemolytic anemia with reticulocytosis, leukopenia, lymphopenia,
thrombocytopenia), 10.) Systemic Symptoms: fever, serum shows Antinuclear (ANA) antibodies⊕ (sensitive, but not specific, also positive in many other
collagen vascular diseases), anti-DS DNA⊕ (high specificity, low sensitivity, poor prognosis due to indication of renal disease), anti-Smith (SM)⊕ (high
specificity, low sensitivity, not prognostic, directed against snRNPs), low C3, C4 and CH50 due to constant activation of classical complement system and
resulting immune complex formation, false ⊕ RPR/VDRL test for Syphilis, elevated PTT (lupus anticoagulant, increased risk of thrombi and miscarriages),
LE cells (neutrophil with phagocytosed DNA), pancytopenia (anemia, leukopenia, thrombocytopenia due to antibodies against RBCs, WBCs, platelets),
Drug-Induced Lupus shows anti-Histone⊕, ANA⊕, but anti-DsDNA⊖, immunofluorescence shows dermal-epidermal junction immune complex
deposition (band test), management dictated by specific organ involvement, balance between treating acute flares and preventing exacerbations: 1.)
Skin Rashes: sunscreen, sun avoidance, topical Corticosteroids, 2.) Arthritis: NSAIDs, analgesics, exercise, low dose Corticosteroids, Methotrexate, 3.)
Renal Disease: Corticosteroids, Azathioprine, Cyclophosphamide, Mycophenolate, Cyclosporine, 4.) CNS Disease: low dose Corticosteroids,
Antidepressants, Antipsychotics, Antiepileptics (Anticonvulsants), 5.) Antiphospholipid Antibody Syndrome: Hydroxychloroquine, estrogen avoidance,
ASA and other anticoagulants, 6.) Severe or Refractory Symptoms: Corticosteroids, Hydrochloroquine, Cyclophosphamide, Azathioprine, anti-TNFs,
major pregnancy-related complications: 1.) Neonatal Lupus Erythematosus (NLE): caused by IgG anti-SS-A crossing placenta (anti-Ro and anti-La),
presents with complete congenital heart block, annular skin rash that resolves after 6 weeks, 2.) Antiphospholipid Antibody Syndrome (APLS): multiple
spontaneous abortions caused by placental thrombosis, prognosis of all types of SLE is variable, common causes of death include CV disease, infections,
and renal disease, medication nonadherence, significant CNS, cardiac, or renal disease with early HTN indicate poor prognosis (“RASH OR PAIN: Rash –
malar or discoid, Arthritis – nonerosive, Serositis, Hematologic disorders – e.g. cytopenias, Oral/nasopharyngeal ulcers, Renal disease, Photosensitivity,
Antinuclear antibodies, Immunologic disorder – anti-dsDNA, anti-Sm, antiphospholipid, Neurologic disorders – e.g. seizures, psychosis”)
• Polymyalgia Rheumatica – rheumatological disorder characterized by joint pain and stiffness without muscle weakness, elderly female (>55), associated
with Giant Cell (Temporal) Arteritis (many consider it the same disease), presents with pain and stiffness in shoulders and hips, difficulty rising from chair
and lifting arms above head, patients complain of shoulder and leg weakness, but claims not always validated during physical exam, systemic symptoms
common also (fever, malaise, weight loss), serum shows markedly elevated ESR, elevated CRP, normal CK, diagnose clinically, treat with low-dose
Corticosteroids (rapid response)
• Rheumatoid Arthritis (RA) – see Musculoskeletal, Skin, and Connective Tissue: Rheumatoid Arthritis
• Scleroderma (Systemic Sclerosis) – triad of autoimmunity, noninflammatory vasculopathy, and collagen deposition with fibrosis, caused by small vessel
endothelial damage which results in stimulation of reactive T-cell collagen synthesis, adult woman of childbearing age, rare in children, 2 major types: 1.)
Diffuse Scleroderma: more serious clinical course (diffuse, rapid progression with early visceral involvement), presentations: Skin: swelling that starts at
the fingers and continues proximally, “tightened” facial features, Raynaud Phenomenon, polyarthralgia, GI: heartburn, dysphagia for solids and liquids,
 reflux (esophageal dysmotility and smooth muscle conversion to collagen), malabsorption and bacterial overgrowth (loss of villi with diverticular
formation), Respiratory: dyspnea (interstitial fibrosis), Renal: vasculitides, infarctions, malignant hypertension, serum shows anti-Scl-70 (anti-DNA
topoisomerase 1) antibody, 2.) Limited Scleroderma/CREST Syndrome: more benign clinical course, presents with CREST: Calcinosis (subcutaneous
calcifications), Raynaud Phenomenon, Esophageal dysfunction (LES sclerosis), Sclerodactyly, Telangiectasias (limited skin involvement, often only face
and fingers), serum shows anti-Centromere antibody (ACA), treat both forms with immunosuppressives for palliation, Corticosteroids (may benefit if
disabling myositis, synovitis, MCTD), various drugs for symptomatic relief, no drug significantly improves disease course, overall course variable, often
progresses slowly, most patients show eventual visceral involvement, poor prognosis if early cardiac, pulmonary, renal manifestations

Infections in Immunodeficiency
• Introduction – B-cell deficiencies tend to produce recurrent bacterial infections, whereas T-cell deficiencies produce more fungal and viral infections

Pathogen T-cells B-cells Granulocytes Complement

Bacteria Sepsis Encapsulated organisms:
Pseudomonas, S. pneumoniae,
H. influenzae Type B, N.
Meningitidis, E. coli,
Salmonella, Klebsiella, GBS
Staph, Burkholderia cepacia, Encapsulated organisms with
Pseudomonas, Serratia, early complement deficiency,
Nocardia Neisseria with late complement
(C5-C9) deficiencies
 Viruses CMV, EBV, JC Virus, chronic Enteroviral encephalitis, - -
respiratory infection with Poliovirus (live vaccine
respiratory and GI viruses contraindicated)
Fungi/Parasites Candida (local), PCP, GI giardiasis (no IgA) Candida (systemic), Aspergillus, -
Cryptococcus Mucor
Grafts and Transplant Rejection
• Introduction – types: 1.) Autograft: from self, 2.) Syngeneic Graft: from identical twin or clone, 3.) Allograft: from nonidentical individual of same
species, 4.) Xenograft: from different species
• Transplant Rejection

Type Onset Pathogenesis Presentation

Hyperacute Minutes – hours Preformed recipient antibodies react to donor
antigens (T2), activate complement
Acute Weeks – months (<6) Exposure to donor antigens induces
cellular/humoral activation of naïve immune cells
Cellular: CD8⊕ T-cells activated against donor
MHCs (T4)
Humoral: similar to hyperacute, except
antibodies develop after transplant
Chronic Months (>6) – years Chronic, low-grade immune response refractory
to immunosuppressants, both cellular and
humoral components (T2, T4), CD4⊕ T-cells
respond to recipient APCs presenting donor
peptides, including allogeneic MHC, T-cells also
secrete cytokines leading to proliferation of
vascular smooth muscle, parenchymal atrophy,
and interstitial fibrosis
Graft-vs-Host Disease Variable Grafted immunocompetent T cells proliferate in
immunocompromised host and reject host cells
with “foreign” proteins, leading to severe organ
dysfunction (T4)
Arterial fibrinoid necrosis and capillary thrombotic
occlusion leads to ischemia/necrosis (gross mottling
and cyanosis), graft must be removed
Cellular: lymphocytic interstitial infiltrate and
endotheliitis
Humoral: C4d deposition, neutrophilic infiltrate,
necrotizing vasculitis
Prevent/reverse with immunosuppression
Dominated by arteriosclerosis
Lungs: bronchiolitis obliterans
Heart: accelerated atherosclerosis
Kidney: chronic graft nephropathy
Liver: vanishing bile duct syndrome
Maculopapular rash, jaundice, diarrhea,
hepatosplenomegaly, usually occurs in bone marrow
and liver transplants (rich in lymphocytes),
potentially beneficial in bone marrow transplant for
leukemia (“graft-versus-tumor effect”)
Immunosuppressants and Targets

• Introduction – agents that block lymphocyte activation and proliferation and reduce acute transplant rejection by suppressing cellular immunity (used
as prophylaxis), frequently combined to achieve greater efficacy with decreased toxicity, additional uses for specific drugs listed below, chronic
suppression increases risk of infection and malignancy
• Calcineurin Inhibitors
o Mechanism: calcineurin inhibitor, binds cyclophilin (Cyclosporin) or FK506 binding protein (FKBP – Tacrolimus), blocks T-cell activation by
preventing IL-2 transcription
o Treats: Psoriasis, RA
o Side Effects: highly nephrotoxic (produces arterial hyalinization and tubular vacuolization), hypertension, hyperlipidemia, neurotoxicity, gingival
hyperplasia and hirsutism (Cyclosporine only), increased risk of diabetes (Tacrolimus)
 o Cyclosporine, Tacrolimus (FK506)

• Sirolimus (Rapamycin)
o Mechanism: mTOR inhibitor, binds FKBP, blocks T-cell activation and B-cell differentiation by preventing response to IL-2
o Treats: kidney transplant prophylaxis specifically (also used in drug-eluting stents, synergistic with Cyclosporine)
o Side Effects: pancytopenia (“pansirtopenia”), insulin resistance, hyperlipidemia, not nephrotoxic
• Basiliximab
o Mechanism: monoclonal antibody against IL-2R
o Treats: kidney transplant prophylaxis specifically
o Side Effects: edema, hypertension, tremor
• Azathioprine
o See General Pathology: Antimetabolites
• Mycophenolate Mofetil
o Mechanism: reversibly inhibits IMP dehydrogenase, preventing purine synthesis of B- and T-cells
o Treats: lupus nephritis
o Side Effects: GI, pancytopenia, hypertension, hyperglycemia, less nephrotoxic and neurotoxic, associated with invasive CMV infection
 • Corticosteroids
o See Muscular System: Anti-inflammatory drugs

Recombinant Cytokines
• Aldesleukin (IL-2)
o Treats: Renal Cell Carcinoma, metastatic melanoma
• Epoetin Alfa (Erythropoietin, EPO)
o Treats: anemias (esp. in renal failure)
• Filgrastim (G-CSF)
o Treats: recovery of bone marrow and WBC counts by granulocyte stimulation
• Sargramostim (GM-CSF)
o Treats: recovery of bone marrow and WBC counts by granulocyte and monocyte stimulation
• IFN-α
o Treats: chronic HBV and HCV, Kaposi Sarcoma, Malignant Melanoma, Hairy Cell Leukemia, condyloma acuminata, Renal Cell Carcinoma
• IFN-β
o Treats: MS
• IFN-γ
o Treats: CGD
• Romiplostim
o Mechanism: thrombopoietin analog
o Treats: thrombocytopenia
• Eltrombopag
o Mechanism: thrombopoietin receptor agonist
o Treats: thrombocytopenia
• Oprelvekin (IL-11)
o Treats: thrombocytopenia

Therapeutic Antibodies – Cancer Therapy

• Alemtuzumab
o Mechanism: antibody against CD52
o Treats: CLL, MS (“ALYMtuzumab treat Chronic Lymphocytic Leukemia”)
• Bevacizumab
o Mechanism: antibody against VEGF
o Treats: colorectal cancer, Renal Cell Carcinoma, non-small cell lung cancer
• Cetuximab
o Mechanism: antibody against EGFR
 o Treats: stage 4 colorectal cancer, head and neck cancer
• Rituximab
o Mechanism: antibody against CD20 (B-cells)
o Treats: B-cell non-Hodgkin lymphoma, CLL, RA, ITP
• Trastuzumab
o Mechanism: antibody against Her2/neu (“tras2zumab”)
o Treats: breast cancer, gastric cancer

Therapeutic Antibodies – Autoimmune Disease Therapy

• Adalimumab, Certolizumab, Golimumab, Infliximab
o Mechanism: soluble TNF-α, Etanercept a decoy TNF-α receptor, not a monoclonal antibody
o Treats: IBD, RA, Ankylosing Spondylitis, Psoriasis
• Daclizumab
o Mechanism: antibody against CD25 (part of IL-2 receptor)
o Treats: relapsing MS
• Eculizumab
o Mechanism: antibody against complement protein C5
o Treats: Paroxysmal Nocturnal Hemoglobinuria
• Natalizumab
o Mechanism: antibody against α4-integrin (mediates WBC adhesion)
o Treats: MS, Crohn Disease
o Side Effects: risk of PML in patients with JC Virus
• Ustekinumab
o Mechanism: antibody against IL-12/IL-23
o Treats: Psoriasis, Psoriatic Arthritis

Therapeutic Antibodies – Miscellaneous

• Abciximab
o Mechanism: antibody against platelet glycoproteins 2b/3a (“2b x 3a = ab6imab”)
o Treats: antiplatelet agent use to prevent ischemic complications in patients undergoing percutaneous coronary intervention
• Denosumab
o Mechanism: antibody against RANKL (inhibits osteoclast maturation, mimics osteoprotegerin)
o Treats: Osteoporosis
• Digoxin Immune Fab
o Mechanism: antibody against Digoxin
o Treats: antidote for Digoxin toxicity
• Omalizumab
o Mechanism: antibody against IgE (prevents IgE binding to FcεRI)
o Treats: refractory allergic asthma
• Palivizumab
o Mechanism: antibody against RSV F Protein
o Treats: RSV prophylaxis in high-risk infants (“PaliVIzumab used for VIrus”)
• Ranibizumab, Bevacizumab
o Mechanism: antibody against VEGF
o Treats: neovascular age-related macular degeneration, proliferative diabetic retinopathy, macular edema
Microbiology Homepage
Gram ⊕ Cocci
• Staphylococcus aureus – G⊕ cocci, catalase⊕, coagulase⊕ (distinguish from other Staph), β-hemolytic, grows in clusters, small yellow colonies on
blood agar, ferments mannitol (turns pink to yellow, contrast other Staph), normal flora of nares, axilla, and groin, virulence factors: 1.) Protein A: binds
Fc component of IgG, forces variable region to face away from bacteria, inhibits complement fixation and phagocytosis, 2.) Enterotoxins: fast-acting,
heat stable (not destroyed by cooking), 3.) Toxic Shock Syndrome Toxin-1 (TSST-1): superantigen, binds MHC 2 and T-cell receptor resulting in polyclonal
T-cell activation, 4.) Coagulase: converts fibrinogen to fibrin clot, 5.) Exfoliatins: skin-exfoliating toxin, causes Scalded Skin Syndrome, 6.) α-toxin: forms
pores in cell membranes, causes hemolysis and tissue damage (C. perfringens and P. aeruginosa have a different α-toxin), transmitted via contact,
droplet, contaminated food (custards, mayonnaise, potato salad, canned meats), associated with surgical wounds, foreign bodies (tampons, surgical
packing or sutures – TSS), severe neutropenia, IV drug use (acute endocarditis), CGD (catalase⊕), CF, presentations: 1.) Impetigo: skin infection caused
by coagulase, exfoliatins, presents with erythematous, honey-colored flaky or crusted lesion (also caused by S. pyogenes), 2.) Gastroenteritis: food
poisoning (salty foods and mayonnaise/custards), preformed enterotoxins A-E (reason for speed of onset), presents with nausea/vomiting, abdominal
pain, nonbloody diarrhea 2-6 hours after ingestion, symptoms start and stop quickly, 3.) Infective Endocarditis: due to fibrin-platelet mesh, presents with
fever, malaise, leukocytosis, heart murmur, 4.) Abscesses and Mastitis: subcutaneous inflammation due to coagulase (forms fibrin clot around itself),
liver abscesses via hematogenous spread, 5.) Toxic Shock Syndrome: caused by TSST-1, associated with prolonged use of vaginal tampons or nasal
packing, presents with desquamating rash on palms and soles, fever, vomiting, rash, hypotension, multiorgan failure, elevated AST, ALT, and direct
bilirubin, 6.) Scalded Skin Syndrome: caused by exfoliative toxin (protease), which is epidermolytic toxins A and B against desmoglein 1 in stratum
granulosum, 7.) Pneumonia: caused by coagulase, cytolysins, presents with typical, acute, productive, rapid-onset pneumonia, patchy infiltrates on X-ray,
possibility of viral superinfection, possible empyema (pus in pleural space), 8.) Surgical Infections: presents with erythema, pain/tenderness at surgical
site, fever, 9.) Osteomyelitis: most common cause, associated with prostheses, neonates, 10.) MRSA: causes serious nosocomial and community-
acquired infections, resistant to Methicillin and Nafcillin due to alteration of PBP, treat 1.) Standard Infection with Nafcillin, Oxacillin, 2.) MRSA with
Vancomycin, Clindamycin, TMP-SMX, 3.) VRSA with Quinupristin, Dalfopristin, 4.) Gastroenteritis is self-limiting
• Staphylococcus epidermidis – G⊕ cocci, catalase⊕, coagulase⊖ (often called “coagulase⊖ Staph”), urease⊕, Novobiocin sensitive (contrast S.
saprophyticus, which is Novobiocin resistant), does not ferment mannitol (contrast S. aureus), normal flora of skin (may contaminate blood cultures),
forms biofilms, infects catheters and prosthetic devices (peritoneal dialysis, Foley catheters, IV lines, prosthetic joints), most common cause of
endocarditis in patients with artificial valves, presents with erythema at entry site, treat with Vancomycin, replacement of infected devices

• Staphylococcus saprophyticus – G⊕ cocci, catalase⊕, coagulase⊖ (often called “coagulase⊖ Staph”), urease⊕, Novobiocin resistant (contrast S.
epidermidis, which is Novobiocin sensitive), normal flora of female genital tract and peritoneum, presents with UTI (2nd most common cause of
uncomplicated UTIs in sexually active young women, E. coli the most common cause), treat with Ampicillin, Cephalexin, or TMP-SMX
• Streptococcus pyogenes (Group A Strep) – G⊕ cocci that grow in pairs or chains, catalase⊖, β-hemolytic, PYR⊕ (pyrrolidonyl arylamidase, compare
Enterococcus, contrast Strep bovis), bacitracin sensitive (contrast Group B Strep), facultative aerobe, virulence factors: EVASION: 1.) M Protein: main
virulence factor, inhibits phagocytosis and complement activation, mediates bacterial attachment, antibodies against it enhance host defenses, but may
cause Rheumatic Fever, 2.) Hyaluronic Acid Capsule: non-immunogenic, 3.) Streptolysin O: immunogenic, lyses RBCs and PMNs, 4.) Streptolysin S: non-
immunogenic, lyses RBCs and PMNs, 5.) Streptodornase: DNase, 6.) C5a Peptidase, 7.) Streptococcal Chemokine Protease, INVASION: 8.) Streptokinase:
dissolves clot, converts plasminogen to plasmin by phosphorylating it, plasmin is fibrinolytic, 9.) Hyaluronidase: dissolves connective tissue, ADHESION:
10.) Protein F, TOXIN: 11.) Pyrogenic Exotoxins: SpeA and SpeC are superantigens causing TSLS, SpeB is a protease causing necrotizing fasciitis, 12.)
Lipoteichoic Acid, transmitted via direct contact or respiratory droplets, reservoir is humans (skin and throat), pyogenic presentations: 1.) Pyogenic
(Strep) Pharyngitis: acute sore throat, beefy red pharynx, petechiae, swollen tonsils and uvula, fever (>100.4°F/38°C), tonsillar exudates (however 70% of
exudative tonsillitis is viral), cervical adenopathy, malaise, headache, and possible tonsillar abscesses, 2.) Cellulitis/Erysipelas: most common cause, 3.)
Impetigo: honey crusted skin lesions (compare S. aureus), toxigenic presentations: 4.) Scarlet Fever: strawberry tongue, blanching, sandpaper-like body
rash sparing face, palms and soles (Spe A, C), Strep pharyngitis, circumoral pallor, erythrogenic toxin⊕, 5.) Streptococcal Toxic Shock Syndrome (STSS):
toxic shock-like toxin (TSLS), presents with nausea/vomiting and diarrhea followed by hypotension, shock, and organ failure, 6.) Necrotizing Fasciitis: Spe
B (compare C. perfringens), immunogenic presentations: 7.) Rheumatic Fever: M protein antibodies cross react with myosin (T2, molecular mimicry),
occurs after Strep pharyngitis but NOT after skin infection, common in children with poor access to health care, presents with JNES criteria: Joints
(polyarthritis),  = Heart (mitral valve damage leading to mitral stenosis, myocarditis, and pericarditis, i.e. pancarditis), Nodules (subcutaneous, appear
on extensor surfaces of forearms OR on elbows and knees), Erythema marginatum, Sydenham Chorea (rapid involuntary movements of hands and face),
prevent with early treatment, histology: interstitial myocardial granuloma (Aschoff body), pathognomonic, contains plump macrophages with abundant
cytoplasm, central, slender, chromatin ribbons (Anitschkow or “caterpillar” cells), 8.) Post-Streptococcal Glomerulonephritis (PSGN): immune deposits in
glomeruli (T3), associated with M12 serotype, occurs 2 weeks after either pharyngitis or impetigo (not preventable), presents with dark brown, “cola- or
tea-colored” urine, facial puffiness, periorbital and generalized edema (sodium and water retention, proteinuria), hypertension, urine shows protein,
blood, possible RBC casts, serum shows decreased C3 (possibly C4 also), increased creatinine, anti-DNase B, and AHase (anti-hyaluronidase), increased
ASO and anti-NAD (from prodromal pharyngitis), note that while Staph aureus also causes impetigo, it does not lead to PSGN, increased age at onset the
worst prognostic factor (>95% of patients age 5-12 recover, but only 60% of adults recover completely), pre-existing kidney disease also a poor
prognostic factor, diagnose with rapid Strep test (ELISA based, misses 25% of infections, culture all ⊖s), ASO titer (⊕ if >200), anti-DNase B if ASO⊖ but
high suspicion, treat with β-lactams (10 days Penicillin G or Amoxicillin), Clindamycin, or Erythromycin + 1st gen. Cephalosporin if Penicillin allergy,
consider prophylactic antibiotics (prolonged low-dose Penicillin) after Acute Rheumatic Fever
• Streptococcus agalactiae (Group B Strep) – G⊕ cocci, β-hemolytic, hippurate⊕ (hydrolyzes sodium hippurate), CAMP test⊕ (increased zone of
hemolysis when plated with S. aureus – unique to Group B Strep), PYR⊖ (pyrrolidonyl arylamidase), bacitracin resistant (contrast Group A Strep, which is
bacitracin sensitive), virulence factors: 1.) Polysaccharide Capsule, 2.) Lipoteichoic Acid: cell wall, repels cationic antimicrobial peptides of innate immune
system, transmitted perinatally during passage through vaginal canal, increased risk with prolonged labor after membrane rupture, reservoir is vagina
and GI tract, associated with neonates, presentations: 1.) Neonatal Septicemia: most common cause, 2.) Neonatal Meningitis: most common cause, 3.)
Neonatal Pneumonia, 4.) Neonatal Osteomyelitis, screen pregnant women at 35-37 weeks with vaginal and rectal swabs, treat with Ampicillin +
Aminoglycosides or Cephalosporin, with intrapartum Ampicillin for mother after 35 weeks in high-risk deliveries

• Streptococcus pneumoniae (“Pneumococcus”, Ungrouped Strep) – “lancet-shaped” G⊕ diplococci (contrast N. gonorrhoea, which is a G⊖ diplococci),
α-hemolytic (contrast Group A and B Strep, which are β-hemolytic), optochin sensitive (contrast Strep viridans), bile sensitive (cannot grow in bile –
contrast Strep viridans, E. faecalis/faecium), Quellung/Neufeld reaction⊕ (antibodies bind to the bacterial capsule which becomes opaque and enlarges,
binds to S. pneumoniae, K. pneumoniae, N. meningitidis, H. influenzae, E. coli, and Salmonella, allowing microscopic visualization), virulence factors: 1.)
Polysaccharide Capsule: main virulence factor (no virulence without it), 2.) IgA Protease: allows for invasion and colonization of mucosa, 3.) Pneumolysin
O: damages respiratory epithelium, 4.) Peptidoglycan and Teichoic Acids: cause virulence in meningitis, transmitted via respiratory droplets, not easily
transmitted, predisposing factors for infection include influenza or measles, CHF, COPD, alcoholism, asplenia, sickle cell anemia (associated with sepsis),
 reservoir is humans (upper respiratory tract), presents with “MOPS” illnesses (most common cause of each in its demographic): 1.) Meningitis: adults,
CSF shows increased PMNs, decreased glucose, increased protein, treat adults with Ceftriaxone/Cefotaxime + Vancomycin 2.) Otitis Media: children,
treat with Amoxicillin (Erythromycin if Penicillin allergy), 3.) Pneumonia: adults (community-acquired), most common cause of typical pneumonia, esp.
in elderly, presents with lobar pneumonia that produces rust-colored sputum (contrast the “red currant jelly” sputum of K. pneumoniae), treat with
Macrolides (Erythromycin), 4.) Sinusitis: children, treat with Amoxicillin (Erythromycin if Penicillin allergy), 5.) Sepsis: asplenic patients, including SCD, 2
vaccines available: 1.) Adult: Pneumococcal Polysaccharide Vaccine (PPV), 23-valent polysaccharide, T-cell independent, IgM only, 2.) Pediatric:
Pneumococcal Capsular Vaccine (PCV), 7-valent conjugated to a protein, T-cell response, IgG

• Streptococcus viridans (Ungrouped Strep) – G⊕ cocci, α-hemolytic (contrast Group A and B Strep, which are β-hemolytic), optochin resistant (contrast
Strep pneumoniae), bile resistant (but rarely grow in bile), not encapsulated, forms biofilms and vegetations using dextran, an insoluble glucose-derived
polysaccharide that allows adherence, requires pre-existing fibrin-platelet aggregates for adherence (why it can infect damaged heart valves), biofilms
adhere to heart valves and tooth enamel, transmitted endogenously, normal flora of oropharynx, presentations: 1.) Dental Caries: S. mutans/mitis,
biofilms form plaque, 2.) Endocarditis: S. sanguis, damaged or prosthetic heart valve (esp. mitral) with dental work, prevent with proper oral hygiene,
historically at-risk patients given prophylactic antibiotics before dental procedures, however this is currently recommended only for the highest-risk
patients (history of endocarditis, artificial valve, or known valvular damage, usually due to previous heart surgery), treat Endocarditis with Penicillin G +
Aminoglycosides

• Enterococcus faecalis/faecium (Group D Strep) – G⊕ cocci, PYR⊕ (pyrrolidonyl arylamidase, compare Strep pyogenes, contrast Strep bovis), bile
resistant (grows in bile, bile esculin agar turns black – contrast Strep pneumoniae), grows in 6.5% NaCl (contrast Strep bovis), E. faecalis more common
 and benign, E. faecium more uncommon and virulent, transmitted endogenously, normal flora of colon, reservoir is humans (urethra or female genital
tract), GI/GU instrumentation or catheterization leads to bacteremia (30% of nosocomial endocarditis), previously damaged heart valves lead to
endocarditis, presentations: 1.) Subacute Endocarditis: esp. in damaged valves, the elderly, or following GI/GU procedures, 2.) UTI, 3.) Biliary Tract
Infection, diagnose with culture on blood agar, determine antibiotic sensitivities, treat with Vancomycin if susceptible (all strains are Penicillin G
resistant), treat Vancomycin-Resistant Enterococci (VRE, important cause of nosocomial infections) with Linezolid, Tigecycline, Streptogramins (e.g.
Quinupristin/Dalfopristin), use prophylactic antibiotics before GI/GU surgery in high-risk patients, resistant to Vancomycin (alteration of D-Ala-D-Ala to
D-Ala-D-Lac in cell wall precursors by bacterial proteins acting as ligases), Penicillins and Penicillinase-Resistant Penicillins (β-lactamases or low-affinity
PBP), Aminoglycosides (production of aminoglycoside-modifying enzymes that transfer acetyl, adenyl, phosphate groups to antibiotic outside of
bacterium, decreasing its ability to bind to ribosomes and exert its antimicrobial effects), TMP-SMX, resistance acquired via plasmids or transposons (not
chromosomally mediated)

• Streptococcus bovis (Group D Strep) – G⊕ cocci in chains, catalase⊖, PYR⊖ (pyrrolidonyl arylamidase, contrast Enterococcus, Strep pyogenes), variable
hemolysis, bile resistant (grows in bile – contrast Strep pneumoniae), does not grow in NaCl (contrast E. faecalis/faecium), not part of normal flora,
colonizes the gut, S. gallolyticus (S. bovis Type 1) associated with colorectal cancer, presentations: 1.) Subacute Endocarditis: mostly mitral/aortic valves,
most cases occur in patients without preexisting valvular abnormality, 2.) UTI, 3.) Septicemia, 4.) Neonatal Meningitis: rare

Lancefield Grouping (Streptococcus Species)

• Introduction – grouping based on differences in C carbohydrate on bacterial wall
• Group A – Streptococcus pyogenes
• Group B – Streptococcus agalactiae
• Group D – Enterococcus faecalis, E. faecium, E. durans (animals), E. bovis (mostly animals, may colonize gut in colorectal cancer)
• Groups C, E-S – appear in animals only
• Ungrouped – Streptococcus pneumoniae, Streptococcus viridans

Gram ⊕ Bacilli (Spore Forming)

• Bacillus anthracis – G⊕ bacilli, spore forming, obligate aerobic, colonies show halo of projections, “rods and chains”, “serpentine”, “medusa head”,
“boxcar-like”, virulence factors: 1.) Polypeptide Capsule: poly-D-glutamate, only bacterium with polypeptide (protein) capsule, immunogenic,
 antiphagocytic, 2.) Anthrax Toxin: contains protective antigen, 3.) Lethal Factor: exotoxin, protease that cleaves MAP kinase, a signal transduction
protein that regulates cell growth, responsible for tissue necrosis of black eschar, 4.) Edema Factor: acts as adenylate cyclase, increases cAMP, causes
fluid to enter intracellular space leading to edema, which inhibits host defenses and phagocytosis, responsible for edematous border of black eschar,
transmitted via inhalation of spores (anthrax), contact with infected animals (spores inhaled from contaminated sheep or goat skin/wool), reservoir is
animals, skin, soil, presentations: 1.) Cutaneous Anthrax: transmitted via contact, caused by lethal factor and edema factor, presents with painless
papule surrounded by vesicles that progresses to a black eschar (black necrotic ulcer with edematous ring), may progress to bacteremia and death, 2.)
Pulmonary Anthrax: transmitted via inhalation of spores (“woolsorter’s disease”), presents with flu-like symptoms with rapid progression to fever,
pulmonary hemorrhage, mediastinitis, shock, and death (near 100% mortality), 3.) GI Anthrax: rare, for all types, widened mediastinum on CXR, diagnose
with G stain and blood culture, treat with Fluoroquinolones (Ciprofloxacin), Doxycycline, Acellular Vaccine Adsorbed (AVA – toxoid vaccine) available,
prognosis good with early antibiotic treatment, worse with pulmonary form, prevent with postexposure prophylaxis (same as treatment antibiotics),
monoclonal antibodies if other therapies not tolerated, complications include bacteremia, sepsis, and meningitis

• Bacillus cereus – G⊕ bacilli, spore forming, toxins: 1.) Emetic Toxin (Cereulide): preformed, associated with fried rice and pasta, presents with
nausea/vomiting (similar to S. aureus) within 1-5 hours, 2.) Diarrheal Toxin (Enterotoxin): produced in vivo, associated with meats and sauces, presents
with watery, nonbloody diarrhea (increased cAMP leads to excretion of Cl- and osmotic water loss, similar to E. coli) and GI pain within 8-18 hours,
transmitted via food kept warm but not hot, esp. Chinese fried rice, presents with Gastroenteritis: food poisoning, with or without vomiting, rapid
symptom onset and resolution, diagnose clinically, with culture and gram stain of food, self-limiting
• Clostridium tetani – G⊕ bacilli, spore forming, obligate anaerobe, “tennis racket” appearance, primary virulence factor is Tetanospasmin (Tetanus
Toxin): spores germinate in tissues and produce exotoxin, a protease that travels to the CNS via retrograde axonal transport, where it binds ganglioside
receptors, cleaves SNARE proteins at pre-synaptic nerve terminals, cleaves synaptobrevin 2, halts fusion of vesicles with neuronal membrane, blocks
GABA and glycine release (inhibits an inhibitor) from Renshaw cells in spinal cord leading to tetany, transmitted via trauma or puncture wounds, esp.
stepping on a nail or being cut with barbed wire (requires low tissue oxygenation), incompletely removed placentas in new mothers, colonization of
umbilical stump in neonates, reservoir is soil, presents with Tetanus: spastic paralysis, risus sardonicus (raised eyebrows with open grin), trismus
(lockjaw due to masseter contraction), opisthotonus (arched back due to spasms of spinal extensors), diagnose clinically, organism rarely isolated, there
is no serum toxin assay for tetanospasmin, treat with hyperimmune human globulin (TIG, antitoxin) to neutralize toxin, Metronidazole or Penicillin,
anticonvulsants (e.g. Diazepam) to treat spasms, wound debridement, toxoid vaccine (toxin conjugated to a protein) available, made of formaldehyde-
inactivated tetanus toxin, infants administered DTaP vaccine at 2 months old, boosters given every 10 years in adults, during 3rd trimester of pregnancy
to prevent neonatal tetanus, following puncture wounds if immune status uncertain, prognosis worse in generalized tetanus, elderly, limited access to
intensive medical care, complications are laryngospasm, fractures, respiratory failure and death
• Clostridium botulinum – G⊕ bacilli, spore forming, obligate anaerobe, primary virulence factor is Botulinum Toxin: heat-labile toxin that cleaves SNARE
protein, blocks ACh vesicle fusion and release at NMJ, causes flaccid paralysis, coded by prophage, absorbed in gut, presentations: 1.) Botulism (Adults):
ingest preformed toxin in canned food (spores germinate in anaerobic alkaline environment – autolysis of bacteria releases toxin), smoked fish or
reheated rice (compare B. cereus), presents with reversible flaccid paralysis, symmetrical limb weakness with absent reflexes, nausea, ptosis, dizziness,
blurred vision (fixed, dilated pupils), dysphagia, (4 D’s: “Diplopia, Dysarthria, Dysphagia, Dyspnea”), treat with respiratory support and antitoxin, 2.)
Botulism/Floppy Baby Syndrome (Infants): ingest spores (not toxin) from dust or honey, toxin produced in gut, presents with constipation or no bowel
movement, difficulty feeding (via dysphagia), limpness, lethargy, poor cry, treat with respiratory support and hyperimmune human globulin (but NO
ANTIBIOTICS – may prolong or worsen course), avoid honey in infants <12 months old, 3.) Botulism (IV Drug Users): traumatic implantation of spores
into wounds, toxin produced in vivo, presents the same as in adults but with no GI symptoms, treat with antitoxin (but cannot inactivate toxin already in
nerves), respiratory support, and Amoxicillin, avoid IV drug use, promptly evaluate wounds, Note: local Botox injections used to treat focal dystonia,
achalasia, muscle spasms, cosmetically for reduction of facial wrinkles

• Clostridium difficile – G⊕ bacilli, spore forming, obligate anaerobe, 2 exotoxins: 1.) Exotoxin A: enterotoxin, binds to intestinal brush border, produces
inflammation, cell death, watery diarrhea, 2.) Exotoxin B: disrupts cytoskeleton integrity by depolymerizing actin, leading to enterocyte death and
necrosis, produces yellow-gray pseudomembrane that coats intestinal mucosa, nosocomial, transmitted endogenously, normal flora of colon, associated
with hospitalized patients on antibiotics, esp. Clindamycin (also Ampicillin, Cephalosporins, Amoxicillin), PPI use, presentations: 1.) Diarrhea, 2.)
Pseudomembranous Colitis, diagnose by detecting one or both toxins (not organisms) in stool via antigen detection or PCR, culture cannot be used, treat
with PO or IV Metronidazole, PO Vancomycin if severe, for recurrent cases, consider repeating prior regimen, Fidaxomicin, or fecal microbiota
transplant
• Clostridium perfringens – G⊕ bacilli, spore forming, obligate anaerobe, “stormy fermentation” in milk media, double zone of β-hemolysis on blood
agar, Nagler reaction used to detect (egg yolk agar with anti-α-toxin on half – blocks the action of the C. perfringens α-toxin, but not the phospholipases
of other Clostridium species), transmission via undercooked food or trauma (esp. military/war), non-motile, reservoir is soil and humans (colon),
associated with soldiers, IV drug users, recent GI surgery, septic abortions, virulence factors in humans (others in farm animals): 1.) α-Toxin: lecithinase
with phospholipase C activity, which disrupts cell membranes leading to hemolysis and tissue destruction, also activates arachidonic acid pathway
leading to edema, produces gas gangrene (H2 and CO2 from bacterial metabolism) and myonecrosis (S. aureus and P. aeruginosa have a different α-
toxin), 2.) Enterotoxin: heat-labile, causes disintegration of epithelial tight junctions in gut, mediated by claudin receptors, toxin also binds to intestinal
epithelium, causes morphological damage, and prevents water reabsorption, presentations: 1.) Gas Gangrene (Myonecrosis): due to wound
contamination with soil or feces, presents with tight tissue, pallor, lack of bleeding, skin tightness, severe pain, blisters or necrotic bullae, crepitation,
foul odor, blebs or gas bubbles, fever and tachycardia, evaluate with surgical exploration, G stain of muscle, culture, treat with debridement, fasciotomy
and/or amputation, Penicillin G, Clindamycin (targets ribosomes, inhibits toxin production), Fluoroquinolone for G⊖ coinfection, 2.) Food Poisoning:
due to reheated meat dishes, enterotoxin produced in intestines, presents with diarrhea and abdominal pain, self-limiting, Note: new research suggests
involvement in MS
Gram ⊕ Bacilli (Non-Spore Forming)
• Corynebacterium diphtheriae – G⊕ bacilli, non-spore forming, granules (volutin) produced on Loeffler coagulated serum medium stain
metachromatically (blue and red), stains with aniline dyes (e.g. methylene blue), Elek test detects toxin, “club-shaped” rods arranged in “V” or “L” shape,
grows on Cystine Tellurite agar, primary virulence factor is AB Exotoxin: encoded by β-prophage, inhibits ribosome function and protein synthesis via
ADP ribosylation of elongation factor 2 (EF-2), inhibits β-oxidation of fatty acids in myocardium leading to cardiac symptoms, consists of A (“active”)
subunit and B subunit (allows A to enter cell), similar to P. aeruginosa toxin, colonizes epithelium but not invasive, “ABCDEFG’s”: ADP ribosylation, Beta-
prophage, Corynebacterium, Diphtheriae, Elongation Factor 2, Granules, bacterium or phage transmitted via respiratory droplets, reservoir is humans
(throat and nasopharynx), endemic to Eastern Europe and Asia (rare in the US due to DTaP vaccine), presents with Diphtheria: pseudomembranous
pharyngitis with grayish-white membranes that can extend into larynx and cause obstruction, lymphadenopathy (“bull neck”), recurrent laryngeal nerve
palsy, myocarditis and cardiomyopathy, neuropathy, paralysis, treat acute infection with diphtheria antitoxin (passive immunization), Erythromycin or
Penicillin, and DPT vaccine to prevent future infections, endocarditis with Penicillin and Aminoglycosides, toxoid vaccine available (natural infection
does not induce immunity), DPT or DTaP given before age 7, Tdap and Td given after age 7 (fewer adverse reactions), causes death in 10% of patients,
usually due to cardiac causes
 • Listeria monocytogenes – small G⊕ bacilli, non-spore forming, β-hemolytic, facultative intracellular, tumbling motility in 22°C broth, actin jet motility in
cells (“rocket tails”, “actin rockets”) allows intracellular movement and cell-to-cell spread across cell membranes (thereby avoiding antibody), can be
cultured in broth as cold as 4-10°C (“cold enrichment”), virulence factor is Listeriolysin O: endotoxin (only G⊕ with endotoxin), which allows it to evade
phagosome killing, cell-mediated immunity required to fight infection, immunocompromised more susceptible, transmitted via food (cheese, deli meats,
coleslaw, hotdogs, unpasteurized milk), across placenta, or via vaginal transmission during birth, reservoir is food (cold growth), animals, plants, soil,
associated with immunocompromised or immunologically immature, pregnant women, presentations: 1.) Pregnant Women: amnionitis, septicemia,
spontaneous abortion, 2.) Infants: granulomatosis infantiseptica (in utero transmission, non-specific symptoms, esp. septicemia, meningitis, pneumonia),
3.) Immunocompromised: meningitis (most common cause in adults with cancer or renal transplant), septicemia, 4.) Healthy: mild, self-limited
gastroenteritis, treat with Ampicillin, add Gentamicin for immunocompromised, pregnant women should avoid cold deli foods

Gram ⊕ Branching Filamentous Bacilli (Fungus Like)

• Actinomyces israelii – G⊕ branching filamentous bacilli (fungus-like), obligate anaerobe (contrast Nocardia, which is an obligate aerobe), not acid-fast
(contrast Nocardia, which stains partially acid-fast), invades tissues with low oxygenation, transmitted endogenously (e.g. during dental procedures),
normal flora of gingiva, GI tract, and vagina, presentations: 1.) Cervicofacial/Pelvic Actinomycosis (PID): eroding abscesses of the mouth or GI tract,
appear in jaw due to trauma or poor hygiene, pelvis due to IUD use, abdomen, or thorax, very invasive but not painful (begins with nontender lump on
jaw), drainage from abscesses produces sinus tracts with thick yellow pus containing microscopic yellow “sulfur granules”, which contain bacteria and
debris (not sulfur), diagnose by visualizing bacilli in “sulfur granules”, 2.) CNS Actinomycosis: solitary brain abscesses (contrast Nocardia, which produces
 multiple foci), treat with Penicillin G or Ampicillin with surgical drainage (“SNAP” = Sulfa for Nocardia, Actinomyces use Penicillin), good prognosis, but
requires prolonged antibiotic treatment, prevent with good oral hygiene, avoidance of IUD use if previous history of infection, complications include
chronic abscesses in abdomen, pelvis, and brain, which usually require surgery

• Nocardia asteroides/brasiliensis – G⊕ branching filamentous bacilli (fungus-like), catalase⊕, urease⊕, obligate aerobe (contrast Actinomyces, which is
an obligate anaerobe), partially acid-fast (contrast Actinomyces, which is not acid-fast – carbol-fuchsin stain taken up by organisms with mycolic acids in
cell wall), no known toxins or virulence factors, transmitted via trauma or airborne, reservoir is soil, but not spore forming (contrast C. tetani and C.
perfringens), associated with men, decreased cellular immunity (HIV, transplant patients, corticosteroid use), and granulocyte deficiency, esp. CGD
(catalase⊕), cutaneous form associated with gardening, construction, carpentry, car accidents, presentations: 1.) Pulmonary Nocardiosis: cavitary
pulmonary lesion often misdiagnosed as TB (will have ⊖ PPD), mostly caused by N. asteroides, 2.) CNS Nocardiosis: hematogenous spread to brain
causing multiple abscesses (contrast Actinomyces, which produces only solitary CNS lesion), mostly caused by N. asteroides, 3.) Cutaneous Nocardiosis:
indurated lesions, cellulitis with draining abscesses, mostly caused by N. brasiliensis via traumatic implantation in immunocompetent, diagnose via
culture, treat with Sulfonamides or TMP-SMX (“SNAP” = Sulfa for Nocardia, Actinomyces use Penicillin), use TMP-SMX and Doxycycline prophylaxis in
immunosuppressed patients, patients tend to relapse despite appropriate treatment, requires prolonged antibiotic treatment, complications include
mycetoma (chronic subcutaneous fungus or fungus-like infection) and disseminated infection
• Tropheryma whipplei – G⊕ bacilli that may stain G⊖ or not at all, intracellular, nearly impossible to culture, stains with Giemsa and some silver stains,
pathogenesis unknown, common in older men, famers and those exposed to animals and soil, presents with Whipple’s Disease: rare systemic infection,
diarrhea or steatorrhea (later in disease course), abdominal pain, weight loss, migratory polyarthritis, fever, neurological symptoms, diagnose with
duodenal biopsy (PAS⊕ macrophages in intestinal lamina propria or mesenteric lymph nodes containing non-acid-fast G⊕ bacilli) or PCR, treat with
Doxycycline + Hydroxychloroquine or Ceftriaxone + TMP-SMX (only SMX component active since bacteria lack dihydrofolate reductase, the target of
TMP), complications include endocarditis (sometimes the only symptom) with dyspnea and edema, skin hyperpigmentation, uveitis, pleural or
peritoneal effusions (“Foamy Whipped Cream in a CAN: Cardiac, Arthralgia, Neurologic symptoms”)
Gram ⊖ Cocci
• Neisseria meningitidis – G⊖ diplococci, “meningococcus”, catalase⊕, oxidase⊕, ferments maltose and glucose (contrast N. gonorrhoeae, which only
ferments glucose), encapsulated (contrast N. gonorrhoeae, which is not encapsulated), often intracellular, culture on blood agar or VPN/Thayer-Martin
agar (Vancomycin, Polymyxin, Nystatin – Neisseria the only genus that grows on it), rarely produces β-lactamases, virulence factors: 1.) Polysaccharide
Capsule: A, B, and C most common, used to classify strains, 2.) IgA Protease: allows oropharynx colonization, 3.) Endotoxin: lipooligosaccharide (LOS),
analogous to LPS from other G⊖ species, excess LOS blebs off bacteria, causes inflammatory response which leads to capillary leakage, hemorrhage,
sepsis, and petechial rash (small hemorrhagic dots), 4.) Pili: enables nasopharyngeal attachment, high antigenic variability allows it to avoid immune
response, bacteria penetrate mucosal epithelium and enter circulation, spreading from pharynx to blood to choroid plexus to meninges, transmitted via
respiratory droplets and oral secretions, reservoir is humans (nasopharynx, 5% of population are carriers), associated with college students (“fresh
meningitis”), military personnel, infants between 6-24 months (maternal antibodies only protect <6 months), C5-C9 complement deficiency increases
susceptibility due to inability to form MAC, presentations: 1.) Meningococcemia: a form of sepsis with abrupt onset of fever, chills, malaise, petechial
rash, gangrene of toes, 2.) Waterhouse-Friderichsen Syndrome: fulminant meningococcemia leading to bilateral hemorrhage into adrenal glands,
produces adrenal insufficiency, fever, shock, DIC, coma, and death within 6-8 hours, 3.) Meningitis: most common in infants, presents with non-specific
findings, diagnose with CSF gram stain, treat children and adults with Ceftriaxone, Cefotaxime or Penicillin G + Vancomycin, neonates with Ampicillin
and Cefotaxime, use Rifampin, Ciprofloxacin, or Ceftriaxone prophylaxis in close contacts, vaccine available, contains capsular polysaccharide chains of
strains Y, W-135, C, and A (most infections in developed countries are strain B), given to teenagers living in close quarters, 15% mortality even with
treatment

• Neisseria gonorrhoeae – G⊖ diplococci, “gonococcus”, catalase⊕, oxidase⊕, not encapsulated (contrast N. meningitidis, which is encapsulated),
ferments glucose only (contrast N. meningitidis, which also ferments mannose), culture on blood agar or VPN/Thayer-Martin agar (Vancomycin,
Polymyxin, Nystatin – Neisseria the only genus that grows on it) or VCN agar (Vancomycin – kills G⊕, Colistin and Trimethoprim – kills G⊖, Nystatin –
kills fungi), often produces β-lactamases (plasmid-mediated), facultative intracellular within PMNs, virulence factors: 1.) IgA Protease: allows epithelial
invasion, 2.) Endotoxin: lipooligosaccharide (LOS), analogous to LPS from other G⊖ species, 3.) Pili: enables mucosal attachment, high antigenic
variability allows it to avoid immune response, bacteria penetrate mucosal epithelium causing inflammation, 4.) Porin and Opa Proteins: outer
membrane, enables epithelial invasion, transmitted via sex (2nd most common STI behind Chlamydia), reservoir is humans (genital tract), C5-C9
complement deficiency increases susceptibility due to inability to form MAC, presentations: 1a.) Gonorrhoea (Men): high fever, urethritis, prostatitis,
epididymitis, orchitis, 1b.) Gonorrhoea (Women): high fever, endocervicitis, PID, creamy, purulent discharge, 2.) Neonatal Conjunctivitis: occurs within
 first 5 days of life (contrast Chlamydia conjunctivitis, which takes >7 days), rapidly causes blindness if untreated, use Erythromycin eyedrops as
prophylaxis, 3.) Septic Arthritis: asymmetric polyarthritis in large joints of a sexually active adult, joint tap shows purulent synovial fluid that doesn’t
gram stain because bacteria are intracellular, 4.) Osteomyelitis: less common, 5.) Fitz-Hugh-Curtis Syndrome: hepatic inflammation, complication of PID
when it spreads to peritoneum, “violin string” adhesions to liver, diagnose with urethral smear (G⊖ diplococci visible within WBCs), treat with
Ceftriaxone + Azithromycin or Doxycycline for possible Chlamydia coinfection, Erythromycin eye drops for neonates (also fights potential Chlamydia
infection), do not use Penicillin, no vaccine available due to rapid antigenic variation of pili, condoms reduce sexual transmission, screen sexually active
women <25, those with multiple sexual partners, and partners of infected patients, complications include epididymitis and prostatitis in men, scarring,
infertility, ectopic pregnancies, and chronic PID in women, arthritis and endocarditis in both sexes

Gram ⊖ Bacilli – Enteric

• Bacteroides fragilis – G⊖ bacilli, anaerobe, virulence factors: 1.) Modified LPS: confers reduced endotoxin activity, 2.) Capsule: antiphagocytic,
transmitted endogenously from abdominal injury or surgery, normal flora of GI tract (Bacteroides family make up 99% of GI flora), also found in mouth
and vagina, reservoir is humans (colon), presentations: 1.) Septicemia, 2.) Peritonitis, 3.) Abdominal Abscesses, 4.) Wound Infections: increasingly
common, 5.) Aspiration Pneumonia: rare, only when part of oral flora, treat with Metronidazole, Clindamycin, Cefoxitin, surgical drainage of abscesses
• Campylobacter jejuni – G⊖ bacilli, “comma”/”s”-shaped bacteria with polar flagella), oxidase⊕, facultative anaerobe, culture on Skirrow agar at 42°C
(thermophilic – “CAMPing in the heat”), primary virulence factor is LT Toxin (similar to E. coli), invades GI mucosa, may spread systemically, transmitted
via poultry or meat, fecal-oral route, unpasteurized milk, contact with infected animals (dogs, cats, pigs) a risk factor, low infectious dose (ID50) needed
(~500 organisms), reservoir is GI tract of poultry, cattle, humans, and others, presentations: 1.) Gastroenteritis: most common cause in US, esp. in
children, 10+ stools per day, abdominal pain, cramping, tenesmus, pseudo-appendicitis, watery diarrhea initially, becomes bloody with pus in stool if
chronic, 2.) Guillain-Barré Syndrome: causes 30% of cases in US, antigenic cross-reactivity between Campylobacter oligosaccharides and
glycosphingolipids on neural tissues, demyelinating disorder with ascending paralysis, 3.) Bacteremia: invasive, penetrates mucosa and enters
bloodstream, 4.) Reactive Arthritis (Reiter’s Syndrome): seronegative spondyloarthropathy characterized by triad of urethritis, conjunctivitis/uveitis,
arthritis (“can’t see, can’t pee, can’t bend a knee/climb a tree”), caused by autoimmune reaction to prodromal urethritis (C. trachomatis) or GI infection
(Salmonella, Shigella, Campylobacter, Yersinia), HLA-B27⊕, young man (<40), rarely children, associated with HIV, gastroenteritis typically self-limited,
supportive treatment with fluid and electrolytes, most strains resistant to Penicillin, Erythromycin, Fluoroquinolones

• Escherichia coli – G⊖ bacilli, oxidase⊖, indole⊕ (contrast Enterobacter cloacae), facultative anaerobe, produces metallic green sheen on Eosin-
Methylene Blue (EMB) agar (contrast other lactose fermenters, which grow as purple/black colonies), lactose fermenting (produces β-galactosidase,
which breaks down lactose into glucose and galactose), sorbitol fermenting (except EHEC, which usually does not), normal flora of colon, pathogenic
when it acquires one or more virulence factors: 1.) P-Pili (Fimbriae): P-fimbriae virulence factor most important for urinary tract colonization (cystitis,
pyelonephritis), 2.) Exotoxin (Verotoxin): LT, ST, Shiga-like, 3.) LPS Endotoxin: Lipid A, causes septic shock, 4.) K Capsule: K-1 capsule allows pneumonia,
meningeal infection (neonates), 5.) Iron-Binding Siderophore, specific pathogenesis varies by strain, strains: 1.) EPEC (“Pediatric”): second most common
cause of diarrhea in infants, adherence to M cells within Peyer’s patches in intestinal submucosa flattens pili and prevents absorption, no toxins
produced, associated with developing countries, presents with diarrhea (dysentery), supportive treatment, 2.) EIEC (“Inflammatory”): bacteria invade
epithelial cells producing necrosis and inflammation, invasion and toxin act synergistically, virulence factor shared with Shigella, blood and WBCs in stool
like Shigellosis, supportive treatment, 3.) ETEC (“Travelers”): no inflammation or invasion, Heat Labile Toxin acts just like Cholera toxin, ADP ribosylation
of G protein stimulates adenylate cyclase, permanently activates Gs (increases cAMP), which increases pumping of Cl- into gut and decreases Na+
absorption, H2O osmotically drawn into gut, produces voluminous watery (“rice-water”) diarrhea, Heat Stable Toxin stimulates guanylate cyclase,
increases cGMP, decreases reabsorption of NaCl and H2O, also causes watery diarrhea (“Labile like the air = cAMP, Stable like the ground = cGMP”),
associated with drinking the water in a developing country like Mexico, supportive treatment + TMP-SMX, 4.) EHEC (“Hamburger”): no epithelial
invasion, pathogenesis caused by toxin only, Shiga-like toxin (verotoxin) inhibits protein synthesis by inhibiting 60S ribosome, produces bloody stool
(dysentery), but without WBCs, O157:H7 strain associated with HUS, Shiga-like toxin damages glomerular endothelial cells, platelets aggregate around
 damaged cells, producing hemolysis with schistocytes, transmitted via undercooked meat or raw, leafy vegetables, young patient (<10) with prodromal
diarrhea who develops acute renal failure, presents with triad of anemia, thrombocytopenia, and acute renal failure, swelling of endothelium narrows
vascular lumen producing microthrombi on damaged epithelium and hemolysis, decreased renal blood flow, platelet consumption, peripheral smear
shows schistocytes (hemolysis), O157:H7 strain does not ferment sorbitol or produce glucuronidase (contrast most other E. coli strains), supportive
treatment, antibiotics contraindicated (may produce HUS) (3 H’s: “Hemorrhagic, Hamburgers, HUS”), 5.) EAEC “Aggregative”: able to adhere to intestinal
cells in an aggregative, “stacked brick” pattern, produces persistent diarrhea in infants in less-developed countries, all forms transmitted endogenously,
via fecal-oral route, or undercooked meat, reservoir is humans (colon) and cow feces, presentations: 1.) Diarrhea: symptoms and treatment vary by
strain, discussed above, generally virulence factors shared by V. cholera, Shigella, and E. coli, 2.) UTI: most common cause, acquisition of pili allows
motility up GU tract, ascending infection may produce pyelonephritis, treat with Fluoroquinolones or Sulfonamides, 3.) Neonatal Meningitis: second
most common cause (after Group B Strep), acquisition of K-1 capsule inhibits phagocytosis, allowing spread to meninges, treat with Ceftriaxone, 4.)
Sepsis: most common cause of G⊖ sepsis, associated with hospitalized patients, treat with Fluoroquinolones or 3rd gen Cephalosporins, 5.) Pneumonia:
nosocomial in neonates, 6.) Cystitis, 7.) Pyelonephritis, distinguish pathogenic strains via immunoassay, serotyping, DNA probes, or PCR

• Enterobacter cloacae – G⊖ bacilli, catalase⊕, oxidase⊖, indole⊖ (contrast E. coli), facultative anaerobe, lactose fermenting (grows pink on
MacConkey agar), transmitted endogenously via aspiration or contamination, motile, reservoir is humans (colon), presentations: 1.) UTI, 2.) Pneumonia,
treat with 3rd gen Cephalosporin + Aminoglycoside or a Carbapenem, use Fluoroquinolone as an alternative, often antibiotic resistant
• Fusobacterium nucleatum – G⊖ bacilli, slender rods with pointed ends, non-spore forming, primary virulence factor is its ability to adhere to biofilms
and previously existing biological damage, esp. in soft tissues, motile and non-motile forms, once thought to be part of normal flora, now considered
always pathogenic, reservoir is animals and humans (mucous membranes, esp. in oropharynx), presentations: 1.) Periodontal Disease, 2.) Jaw Abscesses:
without draining sinus tracts (contrast A. israelii), 3.) Lemierre’s Syndrome: also known as postanginal shock including sepsis and human necrobacillosis,
thrombophlebitis of internal jugular vein that typically occurs when throat infection progresses to peritonsillar abscess, which ruptures internally, then
drains to nearby structures, ultimately infecting the jugular vein, a clot may form, and pieces may break off and travel through the right heart to the
lungs as emboli, blocking pulmonary artery branches, 4.) Topical Skin Ulcers, treat with Penicillin G, Metronidazole, alternatively with Clindamycin,
Cefoxitin, or Chloramphenicol
• Klebsiella (Calymmatobacterium) granulomatosis – G⊖ bacilli, oxidase⊖, urease⊕, facultative anaerobe, lactose fermenting (grows pink on
MacConkey agar), tissue contains Donovan bodies (deep purple rod-shaped oval organisms in cytoplasm of mononuclear phagocytes or histiocytes),
transmitted via contact with open sores, uncommon in developed countries, presents with painless, “beefy-red ulcer” with characteristic rolled edge of
granulation tissue that bleeds readily on contact, lymphadenopathy typically mild or absent (contrast Syphilis, with which it is often mistaken), diagnose
with tissue biopsy using Wright-Giemsa stain (Donovan bodies, bipolar staining), treat with Azithromycin (1st line), Doxycycline, Ciprofloxacin +
Erythromycin, or TMP-SMX for at least 3 weeks to minimize possibility of relapse

• Klebsiella pneumoniae – G⊖ bacilli, oxidase⊖, urease⊕, facultative anaerobe, lactose fermenting (grows pink on MacConkey agar), virulence factors:
1.) Polysaccharide Capsule: large, with O antigen, 2.) Endotoxin, transmitted endogenously via aspiration or contamination, non-motile, reservoir is
humans (colon and upper respiratory tract), presentations: 1.) Pneumonia: lobar, associated with diabetics, alcoholics, and hospitalized patients, forms
abscesses, esp. in upper lobes (CXR may show cavitary lesions), often confused with TB, produces dark red, “currant jelly” sputum (“mucoid-appearing”,
”thick, mucoid, blood-tinged”, contrast “rust-colored” sputum of S. pneumoniae), high mortality, 2.) UTI: hospitalized patients (nosocomial) with Foley
catheters due to fecal contamination, 3.) Sepsis: immunocompromised, 4.) Liver Abscesses: RUQ pain, fever, malaise, most common cause of pyogenic
liver abscesses (along with E. coli), treat with 3rd gen Cephalosporin + Aminoglycoside or a Carbapenem, use Fluoroquinolone as alternative, often
antibiotic resistant, 4 “A”s: Aspiration, Alcoholics, Abscesses, DiAbetics

• Proteus mirabilis – G⊖ bacilli, urease⊕, urease raises urine pH producing kidney stones, non-lactose fermenting, fishy odor, primary virulence factor is
Endotoxin: produces fever and shock, transmitted endogenously, exhibits swarming motility (highly motile) via peritrichous (uniformly distributed on
 surface) flagella (motility may aid entry into bladder), reservoir is humans (colon), water, soil, presentations: 1.) UTI, 2.) Septicemia, 3.) Kidney Stones:
staghorn calculi/struvite stones (ammonium-magnesium-phosphate), treat with Fluoroquinolones, 3rd gen Cephalosporins, TMP-SMX

• Salmonella vs. Shigella – both are G⊖ bacilli, oxidase⊖, non-lactose fermenters, and can invade GI tract via M cells of Peyer’s patches

Salmonella typi Other Salmonella Species Shigella Species

Reservoir Humans only Humans and animals Humans only
Spread Hematogenous Hematogenous Cell-to-cell, not hematogenous
H2S Production Yes Yes No
Flagella Yes Yes No
Virulence Factors Endotoxin, Vi capsule Endotoxin Endotoxin, Shiga toxin (enterotoxin)
Infectious Dose (ID50) High (acid labile) High Low (acid stable)
Antibiotic Effects Prolongs duration of fecal excretion Prolongs duration of fecal excretion Shortens duration of fecal excretion
Immune Response Primarily monocytes PMNs if disseminated Primarily PMNs
GI manifestations Constipation, then diarrhea Diarrhea (possibly bloody) Bloody diarrhea (bacillary dysentery)
Vaccine Oral live-attenuated (S. typi), IM with Vi None None
capsular antigen
Unique Properties Typhoid Fever, treat with Ceftriaxone Transmitted via poultry, eggs, pets, turtles, More to less toxin produced: S.
or Fluoroquinolone, carrier state with avoid antibiotics, more likely to cause dysenteriae, S. flexneri, S. boydii, S. sonnei,
gallbladder colonization gastroenteritis invasion of M cells key to pathogenicity
(organisms producing little toxin still cause
disease)
• Salmonella typhi – G⊖ bacilli, oxidase⊖, facultative anaerobe, non-lactose fermenting, produces H2S (black colonies on Hektoen agar, contrast Shigella,
which produces green colonies), encapsulated, virulence factor is Vi Antigen, which blocks antibody attack on O antigen, detected by Widal test, invades
intestinal mucosa in ileocecal region, replicates within macrophages (facultative intracellular), bacteria progress to mesenteric lymph nodes and blood,
severe inflammation in Peyer’s patches can produce hemorrhage and gut perforation, transmitted via fecal-oral route (4 “F’s” Food, Fingers, Feces,
Flies), acid labile, thus less virulent than Shigella with large infectious dose (ID50) needed, PPIs/pernicious anemia increases susceptibility, motile (flagella
allow heterogeneous dissemination – “salmon swim”), reservoir is humans (can remain in gallbladder chronically), associated with poor hand hygiene,
 poor sanitation, and infected water, travel to developing countries, presents with Typhoid Fever: fever, abdominal pain, constipation or “pea-soup”
diarrhea (leukocytes with monocytic predominance), headache, rose-colored macules on abdomen, may mimic appendicitis, chronic carrier state
possible, treat with Fluoroquinolones (Ciprofloxacin) or 3rd gen Cephalosporins, 3 vaccines available: 1.) Attenuated Oral, 2.) Parenteral Heat-Killed: no
longer used, 3.) Parenteral ViCPS Polysaccharide Capsular

• Salmonella enteritidis – G⊖ bacilli, oxidase⊖, facultative anaerobe, non-lactose fermenting, produces H2S (black colonies on Hektoen agar, contrast
Shigella, which produces green colonies), encapsulated, Type 3 secretion system, virulence factors: 1.) Vi Antigen: blocks antibody attack on O antigen,
detected by Widal test, 2.) Endotoxin: no exotoxin, invades intestinal mucosa in ileocecal region, replicates within macrophages (facultative
intracellular), transmitted via poultry products (eggs, raw chicken) and reptile pets (turtles), acid labile, thus less virulent than Shigella with large
infectious dose (ID50) needed, PPIs/pernicious anemia increases susceptibility), motile (flagella allow heterogeneous dissemination – “salmon swim”),
reservoir is GI tracts of domesticated animals and humans, presentations: 1.) Enterocolitis/Gastroenteritis: 2nd most common cause (C. jejuni most
common), 6-48 hour incubation followed by nausea/vomiting, inflammatory diarrhea with loose, bloody stools, fever, abdominal pain, myalgias,
headache, self-limiting (antibiotics contraindicated), 2.) Septicemia: very young or elderly, 3.) Osteomyelitis: most common cause in Sickle Cell Disease,
treat severe infections with Ampicillin, Fluoroquinolones, or 3rd gen Cephalosporins

• Shigella sonnei/dysenteriae – G⊖ bacilli, oxidase⊖, facultative anaerobe, non-lactose fermenting, does not produce H2S (green colonies on Hektoen
agar, contrast Salmonella, which produces black colonies), Type 3 secretion system, primary virulence factor is Shiga Toxin: produced by S. dysenteriae
 Type 1, neurotoxic, cytotoxic, enterotoxic, “A” subunit inactivates 60S ribosome, inhibiting protein synthesis and killing intestinal cells, bacteria
phagocytized by microfold (M) cells within Peyer’s patches in intestinal submucosa (do not invade lamina propria), escapes phagolysosome before
degraded (facultative intracellular), non-motile, but uses host’s cytoskeleton to create actin tail in order to propel itself from one cell to another (similar
to L. monocytogenes actin rockets), generates inflammatory diarrhea with blood and WBCs, produces very shallow ulcers, transmitted via fecal-oral
route (4 “F’s” Food, Fingers, Feces, Flies), acid stable, thus much more virulent than Salmonella (only ~10 organisms needed for infection), reservoir is
humans (colon), presentations: 1.) Shigellosis: bloody diarrhea with mucus and pus, high fever (>101°F/38.3°C), tenesmus (straining), lower abdominal
cramps, 2.) Hemolytic Uremic Syndrome: S. dysenteriae, Shiga toxin damages glomerular endothelial cells, platelets aggregate around damaged cells,
producing hemolysis with schistocytes, young patient (<10) with prodromal diarrhea who develops acute renal failure, presents with triad of anemia,
thrombocytopenia, and acute renal failure, diagnose with stool culture (not normal flora), treat with Fluoroquinolones, Azithromycin, TMP-SMX, avoid
Ampicillin (many strains resistant)

• Serratia marcescens – G⊖ bacilli, catalase⊕, oxidase⊖, facultative anaerobe, lactose fermenting (grows pink on MacConkey agar), but slowly (may
show up ⊖), transmitted endogenously via aspiration or contamination, motile, reservoir is humans (colon), produces bright red pigment, several
presentations: 1.) UTI, 2.) Pneumonia, 3.) Wound Infection, 4.) Nosocomial Infection, 5.) Septicemia, 6.) Kidney Stones, treat with Cefotaxime or a
Carbapenem, often antibiotic resistant

• Vibrio cholerae – G⊖ bacilli, oxidase⊕, facultative anaerobe, requires NaCl to grow, and grows on 6.5% NaCl, survives on alkaline media (contrast C.
jejuni, which cannot survive on alkaline media), killed by acid (acid labile), curved “comma-shaped” rod with polar flagella, primary virulence factor is
Cholera Enterotoxin: same mechanism as E. coli LT toxin, A and B subunits, B subunit binds to GM1 ganglioside on intestinal epithelium via fimbriae
 (non-invasive), A subunit enters cell, produces ADP ribosylation of G protein, which activates adenylyl cyclase and increases cAMP, producing active
secretion and decreased reabsorption of Na+ and Cl- in gut lumen, H2O follows producing secretory diarrhea, also induces mucin secretion by goblet cells,
transmitted via ingestion of contaminated water or uncooked food (e.g. raw shellfish), motile, reservoir is humans (colon), endemic to developing
countries, presents with Cholera: severe voluminous diarrhea producing dehydration and hypovolemic shock, “rice-water stools” (mucus and sloughed
epithelial cells), diagnose with stool samples, which shows organisms but not WBCs (contrast Campylobacter infection, which produces WBCs in the
stool), treat with fluid and electrolytes, Tetracyclines, Fluoroquinolones, or Macrolides may shorten disease course

• Vibrio parahaemolyticus/vulnificus – G⊖ bacilli, facultative anaerobe, similar lab features and pathogenesis to V. cholerae, V. parahaemolyticus is a
marine bacterium, transmitted via undercooked seafood (leading cause of diarrhea in Japan), presents with 1.) Gastroenteritis: self-limiting watery
diarrhea with cramping and abdominal pain, V. vulnificus presents with 2.) Gastroenteritis: self-limiting, caused by consumption of oysters or
undercooked seafood, or 3.) Cellulitis from swimming in brackish water or shucking oysters, treat with Tetracyclines or 3rd gen Cephalosporins

Gram ⊖ Bacilli – Respiratory

• Bordetella pertussis – small G⊖ bacilli, encapsulated, obligate aerobe, fastidious, culture on Regan-Lowe or Bordet-Gengou media, will not grow on
cotton, thus special swab needed to collect specimens for culture, attaches to ciliated epithelial cells of bronchi via pili (filamentous hemagglutinin), but
does not invade, virulence factors: 1.) Pertussis Toxin: inhibits Gi protein system via ADP ribosylation, increases cAMP, activates protein kinase G and
other intracellular messengers, ribosylation also disables lymphocyte chemokine receptors, decreasing phagocytosis and increasing lymphocytosis
(WBCs get stuck in the bloodstream), increased histamine sensitivity, increased insulin synthesis, 2.) Extracytoplasmic Adenylate Cyclase: also increases
 cAMP, works just like B. anthracis edema factor, decreases neutrophil chemotaxis, decreases superoxide generation, 3.) Filamentous Hemagglutinin: pili
that improve binding to epithelial cells, 4.) Tracheal Cytotoxin: part of peptidoglycan wall, damages ciliated epithelial cells, transmitted via respiratory
droplets, reservoir is vaccinated humans, presents with Whooping Cough, “100 day cough”, which has 4 stages: 1.) Incubation (7-10 days):
asymptomatic, 2.) Catarrhal (1-2 weeks): most contagious phase, similar to mild URI, low grade fever, coryza, conjunctival injection (red eyes),
lacrimation, 3.) Paroxysmal (2-4 weeks): characteristic bursts of nonproductive whooping cough (cough on expiration, “whoop” on inspiration),
posttussive vomiting, leukocytosis, 4.) Convalescent: attacks become less frequent, complications may develop (pneumonia, seizures, encephalopathy),
treat with Erythromycin, 2 vaccines available: 1.) DTaP: Diptheria-Tetanus-acellular Pertussis, contains filamentous hemagglutinin + pertussis toxoid, 2.)
Tdap: given as a booster, compared to childhood DTaP vaccine contains less diphtheria and pertussis, and more tetanus (hence small letters)

• Haemophilus influenzae – G⊖ coccobacilli, fastidious, grows on chocolate agar, requires factors V (NAD+) and X (hematin) for growth, exhibits satellite
phenomenon, growing near S. aureus on blood agar (S. aureus supplies factor V, lyses RBCs, releasing factor X), virulence factors: 1.) Type B Capsule:
most strains encapsulated (SCD patients susceptible), type B causes most severe disease, contains ribose in place of hexose, capsule is polyribosyl-ribitol-
phosphate (PRP), non-encapsulated strains exist (non-typeable), produce mucosal infections (otitis media, sinusitis, conjunctivitis, bronchitis), vaccine
does not confer immunity to non-typeable strains, 2.) IgA Protease: aids colonization, transmitted via respiratory droplets (aerosol), reservoir is
nasopharynx, spreads to lymphatics then to meninges in meningitis, presentations: 1.) Epiglottitis: inflamed “cherry red” epiglottis in children,
inspiratory stridor, and drooling, “thumb sign” on XR, formerly the most common cause, 2.) Meningitis: unvaccinated children 3 months-2 years old,
formerly the most common cause in children aged 1-5, only caused by Type B (capsular) strain, 3.) Otitis Media, 4.) Pneumonia: most commonly in
adults, 5.) Bronchitis, does not cause the flu despite the name, 6.) Sepsis/Septic Arthritis: esp. in asplenic patients (SCD), treat meningitis with
Ceftriaxone, mucosal infections with Amoxicillin + Clavulanate, use Rifampin prophylaxis for close contacts, vaccine available, contains type B capsular
polysaccharide (PRP) conjugated to protein, often Diphtheria toxoid, conjugation improves immune system recognition of polysaccharide and promotes
class switching, only confers immunity to type B, given between 2-18 months, T-cell independent
• Legionella pneumophila – weakly G⊖ bacilli, oxidase⊕, stains with silver stain, facultative intracellular within macrophages, fastidious, culture on
buffered charcoal yeast extract (CYE) with increased iron and cysteine, inhibits phagosome-lysosome fusion, virulence factors: 1.) Endotoxin, 2.) Biofilm,
airborne transmission, esp. air conditioning, no human-to-human transmission, reservoir is water (contaminated air conditioners, hot water tanks),
associated with smokers, chronic lung disease, presentations: 1.) Legionnaire’s Disease: severe, atypical pneumonia, fever, cough, diarrhea (though no
organisms found in GI tract), esp. in a smoker, high fever, low heart rate, headache, confusion, hyponatremia via SIADH, CXR shows patchy infiltrate with
unilobar consolidation, 2.) Pontiac Fever: self-limiting, mild, flu-like illness, diagnose via urine antigen test, treat with Fluoroquinolones (same efficacy as
Macrolides, but with fewer side effects), Erythromycin, Penicillin ineffective (organism intracellular), prevent by decontaminating air conditioners
routinely
• Moraxella catarrhalis – G⊖ diplococcus, oxidase⊕, fastidious, aerobic, primary virulence factor is Trimeric Autotransporter Adhesins (TAAs): enables
adhesion to host cell, transmitted person-to-person (esp. nosocomially) or endogenously (commensal in respiratory tract of children and some adults),
non-motile, associated with COPD, infants, presentations: 1.) Common Cold, 2.) Otitis Media, 3.) Sinusitis, 4.) Pneumonia: common cause of community-
acquired pneumonia, COPD patients especially susceptible, 5.) Nosocomial Infections: associated with pulmonary units and PICUs, 6.) Sepsis: associated
with immunodeficiency, COPD, CF, SLE, leukemia, 7.) Endocarditis: associated with valvular conditions or prostheses, 8.) Septic Arthritis, treat with 2nd or
3rd gen Cephalosporins, TMP-SMX, Macrolides (Azithromycin, Erythromycin), 95% produce β-lactamases (resistant to Penicillin, Ampicillin, and
Amoxicillin)
• Pseudomonas aeruginosa – G⊖ bacilli, catalase⊕, oxidase⊕, obligate aerobe, non-lactose fermenting, contains the pigments pyocyanin (blue) and
pyoverdin (green), fruity, grape-like odor, virulence factors: 1.) Exotoxin A: same mechanism as C. diphtheriae (inhibits ribosome function and protein
synthesis via ADP ribosylation of EF-2), 2.) Endotoxin: produces inflammation, fever, and shock, 3.) Mucoid Polysaccharide Capsule: evades phagocytosis,
may contribute to chronic pneumonia in CF patients due to biofilm formation, 4.) Phospholipase C: secreted, degrades cell membranes, 5.) Pyocyanin:
generates reactive oxygen species, transmitted nosocomially, via water, raw vegetables, flowers, reservoir is water, presentations: 1.) Burns: wound
infection (looks gangrenous, not like impetigo), 2.) Endocarditis: tricuspid valve in IV drug users, 3.) Pneumonia: productive cough with green sputum,
associated with CF, immunocompromised, ICU patients on respirator, 4.) Ecthyma Gangrenosum: rapidly progressive, necrotic skin lesions due to
perivascular invasion and release of exotoxins, associated with catheter infection, immunocompromised, 5.) Otitis Externa: “swimmer’s ear”, malignant
otitis externa seen in diabetics, 6.) UTI: associated with Foley catheters, 7.) Osteomyelitis: caused by trauma or puncture wounds, associated with
diabetics or IV drug users, 8.) Hot Tub Folliculitis: superficial infection of hair follicle due to exposure in a pool/hot tub/spa, 9.) Corneal Infections:
associated with contact lens users, minor trauma, (“PSEUDOMONAS: Pneumonia, pyocyanin, Sepsis, Ecthyma gangrenosum, UTIs, Diabetes, drug use,
Osteomyelitis, esp. puncture wounds, Mucoid polysaccharide capsule, Otitis externa, Nosocomial infections, Exotoxin A, Skin Infections”), treat with
CAMPFIRE drugs: Carbapenems, Aminoglycosides, Monobactams, Polymyxins (e.g. Polymyxin B, Colistin), Fluoroquinolones (Ciprofloxacin, Levofloxacin,
esp. for UTI), thIRd and 4th gen Cephalosporins (Ceftazidime, Cefepime), Extended-Spectrum Penicillins (Piperacillin, Ticarcillin), usually antibiotic
resistant
Gram ⊖ Bacilli – Genitourinary
• Haemophilus ducreyi – G⊖ bacilli, transmitted via sex, reservoir is humans (genitals), presents with Chancroid: do not confuse with chancre of syphilis,
painful ulcerated genital lesion with exudate (“so painful, you do cry”), increases risk of HIV transmission, usually no systemic symptoms, occasional
painful, swollen, matted lymph nodes unilaterally, esp. inguinal (contrast T. pallidum syphilis, which has a painless ulcer, HSV1 and 2 herpes, which has a
 painful ulcer, but systemic symptoms, C. trachomatis lymphogranuloma venereum, which has only painful, matted lymph nodes, but no chancre),
diagnose with PCR, treat with Azithromycin or Ceftriaxone

• Helicobacter pylori – G⊖ bacilli, catalase⊕, oxidase⊕, urease⊕, facultative anaerobe (microaerophilic), grows at 37°C, spiral-shaped, invasive,
virulence factors: 1.) Urease: ammonium produced neutralizes stomach acid creating alkaline environment and allowing survival, 2.) Mucinase: allows
penetration of mucosal layer, transmitted via fecal-oral or oral-oral route, motile (flagellated), reservoir is humans (GI tract, esp. antrum of stomach),
presentations: 1.) Duodenal Ulcers: most common cause (up to 90% of cases), 2.) Gastric (Stomach) Ulcers: second most common cause after ASA, 3.)
Chronic Gastritis: most common cause, presents with gnawing stomach ache that is worse when stomach is empty and relieved by eating, nausea, lack
of appetite, burping and bloating, unintentional weight loss, for all presentations, typically affects pylorus and antrum of stomach, chronic gastric
irritation predisposes to stomach cancer, esp. gastric adenocarcinoma or lymphoma (Marginal Cell Lymphoma/”MALToma”), diagnose with antibody
test, stool antigen test, urease breath test (administer 13C and test for ammonia + 13C-CO2 exhaled), or biopsy during endoscopy, treat with “Triple
Therapy”: Amoxicillin (or Metronidazole or Tetracycline if penicillin allergy) + Clarithromycin + PPI (Omeprazole) or Bismuth (Pepto-Bismol)

Gram ⊖ Bacilli – Zoonotics

• Overview of Zoonotics

Species Disease Transmission and Source

Anaplasma species Anaplasmosis Ixodes ticks (live on deer and mice)
 Bartonella species
Borrelia burgdorferi
Borrelia recurrentis
Brucella species
Campylobacter species
Chlamydia psittaci
Coxiella burnetii
Ehrlichia chaffeensis
Francisella tularensis
Leptospira species
Mycobacterium leprae
Pasteurella multocida
Rickettsia prowazekii
Rickettsia rickettsii
Rickettsia typhi
Salmonella (except typhi)
Yersinia pestis
Cat Scratch Disease, Bacillary Angiomatosis Cat scratch
Lyme Disease Ixodes ticks (live on deer and mice)
Relapsing fever (variable surface antigens) Louse
Brucellosis (undulant fever) Unpasteurized dairy
Bloody diarrhea Feces from infected animals, contaminated meat/food/hands
Psittacosis Parrots, other birds
Q Fever Aerosols of cattle/sheep amniotic fluid
Ehrlichiosis Amblyomma (Lone Star Tick)
Tularemia Ticks, rabbits, deer flies
Leptospirosis Animal urine in water, recreational water use
Leprosy Humans with lepromatous leprosy, armadillos (rare)
Cellulitis, Osteomyelitis Animal bite, cats, dogs
Epidemic Typhus Human-to-human via human body louse
Rocky Mountain Spotted Fever (RMSF) Dermacentor (dog tick)
Endemic Typhus Fleas
Diarrhea, vomiting, fever, abdominal cramps Reptiles and poultry
Bubonic Plague Fleas (rats and prairie dogs are reservoirs)

• Bartonella henselae – G⊖ bacilli, visualize with Warthin-Starry (silver) stain, transmitted via cat or dog bites and scratches, presentations: 1.) Cat
Scratch Disease/Fever: relatively benign, produces lymphadenopathy, 2.) Bacillary Angiomatosis: associated with HIV, often confused with Kaposi’s
sarcoma, produces superficial vascular proliferation, fever, chills, headache, 3.) Endocarditis: culture⊖, treat with Azithromycin or Doxycycline, lesion
must be examined microscopically to differentiate it from HHV-8 Kaposi’s Sarcoma (Kaposi’s has lymphocytic infiltrate, B. henselae has neutrophilic
infiltrate)
• Brucella abortus/ovis/suis – small G⊖ bacilli, aerobic, facultative intracellular within macrophages (prevents phagosome-lysosome fusion), virulence
factor is Endotoxin, produces granulomatous response, transmitted via unpasteurized dairy products, direct contact with infected animals, reservoir is
livestock/farm animals, potential bioterrorism agent, associated with veterinarians, slaughterhouse workers, meat-packers, ranchers, eating dairy
products in Mexico or other developing countries, presents with Brucellosis: high undulant fevers (rise during day, decrease during night), chills/profuse
sweating, anorexia, flu-like symptoms, can last months to years, diagnose with culture (hazardous) or serology, treat adults with Rifampin and
Doxycycline, children with Rifampin and TMP-SMX, complications include hepatosplenomegaly, osteomyelitis (chronic infection)
• Francisella tularensis – small G⊖ coccobacilli, facultative intracellular within macrophages, organism enters at site of infection, then travels in
macrophages to reticuloendothelial organs, where it produces caseating granulomas, transmitted from wild animals to Dermacentor tick/deer flies to
humans, from skinning rabbits via traumatic implantation or inhalation, or from contaminated meat, reservoir is wild animals, esp. rabbits, deer,
rodents, potential bioterrorism agent, presentations: 1.) Ulceroglandular Tularemia: transmitted via tick bite, produces black hole in skin, lymph nodes
become swollen, red, and painful, resembles Bubonic Plague, 2.) Pneumonic Tularemia: transmitted via inhalation of organism or spread from skin,
produces pneumonia, 3.) Oculoglandular Tularemia: eye infection, 4.) Typhoidal Tularemia: GI infection, diagnose with serology (culture is hazardous),
treat with Streptomycin
• Pasteurella multocida – small G⊖ bacilli, catalase⊕, oxidase⊕, facultative anaerobe, not facultative intracellular (contrast most other zoonotics),
exhibits bipolar “safety pin” staining (ends stain darker than middle – compare Yersinia species), culture on 5% sheep’s blood agar, virulence factors: 1.)
Endotoxin, 2.) Capsule, transmitted via animal bites, reservoir is the mouths of cats, dogs, and other animals, presentations: 1.) Cellulitis/Local Abscess:
most common cause of wound infection following dog or cat bite, mouse-like odor (indole⊕ species), do not suture wound, as closed environment
promotes growth of organism, may progress to necrotizing fasciitis, 2.) Osteomyelitis, rarely cultured, treat with Penicillin/Amoxicillin + Clavulanic Acid
or Doxycycline, Amoxicillin for cat bites
• Yersinia enterocolitica – G⊖ bacilli, non-lactose fermenting, does not produce H2S, exhibits cold growth, primary virulence factor is Enterotoxin: similar
to E. coli heat-stable toxin, binds to intestinal wall and invades, then proliferates in mesenteric lymph nodes, same mechanism as Salmonella,
transmitted via pet feces (puppies, Campylobacter can also be spread by dog feces), contaminated milk, pork, associated with day care centers and
northern climates, motile at 25°C, non-motile at 37°C, reservoir is zoonotic, stored blood (iron-loving, most common contaminant), presents with
Gastroenteritis: febrile diarrhea with blood and pus (invasive) in infants, mimics Crohn’s Disease or appendicitis in adolescents (RLQ pain due to
mesenteric adenitis and/or terminal ileitis), produces diarrhea in adults, treatment is supportive, Fluoroquinolones, or 3rd gen Cephalosporins
• Yersinia pestis – small G⊖ bacilli, coagulase⊕, facultative intracellular within macrophages, exhibits bipolar “safety pin” staining (ends stain darker than
middle – compare P. multocida), Type 3 secretion system, virulence factors: 1.) F1 Capsule: antiphagocytic, resists destruction within macrophages, 2.) V
 and W Antigens: unique to Yersinia, unknown function, 3.) Endotoxin: may produce DIC, 4.) Exotoxin, 5.) Yersinia-Associated Outer Proteins: cause
macrophage and neutrophil dysfunction by inhibiting phagocytosis and cytokine production, transmitted from rodents to fleas to humans, then from
human to human, reservoir is rats, squirrels, prairie dogs of Southwest US, potential bioterrorism agent, presentations: 1.) Bubonic Plague: hot, red
swollen lymph nodes, esp. inguinal, skin hemorrhages with black discoloration (“black death”), DIC, 2.) Pneumonic Plague: pneumonia from septic
emboli or inhalation of organisms, highly contagious, diagnose with serology or immunofluorescence (culture is hazardous), treat with Aminoglycosides
(Streptomycin) + Tetracycline, killed vaccine available, prevent with animal control

Gram Variable Bacilli – Vaginal

• Gardnerella vaginalis – Gram variable bacilli (pleomorphic), catalase⊖, oxidase⊕, facultative anaerobe, formerly Haemophilus vaginalis, transmitted
endogenously, associated with sexual activity, but not sexually transmitted, reservoir is humans (vagina), flourishes when normal flora disturbed,
especially following decrease in vaginal Lactobacillus or overgrowth of anaerobic vaginal bacteria, presents with Vaginosis: non-inflammatory, non-
painful, grayish-white vaginal discharge with fishy odor, increased pH >4.5 (contrast C. albicans, which has a normal pH), synergistic with Mobiluncus
(aerobe), diagnose with 10% KOH preparation (Amine whiff test, enhances fishy odor), vaginal smear and wet mount, which shows clue cells (vaginal
epithelial cells stippled along outer margins with bacteria), treat with Metronidazole or Clindamycin
Mycobacteria

• Mycobacterium tuberculosis (TB) – G indeterminate rods, acid-fast (Ziehl-Neelsen stain), slow-growing on Lowenstein-Jensen medium, obligate aerobe,
cell wall contains mycolic acids (long branched-chain saturated fatty acids), UV sensitive, produces niacin and heat-sensitive catalase, transmission via
respiratory droplets, associated with HIV, poverty, IV drug use, travel to a developing country, reservoir is humans (lungs), facultative intracellular within
macrophages, virulence factors: 1.) Immune Response: TB produces no toxins, macrophages cause damage, 2.) Cord Factor: inhibits WBC migration,
produces characteristic serpentine growth pattern, induces TNF-α release (TNF-α inhibitors used for Rheumatoid Arthritis, IBS, and Psoriasis
contraindicated in TB, may lead to reactivation), 3.) Tuberculin: surface protein that triggers cell-mediated immunity leading to caseation and
granulomas, also triggers hypersensitivity reaction, 4.) Sulfatides: surface glycolipids, prevents phagosome-lysosome fusion, presentations: 1.) Primary
Tuberculosis: replication within phagosomes of naïve alveolar macrophages, the body mounts a T-cell response and activates macrophages, which
destroy lung tissue, if immune system intact, organisms walled off in Ghon focus (middle or lower lung) or Ghon complex (fibrocavitary lesion,
calcification of middle or lower lobes with or without hilar/mediastinal lymph node involvement), if immune system compromised, symptomatic TB
develops, may produce fibrosis in lungs 2.) Secondary (Reactivated) Tuberculosis: immune system weakened, can no longer contain infection, which
becomes symptomatic and spreads to multiple organ systems (Miliary TB), produces caseating granulomas (granulomas with Langhans giant cells and
necrotic centers), 3.) Pott’s Disease: vertebral osteomyelitis, associated with immunosuppression, esp. HIV, presents with intractable cough (productive
or nonproductive), hemoptysis, weight loss, chills and night sweats, fatigue, loss of appetite, may show upper lobe cavitation on CXR or tuberculoma
with CNS symptoms, diagnose with: 1.) PPD Skin Test: T4, ⊕ test (“seroconversion”) indicates current/active infection, past exposure (but not
necessarily active disease), or BCG vaccine (live attenuated, not given in US), ⊖ test indicates no infection or anergy (immunocompromised,
malnutrition, steroids, sarcoidosis), 2.) QuantiFERON-TB Gold: IFN-γ release assay (IGRA), measures IFN-γ production with exposure to TB antigens, IFN-γ
produced by activated T-cells, no false ⊕ with BCG vaccine, no need for follow up (contrast PPD), 3.) CXR, 4.) MRI: Pott’s disease, reveals granulomatous
paravertebral mass, may also add ESR or CRP, treat with: 1.) Isoniazid monotherapy: if ⊕ PPD but no evidence of active disease on CXR, 2.) Multiple
Drug Regimen: most common treatment, Isoniazid + Rifampin + Pyrazinamide + Ethambutol for 8 weeks, then Isoniazid + Rifampin for the next 18
weeks, add Streptomycin if resistant, 3.) Prophylaxis: Isoniazid for 9 months for patients who test ⊕ but have no symptoms (some regimens add
Rifampin), Resistance Mechanisms: Isoniazid (mutation of catalase-peroxidase, reduces intracellular transformation to active form), Rifampin (mutation
of DNA-dependent RNA polymerase), Streptomycin (mutation of gene for 30S subunit)
• Mycobacterium leprae – mycobacterium, acid-fast bacilli (cell wall contains mycolic acids), obligate aerobe, obligate intracellular, cannot be cultured in
vitro, UV sensitive, transmitted via respiratory droplets, non-motile, reservoir is humans (mucosa, skin, superficial nerves, preference for cool
temperatures), armadillos, presents as spectrum between 2 forms: 1.) Lepromatous Leprosy (LL): diffuse, “leonine facies” (nasal collapse, loss of
eyebrows, lumpy, nodular earlobes), skin hypopigmentation, thickening, and plaques (poorly-demarcated skin lesions on extensor surfaces), regional
motor and sensory loss caused by bacterial invasion of Schwann cells, testicular destruction, blindness, failed cell-mediated immune response (TH2
respond, but TH1 do not), communicable, sensation in extremities completely lost (“glove and stocking pattern”), lepromin skin test ⊖, many bacteria in
tissue (multibacillary), 2.) Tuberculoid Leprosy (TL): limited hypopigmentation and well-demarcated, hairless skin plaques, decreased sensation, strong
cell-mediated immune response (TH1 respond appropriately), not communicable, numbness in extremities, but sensation not totally lost, lepromin skin
test ⊕, few bacteria in tissue (paucibacillary), diagnose with punch biopsy, lepromin skin test (similar to PPD, not used for diagnosis, but to place
patients on disease spectrum, LL patients test ⊖ since they cannot mount a cell-mediated immune response), treatment regimens (difference between
WHO and US due to forms of administration): 1.) Lepromatous Leprosy (Multibacillary): Dapsone (long course, side effects are hemolysis and
methemoglobinemia) + Rifampin + Clofazimine for 12 months (WHO) or 24 months (US), 2.) Tuberculoid Leprosy (Paucibacillary Single Lesion): Rifampin
+ Ofloxacin + Minocycline single dose (WHO) or Dapsone + Rifampin for 12 months (US), 3.) Tuberculoid Leprosy (Paucibacillary No Lesion): Dapsone +
Rifampin for 6 months (WHO) or 12 months (US), 4.) Pediatric: same as multibacillary (WHO), early diagnosis and treatment critical to prevention of limb
loss, prevent with clinical management of active cases, annual evaluation of household contacts, BCG vaccine given at birth provides partial protection in
endemic areas, complications include repeated injuries due to sensation loss, which may lead to limb loss and deformity
 • Mycobacteria Other Than Tuberculosis (MOTTS) – mycobacteria, acid-fast bacilli (cell wall contains mycolic acids), noncontagious transmission,
reservoir is water, soil, cigarettes, associated with Southeastern US, Runyon’s classification divides MOTTS into groups based on pigment formation,
types: 1.) M. avium intracellulare: also known as Mycobacterium Avium Complex (MAC), most common MOTTS, associated with AIDS patient with CD4
<50, common cause of fever of unknown origin, treat with Macrolide (Clarithromycin and Azithromycin) + Ethambutol, but often drug resistant, 2.) M.
kansasii: second most common cause of lung disease from MOTTS, average age of onset is 60, resembles TB, treat with Rifampin + Ethambutol, 3.) M.
scrofulaceum: cervical lymphadenitis in children (“scruffy little kids”), 4.) M. marinum: hand infection in aquarium handlers, diagnose all types with blood
cultures, lymph node biopsy and culture in lymphadenitis, DNA probe to distinguish MOTTS from M. tuberculosis, difficult to treat due to antibiotic
resistance, prevent with Azithromycin prophylaxis in HIV patients with CD4 <50, complications include disseminated MAC, which can be fatal

Spirochetes
• Borrelia burgdorferi – spirochete, microaerophilic, visualized with light microscopy (bigger than other spirochetes) and on Giemsa and Wright stains,
travels from skin to bloodstream to heart, joints, CNS, arthritis caused by immune complex deposition (T3), transmitted via Ixodes scapularis (deer tick,
also a vector for Anaplasma species and Babesia), 24 hour attachment needed for transfer, reservoir is white-footed mouse (larva) and white-tailed deer
(obligatory host, adult), humans an incidental (“dead end” host), associated with late spring/early summer, Northeastern US (named after Lyme,
Connecticut), campers and hikers, presents with Lyme Disease: 3 stages: 1.) Stage 1: erythema chronica migrans (expanding target-shaped rash, appears
within 1 month), pathognomonic, but not always present, flu-like symptoms, 2.) Stage 2: neurologic symptoms (Bell’s palsy, aseptic meningitis), cardiac
symptoms/carditis (AV block, myocarditis), bilateral Bell’s palsy, migratory myalgias/transient arthritis, 3.) Stage 3: chronic migratory polyarthritis (esp.
knees), encephalopathy (memory problems, cognitive slowing, lymphocytic meningitis, may be subtle), diagnose with ELISA with Western blot for
 confirmation, treat: 1.) Early: Doxycycline, Macrolides, 2.) Late: Ceftriaxone, 3.) Pregnant/Lactating Mother/Child <8: Amoxicillin, Cefuroxime, OspA
flagellar antigen vaccine available, but not in US, Note: Borrelia recurrentis causes relapsing fever

• Leptospira interrogans – long, thin spirochete, G⊖ envelope, but too thin to visualize, “question mark-shaped”, hook-shaped ends, aerobic, visualized
on dark-field microscopy (does not appear on light microscopy), no known toxins or virulence factors, enters humans directly through damaged skin or
mucous membranes, transmitted via contact with animal urine, associated with swimming in infected water, exposure to sewer water, water sports
(esp. surfers), tropical regions, esp. Hawai’i, reservoir is animals, presentations: 1.) Leptospirosis: flu-like symptoms (fever, headaches), myalgias (esp.
calves), jaundice, abdominal pain, photophobia with conjunctival suffusion (eyes red, but no exudates/pus), 2.) Weil’s Disease (Icterohemorrhagic
Leptospirosis): severe form of Leptospirosis due to hematogenous spread, fever, hemorrhage, anemia, hepatic and renal damage produce jaundice and
azotemia, diagnose with serology or culture, treat with Penicillin G or Doxycycline
• Treponema pallidum – thin, helical spirochete, G⊖, but not visualized on G stain, too small to be seen on light microscopy, use darkfield microscopy or
fluorescent antibody (DFA) microscopy, obligate pathogen, not intracellular, all syphilis is a vasculitis, infects small vessels and arterioles, damages
ascending aortic arch via destruction of vasa vasorum, may lead to aortic regurgitation due to stretching of ring around aortic valve, transmitted via sex,
motile, crosses placenta (ToRCHeS infection), reservoir is humans (GU tract), presentations (3 stages + Congenital): 1.) Primary Syphilis: painless chancre
with indurated edge due to ischemic necrosis “primary is painless penis”, heals in 3-6 weeks, diagnose with dark-field or fluorescent microscopy (VDRL
⊕ in ~80%), 2.) Secondary Syphilis: “secondary is systemic”, diffuse, copper-colored maculopapular rash on palms and soles (may also be diffuse) weeks
to months after infection, condyloma lata (smooth, moist, painless wart-like white lesions, but flatter than genital warts/condyloma acuminata) in
perianal region, lymphadenopathy, patchy hair loss, highly infectious with many treponemes present, diagnose with VDRL/RPR (nonspecific) or FTA-ABS
(specific), latent Syphilis (⊕ serology without symptoms) may follow, 3.) Tertiary Syphilis: gummas (granulomatous lesions of skin and bones, soft
growths with firm, necrotic center), aortitis (“tree-barking”) leading to stroke without hypertension, neurosyphilis/tabes dorsalis/“general paresis” due
to demyelination of nerves in dorsal column of spinal cord, leading to loss of vibratory sense, proprioception, and discriminatory touch, may also
produce diffuse pain and gate abnormalities due to loss of proprioception (broad-based ataxia, ⊕ Romberg sign), Charcot joints in knees and hips,
Argyll-Robertson pupils (“prostitute pupils”, accommodate but do not react to light), or “luetic” aortic aneurysm due to dilated anulus, diagnose by
testing CSF with VDRL, FTA-ABS, and PCR, 4.) Congenital Syphilis: stillbirth or hydrops fetalis, CN 8 congenital deafness, rhagades (linear scars at angle of
mouth), snuffles (nasal discharge), bone and teeth abnormalities, including saddle nose (sunken appearance), saber shins (tibial bowing), Hutchinson
teeth (notches in teeth with wide spaces between), mulberry molars (too many cusps on molars), short maxilla, also hepatomegaly, rhinitis, rash, treat
mother early in pregnancy (placental transmission typically occurs after 1st trimester), 2 types of screening tests: 1.) VDRL: quantitative, inexpensive, and
widely available, sensitive but non-specific screening test, Rapid Plasma Antigen (RPR) is newer but similar, infection with syphilis results in cellular
damage and release of specific lipids into the bloodstream, including cardiolipin cholesterol lecithin (glycerophospholipid known as
diphosphatidylglycerol, component of inner mitochondrial membrane and bacterial membranes, only antigenic human glycerophospholipid), antibodies
created against cardiolipin, Venereal Disease Research Laboratory (VDRL) test measures these anti-cardiolipin antibodies using beef cardiolipin, note test
is looking for antibodies against a human cellular lipid, not antibodies against Treponema, aggregation of “flocculation” of sample demonstrates
presence of cardiolipin antibodies in patient’s serum, VDRL becomes ⊖ as disease successfully treated, 1% of adults have false ⊕ VDRL (VDRL false
positives: Viruses, e.g. hepatitis, mono, Drugs, Rheumatic Fever, Lupus and Leprosy), T. pertenue also causes false ⊕ VDRL, 2.) FTA-ABS (specific test):
Treponemal Antibody-Absorption test looks for antibodies against Treponema itself, indirect immunofluorescence of patient serum mixed with whole
killed T. pallidum, increased specificity, ⊕ earlier, remains ⊕ for life, used to confirm ⊕ screening test, interpreting the combination of tests: VDRL+ and
FTA+: active infection, VDRL+ only: probably a false ⊖, FTA+ only: successfully treated, treat with IM Benzathine Penicillin for primary and secondary
disease, IV Penicillin G (“G for gummas”) for congenital and tertiary disease, if allergic to Penicillin, desensitize then use Penicillin, prognosis good if
treated early, complications of late syphilis cannot be cured, prevent using condoms, screening at-risk groups, e.g. MSM, history of incarceration,
commercial sex workers, pregnant women, complications seen in tertiary syphilis include aortic insufficiency, tabes dorsalis, general paresis of the
insane, complications of treatment include the Jarisch-Herxheimer reaction: dying organisms release LPS triggering cytokine release, presents with fever,
chills, headache, and myalgias hours after treatment
 • Treponema pertenue – spirochete, not sexually transmitted, most prevalent in the tropics, presents with Yaws: infection of bone, joints, skin, keloids
during healing may lead to severe limb deformities

Chlamydiaceae
• Chlamydia trachomatis – ovoid bacteria, obligate intracellular parasite (cannot make ATP, requires cells for growth in laboratory), does not produce
spores, but elementary bodies resemble spores when released into the host, membrane contains LPS, but lacks peptidoglycan layer between
membranes, does not G stain (no muramic acid in cell wall), visualize cytoplasmic inclusions on Giemsa or fluorescent antibody stain, 2 forms: 1.)
Reticulate Body: intracellular, metabolically active, replicating form (“reticulate replicates”) via binary fission, inclusion bodies (collections of reticulate
bodies) visible in cytoplasm under light microscopy, 2.) Elementary Body: infectious, inactive, intracellular form, small, dense (“Elementary is Enfectious
and Enters the cell via Endocytosis”), infection of mucosal surfaces leads to granulomatous response and damage, multiple serotypes, each with a
characteristic associated disease, cell wall does not contain peptidoglycan, thus β-lactam antibiotics ineffective, transmitted via sex, passage through
birth canal, trachoma transmitted via hand-to-eye contact and flies, associated with sexually active teens and young adults, non-motile, reservoir is
humans (genital tract, eyes), presentations: 1.) Chlamydia: most common bacterial STD in US, though herpes and HPV more common overall, serotypes
D-K, initial presentation is subacute (often undiagnosed), or with cervical motion tenderness (“chandelier sign”), purulent cervical/penile discharge
(sometimes described as “watery”), complications include non-gonococcal urethritis, cervicitis, salpingitis, PID, infertility, ectopic pregnancy,
conjunctivitis, Reactive Arthritis (Reiter Syndrome): seronegative spondyloarthropathy characterized by triad of urethritis, conjunctivitis/uveitis, arthritis
(“can’t see, can’t pee, can’t bend a knee/climb a tree”), 2.) Congenital Chlamydia: serotypes D-K, conjunctivitis (transmitted to neonates during birth,
most common cause of conjunctivitis in 2nd week of life, contrast N. gonorrhoea conjunctivitis, which occurs within first 5 days of life), pneumonia with
staccato cough, 3.) Lymphogranuloma Venereum: serotypes L1, L2, L3 (“L” for lymphogranuloma), infection of lymph nodes, esp. inguinal, prevalent in
Africa, Asia, and South America, begins as painless genital ulcers on genital mucosa, rectal strictures, progresses within weeks to months to painful,
swollen draining inguinal lymphadenopathy (buboes) that can lead to genital elephantiasis, granulomatous and neutrophilic inflammation, diagnose with
serology using complement fixation, enzyme immunoassay, Nucleic Acid Amplification Test (NAAT), PCR, ⊕ Frei test (now obsolete), distinguish from
granuloma inguinale (donovanosis) caused by Calymmatobacterium granulomatis, where the papule becomes a painless, exophytic mass, 4.) Trachoma:
most common cause of preventable blindness, associated with Africa, serotypes A, B, Ba, C, presents with follicular conjunctivitis with in-turned
eyelashes, treat with Azithromycin (one-time treatment) or Doxycycline, treatment of N. gonorrhoeae with Ceftriaxone monotherapy often inadequate
as it does not cover possible Chlamydia coinfection, Erythromycin eyedrops given at birth as prophylaxis against Chlamydia and N. gonorrhoeae, but PO
form must be given for active Chlamydia conjunctivitis

• Chlamydophila pneumoniae – ovoid, weakly G⊖ obligate intracellular bacteria similar to C. trachomatis, associated with school-aged children and the
elderly, atherosclerosis and coronary artery disease (unknown mechanism), presents with Atypical “Walking” Pneumonia (M. pneumoniae the most
common cause), sputum shows intracytoplasmic inclusions, treat with Macrolides and Tetracyclines
 • Chlamydophila psittaci – small weakly G⊖ obligate intracellular bacteria similar to C. trachomatis, transmitted via poultry, turkeys, parrots and
parakeets and several other birds, reservoir is birds, presentations: 1.) Respiratory Psittacosis: acute onset of atypical pneumonia (“walking pneumonia”)
fever, headache, malaise, muscle aches, dry hacking cough, and bilateral interstitial pneumonia, 2.) Systemic Psittacosis: 1st Week: symptoms mimic
Typhoid Fever with prostrating high fevers, joint pains, diarrhea, conjunctivitis, nose bleeds, low serum WBCs, rose spots (Horder’s spots), headache,
splenomegaly, epistaxis, 2nd Week: resembles acute bacteremic pneumococcal pneumonia with continuous high fevers, cough, and dyspnea, CXR shows
patchy infiltrates or diffuse whiteout of lung fields, BAL shows Leventhal-Cole-Lillie bodies within macrophages, treat with Doxycycline

Rickettsiae
• Anaplasma phagocytophilum – obligate intracellular bacteria, transmitted via Ixodes tick, presents with Human Granulocytic Anaplasmosis: flu-like
symptoms, severe headache, myalgia, flu-like symptoms, nausea/vomiting, morulae (mulberry-like inclusions) within granulocytes (contrast Ehrlichia,
which has morulae in monocytes), but NO rash (contrast Rickettsia species), diagnose with PCR (virtually indistinguishable from Ehrlichia), treat with
Doxycycline

• Coxiella burnetii – G⊖ bacteria, but too small to G stain, aerobic, obligate intracellular (cannot make ATP, needs CoA and NAD+), invades endothelial
cells producing a vasculitis, transmitted via aerosolized cattle/sheep amniotic fluid or placenta (no vector), associated with farmers, veterinarians, esp.
one who delivered baby livestock and was exposed to placental secretions, reservoir is animal feces, endospore form can survive for a long time outside
host, resists heat and drying, presentations: 1.) Acute Q Fever: mild pneumonia, headache with retroorbital pain and photophobias, fever, but NO rash
(contrast Rickettsia species), 2.) Chronic Q Fever: infective endocarditis in patient with valvular disease, may manifest in patient without previous
symptomatic infection, Weil-Felix ⊖ (contrast Rickettsia – patient serum mixed with Proteus antigens, anti-Rickettsial antibodies cross-react and
agglutinate, no longer used), serum shows normal leukocyte count, thrombocytopenia, elevated ALT and AST, treat with Doxycycline, do not wait for lab
confirmation, complications include hepatitis, prevent with pasteurization of milk, acellular vaccine available, only given to at-risk individuals (e.g.
veterinarians and farmers)
• Ehrlichia chaffeensis/ewingii – obligate intracellular bacteria, transmitted via Amblyomma americanum tick (Lone Star tick), reservoir is ticks and deer,
presents with Rocky Mountain Spotted Fever-Like Illness: flu-like symptoms, leukopenia, thrombocytopenia, morulae (mulberry-like inclusions) within
monocytes (contrast Anaplasma, which has morulae in granulocytes), but NO rash (contrast Rickettsia species), diagnose using blood film with Giemsa
stain or with serology, treat with Doxycycline

• Rickettsia prowazekii/rickettsii/typhi – G⊖ coccobacilli, but too small to G stain, aerobic, obligate intracellular (cannot make ATP, needs CoA and
NAD+), invades endothelial cells producing a vasculitis, transmitted via arthropod (vector is disease specific), reservoir is rodents and dogs, all Rickettsial
diseases exhibit classic triad of headache, fever, and rash, presentations: 1.) Rocky Mountain Spotted Fever (RMSF): caused by R. rickettsii, transmitted
via Dermacentor tick (directly through the bite), endemic to South Atlantic states of US despite name (esp. North Carolina), presents after 2-14 day
incubation period with petechial rash caused by small hemorrhages that starts distally on palms and soles and migrate proximally to wrist, ankles, then
trunk (“You drive CARS with your palms and soles: Coxsackievirus A, Rocky Mountain Spotted Fever, Secondary Syphilis”), headache, fever, myalgias,
may progress to hepatosplenomegaly, thrombocytopenia, and DIC, 2.) Endemic Typhus: caused by R. typhi, transmitted via fleas, 3.) Epidemic Typhus:
caused by R. prowazekii, transmitted via human body louse, which defecates near feeding sites, scratching introduces it into the blood (compare T.
cruzi), rapidly spreads throughout population, associated with military recruits and POW camps, presents with myalgias, arthralgias, pneumonia,
encephalitis with dizziness and confusion, coma, for both Endemic and Epidemic Typhus, rash starts centrally and spreads distally without involving
palms, soles, or head (“Rickettsia on the wrists, Typhus on the trunk”), diagnose with serological IFA test, Weil-Felix ⊕ (contrast Coxiella – patient serum
mixed with Proteus antigens, anti-Rickettsial antibodies cross-react and agglutinate, no longer used), treat with Doxycycline, do not wait for lab
confirmation
Mycoplasmataceae
• Mycoplasma pneumoniae – small, free-living bacteria, does not G stain, produces mulberry-shaped colonies on media containing sterols (requires
cholesterol to grow), culture on Eaton’s agar (“fried egg” appearance), no cell wall, plastic, pleomorphic shape with cholesterol-containing membrane
(unique among bacteria), primary virulence factor is Protein P1: used to attach to respiratory epithelium, then invades host cells, once inside causes
damage by metabolic alteration (resource competition), their adherence inhibits ciliary function, they act as superantigen producing IL-1, IL-6, TNF-α and
triggering inflammation, produce H2O2 and superoxides that damage respiratory epithelium, cold agglutinins (IgM that binds RBCs at low body
temperature, also present in EBV and hematologic malignancies) activate complement system, transmitted via respiratory droplet, reservoir is humans
(respiratory tract), presentations: 1.) Atypical “Walking” Pneumonia: most common cause in young adults (<30), esp. among college students, military
recruits in close contact, or prisons, insidious onset, produces pharyngitis, headache, persistent, non-productive, dry hacking cough, CXR shows diffuse
reticulonodular/interstitial infiltrate, looks worse than patient feels, findings may be more consistent with viral pneumonia, 2.) Bronchitis: most common
cause in young adults, 3.) Stevens-Johnson Syndrome (Erythema Multiforme): severe skin reaction, incidence about 7%, diagnose with ELISA or
immunofluorescence, cold-agglutinin ⊕ (non-specific), treat with Tetracyclines, Erythromycin, or Fluoroquinolones, avoid β-lactams (no cell wall)

• Ureaplasma urealyticum – T-strain mycoplasma bacteria, does not G stain, produces urease to break down (“split”) urea, transmission is endogenous,
reservoir is humans (vagina), normal flora of vagina in 60% of women, presentations: 1.) Urethritis, 2.) Prostatitis, 3.) Renal Calculi, treat with
Erythromycin or Tetracyclines
DNA Viruses Introduction
• Introduction – “HHAPPPPy viruses”: Hepadna, Herpes, Adeno, Pox, Parvo, Papilloma, Polyoma, all double stranded except Parvovirus (single stranded),
all have linear genomes except Papilloma and Polyoma (circular, supercoiled) and Hepadna (circular, incomplete), all icosahedral except Pox (complex),
all replicate in nucleus except Pox (carries its own DNA-dependent RNA polymerase)

DNA Viruses – Enveloped

• HSV Type 1 – Herpesvirus, linear ⊕-sense dsDNA, enveloped (via budding off nuclear membrane), transmitted via respiratory secretions and saliva,
initial infection occurs in mucosal epithelium, virus travels up ganglion resulting in lifelong latent infection within trigeminal ganglion, stress triggers
reactivation, similar to HSV-2, presentations (Rule of Thumb: “HSV-1 Infections are above the waste”): 1.) Gingivostomatitis/Herpes Labialis: cold
sores/lip lesions, clear vesicles atop an erythematous base (“dew drops on a rose petal appearance”), 2.) Keratoconjunctivitis: serious, warrants
ophthalmological evaluation, serpiginous corneal ulcers on fluorescein-stain slit-lamp exam, 3.) Temporal Lobe Encephalitis: inferior and medial
temporal lobes, most common cause of sporadic encephalitis in US, produces mental status changes, amnesia, seizures, coma, death, edema and
hemorrhagic necrosis, predilection for temporal lobes produces classic symptoms of aphasia (speech areas), olfactory hallucinations (olfactory cortex),
personality changes (amygdala), CSF shows mildly elevated protein and RBCs, diagnose with CSF PCR, 4.) Meningitis: adolescents and adults, 5.) Herpetic
Whitlow: Herpes rash on the finger, associated with dentists, 6.) Erythema Multiforme: skin hypersensitivity reaction that appears 1-2 weeks after
infection, produces acute, mucocutaneous disease with classic target-shaped lesions with dusky center in a symmetric distribution, moves from hands
and feet centrally, arises in palms/soles, backs of hands and feet, extensor surfaces of forearms and legs, diagnose with PCR, Tzanck smear (outdated –
“Tzank goodness I don’t have Herpes”): smear of opened skin vesicle, used for HSV-1, HSV-2, VZV, ⊕ if multinucleated giant cells, Cowdry type A Bodies
(eosinophilic intranuclear inclusions also in HSV-2, VZV, CMV, contrast cytoplasmic inclusions of Poxviruses), treat with Acyclovir (activated by viral
thymidine kinase) or Valacyclovir
• HSV Type 2 – Herpesvirus, linear ⊕-sense dsDNA, enveloped (via budding off nuclear membrane), transmitted via sex, congenitally (ToRCHeS infection),
initial infection occurs in mucosal epithelium, virus travels up ganglion resulting in lifelong latent infection, stress triggers reactivation, similar to HSV-1,
presentations (Rule of Thumb: “HSV-2 Infections are below the waste”): 1.) Herpes Genitalis: painful inguinal lymphadenopathy, clusters of genital
vesicals with erythematous base, viral latency within sacral nerve ganglia, produces systemic symptoms, e.g. fever, malaise, myalgias, 2.) Neonatal
Herpes: transmitted via passage through birth canal (intrapartum), produces severe infection with encephalitis and herpes lesions, may also be caused
by HSV-1, but less common, 3.) Meningitis: adolescents and adults, diagnose with PCR, Tzanck smear (outdated – “Tzank goodness I don’t have Herpes”):
smear of opened skin vesicle, used for HSV-1, HSV-2, VZV, ⊕ test reveals multinucleated giant cells, Cowdry type A Bodies (eosinophilic intranuclear
inclusions also in HSV-1, VZV, CMV, contrast cytoplasmic inclusions of Poxviruses), viral culture of skin/genitalia, treat/prophylaxis with Acyclovir
(activated by viral thymidine kinase) or Valacyclovir (preferred due to once daily dosing and good bioavailability)
• HSV Type 3/Varicella Zoster Virus (VZV) – Herpesvirus, linear ⊕-sense dsDNA, enveloped (via budding off nuclear membrane), transmitted via
respiratory secretions, initial infection occurs in mucosal epithelium, virus travels up ganglion resulting in lifelong latent infection in trigeminal and dorsal
root ganglia, stress or immunocompromised state triggers reactivation with a dermatomal distribution, rarely crosses midline (if so, indication of
disseminated VZV due to immunocompromise), presentations: 1.) Chickenpox: children, presents with asynchronous rash (contrast synchronous rash of
smallpox) that begins centrally and spreads to face and limbs, clear vesicles atop an erythematous base (“dew drops on a rose petal appearance”), fever,
pharyngitis, malaise, 2.) Shingles: adults >50 or younger adults if immunocompromised, pain and vesicles restricted to a single dermatome, usually on
torso or face (trigeminal), though may occasionally occur on lower limb and in children, caused by reactivation of latent infection, complications include
post-herpetic neuralgia (pain after rash subsides), 3.) Encephalitis: children and adults, esp. immunocompromised, diagnose with CSF PCR, 4.)
Pneumonia: children and adults, 5.) Herpes Zoster Ophthalmicus: vision loss if V1 affected, immunocompromised patient, 6.) Congenital Varicella
Syndrome: ToRCHeS infection, limb hypoplasia, cutaneous dermatomal scarring, blindness, diagnose with PCR, Tzanck smear (outdated – “Tzank
goodness I don’t have Herpes”): smear of opened skin vesicle, used for HSV-1, HSV-2, VZV, ⊕ test reveals multinucleated giant cells, Cowdry type A
Bodies (eosinophilic intranuclear inclusions also in HSV-1, HSV-2, CMV, contrast cytoplasmic inclusions of Poxviruses), treat children >12, adults, and
immunocompromised with Acyclovir (activated by viral thymidine kinase), Famciclovir or Valacyclovir for shingles, Acetaminophen for fever, do not give
ASA due to increased risk of Reye’s Syndrome, prognosis good to excellent in children, more severe course in adults, prevent via postexposure
prophylaxis (VariZIG indicated following exposure in pregnant women with no evidence of immunity, neonates born to infected mothers), live
attenuated vaccine available, given at 12-15 months, then 4-6 years, catch-up doses given in adolescents and adults (recommended if >60),
contraindicated in pregnant women or immunodeficiency states (but can give to HIV patient with CD4 >200), complications include secondary bacterial
infection in children, pneumonia in adults, meningitis (rare), encephalitis may be seen in children and immunosuppressed, Reye’s syndrome
• Epstein-Barr Virus (EBV, HHV-4) – Herpesvirus (γ, HHV-4), linear ⊕-sense dsDNA, enveloped (via budding off nuclear membrane), invades B-cells, binds
to CD21 (receptor for complement Cd3) and acts as mitogen (substance that induces mitosis), produces Downey cells (atypical reactive cytotoxic T-cells,
may be 70% of WBC count), oncogenicity caused by expression of latency-associated membrane protein-1 (LMP-1), transmitted via respiratory
secretions (“kissing disease”), reservoir is humans (B-cells), common in teens and young adults (peak incidence at 15-20 years old), presentations: 1.)
Infectious Mononucleosis: fever, splenomegaly (hepatomegaly less common), pharyngitis with white exudates, lymphadenopathy, esp. posterior cervical
nodes (generalized lymphadenopathy also possible), distinguish from Strep pharyngitis (EBV usually asymptomatic in children, treatment with
Amoxicillin/Ampicillin produces maculopapular rash, which is not an allergic reaction), 2.) Oral Hairy Leukoplakia: AIDS, CD4 <400, benign, white lesions
on lateral borders and dorsum of tongue, resembles Candida, but cannot be scraped off, increased thickness of stratum spinosum, perinuclear
vacuolization of squamous epithelial cells (koilocytic change), 3.) Non-Hodgkin Lymphoma: CNS lymphoma, occurs in brain, late complication of HIV,
lethargy, headache, focal neurologic symptoms and signs, seizures and mental status changes, microscopic dense infiltrates of lymphocytes with
irregular nuclei, 4.) Hodgkin Lymphoma: esp. mixed cellularity type, 5.) Burkitt’s Lymphoma: endemic type, very aggressive cancer of the mandible,
maxilla, or abdomen, 6.) Diffuse Large B-Cell Lymphoma, 7.) Nasopharyngeal Carcinoma: Asian patient, 8.) CNS Lymphoma: HIV patients, 9.) Post-
Transplant Lymphoproliferative Disorder: transplant patients, serum shows marked lymphocytosis (>50%), peripheral smear shows Downy Type 2
atypical cytotoxic T-cells/NK-cells (larger, more cytoplasm, nucleoli), elevated ALT/AST, diagnose clinically, with monospot test (EBV stimulates
heterophile IgM antibody production, which cause agglutination of sheep/horse RBCs), treatment is symptomatic, avoid contact sports for 1 year
following infection due to enlarged spleen
• Cytomegalovirus (CMV, HHV-5) – Herpesvirus (β, HHV-4), linear ⊕-sense dsDNA, enveloped (via budding off nuclear membrane), latency in
mononuclear cells, transmitted congenitally (ToRCHeS infection), via transfusion, sexual contact, saliva, urine, breast milk, transplantation (esp. lung
transplants, prophylaxis with Valganciclovir), presentations: 1.) Mononucleosis: most common infection in immunocompetent, ⊖ monospot test, 2.)
Cytomegalic Inclusion Disease: most common in utero infection in US, highest risk to fetus during 2nd trimester (may cause hydrops fetalis), transmission
risk highest during 2nd trimester, 85% asymptomatic at birth including normal hearing, mother asymptomatic or has mono symptoms, neonate presents
with jaundice, hepatosplenomegaly, thrombocytic purpura, petechiae (“blueberry muffin rash”, compare congenital Rubella), hearing loss (most
common cause of non-hereditary congenital sensorineural deafness, lack of response to loud stimulus), seizures, microcephaly, intracranial
(periventricular or parenchymal) calcifications, ventriculomegaly, mental retardation (most common cause from viral infection), 3.) CMV Retinitis: AIDS,
CD4 <50, “cotton wool spots” on funduscopic exam, “pizza pie” retinopathy, blind spots, flashing lights, vision loss, typically unilateral, may become
bilateral if untreated, 4.) CMV Esophagitis: linear ulcerations (singular, deep, linear, contrast Herpes esophagitis which has multiple shallow lesions), 5.)
CMV Colitis: ulcerated colonic walls produce bloody diarrhea in immunosuppressed patients, 6.) Pneumonia: immunocompromised, transplant patients,
detect via buffy coat culture incubated with fluorescent anti-CMV antibodies, 7.) Nosocomial Infection: neonates in nursery, peripheral smear shows
cells with owl-eye inclusions, ⊖ monospot test, Cowdry type A Bodies (eosinophilic intranuclear inclusions also in HSV-1, HSV-2, VZV, contrast
cytoplasmic inclusions of Poxviruses), treat with Ganciclovir or Foscarnet if virus has UL97 gene mutation (resistant to Ganciclovir), complications
include progressive hearing loss (15% of non-symptomatic patients), typically unilateral but may be bilateral
• HHV Type 6 and 7 – Herpesvirus, linear ⊕-sense dsDNA, enveloped (via budding off nuclear membrane), transmitted via saliva, replicates in
mononuclear CD4⊕ T-cells, may cause immunosuppression, presents with Roseola Infantum (Exanthem Subitum, 6th Disease): children (6 months–2
years), high fever for 4 days that causes febrile seizures followed by diffuse, macular, lacy rash on chest and trunk, but sparing the face (contrast measles
rash, which occurs at the same time as the fever), diagnose clinically, self-limiting, treat symptomatically with cooling measures and fluids (“Roseola:
fever first, Rosie cheeks later”)

• HHV Type 8 – Herpesvirus, linear ⊕-sense dsDNA, enveloped (via budding off nuclear membrane), produces erythematous, violaceous lesions on the
nose, extremities, and mucous membranes, may be a plaque, patch, macule, or nodule, arises from primitive vascular-forming mesenchymal cells, virus
activates vascular endothelial growth factor (VEGF) producing angiogenesis, which produces violaceous color, transmitted via sex, saliva (kissing),
transplants, associated with MSM, immunosuppression, esp. AIDS, elderly Russian men, patients from endemic African regions, presentations: 1.)
Cutaneous Kaposi’s Sarcoma: papular brown, red, purple, or black lesions, 2.) Mucosal Kaposi’s Sarcoma: most commonly hard palate, may appear in GI
tract, 3.) Primary Effusion Lymphoma: B-cell lymphoma, biopsy shows lymphocytic inflammation, lesion must be examined microscopically to
differentiate it from B. henselae bacillary angiomatosis (Kaposi’s has lymphocytic infiltrate, B. henselae has neutrophilic infiltrate), diagnose clinically, via
serology, or PCR, treat with ARVs if patient is immunosuppressed, otherwise no treatment, may be fatal in children
• Hepatitis B – Hepadnavirus, circular ⊕-sense dsDNA, enveloped icosahedral capsid, progresses from partially dsDNA to intermediate ssRNA to fully
dsDNA (upon entry into nucleus, polymerase completes partial dsDNA, host RNA polymerase transcribes mRNA from viral DNA to make viral proteins,
viral DNA polymerase then reverse transcribes viral RNA to DNA, which is genome of progeny virus), replicates in nucleus and cytoplasm, DNA
polymerase (reverse transcriptase) within virion (only Hepatitis virus that has one) has both DNA-dependent and RNA-dependent activities, virus is large,
called a Dane particle (“B is Big like a great Dane”), infected hepatocytes have granular eosinophilic (“ground glass”) appearance due to deposition of
HBsAg in cytoplasm, ballooning degeneration, hepatocyte necrosis, and portal inflammation, pathogenic mechanisms: 1.) Proliferative Phase: viral
antigens expressed on hepatocyte surface, host CD8⊕ T-cells destroy infected hepatocytes (virus does not have cytopathic effect – host immune system
causes the damage), 2.) Integrative Phase: HBV DNA integrated into host genome, risk of HCC remains even after host mounts successful antibody
response, 3.) Immune Complex Deposition: HBsAg and antibodies, produces arthritis, skin damage, and renal insufficiency, transmitted parenterally via
contact with body fluids (esp. in healthcare workers from needle sticks or IV drug users), sex, or perinatally, reservoir is humans (all body fluids),
asymptomatic carrier state possible (up to 3 month incubation period), presentations: 1.) Acute Hepatitis: long asymptomatic incubation period (6-8
months), most common form (>95%) is acute hepatitis with complete resolution, 2.) Fulminant Hepatitis: severe acute hepatitis with rapid hepatic
destruction, 3.) Chronic Hepatitis: may become asymptomatic carrier (antibodies develop, liver is never damaged, still contagious), chronic-persistent
hepatitis, chronic active hepatitis (acute hepatitis lasting longer than 6-12 months), co-infection with HDV, 4.) Primary Hepatocellular Carcinoma: HBV
DNA incorporated into host hepatocyte DNA, triggering malignant growth, liver cell hyperplasia via HBV X protein (HBx) that interferes with p53, 5.)
Cirrhosis: permanent liver scarring and nodular fibrosis, 6.) Congenital Hepatitis: perinatal infection possible if mixing of blood during delivery, 20%
chance of infection if mother is HBeAg ⊖, 95% chance if HBeAg ⊕, higher risk if mother became infected in 3rd trimester, ALT normal early, vertical HBV
transmission may cause hepatocellular carcinoma at age 20-40, 90% chance of becoming chronic (contrast 5-10% chance in adults), mortality 1-2%,
extrahepatic (mostly renal) manifestations: 7.) Systemic: prodromal serum sickness-like illness with rash and arthralgias, 8.) Polyarteritis Nodosa:
systemic vasculitis affecting medium to small arteries, “beads-on-a-string” appearance, presents as reduced GFR (increased creatinine) and HTN, 9.)
Membranous Glomerulonephritis: thick glomerular basement membrane, 10.) Membranoproliferative Glomerulonephritis: deposits in mesangium
extending into glomerulus producing “tram-track” appearance, use liver enzymes to distinguish viral hepatitis (ALT>AST, levels fall once acute phase is
over, but not always back to normal) from alcoholic hepatitis (AST>ALT), 3 antigen-antibody diagnostic parameters: Surface (HBsAg), Core (HBcAg),
Soluble Component of Core (HBeAg), chronological sequence (listed in order of appearance): 1.) Surface Antigen – HBsAg: viral surface antigen (specifies
whether patient is diseased or immune), patients who have it have the disease (chronic, acute, or asymptomatic carrier), precedes onset of symptoms
and liver enzyme elevation, 2.) Soluble Component of Core Antigen – HBeAg: soluble component of viral core (species how infective patient is), patients
who have it are very infective (“Increased E means Enfectious”) and symptomatic, 3.) Core Antigen – HBcAg: viral core antigen (specifies how long the
 infection has been present), antibodies not protective, but reveal stage of infection, seen during “window phase” (active infection, anti-HBsAg beginning
to bind HBsAg, so that neither are detectable, however HBcAg is detectable), 4.) Core Antigen – IgM anti-HBcAg: IgM antibody against viral core antigen
(specifies how long the infection has been present), indicates presence of new infection, arises together with IgG anti-HBcAg, but fades after initial
infection, most specific marker for diagnosis of acute HBV infection because it persists during “window phase”, 5.) Core Antigen – IgG anti-HBcAg: IgG
antibody against viral core antigen (specifies how long the infection has been present), indicates presence of old infection, arises together with IgM anti-
HBcAg, persists after initial infection, 6.) Soluble Component of Core Antigen – anti-HBeAg: antibody against soluble component of viral core (species
how infective patient is), patients who have it have low infectivity, 7.) Surface Antigen – Anti-HBsAg: antibody against viral surface antigen (specifies
whether patient is diseased or immune), patients who have it are immune or cured (no active disease present), use antibodies to distinguished
immunized (anti-HBsAg only) from recovered patient (anti-HBsAg, IgG anti-HBcAg, possibly also anti-HBeAg), treat with Interferon Alfa-2b, Pegylated
Interferon Alfa-2a (Peginterferon) (flu-like side effects), nucleoside analogues (e.g. Lamivudine), Adefovir, Tenofovir, Entecavir, Telbivudine, relapse
possible with all available treatments, recombinant vaccine available containing HBsAg (antigen only without DNA or capsid), given in 3 stages to all
infants (birth, 1-2 months, 6-18 months), adolescents, high-risk populations (e.g. healthcare workers, IV drug users), individuals with other risk factors
for liver disease (e.g. Hepatitis C), recommended for household contacts of HBV patients, donated blood screened for virus, infants born to infected
mothers may also receive passive immunization with HBV vaccine and immunoglobulin at birth (usually transmitted during delivery, HBeAg⊕, >90%
chance of acquiring infection and of developing chronic HBV – contrast adults with <5% chance and children with 20-30% chance of progression to
chronic form)
• Hepatitis B Surface Markers and Infectivity

Infectious Phase HBsAg HBeAg Anti-HBc IgM Anti-HBc IgG Anti-HBs Anti-HBe Comments
Acute HBV   
Window Period   HBsAg/Anti-HBs make each other undetectable
Chronic HBV (very infective)   
Chronic HBV (less infective)    Anti-HBe diminishes infectivity
Recovery    Anti-HBs + Anti-HBe
Immunized  Only Anti-HBs
• Poxvirus – linear ⊕-sense dsDNA, enveloped, replicates in cytoplasm, large (largest DNA virus), molluscum bodies (eosinophilic cytoplasmic inclusion
bodies), replicates in dermis, transmitted via direct contact, fomites, sex, reservoir is humans, associated with AIDS patients, young adults in contact
sports (e.g. wrestling), presents with Molluscum Contagiosum: 1-2 mm flesh-colored, dome-shaped (raised with central dimple, “umbilicated”) lesions,
benign, single (usually adults via sexual transmission) or multiple (suggests patient is immunosuppressed, esp. HIV), arises anywhere except palms and
soles, commonly on trunk, axilla, antecubital fossae, popliteal fossae, treat with Ritonavir or Cidofovir if immunocompromised, otherwise self-limiting
 • Variola – Poxvirus, linear ⊕-sense dsDNA, enveloped, replicates in cytoplasm, large (largest DNA virus), Guarnieri bodies (Type B, intracytoplasmic
acidophilic inclusion bodies within epithelial cells, represent replication sites), dumbbell-shaped core, makes its own envelopes rather than acquiring
them from budding off nucleus or cell membrane, contains DNA-dependent RNA polymerase (RNA polymerase that can read DNA, can make its own
DNA polymerase), following inhalation, virus disseminates through lymphatics leading to viremia and infection of skin and organs, transmitted via
respiratory droplets, reservoir is humans, no animal reservoir due to facilitated eradication, presents with Smallpox: flu-like symptoms for 2-4 days,
synchronous rash that begins in mouth and spreads to body within 24 hours, progress from macules to papules, “pearls of pus”, contrast smallpox (SP)
with chicken pox (CP) (SP: synchronous lesions vs. CP: asynchronous lesions, SP: deep lesions vs. CP: superficial lesions, SP: pox on face vs. CP: pox on
chest), no treatment, live attenuated vaccine available, first vaccine ever developed, Edward Jenner realized milkmaids did not get disease and deduced
the cross-protective effect of cowpox antibodies (gained from contact with infected udders), 30% mortality, survivors scarred for life, virus eradicated in
1977 because vaccine conferred lasting immunity, smallpox only infects humans, only 1 serotype, all infections clinically obvious (no hidden carrier state)

DNA Viruses – Non-Enveloped

• Adenovirus – Adenovirus (~50 serotypes), linear ⊕-sense dsDNA, non-enveloped/naked capsid (largest non-enveloped virus), primary virulence factor is
Penton Fibers: fibers associated with viral capsid that allow attachment to host cell and are also toxic to it, virus produced in permissive host,
transformed in non-permissive host, transmitted via direct contact, respiratory droplets, fecal-oral route, associated with children, military recruits,
swimming pools, ubiquitous reservoir (humans and animals), presentations: 1.) Acute Respiratory Disorder (ARD)/Pneumonia: young adults, highest
incidence in spring and winter, 2.) Pharyngoconjunctivitis: sore throat (most common cause of adenoiditis, tonsillitis), nonpurulent conjunctivitis, fever,
associated with swimming pools, 3.) Epidemic Keratoconjunctivitis: inflammation of both cornea and conjunctiva, “pink eye”, associated with shipyards
and foreign bodies in eye, 4.) Gastroenteritis: associated with day cares, but Rotavirus more common, 5.) UTI/Hemorrhagic Cystitis: most common viral
acute hemorrhagic cystitis in children, esp. boys, presents with gross hematuria, 6.) Intussusception: children, presents with “currant jelly” stool,
diagnose via viral culture (slow but may isolate pathogen) or PCR (fast), self-limiting, live oral enteric-coated vaccine available, given to high-risk groups,
esp. military recruits, infection control includes contact and droplet precaution, chlorination of swimming pools
• Parvovirus B19 – linear ⊖-sense ssDNA (only linear ssDNA virus), non-enveloped/naked icosahedral capsid (smallest icosahedral virus), replicates in
nucleus, immune complex deposition causes erythema infectiosum rash and arthralgias, interferes with erythroid progenitor cells (replicates in bone
marrow, targets P antigen on erythroid precursors (globoside), causes hemolysis, leads to crises in SCD), transmitted via respiratory droplets, fomites,
across placenta (ToRCHeS infection), reservoir is humans (respiratory tract), associated with children (4-12), immunocompromised, presentations: 1.)
Erythema Infectiosum (Fifth Disease): low-grade fever and flu-like symptoms lasting 1 week, “slapped cheek/face” indurated rash that travels down body
in lace-like, reticular pattern (contrast Roseola, which has high grade fever and febrile seizures), 7-10 day incubation period, 2.) Arthralgias: mimics RA
but self-resolving, presents with symmetric involvement of PIP, metacarpal, knee, ankle, associated with adults, “school teacher who becomes ill with
joint pain, arthritis, and edema,” 3.) Aplastic Crisis: associated with SCD, adipose replaces RBC progenitors producing pure RBC aplasia, cobweb
appearance in bone marrow, 4.) Fetus/Pregnant Woman: fluid buildup in fetus produces hydrops fetalis, may cause anemia or CHF in fetus (also occurs
in α-Thalassemia if only Hb barts produced), may lead to spontaneous abortion, mother presents with flu-like symptoms, bone marrow smear with
Giemsa stain shows giant pronormoblasts, with H&E shows circular intranuclear inclusions, self-limiting, use immunoglobulin with transfusion for
aplastic crisis
• BK Virus – Polyomavirus (BK the initials of renal transplant patient in whom it was first isolated), circular dsDNA, non-enveloped/naked capsid, unknown
method of transmission, up to 80% of population infected, presentations: 1.) Primary BK Infection: asymptomatic or mild respiratory illness with fever,
2.) Renal Infection: reactivates in immunosuppression, esp. kidney or bone marrow transplant, presents with nephropathy (renal failure), hemorrhagic
cystitis, increased creatinine, renal tubular and inflammatory cells in urine, diagnose via BK blood test, urine test for decoy cells, or PCR, treat by
reducing immunosuppression (1st line), with Leflunomide (2nd line, pyrimidine synthase inhibitor, immunosuppressive and antiviral)
• Human Papilloma Virus (HPV) – Papillomavirus, circular ⊕-sense dsDNA, naked icosahedral capsid, multiple serotypes (>100, serotype determines
disease), warts are hyperproliferation of keratinized squamous epithelium, inactivation of tumor suppressor genes (e.g. E6 inhibits p53, E7 inhibits Rb,
both inhibit transition from G1 to S phase) may produce malignancy, transmitted via direct contact and fomites, reservoir is humans (skin, genitals),
presentations: 1.) Verruca Vulgaris (Cutaneous Warts): serotypes 1, 2, 4, arises on hands, fingers, soles of feet, 2.) Laryngeal Papillomatosis: serotypes 6,
11, associated with children, acquired during birth (not sexually transmitted), may colonize true vocal cords due to keratinized squamous epithelium,
may present with weak cry, hoarseness, and stridor, 3.) Condyloma Acuminata (Anogenital Warts): serotypes 6, 11, 90% benign, produces koilocytes
(epithelial cells with characteristic enlarged nuclei or two nuclei and hyperchromasia), acquired via sex, 4.) Cervical Intraepithelial Neoplasia: serotypes
16, 18, 31, and 33 are pre-neoplastic, may progress to SCC or spontaneously resolve, 5.) Squamous Cell Carcinoma (SCC): associated with
immunosuppression, esp. AIDS (invasive cervical/anal/penile cancer an AIDS-defining illness), arises in head, neck, anus, or cervix, may present with
post-coital bleeding, diagnose clinically, by visualizing koilocytic cells on biopsy or Pap smear (samples cervical cells from transformation zone, where
squamous epithelium from ectocervix meet columnar epithelium of endocervix), or with PCR, treat warts with cryotherapy, electrocautery, salicylic acid
chemical therapy, subcutaneous Candida injections (activates immune system to area, single injection under largest 1 or 2 warts treats multiple warts),
Imiquimod (induces inflammatory cytokines), Interferon Alfa-2b, Pegylated Interferon Alfa-2a (Peginterferon), Cidofovir, Gardasil vaccine available,
made of capsid proteins, protects against serotypes 6, 11, 16, 18, first vaccine to prevent cancer, recommended for men and women ages 9-26,
complications include excessive wart growth if untreated (may require surgical excision), serotypes 16 and 18 have malignant potential
 • JC Virus – Polyomavirus (John Cunningham virus), circular dsDNA, non-enveloped/naked capsid, transmitted via respiratory droplet, reservoir is humans,
infection of oligodendrocytes leads to demyelination, presents with Progressive Multifocal Leukoencephalopathy (PML): AIDS (CD4 <200, 2-4%) and
transplant patients following viral reactivation, increased risk of contraction associated with Natalizumab and Rituximab, virus targets oligodendrocytes,
produces patches of demyelination leading to white matter damage, presents with headache, loss of coordination, aphasia, memory loss, MRI shows
multiple non-enhancing lesions in white matter, diagnose with ELISA or PCR, treatment is supportive, rapidly progressive, usually fatal (within weeks)

RNA Viruses Introduction

• Introduction
RNA Viruses – ⊕-Sense – Picornaviruses
• Introduction – linear ⊕-sense ssRNA virus, small, non-enveloped/naked icosahedral capsid, resistant to alcohol and detergents, RNA translated into long
polypeptide which is then cleaved by viral proteases to form functional proteins, highest incidence in summer and fall, 3 groups: 1.) Enteroviruses: acid-
stable, fecal-oral transmission, associated with children, causes aseptic (viral) meningitis (most common cause in US), Poliovirus, Coxsackievirus,
Echovirus, 2.) Rhinoviruses: not acid-stable, grows at 33°C, Rhinovirus, 3.) Hepatovirus: Hepatitis A Virus
• Coxsackievirus – Picornavirus, linear ⊕-sense ssRNA virus, small, non-enveloped/naked icosahedral capsid, transmitted via fecal-oral route (acid-stable),
reservoir is humans, 2 strains, both may be asymptomatic or present with mild fever, common cold, rashes, aseptic meningitis, strain-specific illnesses:
1.) Coxsackie A: causes severe infection in lab mice, presents with Herpangina (fever, sore throat, small vesicles on back of the throat), Hand, Foot, and
Mouth Disease (strain A16, fever, oral vesicles, lesions on hands, feet, buttocks), common in summer, 2.) Coxsackie B: causes only mild infection in lab
mice, presents with Dilated Cardiomyopathy (50% of cases, myocardial biopsy shows lymphocytes), Pericarditis (most common cause), Pleurodynia
(pleuritic pain, fever, headache), Bornholm disease (“Devil’s Grip” disease, pleurodynia or myalgias, pleuritic pain like an “iron grip” around chest),
Pancreatitis, diagnose with serology, no treatment
 • Echovirus – Picornavirus, linear ⊕-sense ssRNA virus, small, non-enveloped/naked icosahedral capsid, transmitted via fecal-oral route (acid-stable),
reservoir is humans, seen mostly in children, presents with aseptic meningitis, fever, rash, diagnose with serology, no treatment
• Hepatitis A Virus – Picornavirus, linear ⊕-sense ssRNA virus, small, non-enveloped/naked icosahedral capsid, transmitted via fecal-oral route (acid-
stable), reservoir is humans (3 week incubation period, no carriers), purified from water in developed countries, process requires chlorination, bleach,
UV radiation, or heating water to 85°C for >1 min, may be transmitted in uncooked shellfish from contaminated water, associated with travel to endemic
areas, children most commonly affected, histology: hepatocyte swelling, necrosis, and apoptosis with mononuclear infiltration/inflammation,
presentations: 1.) Subclinical: “anicteric”, i.e. without jaundice, mostly children, older adult who is anti-HAV IgM⊖, anti-HAV IgG⊕, 2.) Acute Viral
Hepatitis: fever, hepatomegaly, jaundice, vomiting (“A” for Acute), smokers often develop aversion to smoking while sick, does not become chronic,
serum lab markers: 1.) anti-HAV IgM: active infection present, best test to detect active infection, 2.) anti-HAV IgG: previous infection, no active disease,
immunity against infection, treat with pooled immune serum globulin (via fractionation of plasma from many donors), killed vaccine available,
recommended for travelers, self-limiting (symptoms last 1 month)

• Poliovirus – Picornavirus, linear ⊕-sense ssRNA virus, small, non-enveloped/naked icosahedral capsid, acid-stable, replicates in lymphoid tissues (esp.
tonsils, Peyer’s patches), 2-3 week latency period, destroys anterior horn of spinal cord (LMNs), transmitted via fecal-oral route (acid-stable), respiratory
droplets during early stages, reservoir is humans, endemic to Nigeria, India, Pakistan, Afghanistan (US polio-free since 1994), presentations: 1.) Paralytic
Poliomyelitis: flaccid asymmetric paralysis, esp. legs, decreased deep tendon reflexes, no sensory loss, may ascend to diaphragm and cause respiratory
paralysis (common cause of death), most common in adults, 2.) Aseptic Meningitis: meningismus and fever, 3.) Mild Illness: asymptomatic or fever, 4.)
Post-Polio Syndrome: progressive muscle atrophy in patient with polio decades ago, diagnose with serology (no virus in CSF), no treatment, 2 vaccines
available: 1.) Salk: formalin-killed virus, injected subcutaneously, induces IgG response, used in developed countries, 2.) Sabin: oral, live attenuated,
induces IgA response, results in infection with nonvirulent strain that spreads to other people increasing population immunity, may cause Vaccine-
Associated Paralytic Poliomyelitis: extremely rare side effect where vaccine strain regains virulence, presents with paralysis in vaccinated individual or
close contact
• Rhinovirus – Picornavirus, linear ⊕-sense ssRNA viruses, small, non-enveloped/naked icosahedral capsid, >100 serotypes, acid-labile, therefore cannot
cause gastroenteritis, grows at 33°C (temperature of upper respiratory tract), enters host cells by attaching to ICAM-1, transmitted via respiratory
droplets or fomites, reservoir is humans (mucous membranes), presents with common cold (most common cause, 2nd is Coronavirus), diagnose clinically,
no treatment, no vaccine due to large number of serotypes

RNA Viruses – ⊕-Sense – Calicivirus

 • Norwalk/Norovirus – Calicivirus, linear ⊕-sense ssRNA virus, non-enveloped/naked icosahedral capsid, RNA translated into long polypeptide which is
cleaved by viral proteases to form functional proteins, transmitted via fecal-oral route, reservoir is humans (GI), associated with children and daycares
(named after Ohio elementary school), cruise ships, shellfish, buffets, presents with Acute Gastroenteritis: 60% of non-bacterial forms, no blood or pus,
explosive watery diarrhea, nausea/vomiting, diagnose with radioimmunoassay or ELISA, no treatment

RNA Viruses – ⊕-Sense – Togaviruses

• Chikungunya Virus – Togavirus, linear ⊕-sense ssRNA virus, enveloped icosahedral capsid, RNA translated into long polypeptide which is then cleaved
by viral proteases to form functional proteins, transmitted via Aedes mosquito (arbovirus), common in Africa, Asia, Europe, Indian and Pacific Ocean
regions, one case in the Caribbean in 2013, presents with fever, arthralgia, headache, myalgia, rash, no treatment (infection typically resolves within 1
week, but arthralgia may last months), no vaccine, prevent by avoiding mosquito bites

• Eastern/Western/Venezuelan Equine Encephalitis Virus (EEEV/WEEV/VEEV) – Togavirus, linear ⊕-sense ssRNA virus, enveloped icosahedral capsid,
RNA translated into long polypeptide which is then cleaved by viral proteases to form functional proteins, transmitted via mosquitos (arbovirus),
associations: 1.) EEEV: freshwater swamps in the Southeast US or Great Lakes area, 2.) WEEV: Southwest, 3.) VEEV: Venezuela, presentations: 1.)
Systemic: chills, fever, malaise, arthralgias, and myalgias (lasts 1-2 weeks), 2.) Encephalitis: fever, headache, irritability/restlessness, drowsiness,
seizures, coma, encephalitis after systemic illness in adults, immediate onset in infants, diagnose with ELISA, no treatment or vaccine, prevent by limiting
mosquito exposure, fatal in 33% of cases, survivors may suffer mild to serious neurologic damage
• Rubella Virus – Togavirus, linear ⊕-sense ssRNA virus, enveloped icosahedral capsid, RNA translated into long polypeptide which is then cleaved by viral
proteases to form functional proteins, transmitted via respiratory droplets, crosses placenta, associated with immigrants, reservoir is humans,
 presentations: 1.) German Measles: mild measles-like disease that lasts 3 days (“3 day measles”), flu-like symptoms, fever, postauricular and occipital
lymphadenopathy, fine truncal rash (red, maculopapular, spreads from forehead to face to torso to extremities, moves faster than measles rash, doesn’t
darken), arthralgias and arthritis (mostly adults), 2.) Congenital Rubella: serious congenital ToRCHeS infection, more profound if mother infected during
first 16 weeks, mother develops rash, lymphadenopathy, arthralgias, fetus develops classic triad of patent ductus arteriosus (or pulmonary artery
hyperplasia, or other congenital heart disease), cataracts and microphthalmia, and sensorineural deafness, purpuric “blueberry muffin” rash due to
dermal extramedullary hematopoiesis, hepatomegaly, microcephaly, pulmonary stenosis, mental retardation, blindness, jaundice, pulmonic stenosis,
radiolucent bone lesions, diagnose with serology, no treatment, live attenuated MMR (measles, mumps, rubella) vaccine available, avoid in
immunocompromised (CD4 <200) or pregnant women (should wait at least a month to get pregnant)

RNA Viruses – ⊕-Sense – Flaviviruses

• Dengue Virus – Flavivirus, linear ⊕-sense ssRNA virus, enveloped icosahedral capsid, non-segmented, transmitted via Aedes aegypti mosquito
(arbovirus), reservoir is humans, monkeys, endemic to equatorial South America, India, Southeast Asia and Southeast US, presentations: 1.) Dengue
Fever: “break bone fever”, painful back, muscle, joint pain, severe headache, fever, rash, thrombocytopenia, 2.) Dengue Hemorrhagic Shock: reinfection
with second serotype (esp. Type 2), hemorrhagic fever leading to shock and renal failure, 10% mortality, diagnose with ELISA, PCR, culture, ⊕ tourniquet
test, no treatment, no vaccine available, infection with 1 strain does not provide immunity against other strains, instead increases likelihood of severe
disease, vector control prevents spread, 20% mortality if untreated, 1% with good treatment
• Hepatitis C Virus – Flavivirus, linear ⊕-sense ssRNA virus, enveloped icosahedral capsid, non-segmented, contains no proofreading 3’ to 5’ exonucleases
in virion-encoded RNA polymerase (results in antigen and envelope glycoprotein variation, host antibody production lags behind antigenic variation of
new mutant strains), transmitted via body fluids, esp. IV drug use, also post-transfusion before screening was done, sexually (less common than HBV),
across placenta, reservoir is humans (short incubation, 6-12 weeks, asymptomatic carrier state possible), presentations: 1.) Acute: usually asymptomatic,
some patients show symptoms initially, e.g. jaundice, RUQ pain, HCV RNA in serum during first 6 months, ALT rises and falls within 6 months, anti-HCV
rises after 2 months due to mutated strains, 2.) Chronic: 80-85% of acute infections become chronic, lymphocytes infiltrate hepatic tract, kill infected
hepatocytes, liver either succumbs to fibrosis and necrosis and becomes cirrhotic or hyper-proliferates leading to malignancy, leading cause of chronic
hepatitis and liver transplants, 3.) Cirrhosis: 20% of acute infections, 4.) Other: Hepatitis B-like illness, membranous glomerulopathy, mixed
cryoglobulinemia (IgM), serum shows anti-HCV antibodies, 3 “C’s”: Changing, Chronic, Cryoglobulinemia, diagnose with HCV RNA quantitation,
genotyping necessary to guide therapy, treatment based on new understanding of HCV replication cycle, goal to decrease HCV levels enough for
sustained virologic response, treat with direct acting retrovirals that target enzymes needed for HCV RNA synthesis: 1.) NS5B RNA-Dependent
Polymerase Inhibitors (“-uvirs”): Sofosbuvir (nucleotide polymerase inhibitor), Dasabuvir (non-nucleotide polymerase inhibitor), 2.) NS3/4A Protease
Inhibitors (‘-previrs”): Grazoprevir, Paritaprevir, Simeprevir, 3.) NS5A Protein (“-asvirs”): exact mechanism unknown, Daclatasvir, Elbasvir, Ledipasvir,
Ombitasvir, 4.) Older Medications: Ribavirin, Interferon-α, now used as adjuncts in refractory patients, may progress to hepatocellular cancer, mortality
0.5-1.0%
• St. Louis Encephalitis Virus (SLEV) – Flavivirus, linear ⊕-sense ssRNA virus, non-segmented, transmitted via Culex mosquito (arbovirus), endemic to US,
often asymptomatic, if symptomatic, presents with mild illness (headache and fever) or with more severe encephalitis (fever, headache, meningismus,
stupor, disorientation, coma, tremors, convulsions, spastic paralysis), diagnose with serology, no treatment, no vaccine available, vector control prevents
spread, mortality 5-30%, elderly more likely to suffer poor outcome
• West Nile Virus – Flavivirus, linear ⊕-sense ssRNA virus, enveloped icosahedral capsid, non-segmented, transmitted via Culex mosquito (arbovirus),
blood transfusion, organ transplantation, across placenta, reservoir is birds, endemic to North America, usually asymptomatic (only 0.5% symptomatic),
if symptomatic, presents with fever, headache, rash, aseptic meningitis, encephalitis, flaccid paralysis, may progress to seizure and coma, diagnose with
CSF serology, no treatment, no vaccine available, vector control prevents spread, elderly more likely to suffer poor outcome
• Yellow Fever Virus – Flavivirus, linear ⊕-sense ssRNA virus, enveloped icosahedral capsid, non-segmented, Councilman bodies in liver (acidophilic
inclusions of condensed nuclear chromatin/apoptotic globules), transmitted via Aedes aegypti mosquito (arbovirus), reservoir is humans, monkeys,
endemic to Africa (90% of cases), presents with Yellow Fever: high fever, bloody (black) vomit, bloody diarrhea, jaundice, headache, photophobia,
musculoskeletal pain (esp. backache), AST>ALT, diagnose with serology, no treatment, live attenuated vaccine available, vector control prevents spread
 • Zika Virus – Flavivirus, linear ⊕-sense ssRNA virus, enveloped icosahedral capsid, non-segmented, transmitted by Aedes mosquito (arbovirus), sex,
congenital, outbreaks more common in tropical and subtropical areas, presentations: 1.) Primary Infection: conjunctivitis, low-grade fever, pruritic rash
(20% of cases), 2.) Congenital Infection: microcephaly or miscarriage, diagnose with RT-PCR or serology, treatment is supportive only, no vaccine

RNA Viruses – ⊕-Sense – Coronavirus

• Coronavirus/SARS-CoV/MERS-CoV – Coronavirus, linear ⊕-sense ssRNA virus, enveloped helical capsid, surface peplomers made of hemagglutinin give
corona-like appearance, transmitted via respiratory droplets, SARS-CoV also via urine/feces and sweat, reservoir is humans, birds and small animals
(SARS-CoV), camels (MERS-CoV), presentations: 1.) Common Cold: second most common cause (15% – most common is Rhinovirus), incidence peaks in
winter and spring, 2.) SARS: atypical pneumonia, initial muscle pain, headache, fever, followed by cough, dyspnea, and pneumonia 2-14 days later, acute
bronchitis that may lead to Acute Respiratory Distress Syndrome (ARDS), outbreaks in Asia and Toronto, 3.) MERS: fever, cough, shortness of breath,
diarrhea, diagnose with antibodies (⊖ finding if no antibodies after 28 days), PCR, or culture, self-limiting, may treat with broad-spectrum antibiotics,
Ribavirin, Corticosteroids (all 3 have questionable efficacy)

RNA Viruses – ⊕-Sense – Retrovirus

• Human Immunodeficiency Virus (HIV) – Retrovirus, linear ⊕-sense ssRNA virus, enveloped, complex and conical capsid, diploid genome, ssRNA
homodimer surrounded by capsid and envelope proteins (p24 capsid protein, gp41 and gp120 envelope proteins), virulence factors: 1.) Env: codes for
envelope glycoproteins, esp. gp120 (outer glycoprotein, enables attachment to host T-cell, binds CD4 and CCR5, allows viral entry via fusion with cell
membrane) and gp41 (transmembrane glycoprotein, enables fusion and entry, “Forty-one enables Fusion”), both formed from cleavage of gp160 in host
ER and Golgi (only protein that is glycosylated then cleaved), 2.) Gag: codes for p24 (nucleocapsid proteins in virion core) and p17 (matrix proteins), 3.)
Pol: codes for reverse transcriptase, integrase (integrates viral DNA into host DNA), aspartate protease (pol mutations confer resistance to reverse
transcriptase and protease inhibitors), 4.) Tat and Rev: regulatory genes required for replication, 5.) Nef: decreases MHC 1 expression on surface of
infected cell, Life Cycle: HIV binds receptor and coreceptor on macrophages (CCR5 – a chemokine receptor, CD4, early stages) or on T-cells (CXCR4, CCR5,
CD4, later stages), CCR5 mutations confer immunity (homozygote) or slower disease course (heterozygote), HIV empties virion contents into infected
cell, synthesizes dsDNA from its own ssRNA using its own reverse transcriptase, inserts viral DNA into host DNA using its own integrase enzyme, host
RNA polymerase synthesizes HIV mRNA, host machinery assembles HIV proteins, HIV cleaves these proteins to form smaller proteins using its own
protease enzymes, a new virus is packaged and buds off host cell, transmitted sexually (most common mechanism, HIV present in seminal fluid and
vaginal/cervical secretions, virus enters body through small mucosal ulcerations in vagina, penis, rectum, or urethra), IV drug use, across placenta (30%
transmission rate), blood transfusion, needle sticks (0.3% risk), reservoir is humans, presents with 4 clinical stages (“4 F’s: Flu-like, Feeling fine, Falling
count, Final crisis”): 1.) Acute: flu- or mono-like illness with fever, cervical lymphadenopathy, possible enlarged tonsils, last several weeks then resolves,
patient immunocompromised (CD4⊕ T-cells destroyed, have not yet recovered) and susceptible to all late stage opportunistic infections (scenario is a
patient with an AIDS-defining illness who tests ⊖ for HIV based on old ELISA test), 2.) Latent: asymptomatic, virus replicates in lymph nodes, lasts up to
10 years, 3.) Late: falling CD4 count leads to full-blown AIDS (when <200), 4.) Final Crisis: most untreated patients eventually die of complications, clinical
symptoms correlate with CD4 counts: CD4 <400: constitutional syndromes (“wasting syndrome”, weight loss, fever, night sweats, adenopathy), bacterial
infections (M. tuberculosis, H. influenzae, S. pneumoniae, Salmonella species), oral thrush (C. albicans), tinea pedis, reactivation of VZV, CD4 <200: PCP
(P. jiroveci pneumonia), C. neoformans, Cryptosporidium, Coccidioidomycoses, reactivation of HSV, Cyclospora cayetanensis, CD4 <100: T. gondii, H.
capsulatum, C. albicans esophagitis, CD4 <50: M. avium-intracellulare (prophylaxis with Azithromycin), CMV retinitis and esophagitis, C. neoformans
meningoencephalitis, other infections in specific populations: 5.) Neonate: ToRCHeS infection, presents with recurrent oral thrush and interstitial
pneumonia, chronic diarrhea, lymphopenia, 6.) HIV Encephalitis: occurs late in disease course, HIV crosses BBB via infected macrophages, produces
inflammation in brain, microglial nodules with multinucleated giant cells, JC virus may cause progressive multifocal leukoencephalopathy, 7.) AIDS
Dementia: mental status changes, depression, ataxia, seizures, urinary and bowel incontinence, 8.) Diffuse Large B-Cell Lymphoma, 2 primary classes of
diagnostic tests (new and old): NEW: 1.) FDA-Approved 4th gen Antigen/Antibody Test: combination that detects HIV-1, HIV-2, and HIV-1 p24 antigen for
acute HIV-1 infection, no further testing required for ⊖ tests (low false-⊖ rate, contrast with older tests that have a false-⊖ “window”), ⊕ results
require further test to distinguish between HIV-1 and HIV-2 strains, OLD: both tests detect antibodies to HIV proteins, antibodies may take 3-6 weeks to
develop, tests can be falsely ⊖ in first 1-2 months of infection, tests can be falsely ⊕ in babies born to infected mothers because anti-gp120 crosses
placenta, IgM against envelope antigens may be normal or elevated (IgM production does not require CD40L on CD4⊕ cells): 2.) ELISA: first step in
diagnosis (screening test), high false ⊕ rate (high sensitivity, low specificity, rules out infection if ⊖), 3.) Western Blot: used to confirm ⊕ ELISA
(confirmation test), high false ⊖ rate (low sensitivity, high specificity, rules in infection if ⊕), 4.) DNA and RNA Nucleic Acid Amplification Test (NAAT):
primarily used to diagnose infants, who would test ⊕ with an ELISA or Western Blot due to passive immunity from infected mother, looks for virus itself
rather than antibodies, in adults, high viral load associated with poor prognosis, may also diagnose clinically with 4.) CD4 Count: <200 (normal 500-
1,500), 5.) HIV-Defining Illness: HIV ⊕ with AIDS-associated illness, e.g. PCP, C. albicans esophagitis, 6.) CD4⊕ Percentage: <14%, PCR viral load tests
used to monitor therapeutic effectiveness, ring enhancing lesion on head MRI should be assessed for either T. gondii or a primary CNS B-cell lymphoma
(associated with EBV), all HIV patients should be treated, esp. those with CD4 <350, high viral load, or pregnant women, complex treatment regimens
with over 25 drugs in multiple classes: 1.) Nucleotide Reverse Transcriptase Inhibitors: “DELTAS Z” drugs, Didanosine (ddl), Emtricitabine (FTC),
Lamivudine (3TC), Tenofovir (TDF), Abacavir (ABC), Stavudine (d4T), Zidovudine (ZDV, AZT, Azidothymidine), 2.) Non-Nucleotide Reverse Transcriptase
Inhibitors: “ENDER” drugs, Efavirenz (EFV), Nevirapine (NVP), Delavirdine (DLV), Etravirine (ETR), Rilpivirine (RPV), 3.) Protease Inhibitors: “RAD LIFTS”
drugs, Ritonavir (RTV), Atazanavir (ATV), Darunavir (DRV), Lopinavir (LPV), Indinavir (IDV), Fosamprenavir (FPV), Tipranavir (TPV), Saquinavir (SQV),
4.) CCR5 Inhibitors: Maraviroc (MVC), 5.) Fusion Inhibitors: Enfuvirtide (T-20), 6.) Integrase Inhibitors: “RED” drugs, Raltegravir (RAL), Elvitegravir (EVG),
Dolutegravir (DTG), Highly Active Antiretroviral Therapy (HAART) combines multiple drugs with multiple mechanisms to prevent resistance, use
Zidovudine in pregnancy and postpartum (14 weeks gestation to 6 weeks postpartum) to prevent mother-to-child transmission
• Time Course of Untreated HIV Infection

Dashed lines on CD4⊕ count indicate moderate immunocompromise (CD4 <400) and when AIDS-defining illnesses emerge (CD4 <200)
• Human T-Cell Lymphotropic/Leukemia Virus – Retrovirus, linear ⊕-sense ssRNA virus, enveloped icosahedral capsid, 2 primary strains: HTLV-1 (more
serious) and HTLV-2 (less serious), transmitted via sex, blood (transfusion or IV drug use), breast feeding, presentations: 1.) Leukemia: HTLV-1, rapidly
 fatal, 2.) Myelopathy: HTLV-1, 3.) Inflammatory Disorder: HTLV-1, uveitis, infectious dermatitis, 4.) Neurologic Disorder: HTLV-2, mild. 5.) Chronic
Pulmonary Infection: HTLV-2, potential treatments include Prosultiamine (vitamin B-1 derivative, shown to reduce viral load and symptoms),
Azacytidine (anti-metabolite), Tenofovir Disoproxil (TDF) (reverse transcriptase inhibitor used for HIV), and some others, no vaccine, though
development feasible based on low antigenic variability, development of natural immunity in humans, and vaccine success in animals

RNA Viruses – ⊕-Sense – Hepevirus

• Hepatitis E Virus – Hepevirus, linear ⊕-sense ssRNA virus, non-enveloped/naked icosahedral capsid, transmitted via fecal-oral route (epidemics arise
from contaminated water during flooding, esp. monsoons), endemic to Asia, Africa, India, Central America, less common in US, presentations (does not
become chronic, similar to Hep A): 1.) Healthy: mild acute hepatitis, 2.) Pregnant: severe hepatitis, 25% mortality in 3rd trimester due to cirrhosis,
“patchy necrosis” on biopsy, serum shows anti-HEV antibodies, self-limiting

RNA Viruses – ⊖-Sense – Bunyavirus

• CA Encephalitis Virus/La Crosse Virus – Bunyavirus, ⊖-sense ssRNA virus, enveloped (from host Golgi bodies) capsule, 3 segments, 1 is ambisense
(contains both ⊕ and ⊖ sense), transmitted via Aedes mosquitos species (arbovirus), associated with midwestern and southern woodlands (esp. North
Carolina and Ohio), more common in warm months, presentations: 1.) Early Systemic Illness: fever, chills, nausea/vomiting, headache, abdominal pain,
2.) Later Encephalitis: fever, drowsiness, disorientation, seizures, paralysis, coma, treatment is supportive, complications include permanent neurologic
damage
• Crimean Congo Fever Virus – Bunyavirus, circular ⊖-sense ssRNA, enveloped (from host Golgi bodies), helical capsid, 3 segments, ambisense,
transmitted via Hyalomma tick, human-to-human, endemic to Africa, the Balkans, the Middle East, and Asia, associated with exposure to livestock,
slaughterhouses, presents with Hemorrhagic Fever: initial fever, increased susceptibility to bleeding (bleeding diathesis), facial and chest flushing,
petechiae, swelling, weakness, malaise followed by headache, sore throat, muscle pain, nausea/vomiting, diarrhea, cough, abdominal pain, bleeding
from mucosal surfaces (mouth, nose, vagina, GI), may lead to hypotension/shock, end-organ failure (liver and kidneys), seizures, tremor, coma, may
cause deafness, diagnose with ELISA, PCR, culture, treatment is supportive, possibly Ribavirin
• Hantavirus – Bunyavirus, circular ⊖-sense ssRNA virus, enveloped (from host Golgi bodies), helical capsid, 3 segments, 1 is ambisense (contains both ⊕
and ⊖ sense), “Sin Nombre” the most common strain, alters lung capillary permeability producing pulmonary edema, transmitted via rodent urine and
feces (only virus of the class that is not an arbovirus), associated with NM, AZ, CO, UT (4 corners area), reservoir is deer mouse, presents with Hantavirus
Pulmonary Syndrome: respiratory distress, pulmonary edema via capillary leak, cough, fever, myalgias, nausea/vomiting, prerenal azotemia and
hypotension, elevated WBCs and RBCs, thrombocytopenia, diagnose with serology, no treatment, 38% mortality
• Sandfly/Rift Valley Fever Virus – Bunyavirus, ⊖-sense ssRNA virus, enveloped (from host Golgi bodies), spherical capsid, 3 segments, 1 is ambisense
(contains both ⊕ and ⊖ sense), primary virulence factor is S Segment Nonstructural Protein (NSs): interferes with host interferon, inhibiting viral
response, transmitted via respiratory droplets, contact with infected animal blood, drinking raw milk from infected animal, various species of Aedes and
Culex mosquitos (arbovirus), associated with the Middle East, Sub-Saharan Africa, reservoir is livestock (cows, sheep, goats) and camels, presentations:
1.) Mild Systemic Illness: fever, dizziness, headache, myalgias, generalized weakness, back pain, weight loss, liver abnormalities, lasts 2-7 days, 2.) Ocular
Disease: blurred and decreased vision 1-3 weeks after onset of systemic symptoms, lesions in macula that may disappear after 10-12 weeks, 50%
experience permanent vision loss, 3.) Meningoencephalitis: severe headaches, confusion, seizures, coma 1-4 weeks after initial symptoms, death rare,
but may cause permanent neurologic deficits, 4.) Hemorrhagic Fever: rare (1% of patients), begins with jaundice and other signs of liver impairment,
 followed by vomiting blood, bloody stools, and mucosal bleeding 2-4 days after systemic symptoms, death usually occurs 3-6 days after, diagnose with
viral isolation in tissues or by detecting anti-viral antibodies with ELISA, supportive treatment only, prevent by vaccinating livestock (must be done
before an outbreak, if done during outbreak, may make it worse), restricting herd movement during outbreak, human vaccine exists, not widely
available, 1% mortality

RNA Viruses – ⊖-Sense – Orthomyxovirus

• Influenza A/B Virus – Orthomyxovirus, linear ⊖-sense ssRNA virus, enveloped, helical capsule, 8 segments, replicates in nucleus (only ⊖-sense RNA
virus that does), virulence factors: 1.) Hemagglutinin Antigen (HA): viral surface glycoprotein, promotes viral entry, binds to sialic acid on cells of upper
respiratory tract and RBCs, H1, H2, H3 are common versions (version determines tropism), anti-HA antibodies protect against future infection, 2.)
Neuraminidase Antigen (NA): glycoprotein, promotes progeny virion release, 3.) Antigenic Drift: minor changes in HA or NA due to random point
mutations, causes epidemics, Influenza A and B, 4.) Antigenic Shift: reassortment of viral genome between different species (e.g. human flu combining
with swine flu), causes pandemics (“sudden shift more deadly than gradual drift”), Influenza A only, transmitted via respiratory droplets, direct contact,
animal-to-human (strain dependent), reservoir is birds (A), pigs (A), humans (A and B), commonly occurs between December and February, Life Cycle:
Hemagglutinin (HA) viral molecule binds to sialic acid residue on membrane of infected cell and is endocytosed, M2 protein (protein channel) creates
proper pH for viral uncoating, once new virions formed, Neuraminidase (NA) cleaves sialic acid residues allow virion release, presents with 1.)
Epidemic/Endemic Influenza: Influenza A (Epidemic) and B (Endemic), small changes in viral genome, late December to early March, fever, chills,
headache, malaise, myalgias, respiratory symptoms, 2.) Pandemic Influenza: Influenza A, dramatic changes in viral genome lead to high susceptibility to
infection worldwide, high risk of bacterial pneumonia or superinfection, esp. S. aureus, S. pneumoniae, H. influenzae, diagnose with culture, detection of
viral proteins, RNA, or antibodies (anti-hemagglutinin IgG and IgA prevent reinfection), treat with Amantadine/Rimantadine (inhibits viral uncoating,
most strains resistant, only works against Influenza A, Influenza B lacks M2 protein), Oseltamivir/Zanamivir (neuraminidase inhibitors, must be given
within 72 hours of initial infection), 2 vaccines available: 1.) Killed: reformulated each fall and offered to at-risk groups (e.g. elderly, healthcare workers),
trivalent (2 strains of Influenza A + 1 strain of Influenza B) or quadrivalent (2 strains of Influenza A + 2 strains of Influenza B, children may receive it if >6
months old), stimulates generation of host antibodies against hemagglutinin, best given in October to allow adequate time to build immunity before
viral exposure, 2.) Live Attenuated: intranasal, temperature-sensitive mutant that replicates in nose but not in lungs, complications include bacterial
pneumonia or superinfection (esp. S. aureus, S. pneumoniae, H. influenzae), Reye’s Syndrome (fatty liver/liver failure, encephalitis, fever, rash, vomiting
if child given ASA, ASA uncouples oxidative phosphorylation in hepatic mitochondria, damage seen microscopically), or Guillain-Barré syndrome
(ascending paralysis, also seen after C. jejuni infection, CSF shows elevated protein, low WBC counts, aka albuminocytologic dissociation
RNA Viruses – ⊖-Sense – Paramyxovirus
• Human Metapneumovirus – Paramyxovirus, ⊖-sense ssRNA, primary virulence factor is Fusion Protein (F): causes cell-cell fusion producing
multinucleated cells, transmission mode unknown, but likely via respiratory droplets, aerosol, or fomites, nosocomial infections reported, presents with
Lower Respiratory Infection: bronchiolitis, pneumonia, second most common cause in young children (after RSV), compared to RSV, occurs in slightly
older children, produces milder disease, coinfection may occur with worse prognosis, no treatment or vaccine
• Mumps Virus – Paramyxovirus, ⊖-sense ssRNA, helical capsule, single serotype, replicates in upper respiratory tract and regional lymph nodes, spreads
to organs hematogenously, parotid glands often involved, virulence factors: 1.) Hemagglutinin Antigen (H): glycoprotein, promotes viral entry, rash
caused by CD8⊕ T-cell damage of infected endothelial cells, 2.) Neuraminidase Antigen (N): glycoprotein, promotes progeny virion release, 3.) Fusion
Protein (F): causes cell-cell fusion producing multinucleated cells, transmitted via respiratory droplets, reservoir is humans (respiratory tract), presents
with Mumps: parotitis, orchitis in more severe cases (unilateral inflammation most common, preserves fertility, infertility a rare complication that
usually occurs after puberty and in bilateral cases), aseptic meningitis, pancreatitis, diagnose clinically or with serology, no treatment for primary
infection, sequela of testosterone deficiency due to testicular damage (acquired hypogonadism) treated with exogenous testosterone, live attenuated
MMR vaccine available
• Parainfluenza Virus – Paramyxovirus, ⊖-sense ssRNA, virulence factors: 1.) Hemagglutinin Antigen (H): glycoprotein, promotes viral entry, rash caused
by CD8⊕ T-cell damage of infected endothelial cells, 2.) Neuraminidase Antigen (N): glycoprotein, promotes progeny virion release, 3.) Fusion Protein
(F): causes cell-cell fusion producing multinucleated cells, transmitted via respiratory droplets, transmitted via respiratory droplets, reservoir is humans
(respiratory tract), common in infants, children, and adults, presentations: 1.) Croup/Acute Laryngotracheobronchitis: children (most common cause),
infection of larynx and associated structures, swelling of airway produces stridor (wheezing sound) and croup (“seal-like” barking cough), infants also
present with colds, bronchiolitis, and pneumonia, CXR shows “steeple sign” (narrowing of upper trachea and subglottic region due to inflammation and
swelling), may produce pulsus paradoxus due to upper airway obstruction, 2.) Severe Cold: adults, diagnose with PCR, treatment supportive only

• Respiratory Syncytial Virus (RSV) – Paramyxovirus, ⊖-sense ssRNA, virulence factor: 1.) Fusion Protein (F): causes cell-cell fusion producing
multinucleated cells, unlike other paramyxoviruses, does not contain HA or NA, infects respiratory endothelium by binding to G protein, transmitted via
respiratory droplets, reservoir is humans (respiratory tract), presents with: 1.) Infants (<6): typical pneumonia (most common cause, may be
nosocomial), bronchiolitis (most common cause) with wheezing, atypical pneumonia, 2.) Adults: common cold, diagnose with IFA, ELISA, PCR, treat
adults with Ribavirin (not recommended for children or pregnant women), Palivizumab (monoclonal antibody against protein F) used as prophylaxis in
high-risk (premature) infants (“Palivizumab for Paramyxovirus Prophylaxis in Premies”)

• Rubeola Virus – Paramyxovirus, ⊖-sense ssRNA, enveloped, single serotype, virulence factors: 1.) Hemagglutinin Antigen (H): glycoprotein, promotes
viral entry, but no neuraminidase, rash caused by CD8⊕ T-cell damage of infected endothelial cells, 2.) Fusion Protein (F): causes cell-cell fusion
producing multinucleated cells, seen as Warthin-Finkeldey multinucleated giant cells in Giant Cell Pneumonia, virus infected cells destroyed by T-cells in
capillaries produce rash, do not confuse with Roseola (caused by HHV-6), transmitted via respiratory droplets, reservoir is humans (respiratory tract),
presents with Measles: 3 “C’s” of measles prodrome: Cough, Coryza, Conjunctivitis with photophobia, Koplik spots (bright red spots with blue-white
centers on buccal mucosa, diagnostic), very high fever (40°C), maculopapular rash 1-2 days after Koplik spots disappear (pruritic, red, flat-to-slightly-
bumpy, begins on head behind ears and moves down to trunk and extremities, more likely than Rubella to be confluent), diagnose with serology,
treatment is supportive (vitamin A reduces morbidity and mortality, esp. in malnourished children), live attenuated MMR vaccine available, Palivizumab
prevents pneumonia in infants, complications: 1.) Subacute Sclerosing Panencephalitis (SSPE): rare encephalitis arising many years after measles
infection, virus contains mutated or absent matrix (M) protein that prevents mature (enveloped) virion particles from forming, as virus continues to
replicate intracellularly, viral nucleocapsids accumulate within neurons and oligodendrocytes forming intranuclear inclusions and leading eventually to
widespread inflammation, demyelination, and gliosis, “patient with history of measles or never vaccinated/immigrant who 5-15 years later develops
personality changes, seizures myoclonia, ataxia, coma, death,” diagnose with high titers of anti-Rubeola antibodies in CSF (oligoclonal bands),
relentlessly progressive and fatal, 2.) Encephalitis: 1:2000, 3.) Giant Cell Pneumonia: rare, associated with immunosuppression, lymphadenitis with
Warthin-Finkeldey multinucleated giant cells in a background of paracortical hyperplasia, 4.) Pregnancy: not teratogenic but causes spontaneous
abortion in 20% of cases
RNA Viruses – ⊖-Sense – Rhabdovirus
• Rabies Virus – Rhabdovirus, linear “bullet-shaped” ⊖-sense ssRNA, enveloped, helical capsid, Negri bodies (eosinophilic cytoplasmic inclusions
composed of virions, found in cytoplasm of pyramidal cells within the hippocampus and in the soma of Purkinje cells within the cerebellum,
pathognomonic), incubation period of weeks to months (allows for postexposure immunization), virus glycoprotein binds to peripheral nicotinic ACh
receptors in postsynaptic junction of NMJ, travels up axons to DRG via retrograde axoplasmic transport (uses dynein motor proteins) at a rate of 1-3 mm
per day (causes tingling and muscle spasms as it travels), enters spinal cord and rapidly infects brain, transmitted via animal contact or bite, aerosol,
corneal/organ transplant, reservoir is animals, in US most commonly bats, squirrels, foxes, raccoons, skunks, internationally dogs, aerosol transmission
(e.g. bat caves) also possible, presents with Rabies: high fever and flu-like malaise, then agitation, photophobia, hydrophobia (brainstem infection leads
to painful pharyngeal contractions when swallowing liquids), hypersalivation (“foaming at the mouth”), then seizures, disorientation, hallucination,
paralysis, coma, death due to respiratory dysfunction, diagnose clinically, by visualizing Negri bodies on brain biopsy, with PCR, treat via postexposure
prophylaxis (if bitten by rapid animal, or if bite cannot be ruled out, treatments stimulate immune system while virus still in incubation phase, includes
wound cleaning) with Human Rabies Immunoglobulin (HRIG) (passive immunization) and 5 does of killed rabies virus (active immunization),
combination example of active-passive immunity, killed rabies vaccine available, indicated for animals and high-risk individuals, active rabies nearly
always deadly (only 1 confirmed case of recovery), complications include cardiac arrest, respiratory failure, acute renal failure

RNA Viruses – ⊖-Sense – Arenavirus

• Lassa Fever Virus – Arenavirus, circular, ⊖-sense ssRNA, enveloped, helical capsid, pleomorphic, 2 segments, 1 ambisense, virions contain ribosomes,
have sandy appearance, transmitted via rodents, human-to-human, reservoir is rodents, humans, highly contagious, associated with West Africa,
 presents with Hemorrhagic Fever: initial fever, increased susceptibility to bleeding (bleeding diathesis), facial and chest flushing, petechiae, swelling,
weakness, malaise followed by headache, sore throat, muscle pain, nausea/vomiting, diarrhea, cough, abdominal pain, bleeding from mucosal surfaces
(mouth, nose, vagina, GI), may lead to hypotension/shock, seizures, tremor, coma, may cause deafness, diagnose with serology in level 4 isolation, treat
with Ribavirin, supportive therapy, 50% mortality
• Lymphocytic Choriomeningitis Virus (LCMV) – Arenavirus, circular, ⊖-sense ssRNA, spherical envelope, helical capsid, pleomorphic, 2 segments, 1
ambisense, virions contain ribosomes, have sandy appearance, inactivated by heating, low pH, irradiation, and detergents, transmitted via rodents,
reservoir is rodents, associated with Europe, the Americas, Australia, and Japan, presents initially 8-13 days after exposure with flu-like symptoms, then
a few days of recovery, then meningitis, encephalitis, or meningoencephalitis, may produce acute hydrocephalus, infection during pregnancy may lead
to abortion or birth defects, supportive treatment only, children may require VP shunt for hydrocephalus, very low mortality

RNA Viruses – ⊖-Sense – Filovirus

• Ebola and Marburg Viruses – Filovirus, linear ⊖-sense ssRNA, enveloped, helical capsid, filamentous shape, infects macrophages, monocytes,
endothelial cells, and hepatocytes, transmitted via direct contact (including ingestion) with primates (apes/monkeys) or bats, human-to-human via
contact with bodily fluids or fomites (including dead bodies), high incidence of nosocomial infection, unknown reservoir, incubation period of up to 21
days, presents with Hemorrhagic Fever: initial fever, increased susceptibility to bleeding (bleeding diathesis), facial and chest flushing, petechiae,
swelling, weakness, malaise followed by headache, sore throat, muscle pain, nausea/vomiting, diarrhea, cough, abdominal pain, bleeding from mucosal
surfaces (mouth, nose, vagina, GI), may lead to hypotension/shock, end-organ failure (liver and kidneys), seizures, tremor, coma, may cause deafness,
diagnose with RT-PCR within 48 hours of symptom onset, or culture in level 4 isolation, quarantine patient, supportive treatment only, strict isolation of
infected individuals and barrier practices for healthcare workers key to preventing transmission, 50% mortality

RNA Viruses – ⊖-Sense – Deltavirus

• Hepatitis D Virus – Deltavirus, circular ⊖-sense ssRNA, enveloped capsid, requires Hepatitis B coinfection (HBsAg required for infection), may occur as
coinfection (simultaneous transmission with HBV) or as a superinfection (HDV transmitted to patient already infected with HBV), transmitted via sex or
parenterally (IV drug use, blood transfusions), carrier state possible, associated with Mediterranean region, sub-Sharan Africa, Middle East, northern
South America, treat with Pegylated Interferon Alfa-2a (Peginterferon) (flu-like side effects, 20% effectiveness),

RNA Viruses – Double Stranded – Reovirus

 • Colorado Tick Fever Virus (Coltivirus, CTV) – Reovirus, linear dsRNA, non-enveloped/naked capsid, 12 segments, replicates in cytoplasm, transmitted via
Dermacentor tick, rare cases of transmission via blood transfusions, common in western US and Canada, esp. mountainous areas of Colorado and Idaho,
associated with young males, campers, presentations: 1.) Early Systemic Illness: fever, chills, headache, retroorbital pain, photophobia, myalgias,
malaise, abdominal pain, hepatosplenomegaly, nausea/vomiting, flat or pimply rash, 2.) Later Reactivation: high fever with increase in symptoms,
diagnose clinically, with complement fixation to CTV, immunofluorescence, serum may show leucopenia, thrombocytopenia, and mildly elevated liver
enzymes, treat by ensuring tick removal, with Acetaminophen and analgesics for fever and pain, avoid ASA and other salicylates (may lead to Reye’s
Syndrome or thrombocytopenia), other complications include aseptic meningitis, encephalitis, and hemorrhagic fever (all rare)
• Reovirus – Reovirus, linear dsRNA, non-enveloped/naked, double-shelled icosahedral capsid, 10-11 segments, replicates in cytoplasm, contains
polymerase, transmission via fecal-oral route, respiratory droplets, presentations: 1.) Common Cold, 2.) Gastroenteritis, diagnose with serology, self-
limiting, live attenuated vaccine available, may cause intussusception (“currant jelly” stools)

• Rotavirus – Reovirus, linear dsRNA, non-enveloped/naked, double-shelled icosahedral capsid, 10-11 segments, replicates in cytoplasm, contains
polymerase, infects small intestine epithelium, causes destruction and atrophy of intestinal villi leading to decreased absorption of Na+ and loss of K+,,
primary virulence factor is NSP4: viral enterotoxin that increases Cl- permeability leading to secretory (isotonic) diarrhea, transmission via fecal-oral
route, associated with children (near universal infection by age 5), daycares, kindergartens, most common in winter months, presents with Severe
Gastroenteritis: most common cause of severe diarrhea in young children, leading cause of infant mortality, toxin mediated, fever, severe explosive,
dehydrating secretory (watery) diarrhea, vomiting, diagnose with ELISA (stool sample), self-limiting (symptoms typically resolve in 3-7 days), supportive
therapy (IV fluids and electrolytes depending on severity of dehydration), live attenuated oral vaccine available, first dose given at 2 months old (before
3 months old due to decreased efficacy and increased risk of side effects after), minimum dosing interval is 4 weeks, maximum age for any dose is 8
months old, past versions of vaccine associated with intestinal intussusception due to enlargement of Peyer’s patches, CDC recommends routine
vaccination for all infants, first infection typically most severe, complications include dehydration, metabolic acidosis, persistent disease in
immunocompromised children

Mycoses (Fungi) Introduction

• Introduction – eukaryotic, includes 1.) Yeasts: unicellular fungi, spherical to ellipsoidal, reproduce by budding (slower than bacteria), buds that do not
separate form long chains called pseudohyphae (e.g. C. albicans), 2.) Mold: multicellular colonies, clumps of intertwined branching hyphae, grow by
longitudinal extension, produce spores, 3.) Dimorphic Fungi: mold or yeast depending on environmental conditions, (“mold in the cold” – 25°C, yeast in
tissue “yeast in heat” – 37°C) (Histoplasma, Blastomyces, Coccidioides, Sporothrix), morphology: 1.) Spores: reproductive structure, adapted for
 dispersal, 2.) Conidia: asexual spores (most fungi), may be blastoconidia or arthroconidia (Coccidioides, Histoplasma), 3.) Hyphae: long, threadlike,
branching, filamentous tubular structure, fungal cells attached end to end, grow by extending from ends of tubules, 4.) Cell Membrane: innermost layer
(within cell wall), contains ergosterol, analogous to cholesterol, Amphotericin B and Nystatin bind to ergosterol, Ketoconazole inhibits ergosterol
synthesis, 5.) Cell Wall: surrounds cell membrane, potent antigens, contains complex carbohydrates, explains calcifications in chronic infections, 6.)
Capsule: polysaccharide coating, surrounds cell wall, antiphagocytic virulence factor, visualized with India Ink Stain (Cryptococcus)

Systemic Mycoses

• All – dimorphic, mold in soil (“mold in the cold” – 25-30°C), yeast in tissue/at
body temperature (“yeast in the heat” – 35-37°C) except Coccidioides immitis, which
is a spherule (not a yeast) in tissue, grows in blood agar, endemic to particular area,
fungi inhaled as spores, infects lungs then spreads hematogenously, presentations:
1.) Asymptomatic: majority of cases, most never visit doctor, 2.) Pneumonia: fever,
cough, may be acute or chronic, presents like TB, 3.) Disseminated Disease: fever,
malaise, meningitis, lytic bone lesions, skin granulomas, associated with
immunocompromised, diagnose with 1.) CXR, 2.) Biopsy: silver stain or KOH prep,
culture on Sabouraud’s or blood agar, 3.) Delayed Hypersensitivity Reaction: similar
to PPD, shows previous exposure, reacts to coccidioidin, histoplasmin g, treat local
infection with Fluconazole or Ketoconazole, systemic or serious infection with
Amphotericin B (may cause nephrotoxicity, hypokalemia), Note similarities with TB:
inhaled lung infection, severity ranges from asymptomatic to chronic, granulomas,
cavitations, and calcifications in the lungs, hematogenous dissemination, PPD-like
hypersensitivity reaction, but NOT transmitted person-to-person like TB
• Blastomyces dermatitidis – round, broad-based budding yeast with thick, double refractive walls, same size as RBC (RBC: Histo = smaller, Cocci = larger,
Paracocci = much larger), rarest, but most serious fungus in the group, transmitted via inhalation of spores, endemic to Mississippi River valley and
eastern US (often described as “Great Lakes and Ohio River valley” to distinguish it from Histo), reservoir is soil and rotting wood, presents with
Blastomycosis: chronic inflammatory lung disease, granulomatous nodules, dissemination to skin (ulcerative or verrucous lesion that resembles SCC) and
bones (osteomyelitis), patchy, alveolar infiltrates on lung exam, diagnose with KOH stain and culture, CXR, urine rapid antigen test, treat with
Itraconazole for 6-12 months if local (pneumonia), Amphotericin B if systemic or meningitis
• Coccidioides immitis – exists as a spherule containing endospores in tissue (NOT as a yeast), larger than a RBC (RBC: Histo = smaller, Blasto = same size,
Paracocci = much larger), transmitted via inhalation of arthroconidium, reservoir is soil and dust, endemic to southwest US (AZ, NM, southern CA, San
Joaquin Valley – “San Joaquin Fever”), increased incidence after earthquakes (causes release of spherules from soil) or dust storms, opportunistic
infection in HIV, presents with Coccidioidomycosis: mild pneumonia, nonproductive cough, fever, sweats, arthralgias (“desert rheumatism”), chest pain,
dyspnea, erythema nodosum (painful red nodules, esp. on shins in immunocompetent – like Blasto, “desert bumps”) or multiforme, usually self-limiting
in immunocompetent, may show cavities or nodules in lungs, disseminate to skin and bones (osteomyelitis), or cause meningitis if
immunocompromised, diagnose with KOH stain and culture, CXR, urine or serum rapid antigen test (IgM indicates recent infection), treat with PO
Itraconazole or Fluconazole if symptoms persist beyond 8 weeks, Amphotericin B if systemic or meningitis
• Histoplasma capsulatum – NOT encapsulated (despite name), smaller than a RBC (RBC: Blasto = same size, Cocci = larger, Paracocci = much larger),
transmitted via inhalation of spores, endemic to midwestern and central US, esp. Mississippi and Ohio River valleys, associated with cave
exploring/spelunking, exposure to bird (esp. starlings) or bat droppings, chicken farms, invades macrophages, oval yeast cells (“oval bodies”) seen within
macrophages, presents with Histoplasmosis: pneumonia, hilar lymphadenopathy, ulcerated tongue lesions, erythema nodosum (painful red nodules,
esp. on shins in immunocompetent, in Cocci also), in immunocompromised may present as hepatosplenomegaly with liver and spleen calcifications
(targets reticuloendothelial system, lots of macrophages in liver and spleen), diagnose with KOH stain of tissue or respiratory sample (kills everything but
fungus – oval bodies in macrophages), culture (time-consuming and impractical), urine or serum rapid antigen test, treat local infection with PO
Itraconazole or Ketoconazole, systemic infection with Amphotericin B
 • Paracoccidioides brasiliensis – budding yeast with multiple buds from a central vacuole, “captain’s wheel” appearance on microscopy, much larger than
RBC (RBC: Histo = smaller, Cocci = larger, Blasto = same size), transmitted via respiratory droplets, males > females, endemic to Central and South
America (“Brasiliensis”), presents with Paracoccidioidomycosis: pneumonia, lymphadenopathy (cervical, axillary, inguinal), granulomas in lungs, mucosal
ulcers in upper respiratory tract, esp. gums (ragged borders with small spots of hemorrhage), treat local infection with PO Itraconazole or Ketoconazole,
systemic infection with Amphotericin B

Cutaneous Mycoses
• Dermatophytes (Trichophyton, Microsporum, Epidermophyton) – dermatological monomorphic filamentous fungus, types: 1.) Trichophyton: infects
skin, hair, and nails, 2.) Microsporum: infects hair and skin, reservoir is pets, 3.) Epidermophyton: infects nails, skin, infections don’t disseminate,
associated with athletes, esp. swimmers and wrestlers, presents with Tinea (“Ringworm”), named based on location: Tinea capitis (head and scalp,
lymphadenopathy, alopecia, scaling), pedis (athlete’s foot, interdigital, moccasin distribution, or vesicular type), cruris (inguinal region, jock itch, no
central clearing), corporis (torso, erythematous scaling rings/”ringworm” with central clearing, acquired via contact with infected cat or dog), unguium
(nails) aka onychomycosis, all forms are pruritic, diagnose with 1.) Nail and Skin Scrapings: treat with KOH (arthroconidia and branching, septate hyphae
visible), 2.) ID Reaction: hypersensitivity response to fungal antigens, 3.) Wood’s Lamp: UV A light shined on skin, enhances color contrast, only used for
Microsporum, 4.) Culture: usually not necessary, treat by keeping infected area dry, topical or PO Clotrimazole, PO Terbinafine (Griseofulvin an
outdated alternative with GI side effects, poorly tolerated) for tinea capitis or onychomycosis, hepatotoxic, must monitor liver function tests

• Malassezia furfur/globosa – yeast-like dermatologic fungus (infects stratum corneum), not a dermatophyte despite name, “spaghetti and meatballs”
appearance on KOH mount due to yeast clusters with short, curved septate hyphae, associated with hot, humid weather (more common in summer),
premature infants (or adults) receiving parenteral lipid supplements or total parenteral nutrition (TPN), degrades lipids producing acids which destroy
melanocytes, presents with Pityriasis/Tinea Versicolor: hyper- or hypopigmented spots on back and chest (“blotchy suntan”), or pink patches, fungi
inhibit melanin, enlarge melanocytes, infected skin doesn’t tan, doesn’t itch (less pruritic than dermatophytes), diagnose with: 1.) Wood’s Lamp: UV A
light shined on skin, enhances color contrast, 2.) Skin Scrapings: treat with KOH, 3.) Culture: usually not necessary, treat with Selenium Sulfide (Selsun),
topical Miconazole, or PO Ketoconazole
 • Sporothrix schenckii – dimorphic, cigar-shaped yeast seen in pus at 37°C, septate hyphae and conidia present at 25°C, lives on plants, transmitted via
traumatic implantation (e.g. from a rose thorn), associated with gardeners (“rose gardener’s disease”), basket makers, presents with 1.) Sporotrichosis:
nodular skin lesions with ascending lymphangitis (begins at point of entry and track up arm along lymph nodes), necrotic and ulcerative skin lesions
develop as disease progresses, little systemic involvement, 2.) Pulmonary Sporotrichosis: associated with alcoholics and homeless, diagnose with: 1.)
Biopsy: reveals histiocytes, multinucleated giant cells, cigar-shaped budding yeasts, 2.) Culture: may be necessary to determine identity, treat with PO
Itraconazole for 3-6 months, alternatively Super Saturated Potassium Iodide (SSKI), Terbinafine (but cannot use any of these during pregnancy), or
thermotherapy, treat lung infection with Amphotericin B, surgical resection of infected tissue

Opportunistic Fungi
• Aspergillus flavus/fumigatus – monomorphic fungus with septate hyphae that branch at acute (~45°) angles (Mucor branches at right angles), stalks
with fruiting bodies (conidia in radiating chains at the end of conidiophores, rare), catalase ⊕ (also Candida, S. Aureus, P. cepacia, S. marcescens, S.
epidermidis, Nocardia, patients with CGD susceptible), recycler, found in compost piles, transmitted via inhalation of spores, virulence factor of A. flavus
is Aflatoxin, associated with peanuts and grain crops, causes liver damage, increases risk for hepatocellular carcinoma (aflatoxin B1 causes C-G to T-A
mutation in codon 249 of p53), presentations: 1.) Allergic Bronchopulmonary Aspergillosis (ABPA): asthma-like allergic reaction in airways with proximal
bronchiectasis, T1 (shows IgE/eosinophilia) and T4 reactions, mucus plugs form but do not penetrate tissue, associated with asthma, CF, presents with
wheezing, fever, and migratory pulmonary infiltrate, treat with systemic Corticosteroids and PO Itraconazole, 2.) Aspergilloma: mycetoma, “fungus ball”
forms in pre-existing lung cavitation, associated with Klebsiella, TB or other granulomatous disease, gravity dependent (settles to bottom of lungs in
upright CXR), treat with surgical removal, 3.) Angioinvasive Aspergillosis: invasive lung infection initially, then may disseminate quickly, associated with
immunocompromised (esp. neutropenia from Leukemia or Lymphoma), CGD, presents with pleuritic pain, fever and hemoptysis in lungs, infiltrates on
CXR and CT, invasion to kidneys leads to renal failure, to heart produces endocarditis, to brain produces ring-enhancing lesions (compare Toxo,
glioblastoma, but not TB), CNS version may present with seizures, focal neurologic findings, cough, pneumonia (patient with a history of TB could be TB
or Aspergillus), may spread to paranasal sinuses causing necrosis of nose (could also be Mucor), treat with Voriconazole, Amphotericin B, or
Caspofungin
• Candida albicans – dimorphic yeast with pseudohyphae and budding at 20°C (NOT a mold like other fungi), germ tube (hyphae) formation at 37°C
(diagnostic), true hyphae sprout from yeast, seen on light microscopy, catalase ⊕ (also S. Aureus, P. cepacia, S. marcescens, S. epidermidis, Nocardia,
Aspergillus, patients with CGD susceptible), associated with infants (diaper rash), immunocompromised (most common infection), oral steroid use,
diabetes, IV drug use, Penicillin/Cephalosporin use, normal flora of oral and mucocutaneous surfaces (may contaminate sputum samples), superficial
candidiasis prevented by Helper T-cells, disseminated candidiasis prevented by neutrophils, presentations: 1.) Oral Thrush: diabetes, neonates,
immunocompromised, neutropenia, or inhaled steroids, can be scraped off (contrast Leukoplakia, a neoplasia which can’t be scraped off), 2.) Candida
Intertrigo: within skin folds, 3.) Candida Vulvovaginitis (Yeast Infection): thick white discharge, dysuria, swelling, pruritus (all non-specific), pH does not
increase above 4 (contrast G. vaginalis and T. vaginalis, where pH >4.5), associated with diabetes, antibiotics, and birth control use, diagnose with KO
prep of sample, 4.) Diaper Rash: erythematous, 5.) Perleche: cracks at corner of mouth, associated with malnutrition, presents in immunocompromised
(esp. AIDS or neutropenic – local infection due to T-cell deficiency, systemic infection due to neutropenia), 6.) Esophagitis: AIDS-defining illness (CD4
<100), very rare in immunocompetent, 7.) Endocarditis: tricuspid valve, associated with IV drug use, 8.) Septicemia/ Disseminated Candidiasis: due to
inborne catheter (e.g. subclavian catheter), associated with neutropenia from pharmacological immunosuppression (transplant patient) or CGD, 9.)
Chronic Mucocutaneous Candidiasis, treat with PO Itraconazole or Fluconazole, Nystatin for superficial infection, esp. oral/esophageal forms (“swish
and/or swallow”), treat systemic infection with Amphotericin B, or if resistant, Caspofungin, treat vulvovaginitis with a topical -azole and PO Fluconazole
• Cryptococcus neoformans – monomorphic yeast, 5-10 μm, unequal budding with narrow base (narrow budding), polysaccharide capsule (unique among
fungi), wide capsular halo on staining, urease ⊕ (unique among fungi), transmitted via inhalation of pigeon droppings, then spreads hematogenously to
brain, reservoir is soil, associated with immunocompromised, presentations: 1.) Meningitis/Encephalitis: associated with AIDs and Hodgkin’s Lymphoma
(most common cause in each, also most common cause of fungal meningitis), “soap bubble” lesions in brain, 2.) Pneumonia: associated with pigeon
breeders, presents with cough and dyspnea, 3.) Skin and Bone Infections (Osteomyelitis), diagnose with 1.) Sabouraud’s Agar (urease ⊕), 2.) India Ink:
negative stain, characteristic image, 3.) Mucicarmine Stain: red inner capsule, 4.) Methenamine Silver Stain (GMS), 5.) Latex Agglutination Test: most
specific, detects repeating polysaccharide capsular antigen in CSF, treat meningitis/encephalitis with Amphotericin B + Flucytosine for 10 weeks, then
Fluconazole
• Mucormycosis, Rhizopus – filamentous fungi, irregular, broad, non-septate hyphae with wide-angle branching, transmitted via inhalation of spores,
reservoir is soil, associated with acidosis, esp. diabetic ketoacidosis (it produces ketone reductase, allowing it to thrive in ketotic conditions) and
neutropenia, fungus proliferates in blood vessel walls, penetrates brain via cribriform plate, presents as Rhinocerebral Infection (Mucormycosis): frontal
lobe abscess, cavernous sinus thrombosis, paranasal swelling, headache, facial pain (may have cranial nerve involvement), hemorrhage from nose and
eyes, penetrates blood vessel walls causing black, necrotic eschar on face (it eats your face off), treat with Amphotericin B and surgical debridement,
rapid progression and very poor prognosis

• Pneumocystis jiroveci (carinii) – disc-shaped (ovoid, “ping-pong shaped”) yeast that was once classified as a protozoan, obligate extracellular parasite,
transmitted via inhalation, associated with immunosuppression, esp. AIDS (AIDS-defining illness) and malnourished or premature infants, kills type 1
pneumocytes (gas exchange), type 2 pneumocytes (surfactant, stem cells) over-replicate and damage alveolar epithelium, fluid leaks into alveoli
producing exudate, honeycomb appearance on H&E, presents with Pneumocystis Carinii Pneumonia (PCP): diffuse interstitial pneumonia with fever,
non-productive cough, dyspnea, patchy infiltrates (no consolidations) with “ground glass” appearance bilaterally on CXR (if anything – often nothing on
CXR), diagnose with 1.) BAL, 2.) Lung Biopsy, 3.) Methenamine Silver Stain (GMS): disc-shaped yeasts in lung tissue, cysts in tissues, 4.) CXR, treat with
TMP-SMX, if sulfa allergy with Pentamidine, Atovaquone, treat HIV patients prophylactically with TMP-SMX when CD4 <200, if sulfa allergy with
Dapsone

• Microsporidium – G⊕ fungus once classified as a protozoan, spore forming, acid-fast, transmitted via ingestion of spores (fecal-oral), presents with
severe diarrhea in AIDS patients, no treatment (or restore immune state via HAART)
Protozoa – GI
• Cryptosporidium parvum (Isospora belli, Cyclospora cayetanensis) – unicellular protozoan that produces oocysts, each composed of 4 motile
sporozoites, acid-fast, after ingestion, sporozoites released, attach to small intestinal wall (may also cause colitis), transmitted via ingestion of oocysts
(fecal-oral), esp. in contaminated water, associated with immunocompromised, campers, those who work with animals, exposure to unpurified water,
presentations: 1.) Immunocompromised: severe diarrhea (many liters per day), 2.) Immunocompetent: mild diarrhea, diagnose with Stool O&P (cysts in
stool), acid-fast stain, antigen detection, treat immunocompromised with Nitazoxanide, Spiramycin, Azithromycin, illness in immunocompetent is self-
limiting (supportive treatment only), prevent by filtering city water supplies (Crypto highly resistant to chlorination, must filter it out)

• Entamoeba histolytica – protozoan with trophozoites and cysts, cysts infective when ingested, differentiates into trophozoites in GI tract, spreads to
liver via portal circulation, transmitted via ingestion of cysts (fecal-oral), associated with MSM (oral-anal transmission), exposure to unpurified water,
presentations: 1.) Liver Abscesses: red-brown, right lobe, usually solitary, consistency of anchovy paste, presents with RUQ pain, don’t operate (contrast
Echinococcus), 2.) Intestinal Amebiasis: dysentery (invasive, blood and pus in stool), diagnose with 1.) Stool O&P: cysts with up to 4 nuclei or
trophozoites in stool, 2.) Serology: endocytosed RBCs in amoeba cytoplasm or serum antibodies, 3.) Intestinal Biopsy: shows flask-shaped colonic ulcers,
treat with Metronidazole if symptomatic, Iodoquinol and Paromomycin if asymptomatic cyst passers (both luminal agents that eliminate cysts),
Corticosteroids contraindicated (bowel perforation) (“Entamoeba eats Erythrocytes”)

• Giardia lamblia – pear-shaped, binucleate, flagellated protozoan with trophozoites and cysts, cysts differentiate into trophozoites after ingestion,
protozoan attaches to, but does not invade, duodenal lining leading to malabsorption, transmitted via ingestion of cysts (fecal-oral), esp. in
contaminated water, associated with campers, hikers/backpackers, hunters, exposure to unpurified water, Selective IgA Deficiency, Bruton’s
 Agammaglobulinemia, CVID (IgA needed to fight Giardia), presents with Giardiasis: fatty, foul-smelling diarrhea (steatorrhea, may be explosive), bloating
and flatulence, chronically may lead to significant weight loss, vitamin (A, D, E, K) deficiencies due to malabsorption, diagnose with 1.) Stool O&P:
multinucleated cysts or trophozoites in stool, 2.) ELISA Stool Antigen Test, treat with Metronidazole if symptomatic, otherwise only if
immunocompromised

Protozoa – CNS
• Acanthamoeba polyphaga – free-living protozoan with trophozoites and cysts, transmitted via contaminated contact lens solution containing airborne
cysts, presentations: 1.) Granulomatous Amebic Encephalitis (GAE): granulomatous brain infection, fatal within 1 year, treat with Ketoconazole and
Sulfamethazine, but rarely successful, 2.) Keratitis: corneal infection, diagnose with biopsy (star-shaped or “spiky” cysts present), treat with topical
Miconazole
• Naegleria fowleri – free-living amoeba, transmitted via warm freshwater (compare L. interrogans), amoeba enters brain via cribriform plate (compare
Mucor), associated with swimmers, freshwater sports, backpacking, hot springs, exposure to stagnant fresh water (e.g. nasal irrigation, contact lens
solutions), presents with Primary Amebic Meningoencephalitis (PAM): severe prefrontal headache, nuchal rigidity, fever, altered mental status, altered
sense of smell, 95% mortality in 1 week, diagnose with LP (trophozoites/amoeba present in CSF, high neutrophils, low glucose, high protein), treat with
intrathecal Amphotericin B, but rarely successful

• Toxoplasma gondii – obligate, intracellular, parasitic protozoan, tachyzoites seen on biopsy, transmitted via contact with oocysts in cat feces, meat (esp.
pork), or across placenta (ToRCHeS infection, pregnant women should avoid cats and cleaning litter boxes), associated with immunosuppression, esp.
 AIDS (may mention other AIDS-related illness like PCP), presentations: 1.) Immunocompetent: flu-like illness, lymphadenopathy, 2.) Pregnant: congenital
toxoplasmosis in fetus, occurs if mother acquires primary infection during first 6 months of pregnancy, triad of hydrocephalus, intracranial calcifications,
and chorioretinitis (yellow/white lesions on funduscopic exam), may lead to mental retardation, seizures, blindness, deafness, and death in infant,
asymptomatic or lymphadenopathy (rare) in mother, 3.) AIDS: brain abscesses, seizures, headaches, ring-enhancing lesions on imaging (use biopsy to
distinguish from CNS lymphoma, a solitary infection with uniform enhancement, distinguish from glioblastoma, a solitary ring-enhancing lesion), AIDS-
defining illness, use TMP-SMX prophylaxis when CD4 <100 and ⊕ for toxoplasma IgG, diagnose with imaging, serology, biopsy, treat with Sulfadiazine,
Pyrimethamine (also used in malaria)

• Trypanosoma brucei gambiense/rhodesiense – parasitic protozoan, trypomastigotes (motile, single flagellated form), transmitted via tsetse fly (painful
bite), endemic to western and southeastern Africa (“African trypanosome”), spreads to CNS, lymph nodes, and blood, presents with African Sleeping
Sickness: recurrent, undulating fevers (due to variable surface glycoproteins which undergo constant antigenic variation), cervical and axillary
lymphadenopathy, drowsiness progressing to coma and death, diagnose with blood smear and LP (trypomastigotes present in CSF or blood), treat with
Suramin for acute disease with no CNS involvement (“Suramin for serum”), Melarsoprol for chronic disease with CNS penetration (very toxic drug)

Protozoa – Visceral
• Leishmania donovani/braziliensis – intracellular parasitic protozoan, promastigote the infectious form, amastigote the non-flagellated form, transmitted
via sandfly (promastigote), reservoir is humans, rodents, wild animals, donovani strain common in Middle East and Africa, braziliensis strain common in
South America, presentations: 1.) Cutaneous Leishmaniasis: Leishmania braziliensis, disfiguring ulcers (resemble syphilitic gummas), treat with Sodium
 Stibogluconate, 2.) Mucocutaneous Leishmaniasis: parasite attacks mucosal-dermal junction of nose and mouth producing multiple lesions, may
obliterate nasal septum and buccal cavity leading to death via secondary infection, 3.) Visceral Leishmaniasis: parasite infects macrophages, which
migrate to spleen, liver, and bone marrow, hyperpigmented spots (kala-azar), spiking/intermittent fevers, weight loss, hepatosplenomegaly with
abdominal swelling, jaundice, common in malnourished children, often fatal, serum shows pancytopenia, reticuloendothelial cells with Giemsa stain
show extracellular amastigotes (nucleus with bar-shaped kinetoplast), amastigotes within macrophages (round/oval shape with large nucleus), diagnose
with bone marrow, liver, or spleen biopsy, treat with Amphotericin B and Fluconazole, nearly 100% mortality within 2 years if untreated

• Trypanosoma cruzi – parasitic flagellated protozoan, trypomastigote the motile flagellated form, “the American trypanosome”, tunnels into tissue, feeds
on blood and lymph, transmitted via reduviid bug (triatomine, “kissing bug”, painless bite, esp. around mouth, defecates on wound, transmits
trypanosomes in feces, introduced into wound by scratching), endemic to South America, presentations: 1.) Acute Chagas’ disease: Romaña sign
(painless unilateral periorbital swelling, early sign of disease, caused by feces being rubbed into eye, or unilateral bite), chagoma (hardened red area) at
entry site, fever, malaise, lymphadenopathy, tachycardia and EKG changes, CNS symptoms, 2.) Chronic Chagas’ disease: dilated cardiomyopathy with
apical atrophy (burrows into endocardium, common cause of mortality, compare Coxsackie virus), arrhythmias, megacolon, megaesophagus, diagnose
via blood smear (trypomastigotes), xenodiagnosis (lab-grown bugs feed on patient, examined 1 month later for parasites), trypanosomes also may also
be present in myocytes during heart biopsy – rarely done), treat with Nifurtimox, Benznidazole

Protozoa – Hematologic
• Babesia microti – parasitic protozoan, invasion of RBCs, but no invasion of liver cells (contrast Plasmodium species), transmitted by the Ixodes (deer) tick
(also a vector for Borrelia burgdorferi, coinfection common), reservoir is white-footed mouse, associated with northeastern coast US (e.g. Nantucket
Island), presents with Babesiosis: “Texas Fever”, mild malaria-like illness (25-50% subclinical or mild), irregularly cycling fevers, hemolytic anemia,
hemoglobinuria, jaundice, more severe in asplenic patients (Sickle Cell Disease), thin peripheral smear shows intraerythrocytic ring inclusions (resemble
Plasmodium species), thick peripheral blood smear shows 4 merozoites adhering to RBC in shape of “Maltese cross”, treat with Atovaquone and
Azithromycin or Quinine and Clindamycin

• Plasmodium vivax/ovale/malariae/falciparum – parasitic protozoan, 2 hosts with complex life cycle, PHASE 1: asexual phase with 2 stages, occurs in
humans, Exoerythrocytic Stage occurs in liver, 1.) Sporozoites: motile, spindle-shaped forms, migrate through blood, invade liver parenchyma, 2.)
Trophozoites: balls of sporozoites within liver cell, undergo nuclear division without cytoplasmic partitioning of newly-formed nuclei, 3.) Schizont: cell
with thousands of nuclei, 4.) Merozoites: distinct cell formed as cytoplasmic membrane surrounds each nuclei within schizont, liver cells lyse, releasing
them into blood, Erythrocytic Stage occurs in RBCs (merozoites formed in liver enter RBCs), 5.) Trophozoites: reformed from merozoites, shaped like
diamond ring with nucleus as “diamond”, 6.) Schizont: trophozoites undergo nuclear division to form multinucleated schizonts, 7.) Merozoites:
cytoplasmic membrane forms around each nuclei within schizont, merozoites in a rosette shape, RBCs lyse, releasing merozoites into blood, 8.)
Hypnozoites: P. vivax and P. ovale only, dormant forms remain in liver, may cause relapsing malaria years later (why people who have had malaria can’t
donate blood), PHASE 2: sexual phase occurs in Anopheles mosquito (Sporogonic Cycle): 9.) Gametocytes: within the human, some merozoites change
into male and female gametocytes, taken up by Anopheles mosquito, 10.) Oocyst: male and female gametocytes fuse in mosquito stomach, forming
oocyst, 11.) Sporozoites: oocyst divides into many sporozoites, which can then be injected into a human to restart the cycle (back to Step 1),
pathogenesis caused by RBC lysis and agglutination, RBC rupture correlates with fever spikes (lysis among RBCs synchronized), Hb metabolized, all forms
transmitted via Anopheles mosquito, 7-30 day incubation period, increased susceptibility in pregnant women, associated with travel to endemic
countries, reservoir is humans (RBCs, hepatocytes), all forms present with cyclic fevers in 48-72 hour intervals with shaking chills and soaking sweats
(associated with RBC schizont rupture), hemolytic anemia (pallor, fatigue/sleepiness, malaise, jaundice), hepatosplenomegaly without
lymphadenopathy, hemorrhage and ischemia in post-capillary venules throughout body, may have pain behind eyes, severe forms may present with
cerebral malaria, severe hemolytic anemia, hemoglobinuria, ARDS, coagulation abnormalities, acute renal failure, hyperparasitemia (>5% of RBCs
infected), hypoglycemia (also in pregnant women with uncomplicated malaria), metabolic acidosis (associated with hypoglycemia), 4 species with
idiosyncratic features: 1.) P. Falciparum: banana-shaped, most common and deadly species, malignant tertian malaria, irregular fever spikes (36-48
hours), may present with Cerebral Malaria: lysed RBCs occlude brain perfusion (also kidneys and lungs), presents with abnormal behavior, impaired
consciousness, seizures, coma, no hypnozoites, peripheral smear may show Rouleaux formation, 2.) P. vivax/ovale: benign tertian malaria (48 hour fever
spikes, tertian because days 1 and 3 each counted), hypnozoites, P. vivax may show Schüffner’s dots in RBCs, 3.) P. malariae: quartan malaria (72 hour
fever spikes), recrudescence (symptoms recur from RBC reservoir of organisms), no hypnozoites, serum shows mild anemia, mild thrombocytopenia,
elevated bilirubin and aminotransferases, may show elevated BUN, creatinine, lactate dehydrogenase, diagnose with peripheral smear (shows
trophozoites and schizonts), Giemsa stain, rapid antigen tests (expensive, many false ⊖s), treat with Chloroquine (blocks Plasmodium heme
polymerase, kills erythrocyte form, retinopathy with long-term use, P. vivax, ovale, malariae sensitive, P. falciparum resistant), Primaquine (used for P.
vivax/ovale to kill latent hypnozoites, causes severe anemia in G6PD deficiency), Mefloquine (Lariam), Artemether-Lumefantrine (Coartem) or
Atovaquone/Proguanil (Malarone – severe P. falciparum), IV Artesunate or IV Quinine (very severe malaria, used with Doxycycline or Clindamycin, test
for G6PD Deficiency, Quinine causes cinchonism: headaches, flushing, blurred vision, tinnitus), Pyrimethamine/Sulfadoxine (all for Chloroquine-
resistant P. falciparum, Pyrimethamine a dihydrofolate reductase inhibitor also used for Toxoplasmosis), prevent with mosquito control (bed nets, long-
sleeved clothes, DEET or other insect repellant), Atovaquone/Proguanil (Malarone) typically used for chemical prophylaxis in travelers, also Mefloquine
(Lariam), Chloroquine, Primaquine, Doxycycline second line (cheaper, but more side effects, esp. GI, photosensitivity, vivid dreams), various genetic
deficiencies confer resistance to malaria, esp. against P. falciparum: SCD, HbS, HbSC Disease, Thalassemia (P. falciparum), absence of Duffy (Fy) antigen
on RBC (P. vivax), nearly all mutations most common in African Americans
Protozoa – STD
• Trichomonas vaginalis – motile trophozoites with corkscrew appearance, transmitted via sex, males are asymptomatic carriers, cannot form cysts and
does not exist outside human host, presentations: 1.) Vaginitis: itching, burning on urination, foul-smelling, frothy, greenish discharge, increased pH >4.5
(contrast C. albicans, which has a normal pH), 2.) Cervicitis: strawberry-colored mucosa (“strawberry cervix”) due to capillary dilation with areas of
punctate hemorrhage, diagnose by visualizing motile trophozoites in vaginal discharge on a wet mount or in urine, treat with Metronidazole, also treat
sexual partners (distinguish from Gardnerella vaginalis, which is a G⊖ organism that produces clue cells)

Introduction to Helminths
• Immune Response to Helminths – eosinophils act via T1 and T2 hypersensitivity reactions: 1.) T1: neutralization of histamine and leukotrienes, 2.) T2:
eosinophils attach to helminth surface via IgE and release cytotoxins contained in granules (e.g. major basic protein)
• Nematode Routes of Infection

Route of Infection Organisms

Ingestion (eggs) Enterobius vermicularis, Ascaris lumbricoides, Toxocara canis, Trichuris trichiura (don’t EATT these”)
Ingestion (larvae) Trichinella spiralis
Cutaneous Strongyloides stercoralis, Ancylostoma braziliense/caninum/duodenale, Necator americanus (“avoid the SANd”)
Bites Loa loa, Onchocerca volvulus, Wuchereria bancrofti, Dracunculus medinensis
Tapeworms (Cestodes)
• Diphyllobothrium latum – intestinal (fish) tapeworm, can grow very large, transmitted via ingestion of larvae in raw freshwater fish, absorbs vitamin B12,
may present with megaloblastic anemia, diagnose with stool O&P (proglottids), treat with Praziquantel
• Echinococcus granulosus/multilocularis – intestinal (sheep) tapeworm, transmitted via ingestion of eggs in dog feces (dogs are definitive host, sheep,
goats, pigs are intermediate hosts, humans are incidental host), eggs hatch in intestine, larvae spread through body, associated with immigrants, people
who grow up on farms or where dogs and livestock raised together, presents with: Hydatid Cysts: cysts in organs, esp. liver, CT shows “egg shell”
calcifications in liver, peripheral smear shows eosinophilia, treat with Albendazole/Mebendazole, surgical resection, surgeons inject cysts with ethanol
or hypertonic saline to kill them before removal to prevent anaphylaxis due to antigen release from cysts

• Taenia solium – intestinal (pork) tapeworm, long and flat with scolex (hooks, contrast T. saginata, which has no hooks), transmitted via ingestion of
encysted larvae (cysticerci) in undercooked pork (intermediate host), associated with unsanitary food prep (fecal contamination), immigrants, farmers,
presentations: 1.) Taeniasis: ingestion of cysts or larvae, asymptomatic, if symptoms, GI problems, malabsorption, 2.) Cysticercosis: ingestion of eggs (not
encysted larvae), eggs hatch and larvae migrate through body, penetrate tissue, and encyst forming cysticerci (tender, non-painful lumps), 3.)
Neurocysticercosis: same as Cysticercosis, but larvae encyst in the brain causing “swiss cheese” lesions on CT/MRI, headaches, seizures, increased ICP
(hydrocephalus), treat neurocysticercosis with Albendazole/Mebendazole, Praziquantel is second line, Prednisone or Dexamethasone used to prevent
inflammatory reaction from dying organisms, anticonvulsants used for seizures
• Taenia saginata – intestinal (beef) tapeworm, transmitted via ingestion of encysted larvae (cysticerci) in undercooked beef (intermediate host),
associated with unsanitary food prep, presents with Taeniasis: ingestion of cysts, larvae, or eggs, asymptomatic, if symptoms, GI problems,
malabsorption, no cysticercosis with ingestion of eggs (contrast T. solium), treat with Praziquantel, Niclosamide

•
Flukes (Trematodes)
• Introduction

• Clonorchis sinensis – Chinese liver fluke, transmitted via encysted larvae in undercooked fish (definitive host, snails are intermediate host), larvae
mature in humans and reside in biliary system, produces inflammation of the biliary tract, presents with: Biliary Tract Fibrosis: may lead to pigmented
gallstones and cholangiocarcinoma, diagnose with Stool O&P (operculated eggs), treat with Praziquantel

• Paragonimus westermani – transmitted via undercooked crab meat and crayfish (definitive host, snails are intermediate host), ingested larvae mature
and travel to lung, common in Asia and South America, produces lung inflammation with chronic cough and hemoptysis (mimics TB), possible secondary
bacterial infection, treat with Praziquantel
• Schistosoma mansoni/japonicum/haematobium – blood fluke, differentiate based on spine morphology (S. mansoni has large lateral spine, S.
japonicum has small spine, S. haematobium has large terminal spine), transmission via larval penetration of human skin, schistosomes mature in
freshwater snails (intermediate host), free-living cercariae (mature larvae) penetrate human swimmer’s skin, migrate to liver and mature, lay eggs which
migrate against portal flow to mesenteric veins (S. mansoni/japonicum) or veins surrounding bladder (S. haematobium) and lay eggs, eggs excreted or
disseminated hematogenously to organs, granulomas and fibrosis develop around deposited eggs, eggs can only hatch if excreted and reach freshwater
(no reproduction within humans), presentations: 1.) Dermatitis: caused by cercariae penetrating skin, “swimmer’s itch”, 2.) Katayama Fever: fever, hives,
cough, weight loss, 4-8 weeks after initial infection, 3.) Chronic Fibrosis/Cirrhosis: caused by deposition of eggs, symptoms vary by location of eggs,
include venous walls of liver (S. mansoni/japonicum, portal hypertension, jaundice), veins of bladder (S. haematobium, hematuria), CNS (brain or spinal
cord injury), 4.) Bladder Cancer: S. haematobium, chronic infection can lead to SCC of the bladder, histological keratin pearls, diagnose with Stool O&P,
treat with Praziquantel
Roundworms (Transmitted via Ingestion of Eggs)
• Ascaris lumbricoides – giant roundworm, most common helminth parasite worldwide, life cycle progresses from intestines to lungs to intestines, eggs
ingested (fecal-oral), larvae penetrate intestinal wall, hematogenous dissemination to lungs, growth in alveoli, larvae coughed up, then swallowed,
mature in intestines, eggs excreted in feces, transmitted via ingestion of eggs, associated with mountainous southern US, presents with Ascariasis: GI
and pulmonary symptoms (most common helminthic cause), peripheral smear shows eosinophilia, diagnose with Stool O&P (knobby-coated oval eggs),
treat with Pyrantel Pamoate, Albendazole/Mebendazole, complications include intestinal obstruction (possibly precipitated by drug therapy as worms
die), esp. at ileocecal valve, biliary obstruction, intestinal perforation
 • Enterobius vermicularis – pinworm, most common helminth parasite in US, transmitted via ingestion of eggs in contaminated food (fecal-oral), hand-to-
mouth after scratching perpetuates infection, presents with Perianal Pruritus: intestinal infection with anal itching, diagnose with scotch tape on anal
area to detect microscopic eggs, treat with Albendazole/Mebendazole, Pyrantel Pamoate

• Toxocara canis – dog roundworm, transmitted via ingestion of eggs (food contaminated with cat or dog feces), larvae infect host, never mature,
presents as: Visceral/Ocular Larva Migrans: larvae migrate to blood through intestinal wall, wander throughout body producing inflammation and
granulomas, produces myocarditis, liver damage, may cause visual impairment or blindness if they reach the eyes, seizures and coma in the CNS,
peripheral smear shows eosinophilia, treat with Albendazole/Mebendazole
• Trichuris trichiura – whipworm, slow life cycle, transmitted via ingestion of eggs (fecal-oral), presents with Trichuriasis: light infections asymptomatic, if
symptoms, abdominal pain, fatigue, and diarrhea (may be bloody), rectal prolapse in children (heavy infection), treat with Albendazole/Mebendazole

Larval Parasites (Transmitted via Ingestion of Larvae)

• Trichinella spiralis – roundworm, transmitted via ingestion of larvae in undercooked meat, esp. pork, fecal-oral route (less-likely), cysts travel from GI
tract to striated muscle, brain, and other organs where they form cysts, associated with unsanitary food prep, presents with Trichinosis: fever,
nausea/vomiting, diarrhea, abdominal discomfort, muscle inflammation and pain/discomfort, subconjunctival hemorrhages, splinter hemorrhages,
periorbital edema, cardiomyopathy and arrhythmia are major causes of death, peripheral smear shows eosinophilia, treat with
Albendazole/Mebendazole, but difficult to eradicate

Larval Parasites (Transmitted via Cutaneous Penetration of Larvae)

• Ancylostoma braziliense/caninum/duodenale, Necator americanus – hookworm, larvae in soil penetrate skin, eggs present in feces, autoinfection
perpetuates indefinitely if untreated, presentations: 1.) Cutaneous Larva Migrans: “creeping eruption” caused by light infection, raised red, itchy
serpiginous rash that moves as larvae move, associated with walking barefoot on contaminated beach, 2.) Systemic Infection: heavy infection,
abdominal pain, diarrhea, loss of appetite, weight loss, fatigue, iron deficiency (microcytic hypochromic) anemia (sucks blood from intestinal wall), 3.)
Pneumonitis: if migration to lungs, wheezing, cough, pneumonia-like symptoms, peripheral smear shows eosinophilia, diagnose with Stool O&P (eggs),
treat with Albendazole/Mebendazole, Pyrantel Pamoate
• Strongyloides stercoralis – threadworm, larvae in soil penetrate skin, eggs not present in feces (only larvae), autoinfection perpetuates indefinitely if
untreated (lays eggs in intestinal wall, larvae hatch, penetrate intestinal wall, enter bloodstream, travel to lungs to reinitiate cycle), presentations: 1.) GI:
vomiting, diarrhea, malabsorption, anemia, ulcers, bloody stools (may mimic peptic ulcer disease), 2.) Pneumonitis: wheezing, cough, pneumonia-like
symptoms, peripheral smear shows eosinophilia, diagnose with Stool O&P (rhabditiform larvae), treat with Albendazole/Mebendazole, Ivermecti
Arthropod-Borne Parasites
• Dracunculus medinensis – guinea worm, transmitted via drinking water infected with copepods (small crustaceans, intermediate host), larvae penetrate
host stomach and intestinal wall, mature in abdominal cavity, then females migrate to skin, esp. in lower extremities, eradicated except in Africa,
presents with skin inflammation and painful ulcer as worm erupts through skin (female exposes uterus in order to transmit eggs), peripheral smear
shows eosinophilia, treat with Niridazole, slow removal of worm with a stick
• Loa loa – African eye worm, transmitted via Chrysops (deer) fly, horse fly, mango fly, presentations: 1.) Conjunctivitis: worms in conjunctiva, 2.) Calabar
Swelling: painful, subcutaneous swelling of skin (transient angioedema), peripheral smear shows eosinophilia, diagnose with blood smear (microfilariae),
treat with Diethylcarbamazine, Albendazole/Mebendazole
• Onchocerca volvulus – transmitted via female blackfly, bites host, deposits larvae in skin, larvae penetrate skin, mature into adults, and produce
microfilariae, which migrate throughout body, esp. to eyes causing blindness, common around rivers in Africa, Central, and South America,
presentations: 1.) Onchodermatitis: scattered pruritic papules, thickened, hyperpigmented skin (“lizard skin”) due to loss of elastic fibers,
hypopigmented skin may occur on shins of older patients, 2.) River Blindness: blindness (second most common cause of infectious blindness after C.
trachomatis), allergic reaction to microfilariae also possible, peripheral smear shows eosinophilia, diagnose with skin biopsy (microfilariae), treat with
Ivermectin (“black flies, black skin nodules, black sight”)
• Wuchereria bancrofti – parasitic roundworm, mosquitos bite host, larvae penetrate skin and enter lymphatics, produce microfilariae, transmitted via
female mosquito bite (arbovirus), symptoms develop 9-12 months after bite, presents with Elephantiasis: worms invade lymph nodes, lymphatic vessel
blockage leads to inflammation, severe lymphedema with swelling and disfiguration of extremities, microfilariae travel to lungs producing cough,
peripheral smear shows eosinophilia, diagnose with thick blood smear (microfilariae), treat with Diethylcarbamazine
Ectoparasites
• Sarcoptes scabiei – mite that burrows into stratum corneum of skin, transmitted via skin-to-skin contact (most common) or fomites, common in
children, crowded populations (jails, nursing homes), presents with Scabies: pruritus (worse at night) and serpiginous burrows in lines in webspace of
hands and feet, treat with Permethrin cream, by washing/drying all clothing/bedding, treat close contacts

• Pediculus humanus/Pthirus pubis – blood-sucking lice that causes intense pruritus with associated excoriations, commonly on scalp and neck (head lice)
or waistband and axilla (body lice), transmits Rickettsia prowazekii (epidemic typhus), Borrelia recurrentis (relapsing fever), Bartonella quintana (trench
fever), treat with Pyrethroids, Malathion, or Ivermectin lotion, and nit combing, children with head lice can be treated at home without interrupting
school attendance
 • Parasite Hints

Association Organism
Biliary tract disease, cholangiocarcinoma Clonorchis sinensis
Brain cysts, seizures Taenia solium (neurocysticercosis)
Hematuria, SCC of the bladder Schistosoma haematobium
Liver (hydatid) cysts Echinococcus granulosus
Microcytic anemia Ancylostoma braziliense/caninum/duodenale, Necator americanus
Myalgias, periorbital edema Trichinella spiralis
Perianal pruritus Enterobius vermicularis
Portal hypertension Schistosoma mansoni/japonicum
Vitamin B12 deficiency Diphyllobothrium latum
Miscellaneous Micro
• Balantidium coli – parasitic ciliated alveolate, trophozoite (2 nuclei: long, “sausage-shaped” macronucleus with small, spherical micronucleus) and cyst
forms, transmitted via fecal-oral route (contaminated water), reservoir is pigs, presents with either diarrhea or constipation (suspect if diarrhea with
recent exposure to amoeba, e.g. related to travel), treat with Tetracyclines, Carbarsone (organoarsenic), Metronidazole, or Diiodohydroxyquinoline
 • Prions – infective proteins, only infectious agent not containing DNA or RNA, when prions infect organisms, they cause normal (predominantly α-helical)
prion proteins (PrPC) to misfold and assume the (β-pleated) pathogenic prion form (PrPSc), these proteins accumulate causing disease and forming
amyloid aggregates containing β-pleated sheets, PrPSc resists protease degradation and facilitates conversion of still more PrPC to PrPSc, in all prion
diseases, accumulation of PrPSc results in spongiform encephalopathy, dementia, ataxia, and death, transmitted via CNS-related tissue (iatrogenic CJD) or
food contaminated by BSE infected animal products (variant CJD), resistant to standard sterilizing procedures, including standard autoclaving,
presentations: 1.) Creutzfeldt-Jakob Disease: rapidly progressive dementia, human form of “mad cow disease” (“variant” CJD), typically sporadic (some
familial forms), 2.) Bovine Spongiform Encephalopathy (BSE): “mad cow disease”, 3.) Gerstmann-Sträussler-Scheinker Syndrome: inherited, genetic
alteration in PrP, most common form in developed countries, 4.) Kuru: cannibalism in Papua New Guinea, diagnose with biopsy (spongiform
degeneration), CSF shows 14-3-3 protein

Bacterial Structures
• Appendages
o Flagella: protein filament tails allowing movement and chemotaxis, V. cholerae has 1 flagellum, E. coli has many, S. dysenteriae has none
o Pili (Fibriae): made of glycoproteins, shorter than flagella and immobile, allows some bacteria to adhere to host (Neisseria species, E. coli), sex
pili are specialized for conjugation rather than for virulence
• Specialized Structures
o Endospores: keratin-like coat, dipicolinic acid (may confer heat resistance), peptidoglycan, DNA, G⊕ species only (Bacillus and Clostridium),
dormant form with no metabolic activity, confers resistance to hot/cold, wet/dry, and host chemical defenses, must autoclave to kill (steaming
at 121°C for 15 min), formed at end of stationary phase when nutrients sparse, Examples: B. anthracis (anthrax), B. cereus (food poisoning), C.
botulinum (botulism), C. difficile (pseudomembranous colitis), C. perfringens (gas gangrene), C. tetani (tetanus)

• Cell Envelope
o Capsule: organized, discrete polysaccharide layer (except B. anthracis, which is made of poly-D proteins), prevents phagocytosis
o Glycocalyx: loose polysaccharide network that aids bacteria in adherence to host surfaces, e.g. in catheter-associated infection
o Outer Membrane (G⊖):
 Outer Leaflet: contains endotoxin (LPS/LOS, lipid A induces TNF and IL-1, O polysaccharide component antigenic), embedded proteins
like porins (transport across outer membrane), and other outer membrane proteins (OMPs, most antigenic)
 Inner Leaflet: contains phospholipids
o Periplasm (G⊖): space between outer membrane and cytoplasmic membrane (peptidoglycan in middle), contains β–lactamases and other
hydrolytic enzymes (accumulates components exiting G⊖ cells)
o Cell Wall (G⊕): peptidoglycan sugar backbone with peptide side chains cross-linked by transpeptidase, contains major surface antigens of G⊕
bacteria (esp. lipoteichoic acid, which induces TNF-α and IL-1), net-like structure provides rigid support, protects against osmotic pressure
damage, Mycoplasma has no cell wall, Mycobacteria have an unusual cell wall
o Cytoplasmic Membrane: phospholipid bilayer sac with embedded proteins (e.g. PBPs), and other enzymes, lipoteichoic acids (G⊕ only, induce
TNF-α and IL-1) extend from membrane to exterior, site of oxidative and transport enzymes, PBPs involved in cell wall synthesis
• Cell Components
o Ribosome: 30S and 50S subunits, used for protein synthesis
o Plasmid: DNA separate from chromosomal DNA (replicates independently), may contain genes for antibiotic resistance and toxin
Bacterial Taxonomy
Morphology G⊕ Examples G⊖ Examples
Cocci (spherical) Staphylococcus (clusters) M. catarrhalis
Streptococcus (chains or pairs) Neisseria
Enterococcus (pairs or short chains)
Coccobacilli (hemi-spherical/rods) Haemophilus
Chlamydia
Bordetella
Pasteurella
Brucella
Bacilli (rods) Bacillus Enteric:
Clostridium Bacteroides
Corynebacterium Campylobacter
Gardnerella (G variable) E. coli
Lactobacillus Enterobacter
Listeria Fusobacterium
Mycobacterium (acid fast) Helicobacter
Propionibacterium Klebsiella
Proteus
Pseudomonas
Salmonella
Serratia
Shigella
Vibrio
Yersinia
Bordetella
Respiratory:
Burkholderia cepacia
Haemophilus (pleomorphic)
Legionella (silver stain)
Zoonotic:
Bartonella
Brucella
Francisella
Pasteurella

Branching Filamentous (fungus-like) Actinomyces

Nocardia
 Pleomorphic (no cell wall)
Spiral (spirochetes)
Bacterial Mutation
• Transformation
• Conjugation
• Transduction
Anaplasma, Ehrlichia
Chlamydiae (Giemsa stain)
Rickettsiae (Giemsa stain)
Mycoplasma (contains sterols which don’t G stain)
Borrelia (Giemsa stain)
Leptospira
Treponema
Stains
• Gram Stain – G⊕ bacteria have a thick peptidoglycan layer in their cell walls that holds crystal violet stain, they stain VIOLET, G⊖ bacteria cannot hold
the crystal violet stain and are instead stained by the safranin counterstain, they stain RED/PINK, 1st line test in bacterial identification
• Organisms that Gram Stain Poorly – Treponema and Leptospira (too thin to be visualized, use darkfield microscopy or fluorescent antibodies),
Mycobacteria (cell wall has high lipid content, use acid-fast stain), Mycoplasma and Ureaplasma (no cell wall), Legionella (intracellular parasite, use silver
stain), Rickettsia, Chlamydia, Bartonella, Anaplasma, Ehrlichia (intracellular parasite, cell wall does not contain peptidoglycan, Chlamydia have decreased
muramic acid) (“These Little Microbes May Unfortunately Lack Real Color But Are Everywhere”)
 • Giemsa Stain – bluish color represents stained rRNA, Chlamydia, Borrelia, Rickettsia, Trypanosomes, Plasmodium (“Certain Bugs Really Try my Patience”)
• Osmium Tetroxide – stains fat black
• Periodic Acid-Schiff Stain (PAS) – used to detect polysaccharides such as glycogen and mucopolysaccharides such as glycoproteins, glycolipids, and
mucin, used to diagnose Whipple disease, caused by Tropheryma whippelii

• Red Safranin O – stains cartilage, mast cell granules, and mucin red

• Ziehl-Neelsen (Carbol-Fuchsin) Stain – taken up by acid-fast organisms and organisms with mycolic acids in their cell wall, Mycobacteria, Nocardia
(partially acid-fast), Cryptosporidium oocysts, current standard of care is Auramine-Rhodamine Stain for screening (inexpensive, more sensitive, less
specific)
• India Ink Stain – not taken up by thick polysaccharide capsule, creating a transparent halo, C. neoformans (Mucicarmine Stain can also be used to stain
capsule red)
• Silver Stain – used for Fungi (P. jirovecii, Coccidioides, Legionella, H. pylori
• Fluorescent Antibody Stain – used to identify many bacteria and viruses, e.g. FTA-ABS for syphilis

Growth Media
• Properties – the same media can possess both or neither of these properties
o Selective Media: favors growth of a particular organism while preventing growth of other organisms, e.g. Thayer-Martin agar contains
antibiotics that allow the selective growth of Neisseria by inhibiting growth of other organisms
 o Indicator (Differential) Media: Yields a color change in response to metabolism of certain organisms, e.g. MacConkey agar contains a pH
indicator, a lactose fermenter like E. coli will convert lactose to acidic metabolites, producing a color change

Special Culture Requirements

Organism Culture Requirement
H. influenzae Chocolate agar, which contains factor V (NAD+), factor X (hematin, precursor of hemin)
N. gonorrhoeae, N. meningitidis Thayer-Martin media, aka VPN: Vancomycin (inhibits G⊕), Polymyxin (Trimethoprim + Colistin), inhibits G⊖),
Nystatin (inhibits fungi)
B. pertussis Regan-Lowe medium (charcoal, blood, antibiotic), Bordet-Gengou agar (“BORDETella” potato extract), collect
sample with calcium alginate swab
C. diphtheriae Cysteine-tellurite agar (forms metachromatic granules detected with methylene blue stain), Löffler’s medium
M. tuberculosis Löwenstein-Jensen agar
E. coli, K. pneumoniae, S. marcescens, MacConkey’s agar (pink colonies due to acid production by fermentation, contains bile to inhibit growth of
E. cloacae unwanted organisms), Eosin-Methylene Blue (EMB) agar (also used for lactose fermenters, E. coli produces
metallic green sheen)
M. pneumoniae Eaton’s agar, takes a long time to grow
L. pneumophila Charcoal yeast extract agar buffered with cysteine and iron
Vibrio species Requires NaCl, can grow in 6.5% NaCl
E. faecium/faecalis Can grow in 6.5% NaCl, differentiates it from S. bovis (GDS)
S. aureus Can grow in high levels of NaCl
K. pneumoniae, S. bovis, E. Can grow in bile
faecium/faecalis
Brucella, P. multocida, F. tularensis Cysteine
Fungi Sabouraud’s agar (esp. dermatophytes), fungi causing systemic illnesses take a long time to grow
Aerobes and Anaerobes
• Aerobes – use O2-dependent system to generate ATP
• Anaerobes – lack catalase and/or superoxide dismutase (more susceptible to oxidative damage), generally foul-smelling (short-chain fatty acids), difficult
to culture, produce gas in tissue (CO2 and H2), normal flora of GI tract, typically pathogenic elsewhere, Aminoglycosides ineffective against anaerobes
because they require O2 to enter bacteria (“AminO2glycosides”)
• Facultative Anaerobes – use fermentation and other non-oxygen-dependent pathways to generate ATP but are not killed by O2
• Microaerophiles – requires O2, but low levels
• Growth Level in Test Tube:
o Aerobes: growth at top
o Microaerophiles: growth just below surface
o Facultative Anaerobes: growth throughout
 o Aerotolerant Anaerobes: some growth at bottom
o Anaerobes: growth at bottom

Aerobic State Organism

Aerobes Nocardia, Pseudomonas, Mycobacteria (reactivation of M. tuberculosis following immunocompromise or TNF-α inhibitor use
has predilection for lung apices due to high oxygenation) (“Nagging Pests Must Breathe”)
Anaerobes Clostridium, Bacteroides, Fusobacterium, Actinomyces (“Anaerobes “Can’t Breathe Fresh Air”)
Microaerophiles C. jejuni, H. pylori, B. burgdorferi (“a bit of air for ‘bacter”)
Facultative Anaerobes Streptococci, Staphylococci, enteric G⊖ bacteria
Parasites
• Obligate Intracellular Parasites – must live within cells, protected from B-cell defenses, cannot be cultured on inert media, Bacteria: Chlamydia (can’t
make ATP), Rickettsia (can’t make enough ATP), M. leprae, Coxiella, Viruses: all, Protozoa: Plasmodium, T. gondii, Babesia, L. donovani, T. cruzi
• Facultative Intracellular Parasites – can live and reproduce inside or outside cells, Bacteria: Salmonella, Neisseria, Brucella, Mycobacterium, Listeria,
Francisella, Legionella, Yersinia pestis (Some Nasty Bugs May Live FacultativeLY”), Fungi: H. capsulatum, Helminths: E. vermicularis
• Other Obligate Parasites – live outside cells, but cannot be cultured on inert media, Bacteria: T. pallidum, Fungi: P. jiroveci
• Common Disease-Causing Intracellular Organisms
Hemolysis
• G⊕ cocci, type of RBC hemolysis on blood agar generally used to distinguish strains of Streptococcus, but S. aureus and L. monocytogenes also have
characteristic hemolytic properties

Type Appearance Organisms

α Dark and greenish (partial hemolysis without clearing) S. pneumoniae, S. viridans (ungrouped Strep), sometimes E. faecalis (GDS)
β Transparent (complete hemolysis with clearing) S. aureus, S. pyogenes (GAS), S. agalactiae (GBS), L. monocytogenes
γ Unchanged (no hemolysis) E. faecalis (GDS)

Drug Resistance
Drug Resistant Organism Resistance Mechanism
C. jejuni, E. faecalis, N. gonorrhoeae, G⊖ bacteria Β-lactamase, ESBL, mutated PBP, mutated porin protein
Penicillin (outer layer inhibits entry, resistant to Penicillin G, may
be susceptible to derivatives like Ampicillin)
Ampicillin Shigella dysenteriae Β-lactamase, ESBL, mutated PBP, mutated porin protein
Methicillin MRSA (alteration of PBP) Β-lactamase, ESBL, mutated PBP, mutated porin protein
Vancomycin E. faecalis (VRE), VRSA, G⊖ (outer layer inhibits entry) Mutated peptidoglycan cell wall (D-Ala-D-Ala to D-Ala-D-Lac),
impaired influx/increased efflux
Quinolones Enterococcus Mutated DNA gyrase, impaired influx/increased efflux
Ceftriaxone S. pneumoniae (some strains)
Aminoglycosides Obligate anaerobes (Aminoglycosides require O2 to Aminoglycoside-modifying enzymes, mutated ribosomal subunit
enter cell), Enterococcus protein, mutated porin protein
 TMP-SMX Enterococcus
Tetracyclines Inactivated enzyme, impaired influx/increased efflux
Chloroquine P. falciparum (some strains)
Bacitracin S. agalactiae
Optochin S. viridans
Isoniazid/Rifampin Multi-drug resistant tuberculosis (MDRT) Mutated RNA polymerase
Other Bacterial Characteristics
• Encapsulated – typically cause meningitis, produce IgA protease, undergo transformation (take up DNA from their environment), capsules act as
antiphagocytic virulence factors, encapsulated organisms cleared by opsonization (antibodies bind to capsule to aid in phagocytosis by macrophages and
neutrophils, clearance depends on C3 complement protein and functional spleen), asplenics (including SCD) have decreased opsonizing ability, increased
risk of infection by encapsulated organisms (give vaccine for S. pneumoniae, H. influenzae, and N. meningitidis), Quellung reaction used to visualize S.
pneumoniae, H. influenzae, N. meningitidis, K. pneumoniae (antibodies bind to capsule), capsular polysaccharide + protein conjugate serve as antigens in
vaccines, Examples: Pseudomonas, H. Influenzae type B, N. meningitidis, E. coli, Salmonella, Klebsiella, GBS
• Encapsulated Bacteria Vaccines – some vaccines containing polysaccharide capsule antigens are conjugated to a carrier protein, enhancing
immunogenicity by promoting T-cell activation and subsequent class switching, polysaccharide antigen alone can’t be presented to T-cells, Examples:
Pneumococcal vaccines PCV13 (conjugate, given to children) and PPSV23 (unconjugated polysaccharide, given to adults), H. influenzae type B
(conjugate), Meningococcal (conjugate, excludes strain B)
• Urease ⊕ – use urease to hydrolyze urea to ammonia and CO2, increases pH, predisposes to struvite (ammonium magnesium phosphate) stones, esp.
Proteus, Examples: U. urealyticum, C. neoformans, K. pneumoniae, Nocardia, Proteus, H. pylori (“Urease Contaminates Kidneys, Now Peeing Hurts”)
• Catalase ⊕ – use catalase to decompose peroxide into water and oxygen (bubbles) before host can use it to fight infection, normally peroxide is
converted within macrophages to microbicidal products by myeloperoxidase (MPO), in Chronic Granulomatous Disease (CGD), NADPH oxidase is
deficient, bacteria normally produce enough peroxide to make up for this, however catalase ⊕ organisms break down the peroxide they make so that it
cannot be used, susceptible to catalase ⊕ organisms, used to distinguish Staph from Strep species, Examples: Staphylococci (all species), Nocardia,
Serratia, Aspergillus, Candida, E. coli, Pseudomonas, Listeria, B. cepacia, H. pylori

• Coagulase ⊕ – coagulates blood, distinguishes S. aureus from other Staph species, Examples: S. aureus, Y. pestis
• Oxidase ⊕ – Examples: Neisseria, most G⊖ bacteria
Pigment Producing Bacteria
Organism Pigment
P. aeruginosa Blue-green “pyocyanin” and “pyoverdin”, ubiquitous in blue-green water
A. israelii Yellow “sulfur” granules (composed of filaments of bacteria)
S. aureus Yellow “golden”
S. marcescens Red
Biofilm Producing Bacteria
• Biofilm Production – foreign bodies become quickly coated with a layer of host proteins, free-living planktonic bacterial cells adhere to these leading to
irreversible binding with bacterial growth and division, intermicrobial communication induces exopolysaccharide production, mature multicellular
biofilm mass forms with decreased susceptibility to antimicrobial agents and host defense cells, detachment may occur with reversion of bacteria to
planktonic life cycle, promoting bacterial dispersion

Organism Biofilm Characteristic

S. epidermidis Catheter and prosthetic devices
S. viridans (mutans/sanguinis) Dental plaques, infective endocarditis (mitral/previously damaged valves)
P. aeruginosa Respiratory tree colonization in CF patients, ventilator-associated, contact lens-associated keratitis
H. influenzae (nontypeable, unencapsulated) Otitis media
Bacterial Virulence Factors
• Protein A – binds Fc region of IgG, prevents opsonization and phagocytosis, expressed by S. aureus
• IgA Protease – enzyme that cleaves IgA, allowing bacteria to adhere to and colonize mucous membranes, secreted by S. pneumoniae, H. influenzae type
B, and Neisseria
• M Protein – helps prevent phagocytosis, expressed by GAS, shares similar epitopes to human cellular proteins (molecular mimicry), possibly underlies
autoimmune response in Aacute Rheumatic Fever

Bacterial Secretion Systems

• Type 3 Secretion System – most clinically relevant type, “injectisome”, needle-like protein appendage facilitates direct delivery of toxins from certain
G⊖ bacteria to eukaryotic host cell, Examples: Pseudomonas, Salmonella, Shigella, E. coli

Type Structure Common Organisms

Type 1 3 components: 1.) ATPase binding cassette (ABC) transporter, 2.) Membrane Most pathogenic G⊖
fusion protein, 3.) Pore-forming outer membrane protein
Type 2 General Secretary Proteins (GSPs) with 4 components: 1.) Outer membrane Most pathogenic G⊖
complex, 2.) Inner membrane complex, 3.) Secretory ATPase, 4.) Pseudopilus
Type 3 Related to bacterial flagella, 3 components: 1.) Basal body, 2.) Inner rod, 3.) Salmonella, Shigella, Y. pestis, P. aeruginosa, pathogenic E. coli
Needle complex
Type 4 11-13 core proteins that form a channel H. pylori, B. pertussis, L. pneumophila
Type 5 Inner membrane with a β-channel pore in outer membrane Many environmental and pathogenic bacteria
Type 6 13 core proteins, cytosolic cylinder with membrane associated structure Y. pestis, Salmonella, E. coli
anchoring it to cytoplasm
Type 7 Unknown, but required for S. aureus virulence S. aureus, Mycobacteria
Exotoxins vs. Endotoxins
Exotoxin Endotoxin
Species G⊕ and G⊖ G⊖ and L. monocytogenes
Protein Location Secreted from cell Part of cell (LPS) membrane that fragments off
Chemistry Polypeptide Lipid A component of LPS (released when lysed)
Gene Location Plasmid or bacteriophage Bacterial chromosome
Toxicity High (1 μg fatal dose) Low (100+ μg fatal dose)
Clinical Effects Various Fever, shock (hypotension), DIC
Mode of Action Various Induces TNF, IL-1, IL-6
Antigenicity Highly antigenic (host forms antitoxins, high titer antibodies) Poorly antigenic
Vaccine Vaccine available (toxoid) No vaccine available
 Heat Stability Heat labile (rapidly destroyed at 60°C except Staph Heat stable (at 100°C for 1 hour)
enterotoxin and E. coli heat-stable toxin)
Example Tetanus, botulinum, diphtheria Meningococcemia, G⊖ sepsis
Exotoxins
• Introduction – Proteins released by both G⊕ and G⊖ bacteria, all major G⊕ bacteria produce exotoxin except L. monocytogenes (produces endotoxin),
exotoxins not heat stable, rapidly destroyed at 60°C (except S. aureus enterotoxin and E. coli heat-stable toxin)

Organism Toxin Mechanism Manifestation

Inhibits Protein Synthesis
C. diphtheriae Diphtheria toxin Inactivates Elongation Factor (EF-2) via Pharyngitis with pseudomembranes in throat and
ADP ribosylation severe lymphadenopathy (“bull neck”)
P. aeruginosa Exotoxin A* Inactivates Elongation Factor (EF-2) via Host cell death
ADP ribosylation
Shigella species Shiga toxin (ST)* Inactivates 60S ribosome by removing GI mucosal damage leading to dysentery, also
adenine from rRNA enhances cytokine release, causing HUS
E. coli (EHEC) Shiga-like toxin (SLT)* Inactivates 60S ribosome by removing Enhances cytokine release, causing HUS (esp. in EHEC
adenine from rRNA 0157:H7), unlike Shigella, does not invade host cells
Increases Fluid Secretion
E. coli (ETEC) Heat-labile toxin (LT)* Activates adenylate cyclase, increases Watery diarrhea
cAMP, increases Cl- secretion, causing
osmotic water loss
Heat-stable toxin (ST) Activates guanylate cyclase, increases
cGMP, decreases NaCl reabsorption,
causing osmotic water loss
B. anthracis Edema toxin* Mimics adenylate cyclase, increases cAMP Edematous border of black eschar in cutaneous
anthrax
V. cholerae Cholera toxin* Activates adenylate cyclase by Voluminous watery (“rice-water”) diarrhea
permanently activating Gs, increases
cAMP, increases Cl- secretion, causing
osmotic water loss
Inhibits Phagocytosis
B. pertussis Pertussis toxin* Activates adenylate cyclase by disabling Gi, Whooping cough, cough on expiration, “whoop” on
increases cAMP, impairs phagocytosis inspiration, toxin may not actually cause cough
Inhibits NT Release
C. tetani Tetanospasmin* Cleaves SNARE (soluble NSF attachment Spastic paralysis, risus sardonicus and “lockjaw”,
protein receptor) required for NR release prevents release of inhibitory GABA and glycine NTs
via vesical fusion from Renshaw cells in spinal cord
 C. botulinum Botulinum toxin* Cleaves SNARE (soluble NSF attachment Flaccid paralysis, floppy baby syndrome, prevents
protein receptor) required for NR release release of stimulatory ACh at NMJ
via vesical fusion
Lyses Cell Membranes
C. perfringens Alpha toxin Phospholipase (lecithinase) that degrades Gas gangrene via degradation of phospholipids
tissue and cell membranes leading to myonecrosis and hemolysis
S. pyogenes Streptolysin O Protein that degrades cell membrane Lyses RBCs, contributes to β-hemolysis, ASO host
antibodies formed
Causes Superantigen Shock
S. aureus Toxic Shock Syndrome Binds to MHC 2 and TCR outside of antigen Toxic Shock Syndrome: fever, rash, shock, others
Toxin (TSST-1) binding site leading to overwhelming cause scalded skin syndrome (exfoliative toxin) and
release of IL-1, IL-2, IFN-γ, and TNF-α food poisoning (heat stable enterotoxin)
S. pyogenes Exotoxin A (TSLS) Binds to MHC 2 and TCR outside of antigen Toxic Shock-Like Syndrome: fever, rash, shock, Scarlet
binding site leading to overwhelming Fever
release of IL-1, IL-2, IFN-γ, and TNF-α
• *AB toxin, 2-component toxin (3-component in B. anthracis) where B enables binding and triggers uptake (endocytosis) of the active A component,
which are usually ADP ribosyltransferases, others have enzymatic activities

Endotoxins
• Introduction – Lipopolysaccharide (LPS) found in cell wall of G⊖ bacteria (cocci and bacilli), composed of O antigen + core polysaccharide + lipid A (toxic
component), not a protein, but rather a normal component of the cell membrane that fragments/blebs off or is released upon bacterial lysis, antibiotic
treatment may cause large release of endotoxin, heat stable (can withstand 100°C for 1 hour), activates: 1.) Macrophages: binds TLR4, induces IL-1 and
IL-6 (fever), TNF-α (fever and hypotension), NO (hypotension), 2.) Complement Cascade: via C3a and C5a (histamine release, hypotension and edema,
neutrophil chemotaxis), 3.) Coagulation Cascade: via factor 12, activating coagulation cascade and leading to DIC (ENDOTOXINS mnemonic: “Edema, NO,
DIC/Death, Outer membrane, TNF-α, O-antigen + core polysaccharide + lipid A, eXtremely heat stable, IL-1/6, Neutrophil chemotaxis, Shock”)
Viral Envelopes

• Introduction – enveloped viruses usually acquire their envelope from the host cell’s plasma membrane as they exit the cell, exceptions include
Herpesviruses (acquire envelope from host nuclear membrane) and Bunyaviruses (acquire membrane from host Golgi bodies)
• DNA Enveloped Viruses – Herpesviruses, HBV, Smallpox virus
• DNA Nucleocapsid/Naked Viruses – Adenovirus, Papillomavirus, Parvovirus, Polyomavirus, Calicivirus, Picornavirus, Reovirus, Hepevirus
• RNA Enveloped Viruses – Influenza virus, Parainfluenza virus, RSV, Measles virus, Mumps virus, Rubella virus, Rabies virus, HTLV, HIV
• RNA Nucleocapsid/Naked Viruses – Picornaviruses (Poliovirus, Coxsackievirus, Echovirus, HAV, Rhinovirus), Reoviruses (Reovirus, Rotavirus, Colorado
Tick Fever virus), Caliciviruses (Norwalk virus)
Viral Genetics
• Recombination – exchange of genes between 2 chromosomes, crossing over occurs in regions of significant base sequence homology

• Reassortment – viruses with segmented genomes exchange segments, analogous to high-frequency recombination, Example: Influenza pandemics (e.g.
2009 H1H1 Influenza virus strain) via antigenic shift (complex reassortment between human, swine and avian viruses)
• Complementation – 2 viruses infect a cell, but one is mutated and has a non-functional protein, the non-mutated virus helps the mutant by making the
protein for both, Example: HDV requires presence of replicating HBV to supply HBsAg, the envelope protein for HDV
• Phenotypic Mixing – 2 viruses infect a cell, progeny viruses contain coat proteins from both viruses, but genetic material is not altered, pseudovirion
may be formed, where the viral coat is made entirely from another virus (nucleic acid and coat are completely mismatched), protein coat determines
tropism (infectivity) of hybrid virus, however viral progeny will have coat coded for by genetic material inside (i.e. a hybrid virion cannot produce a
hybrid virion since the coat is not coded for by the DNA inside)
Viral Stranding and Segmentation
• ⊕-Sense RNA – just like mRNA, can be read by host’s translational machinery to make viral proteins, purified nucleic acids infectious (dsDNA also)
• ⊖-Sense RNA – complementary to mRNA, must be transcribed into ⊕-sense RNA by virus’ own RNA-dependent RNA polymerase, which all ⊖-sense
RNA viruses carry in their capsid, purified nucleic acids not infectious (dsRNA not infectious either), Examples: Arenavirus, Bunyavirus, Paramyxovirus,
Orthomyxovirus, Filovirus, Rhabdovirus (“Always Bring Polymerase or Fail Replication”)
• Strand Direction/Sense in RNA Viruses – all ⊕-sense except Reovirus
• Strand Direction/Sense in DNA Viruses – most DNA viruses are double stranded, and thus have a ⊕ and a ⊖ strand (except Parvoviruses, which are
single stranded), however for DNA viruses “⊕ strand” refers to the one that is read, whereas “⊖ strand” refers to the one that is ignored
 • RNA Virus Replication Location – cytoplasm except Influenza virus and Retroviruses
• DNA Virus Replication Location – nucleus except Poxvirus (“pox is out of the box”)
• Segmented Genomes – viral genomes are sometimes split into separate parts (segmenting)
• Segmented Viruses – Bunyaviruses (Hantavirus, CA Encephalitis virus), Orthomyxoviruses (Influenza virus), Arenaviruses (Lassa Fever virus, LCMV),
Reoviruses (Reovirus, Rotavirus, Colorado Tick Fever virus) (BOAR – Bunyavirus, Orthomyxovirus, Arenavirus, Reovirus)
• Viral Receptors

Virus Receptors
CMV Cellular integrins (heparin sulfate)
EBV CR2 (CD21)
HIV CD4, CXCR4, CCR5
Parvovirus B19 P antigen on RBCs
Rabies Nicotinic ACh receptor
Rhinovirus ICAM-1 (CD54)
Arboviruses
• Introduction – Arthropod-borne virus, common vectors include mosquitos, fleas, and ticks
• Most Common Arboviruses – Flaviviruses (Yellow Fever virus, Dengue Fever virus, West Nile virus, St. Louis Encephalitis virus, Zika virus), Togaviruses
(Eastern/Western/Venezuelan Equine Encephalitis viruses, Chikungunya virus), Bunyaviruses (California Encephalitis virus)
• Most Common Vectors – Ixodes (deer) tick (B. burgdorferi, Babesia, Ehrlichia), Dermacentor (dog) tick (Rickettsia species, F. tularensis, Colorado Tick
Fever Virus), Aedes aegypti mosquito (Zika virus, Yellow Fever Virus, Dengue Fever virus, Chikungunya virus), Culex mosquito (West Nile virus, St. Louis
Encephalitis virus), Anopheles mosquito (Plasmodium species), variety of mosquito species (W. bancrofti)

Normal Flora
• Neonates – fetal GI tract is sterile, rapidly colonized after birth, infants delivered via C-section have unstable flora longer

Location Organism
Skin S. epidermidis
Nose S. epidermidis, S. aureus (25% of population)
Oropharynx S. viridans
Dental Plaque S. mutans
Colon Bacteroides (99% of GI bacteria), E. coli
Vagina Lactobacillus, colonized by E. coli and GBS
Meningitis
• Introduction – Inflammation of the meninges (contrast encephalitis, which is inflammation of brain parenchyma), bacterial meningitis may be life-
threatening, aseptic meningitis more common than bacterial, often caused by viruses, esp. Enteroviruses, more common in children and during the
summer, all meningitis presents with fever, headache, altered mental status, neck stiffness, H. influenzae meningitis has decreased due to conjugate
vaccine, cases now seen mostly in unimmunized children

Age Organism
Neonates (0-6 weeks) GBS, E. coli, L. monocytogenes
Children (6 months – 6 years) S. pneumoniae, N. meningitidis, H. influenzae, Enteroviruses (Coxsackievirus, Poliovirus, Echovirus)
Adults (18-40) S. pneumoniae, N. meningitidis, HSV-1 and 2, Enteroviruses (Coxsackievirus, Poliovirus, Echovirus)
Elderly (>40) S. pneumoniae, L. monocytogenes, G⊖ rods
Immunocompromised S. pneumoniae, L. monocytogenes, N. meningitidis, CMV, JC Virus, C. neoformans, T. gondii (brain abscesses)
Aseptic Causes HSV-1 and 2, Enteroviruses (Coxsackievirus, Poliovirus, Echovirus), HIV, N. fowleri, C. neoformans (HIV), West Nile Virus,
LCMV, VZV
• CSF Findings in Meningitis

Meningitis Type Opening Pressure Cell Type Increased Protein Glucose

Bacterial  PMNs  
Fungal/TB  Lymphocytes  
Viral  or Normal Lymphocytes  or Normal Normal
• Infections Causing Brain Abscesses – most commonly S. viridans and S. aureus, if prodromal dental infection or extraction, oral anaerobes commonly
involved, multiple abscesses usually due to bacteremia, single lesion from contiguous sites (e.g. otitis media and mastoiditis spreading to temporal lobe
and cerebellum, sinusitis or dental infection spreading to frontal lobe), in AIDS may be caused by Toxoplasma reactivation
• Meningitis Treatment

Age Treatment
Neonates (0-4 weeks) IV Ampicillin + Cefotaxime or an Aminoglycoside (e.g. Gentamicin, Tobramycin)
Children (1 month – 18 years) IV Vancomycin + Cefotaxime or Ceftriaxone, add Ampicillin if L. monocytogenes suspected
Adults (18-40) IV Vancomycin + Cefotaxime or Ceftriaxone
Elderly (>40) IV Vancomycin + Cefotaxime or Ceftriaxone + Ampicillin to cover L. monocytogenes
Respiratory Tract Infections
• Introduction

Pneumonia
• Typical vs. Atypical Pneumonia – Atypical pneumonia (“walking pneumonia”) is the type of pneumonia not caused by one of the more traditional
pathogens. The term was introduced in the 1930s and was contrasted with the bacterial pneumonia caused by S. pneumoniae, at that time the best
known and most commonly occurring form of pneumonia. The distinction was historically considered important, as it differentiated those more likely to
present with "typical" respiratory symptoms and lobar pneumonia from those more likely to present with "atypical" generalized symptoms (such as
fever, headache, sweating and myalgias) and bronchopneumonia. In atypical pneumonia, the patient does not feel as seriously ill as their X-Ray
indicates.
• Most Common Causes of Typical Pneumonia – S. pneumoniae, H. influenzae, M. catarrhalis
• Most Common Causes of Atypical Pneumonia – M. pneumoniae, C. pneumoniae, L. pneumophila
 Age Organism
Neonates (<4 weeks) GBS, E. coli, Parainfluenza
Infants (<2) B. pertussis, S. pneumoniae, C. trachomatis, HHV-6, RSV
Children (<5) S. pneumoniae, H. influenzae (unimmunized), CMV, Adenovirus, Influenza, Parainfluenza, Metapneumovirus
Older children (5-15) C. pneumoniae, M. pneumoniae
Young adults (15-24) C. trachomatis (sexually active), EBV
Adults (25-40) S. pneumoniae, C. pneumoniae, M. pneumoniae
Older adults (40-65) S. pneumoniae, H. influenzae, M. pneumoniae, anaerobes, viruses
Elderly (>65) S. pneumoniae, H. influenzae, K. pneumoniae, L. pneumophila, Influenza, Parainfluenza, Metapneumovirus, RSV
Alcoholics K. pneumoniae, anaerobes usually due to aspiration (Peptostreptococcus, Fusobacterium, Prevotella, Bacteroides)
IV Drug Use S. aureus, S. pneumoniae
Atypical L. pneumophila, C. pneumoniae, C. psittaci, M. pneumoniae
Immunocompromised S. aureus, enteric G⊖ rods, fungi, viruses (e.g. CMV), P. jirovecii (HIV),
Nosocomial S. aureus, S. marcescens, P. aeruginosa, other enteric G⊖ rods
Cystic Fibrosis P. aeruginosa, S. aureus, S. pneumoniae, Burkholderia cepacia
Post-Viral S. aureus, S. pneumoniae, H. influenzae
• Empiric Treatment: Cephalosporin (e.g. Ceftriaxone) for G⊕, Macrolide (e.g. Azithromycin) for G⊖
• Acute bronchitis almost always caused by a virus

Foodborne Illness
• Neonates – fetal GI tract is sterile, rapidly colonized after birth, infants delivered via C-section have unstable flora longer

Organism Source of Infection

B. cereus Reheated rice, food kept warm but not hot
C. botulinum Improperly canned foods (toxins), raw honey (spores)
C. perfringens Reheated meat
E. coli O157:H7 Undercooked meat
L. monocytogenes Deli meats, soft cheeses
Salmonella Poultry, meat, eggs
S. aureus Meats, mayonnaise, custard (preformed toxin)
V. parahaemolyticus/vulnificus Contaminated seafood, also causes wound infections from contact with contaminated water or shellfish
Diarrhea and Food Poisoning by Organism
Organism Transmission Comments
G⊕
S. aureus Custards, mayonnaise/potato salad, canned meats Symptoms start and end quickly
B. cereus Reheated rice, food kept warm but not hot Symptoms start and end quickly
C. botulinum Canned food, home canned alkaline vegetables, honey in infants
C. perfringens Reheated meat Watery
C. difficile Endogenous/nosocomial, not caused by food poisoning Watery
G⊖
E. coli (EHEC – no invasion, no WBCs) Undercooked meat, contaminated food, fecal-oral Bloody
E. coli (EIEC – invasion with WBCs) Undercooked meat, contaminated food, fecal-oral Bloody
E. coli (ETEC – no invasion, no WBCs) Undercooked meat, contaminated food, fecal-oral Watery (rice-water resembling cholera)
S. enteritidis Chicken products (eggs, raw chicken) Bloody or watery
S. dysenteriae Fecal-oral Bloody
C. jejuni Poultry, unpasteurized milk, fecal-oral Bloody with pus
V. cholerae Fecal-oral Watery (rice-water)
V. parahaemolyticus/vulnificus Seafood, sushi
G⊖ Zoonotics
Y. enterocolitica Contaminated milk, pork, pet feces Bloody
Brucella Unpasteurized dairy
DNA Viruses
Adenovirus Fecal-oral Watery, pediatric
RNA Viruses
Norwalk virus Fecal-oral Watery, pediatric
Reovirus Fecal-oral
Rotavirus Fecal-oral Watery, infant mortality
Protozoa
G. lamblia Fecal-oral Watery, campers/hikers
E. histolytica Fecal-oral Bloody or watery
Cryptosporidium Fecal-oral Watery, AIDS
Helminths
T. solium Undercooked beef Neurocysticercosis
T. saginata Undercooked pork
D. latum Undercooked fish
Diarrhea and Food Poisoning by Diarrhea Type
Organism Comments
Bloody Diarrhea
Campylobacter Comma- or S-shaped organisms, growth at 42°C
E. histolytica Protozoan, amebic dysentery, liver abscess
Enterohemorrhagic E. coli (EHEC) O157:H7, can cause HUS, makes Shiga-like toxin
Enteroinvasive E. coli (EIEC) Invades colonic mucosa
Salmonella (non-typhoidal) Lactose ⊖, flagellar motility, has animal reservoir, esp. poultry and eggs
Shigella Lactose ⊖, very low ID50, produces Shiga toxin, human reservoir only, bacillary dysentery
Y. enterocolitica Day care outbreaks, pseudoappendicitis
Watery Diarrhea
C. difficile Pseudomembranous colitis, associated with antibiotics (esp. Clindamycin) and PPIs, occasionally bloody diarrhea
C. perfringens Also causes gas gangrene
Enterotoxigenic E. coli (ETEC) Traveler’s diarrhea, produces heat-labile (LT) and heat-stable (ST) toxins
Protozoa Giardia, Cryptosporidium
V. cholerae Comma-shaped organisms, rice-water diarrhea, often from infected seafood
Viruses Rotavirus, Norovirus, Adenovirus
Hepatitides
• Introduction – Hepatitis viruses primarily infect hepatocytes, 4 are RNA viruses (HAV, HCV, HDV, HEV), 1 is a DNA virus (HBV), presents with fever,
jaundice, elevated liver enzymes (ALT>AST in viral hepatitis, AST>ALT in alcoholic hepatitis), HBV and HCV produce chronic active hepatitis, liver cirrhosis,
and hepatocellular carcinoma, HAV, HDV, and HEV produce acute hepatitis, HAV and HEV are transmitted via fecal-oral route (“vowels attack your
bowels”), not destroyed in gut

HAV HBV HCV HDV HEV

Family Picornavirus Hepadnavirus Flavivirus Defective Deltavirus Hepevirus
Genome Naked RNA Enveloped DNA Enveloped RNA Enveloped RNA (circular) Naked RNA
Transmission Fecal-oral Parenteral, sex, perinatal Parenteral or sex Parenteral, sex, perinatal Fecal-oral (esp. water)
Incubation Short (3 weeks) Long (3 months) Long (6-12 weeks) Short (superinfection) or Short
long (coinfection)
Disease Mild acute only Acute, Chronic (20%), Acute, Chronic (70%), Coinfection or Mild acute only,
Cirrhosis, Carcinoma Cirrhosis, Carcinoma superinfection with HBV fulminant in pregnancy
 Prognosis Good Full resolution (adults), Most develop stable Superinfection carries High mortality in
worse prognosis chronic form worse prognosis pregnant women
(neonates)
Mortality <0.5% 1-2% 0.5-1% High 1-2% or 25% if 3rd trim.
Carrier State No Yes Yes Yes No
Liver Biopsy Hepatocyte Granular eosinophilic Lymphoid aggregates Similar to HBV Patchy necrosis
swelling, “ground glass” with focal areas of
monocyte appearance, cytotoxic T- macrovesicular
infiltration, cells mediate damage steatosis
Councilman
bodies
Vaccine Yes Yes No (clinical trials) No No (clinical trials)
Mnemonic A for Acute only B for Bad, big like “great C for Chronic, Carrier D for Dependent, E for Enteric, East,
dane” Defective Epidemic
• Hepatitis Serologic Markers

Marker Indication
Anti-HAV (IgM) IgM antibody to HAV, best test to detect acute Hepatitis A
Anti-HAV (IgG) IgM antibody indicates prior HAV infection and/or prior vaccination, protects against reinfection
HBsAg Antigen found on the surface of HBV, indicates Hepatitis B infection
Anti-HBs Antibody to HBsAg, indicates immunity to Hepatitis B due to vaccination or recovery from infection
Anti-HBs only Indicates immunity to Hepatitis B due to vaccination
Anti-HBs + Anti-HBc Indicates immunity to Hepatitis B due to recovery from infection
HBcAg Antigen associated with core of HBV
Anti-HBc Antibody to HBcAg, IgM = acute/recent infection, IgG = prior exposure or chronic infection, IgM anti-HBc may be sole
positive marker during window period
HBeAg Secreted by infected hepatocyte into circulation, not part of mature HBV virion, indicates active viral replication and
therefore high transmissibility and poorer prognosis
Anti-Be Antibody to HBeAg, indicates low transmissibility
• Extrahepatic Manifestations of Hepatitis B and C

System Hepatitis B Hepatitis C

Hematologic Aplastic anemia Essential mixed cryoglobulinemia, increased risk of B-cell Non-Hodgkin
Lymphoma, ITP, autoimmune hemolytic anemia
Renal Membranous GN progressing to Membranoproliferative GN Membranoproliferative GN progressing to Membranous GN
Vascular Polyarteritis Nodosa Leukocytoclastic vasculitis
Dermatologic - Sporadic Porphyria Cutanea Tarda, Lichen Planus
Endocrine - Increased risk of Diabetes Mellitus, autoimmune hyperthyroidism
Urinary Tract Infections (UTIs)
• Urinary Tract Infection (Acute Bacterial Cystitis) – women affected more frequently than men (10x) due to shorter urethra colonized by fecal flora,
closer proximity of urethra to anus, and colonization of vagina by fecal flora, leading cause of UTIs is urinary catheters, other predisposing factors include
diabetes, pregnancy, renal surgery, congenital defects (GU malformations), impaired bladder emptying, vesicoureteral reflux (urine backflow from
bladder into ureters), BPH, sexual intercourse (“honeymoon cystitis”), presentations: 1.) Cystitis: bladder infection, presents with dysuria, polyuria,
urgency, suprapubic pain, WBCs in urine, but no casts, systemic symptoms (e.g. fever) uncommon, primarily caused by ascension of microbes from
urethra to bladder, arises in male infants with congenital defects or in adults due to vesicoureteral reflux, in the elderly due to prostatic enlargement, 2.)
Pyelonephritis: infection reaches upper urinary tract or kidney, presents with fever, chills, flank pain, costovertebral angle (CVA) tenderness, hematuria
and WBC casts in urine, diagnose with ⊕ Leukocyte Esterase Test (indicates bacterial UTI, evidence of WBC activity), ⊕ Nitrite Test (indicates G⊖ UTI,
bacterial reduction of urinary nitrates), ⊕ Urease Test (indicates bacterial UTI by urease-producing bacteria, esp. S. saprophyticus, Proteus, Klebsiella),
sterile pyuria and ⊖ urine cultures suggest urethritis via N. gonorrhoea or C. trachomatis
• UTIs by Type

Disorder Common Organism Symptoms Laboratory

Urethritis N. gonorrhoeae, C. trachomatis Pain/burning on urination, urgency or frequent urination UA: WBC⊕
Cystitis E. coli, S. saprophyticus, P. Asymptomatic or symptomatic, suprapubic pain and UA & Micro: Leukocyte Esterase⊕,
mirabilis, Klebsiella, Enterococci tenderness, frequent urination Nitrates⊕, Bacteria⊕, WBC⊕, RBC⊕
(occasionally)
Pyelonephritis Same as cystitis Flank pain, costovertebral angle tenderness, fever, chills, UA & Micro: same findings as in
hematuria with casts cystitis + WBC casts (indicating renal-
based pyuria)
CBC:  WBC
• UTIs by Organisms
 Organism Comments
G⊕
S. Saprophyticus Second most common cause, esp. in young, sexually active females
Enterococcus Often nosocomial and drug resistant
G⊖
E. coli Most common cause, colonies show metallic sheen on EMB agar
K. pneumoniae Third most common cause, large mucoid capsule and viscous colonies
Proteus mirabilis Motility causes “swarming” on agar, produces urease, urine has ammonia scent, associated with struvite stones
P. aeruginosa Indwelling catheters, blue-green pigment and fruity odor, often nosocomial and drug resistant
Enterobacter cloacae
S. marcescens Some strains produce a red pigment, often nosocomial and drug resistant
Pelvic Inflammatory Disease (PID)
• Introduction – generic term for inflammation of uterus, fallopian tubes, or ovaries, caused by ascending infection of reproductive organs (ascends like a
UTI of the reproductive tract), may produce scar tissue leading to infertility, ectopic pregnancy, and chronic pain, 750,000 women per year in the US, 10-
15% become infertile as a result, presentations: 1.) Salpingitis: risk factor for ectopic pregnancy, infertility, chronic pelvic pain, and adhesions, 2.)
Endometritis, 3.) Hydrosalpinx, 4.) Tubo-Ovarian Abscess, serious complication is Fitz-Hugh Curtis Syndrome: infection spreads to liver capsule causing
inflammation and scar tissue (perihepatitis), parietal peritoneum adheres to liver via “violin-string” adhesions
• Common Causes of Pelvic Inflammatory Disease – C. trachomatis (subacute, often undiagnosed, most common STI in the US, cervical motion
tenderness aka “chandelier sign”, purulent cervical discharge), N. gonorrhoeae (acute), Ureaplasma urealyticum, M. pneumonia, G. vaginalis, T. vaginalis
Common Vaginal Infections
Organism Signs and Symptoms Lab Findings Treatment
Bacterial Vaginosis No inflammation, thin white discharge with fishy odor Clue cells, pH >4.5 Metronidazole
Trichomonas Vaginitis Inflammation (“strawberry cervix”), frothy, yellow-green, Motile trichomonads, pH >4.5 Metronidazole
foul-smelling discharge (treat partners also)
Candida Vulvovaginitis Inflammation, thick, white, “cottage cheese” discharge Pseudohyphae, pH normal (4.0 – 4.5) -azoles

Sexually Transmitted Infections (STIs)

Organism
N. gonorrhoeae
H. ducreyi
K. (Calymmatobacterium)
granulomatosis
T. pallidum – Primary
T. pallidum – Secondary
T. pallidum – Tertiary
C. trachomatis (D-K)
C. trachomatis (L1-L3)
HPV 6 and 11
HSV-2 (HSV-1 less commonly)
HBV
HIV/AIDS
Disease Key Associations and Clinical Features
Gonorrhea No capsule, ferments glucose but not maltose, no vaccine, urethritis,
cervicitis, PID, prostatitis, epididymitis, arthritis, creamy purulent discharge
Chancroid Painful genital ulcer with exudate, inguinal adenopathy
Granuloma Inguinale (Donovanosis) Cytoplasmic Donovan bodies (bipolar staining) seen on microscopy, not
common in US, painless, beefy red ulcer that readily bleeds on contact
Primary Syphilis Painless chancre
Secondary Syphilis Fever, lymphadenopathy, skin rashes, condylomata lata
Tertiary Syphilis Gummas, tabes dorsalis, general paresis, aortitis, Argyll Robertson pupil
Chlamydia Reticulocyte and elementary bodies, urethritis, cervicitis, epididymitis,
conjunctivitis, reactive arthritis, PID
Lymphogranuloma Venereum Reticulocyte and elementary bodies, lymphatic infection, painless genital
ulcers, painful lymphadenopathy (buboes)
Condyloma Acuminata (genital warts) Koilocytes
Genital herpes Painful penile, vulvar, or cervical vesicles and ulcers, can cause systemic
symptoms such as fever, headache, myalgia
Hepatitis B Acute or chronic hepatitis, hepatocellular carcinoma, liver cirrhosis, jaundice
AIDS Kaposi’s sarcoma, lymphoma, opportunistic infections
Gardnerella vaginalis Vaginosis (a type of vaginitis) Clue cells, fishy odor, G variable
Trichomonas vaginalis Vaginitis Protozoa, corkscrew motility on wet mount, vaginitis, strawberry cervix
• Sexually Transmitted Lesions (Painful vs. Nonpainful)

Organism Disease Features of Primary Lesion Painful

Haemophilus ducreyi Chancroid (not chancre)
HSV 1 and 2 Genital Herpes
Klebsiella granulomatis Granuloma Inguinale
(Donovanosis)
Treponema pallidum Syphilis (chancre not chancroid)
Chlamydia trachomatis Lymphogranuloma Venereum
Multiple, deep ulcers, base may have gray to yellow exudate Yes
Multiple, small, grouped ulcers, shallow with erythematous base Yes
Extensive, progressive ulcerative lesions without lymphadenopathy, base may No
have granulation-like tissue
Single, indurated, well-circumscribed ulcer with clean base No
Small, shallow ulcers with large, painful, coalesced inguinal lymph nodes (buboes) No
Osteomyelitis
• Osteomyelitis – elevated C-reactive protein (CRP) and erythrocyte sedimentation rate common but nonspecific, MRI best (most sensitive test) for
detecting acute infection and detailing anatomic involvement, radiographs insensitive early, but can be useful in chronic osteomyelitis

• Infectious Arthritis – N. gonorrhoea the most common cause in sexually active young adults, S. aureus the most common cause in everyone else
• Hematogenous Osteomyelitis – most commonly affects male children, arises in metaphysis of long bones as this region contains slow-flowing, sinusoidal
vasculature conducive to microbial passage, necrotic bone may become reservoir for infection covered with new, poorly constructed bone if untreated,
in adults vertebral body is most common location, esp. in Pott’s disease

Organism Comments
G⊕
S. aureus Most common cause, esp. of hematogenous osteomyelitis, prosthetics, vertebrae, neonates, SCD, IV drug use, assume if
no other information given
S. epidermidis Prosthetics
GAS Second most common cause of hematogenous osteomyelitis
 GBS Neonates
G⊖
Salmonella enteritidis Most common cause in SCD
E. coli Second most common cause in SCD
P. aeruginosa Trauma (e.g. puncture wound), diabetics, IV drug use
N. gonorrhoeae STD that can lead to osteomyelitis (rare), or more commonly to septic arthritis
G⊖ Zoonotics
P. multocida Animal bites or scratches
Mycobacteria
M. tuberculosis Vertebral osteomyelitis (Pott disease)
Fungi
C. albicans IV drug use
Rashes
• Causes of Palm and Sole Rash – Graft vs. Host Disease, contact dermatitis, endocarditis, Kawasaki Disease, N. meningitidis (disseminated
meningococcemia), Parvovirus B19 (papular-pruritic “gloves and stockings/socks syndrome”), Scabies, Toxic Shock Syndrome, Syndrome/Toxic Epidermal
Necrolysis, Staphylococcal Scalded Skin Syndrome, Tinea corporis

Organism Disease Rash Progression Other Symptoms

G⊕
S. aureus Toxic Shock Sunburn-like (diffuse, Proximal  distal High fever, severe systemic
Syndrome erythematous, macular) with symptoms
desquamation of palms and soles
S. pyogenes Scarlet Fever Erythematous, sandpaper-like Proximal  distal Fever, sore throat, nausea
G⊖
N. meningitidis Meningococcemia Petechial Fever, chills, malaise
G⊖ Chlamydiaceae
R. rickettsii RMSF Petechial Distal  Proximal
Spirochetes
T. pallidum Secondary Syphilis Copper colored, maculopapular Palms and soles or diffuse Condyloma lata
B. burgdorferi Lyme Disease Erythema chronica migrans Expanding target-shaped
red rash
DNA Viruses
VZV Chickenpox Asynchronous Proximal  distal Fever, malaise, pharyngitis
HHV-6 Roseola Maculopapular (rose-colored Diffuse High fever (febrile seizures) then
macules) following fever rash, infants
 Parvovirus B19 Erythema “Slapped cheek” rash Face  Body Hydrops fetalis in pregnant women
Infectiosum
RNA Viruses
Coxsackievirus A Hand, Foot, and Vesiculae Palms and soles only Vesicles and ulcers in mouth
Mouth Disease
Rubella virus German Measles Maculopapular (pink macules and Head  Body (last 3 days) Postauricular lymphadenopathy,
papules, remain discrete, produce congenital rubella in fetus
desquamating truncal rash)
Rubeola virus Measles Maculopapular Head  Body, becomes 3 “C’s”: Cough, Coryza, Conjunctivitis
confluent as it spreads with photophobia, Koplik spots
Mumps virus Mumps None None Parotitis, orchitis
AIDS Infections by Organism
Organism Disease Comments
Mycobacteria
M. avium-intracellulare TB-like CD4 <50
G⊖ Zoonotics
B. henselae Bacillary Angiomatosis Superficial vascular proliferation
DNA Viruses
CMV CMV retinitis, pneumonia CD4 <50, “cotton wool spots” on funduscopic exam, Cowdry A
bodies
EBV Oral Hairy Leukoplakia, Non-Hodgkin’s Lymphoma CD4 <400
HPV SCC Anus or cervix
VZV CD4 <200
HHV-8 Kaposi’s Sarcoma
JC Virus Progressive Multifocal Leukoencephalopathy (PML) CD4 <200, white matter damage in CNS, demyelination
Fungi
H. capsulatum Histoplasmosis (pneumonia), hepatosplenomegaly, fever Disseminated disease only in immunocompromised
C. albicans Thrush, esophagitis CD4 <100, white plaque on oral mucosa that can be scraped off
C. neoformans Meningitis, encephalitis Most common meningitis in AIDS
A. fumigatus Invasive Aspergillosis Pleuritic pain, hemoptysis
P. jirovecii (PCP) PCP Pneumonia CD4 <200
Protozoa
Cryptosporidium Diarrhea Acid-fast cysts in stool
T. gondii Brain abscesses CD4 <100, ring-enhancing lesions
AIDS Infections by CD4 Count
• Common Diseases of HIV-Positive Adults – as CD4⊕ cell count falls, increased risk of reactivation of past infections (e.g. TB, HSV, shingles),
dissemination of bacterial and fungal infections (e.g. Coccidioidomycosis), and development of non-Hodgkin lymphomas

Organism Presentation Finding

CD4 <500
B. henselae Bacillary angiomatosis Neutrophilic inflammation on biopsy (contrast HHV-8)
C. albicans Oral thrush Scrapable white plaque, pseudohyphae on microscopy
EBV Oral hairy leukoplakia Unscrapable white plaque on lateral tongue
HHV-8 Kaposi sarcoma Lymphocytic inflammation on biopsy (contrast B. henselae)
HPV SCC of anus (MSM) or cervix (women) -
CD4 <200
H. capsulatum Fever, weight loss, fatigue, cough, dyspnea, diarrhea, Oval yeast cells within macrophages
nausea/vomiting
P. jirovecii Pneumocystis pneumonia “Ground glass” opacities on CXR
HIV Dementia -
JC Virus (reactivation) Progressive Multifocal Leukoencephalopathy Nonenhancing areas of demyelination on MRI
CD4 <100
A. fumigatus Hemoptysis, pleuritic pain Cavitation or infiltrates on chest imaging
C. albicans Esophagitis White plaques on endoscopy, yeast and pseudohyphae on biopsy
C. neoformans Meningitis Encapsulated yeast on India ink stain or capsular antigen ⊕
Cryptosporidium Chronic, watery diarrhea Acid-fast oocysts in stool
T. gondii Brain abscesses Multiple ring-enhancing lesions on MRI
EBV B-cell lymphoma (e.g. non-Hodgkin or CNS lymphoma) CNS lymphoma ring enhancing, may be solitary (compare T. gondii)
CD4 <50
M. avium-intracellulare Nonspecific systemic symptoms (fever, night sweats, -
weight loss) or focal lymphadenitis
CMV Retinitis, esophagitis, colitis, pneumonitis, encephalitis Linear ulcers on endoscopy, cotton wool spots on funduscopy,
biopsy reveals cells with intranuclear (“owl eye”) inclusion bodies
ToRCHeS Infections
• Introduction – infections transferred from mother to fetus, most transplacental, some during delivery (esp. HSV-2, GBS also), present with nonspecific
symptoms common to multiple infections: hepatosplenomegaly, fever, poor feeding, growth retardation, jaundice, thrombocytopenia, hearing
impairment, mental retardation, autism, death
o T = Toxoplasma gondii
o O = Other (Coxsackievirus B, Poliovirus, Parvovirus B19, Zika virus, L. monocytogenes)
o R = Rubella
o C = Cytomegalovirus (CMV)
o H = HIV
o H = Herpes Simplex Virus (HSV-2 more common, but HSV-1 still possible)
o S = Syphilis

Organism Maternal Transmission Maternal Manifestation Neonatal Manifestation

Cat feces, ingestion of
Toxoplasma gondii undercooked meat
Rubella Respiratory droplets
CMV Sex, organ transplantation
HIV Sex, needlestick
Usually asymptomatic, lymphadenopathy (rare)
Rash, lymphadenopathy, polyarthritis, polyarthralgia
Usually asymptomatic, mononucleosis-like illness
Variable depending on CD4 count
Classic triad: chorioretinitis,
hydrocephalus, intracranial calcifications,
+ “blueberry muffin rash”
Classic triad: cataracts, deafness, patent
PDA + “blueberry muffin rash”
Hearing loss, seizures, petechial rash,
“blueberry muffin rash”, periventricular
calcifications
Recurrent infections, chronic diarrhea
 HSV-2 Skin or mucous membrane Usually asymptomatic, herpetic (vesicular) lesions Meningoencephalitis, herpetic (vesicular)
contact lesions
Syphilis (T. pallidum) Sex Chancre (primary) and disseminated (secondary) Often results in still birth, hydrops fetalis,
stages most likely to result in fetal infection if child survives, presents with facial
abnormalities (notched teeth, saddle
nose, short maxilla, mulberry molars),
saber shins, CN8 deafness
Nosocomial Infections by Organism
Organism Comment
G⊕
Staphylococcus aureus Wound infection
G⊖
E. coli UTI, urinary catheterization
P. aeruginosa Burns, respirators (“AIRuginosa)
L. pneumophila Water aerosols
P. mirabilis UTI, urinary catheterization
DNA Viruses
CMV Neonates in nursery
HBV Healthcare workers in dialysis unit
RNA Viruses
RSV Neonates in nursery
Fungi
C. albicans Total parenteral nutrition (TPN)
Nosocomial Infections by Risk Factor
Risk Factor Organism Characteristic Signs and Symptoms
Antibiotic Use C. difficile (esp. Clindamycin) Watery diarrhea, leukocytosis
Aspiration (altered Polymicrobial, G⊖, often anaerobes Right lower lobe (patient supine) or right upper/middle lobe (patient recumbent),
mental status, age) purulent malodorous sputum
Ulcers, Wounds, Drains S. aureus (incl. MRSA), G⊖ anaerobes Erythema, tenderness, induration, drainage from surgical wound sites
IV Catheters S. aureus (incl. MRSA), S. epidermidis Erythema, induration, tenderness, drainage from access sites
(long-term), Enterobacter
Ventilators, Intubation Late Onset: P. aeruginosa, Klebsiella, New infiltrate on CXR, increased sputum production, sweet (fruity) odor
Acinetobacter, S. aureus (Pseudomonas)
Dialysis, Needle Stick HBV, HCV Jaundice
Urinary Catheters E. coli, Klebsiella, Proteus Dysuria, leukocytosis, flank pain or costovertebral angle tenderness
 Water Aerosols Legionella Pneumonia, GI symptoms (nausea/vomiting), neurologic abnormalities, hyponatremia

Vaccines
• Introduction – Live vaccines stimulate mucosal IgA production more strongly than killed vaccines, Routinely Given in Pregnancy: Diphtheria, Tetanus,
Influenza, HBV
• Live, Attenuated – microorganism loses its pathogenicity but retains capacity for transient growth within inoculated host, induces both humoral and
cell-mediated immunity, Pro: induces strong, often lifelong immunity (no booster needed), Con: relatively unstable (rarely reverts to virulent strains),
often contraindicated in pregnancy and immunodeficiency, Example: Measles, Mumps, Rubella (MMR – can be given to HIV patients with CD4 >200),
Sabin Polio (PO), VZV, Smallpox, Yellow Fever, Typhoid (PO), Rotavirus, F. tularensis, Influenza (nasal spray), BCG (tuberculosis), Adenovirus (enteric-
coated capsules)
• Inactivated or Killed – pathogen inactivated by heat or chemicals, maintaining epitope structure on surface antigens important for immune response,
induces only humoral immunity, Pro: safer than live vaccines (relatively stable, no possibility of reversion to pathogenic form), Con: weaker immune
response (boosters usually needed), Example: Rabies, Influenza (injection), Salk Polio (injection, primary form), HAV, Japanese Encephalitis, V. cholerae
• Recombinant – harmless virus engineered to produce antigenic protein of target virus, Example: HBV (HBsAg surface antigen), HPV (6, 11, 16, 18), B.
burgdorferi (surface protein)
• Toxoid – chemically modified toxins, Example: Tetanus, Diphtheria, Pertussis (Tdap, DTaP)
• Subunit – presents only viral antigen to host, made of capsular polysaccharides, used for encapsulated bacteria, promotes T-cell recognition and class
switching, Example: H. influenzae (polysaccharide conjugated to diphtheria toxoid), N. meningitidis, Pneumococcal (adult version not conjugated = IgM
only, infant version conjugated = IgG), Typhoid (injected)
CDC Recommended Vaccine Schedule
Vaccine Dosing Schedule
Core Vaccines
Hepatitis B 1st Dose: Birth, 2nd Dose: 1-2 months, 3rd Dose: 6-18 months
Rotavirus 1st Dose: 2 months, 2nd Dose: 4 months
Diphtheria, Tetanus, acellular Pertussis (DTaP) 1st Dose: 2 months, 2nd Dose: 4 months, 3rd Dose: 6 months, 4th Dose: 15-19 months, 5th Dose: 4-6 years
H. influenzae 1st Dose: 2 months, 2nd Dose: 4 months, 3rd Dose: 6 months or 12-18 months
Pneumococcal conjugate 1st Dose: 2 months, 2nd Dose: 4 months, 3rd Dose: 6 months, 4th Dose: 12-18 months
Inactivated Poliovirus 1st Dose: 2 months, 2nd Dose: 4 months, 3rd Dose: 6-19 months, 4th Dose: 4-6 years
Influenza Annual starting at 6 months
Measles, Mumps, Rubella (MMR) 1st Dose: 12-18 months, 2nd Dose: 4-6 years
VZV 1st Dose: 12-18 months, 2nd Dose: 4-6 years
Hepatitis A 2 dose series between 12-19 months
Meningococcal 1st Dose: 11-12 years, 2nd Dose: 16-18 years (booster)
Additional Vaccines
Tetanus, Diphtheria, acellular Pertussis (>7 yrs) 11-12 years
HPV 3 dose series between 11-12 years
Infections in Unimmunized Children by Organism
Organism Comment
G⊕
C. diphtheriae Diphtheria (pseudomembranous pharyngitis, lymphadenopathy)
G⊖
H. influenzae type B Meningitis, epiglottitis
RNA Viruses
Poliovirus Paralytic poliomyelitis, meningitis
Rubella virus Rubella
Rubeola virus Measles
Infections in Unimmunized Children by Presentation
Presentation Findings/Labs Organism
Rash Rash begins at head and moves down with postauricular lymphadenopathy Rubella Virus
Rash begins at head and moves down, rash preceded by cough, coryza, conjunctivitis, Koplik spots Rubeola Virus
Meningitis Microbe colonizes nasopharynx H. influenzae type B
 May also lead to myalgia and paralysis Poliovirus
Epiglottitis Fever with dysphagia, drooling, and difficulty breathing due to edematous “cherry red” epiglottitis, H. influenzae type B (may cause
“thumbprint sign” on X-ray epiglottitis in immunized also)
Pharyngitis Grayish oropharyngeal exudate (“pseudomembranes”) obstruct airway, painful throat (“bull neck”) C. diphtheriae (toxin causes
pharyngeal, cardiac, and CNS
necrosis)
Bug Hints (If All Else Fails)
Presentation Organism
Asplenic patient (surgical or SCD) Encapsulate microbes (Step pneumoniae, H. influenzae type B, N. meningitidis)
Branching rods in oral infection, sulfur granules Actinomyces israelii
CGD Catalase ⊕ organisms, esp. Staph aureus
“Currant jelly” sputum Klebsiella
Dog or cat bite Pasteurella multocida
Facial nerve palsy (typically bilateral) Borrelia burgdorferi (Lyme disease)
Fungal infection in diabetic or immunocompromised patient Mucor or Rhizopus species
Health care provider HBV (from needlestick)
Neutropenic patients Candida albicans (systemic), Aspergillus
Organ transplant recipient CMV
PAS⊕ Tropheryma whipplei (Whipple disease)
Pediatric infection Haemophilus influenzae (including epiglottitis)
Pneumonia in CF, burn infection Pseudomonas aeruginosa
Pus, empyema, abscess Staph aureus
Rash on hands and feet Coxsackie A Virus, Rickettsia rickettsii, Syphilis from Treponema pallidum (CARS)
Sepsis/meningitis in newborn Strep agalactiae (GBS)
Surgical wound Staph aureus
Traumatic open wound, gas gangrene Clostridium perfringens
Overview of Antimicrobials
 • Common Antibiotic Resistance Mechanisms

Cell Wall Synthesis Inhibitors

• Prototypical Penicillins
o Mechanism: D-Ala-D-Ala structural analog, binds penicillin-binding proteins (PBPs, transpeptidases), blocks transpeptidase cross-linking of
peptidoglycan in cell wall, activates autolytic enzymes, bactericidal, penicillinase sensitive
o Treats: Bactericidal for G⊕ cocci, G⊕ rods, G⊖ cocci, spirochetes, Strep pharyngitis, RF, intrapartum GBS prophylaxis
 G⊕: S. pneumoniae, pyogenes, viridans, bovis, agalactiae, Actinomyces, C. perfringens
 G⊖: N. meningitidis, Pasteurella
 Spirochetes: T. pallidum
o Side Effects: hypersensitivity (T1 IgE-mediated, <10%, i.e. low cross-reactivity with Cephalosporins), direct Coombs⊕ (autoimmune) hemolytic
anemia, interstitial nephritis
o Resistance: penicillinase (β-lactamase) cleaves β-lactam ring, transferred via plasmids
o Penicillin G (IV, IM), Penicillin V (PO, acid stable, 4x/day dosing, poor bioavailability, narrow spectrum only for minor infections)
• Penicillinase-Resistant Penicillins
o Mechanism: same as Penicillin, narrow spectrum
o Treats: empirical treatment of skin and soft tissue infections (e.g. folliculitis, abscesses), Staph endocarditis or osteomyelitis
  G⊕: S. aureus (except MRSA)
o Side Effects: hypersensitivity, interstitial nephritis
o Resistance: contains bulky R-groups that prevent β-lactamase binding, MRSA still resistant due to altered PBP
o Methicillin (no longer used clinically), Dicloxacillin, Nafcillin, Oxacillin
• Penicillinase-Sensitive Penicillins
o Mechanism: same as Penicillin, wider spectrum (includes more G⊖), penicillinase-sensitive
o Treats: Strep pharyngitis, sinusitis, otitis, URI infections (Amoxicillin), aspiration pneumonia, H. pylori gastritis, Lyme Disease (early stages or
young children), meningitis in very old or young (L. monocytogenes), prophylaxis against encapsulated bacteria in asplenic patients, dental
procedure prophylaxis in endocarditis risk patients
 G⊕: S. faecium/faecalis (enterococci, GDS)
 G⊖: H. influenzae, H. pylori, E. coli, L. monocytogenes, P. mirabilis, Salmonella, Shigella
o Side Effects: hypersensitivity, rash (with EBV, not an allergic reaction), Stevens-Johnson Syndrome, pseudomembranous colitis, liver injury
o Resistance: penicillinase (β-lactamase) cleaves β-lactam ring, transferred via plasmids, use with Clavulanic Acid
o Amoxicillin (better PO availability), Ampicillin, Ampicillin + Sulbactam (Unasyn), Amoxicillin + Clavulanic Acid (Augmentin)
• Antipseudomonal Penicillins
o Mechanism: same as Penicillin, extended spectrum, penicillinase-sensitive
o Treats: empiric treatment of nosocomial pneumonia, G⊖ sepsis
 G⊖: Pseudomonas species, bacilli
o Side Effects: hypersensitivity
o Resistance: penicillinase (β-lactamase) cleaves β-lactam ring, transferred via plasmids, use with β-lactamase inhibitors
o Piperacillin, Ticarcillin, Ticarcillin + Clavulanic Acid (Timentin)
• B-lactamase Inhibitors
o Mechanism: often added to Penicillins to prevent destruction by penicillinase (β-lactamase)
o Clavulanic Acid, Avibactam, Sulbactam, Tazobactam
• 1 Gen Cephalosporins
st

o Mechanism: β-lactam cell wall synthesis inhibitors that are less susceptible to penicillinases (β-lactamases), bactericidal
o Treats:
 G⊕: surgical prophylaxis against S. aureus wound infections (Cefazolin)
 G⊖: P. mirabilis, E. coli, Klebsiella
 Organisms Not Covered by 1st-4th Gen Cephalosporins: LAME: Listeria, Atypicals (Chlamydia, Mycoplasma), MRSA, Enterococcus (S.
faecium/faecalis)
o Side Effects (all Cephalosporins): hypersensitivity (T1 IgE-mediated, <10%, i.e. low cross-reactivity with Penicillins), direct Coombs⊕
(autoimmune) hemolytic anemia, disulfiram-like reaction (severe flushing, tachycardia, hypotension), vitamin K deficiency, drug interaction
(increases nephrotoxicity of Aminoglycosides)
o Resistance (all Cephalosporins): same mechanism as Penicillins, resistance occurs via alteration of PBP
o Cefazolin, Cephalexin
• 2nd Gen Cephalosporins
o Treats: G⊕, H. influenzae, Enterobacter aerogenes, Neisseria species, S. marcescens, P. mirabilis, E. coli, Klebsiella
o Cefaclor, Cefoxitin, Cefuroxime
• 3rd Gen Cephalosporins
o Treats: serious G⊖ resistant to other β-lactams, can cross blood-brain barrier, meningitis, pneumococcal pneumonia, gonorrhoea, and
disseminated Lyme Disease (Ceftriaxone), Pseudomonas (Ceftazidime)
o Ceftriaxone, Cefotaxime, Cefpodoxime, Ceftazidime
• 4th Gen Cephalosporins
o Treats: G⊖ with increased activity against Pseudomonas and G⊕
o Cefepime
• 5 Gen Cephalosporins
th

o Treats: broad G⊕ and G⊖ coverage including Listeria, MRSA, E. faecalis (contrast 1st-4th gen Cephalosporins), but does not cover Pseudomonas
o Ceftaroline
• Carbapenems
o Mechanism: broad-spectrum, β-lactamase-resistant, always administered with Cilastatin (renal dehydropeptidase 1 inhibitor) to decrease its
deactivation in renal tubules (occurs less with Meropenem, “the kill is lastin’ with Cilastatin”)
o Treats: G⊕ cocci, G⊖ bacilli and anaerobes, wide spectrum but significant side effects limit use to life-threatening infections after other drugs
have failed
o Side Effects: GI, skin rash, CNS toxicity (seizures, less with Meropenem) at high plasma levels
o Imipenem, Meropenem, Ertapenem (newer, limited Pseudomonas coverage), Doripenem (newer)
• Monobactams
o Mechanism: prevents peptidoglycan cross-linking by binding to penicillin-binding protein 3, β-lactamase-resistant, synergistic with
Aminoglycosides, no cross-allergenicity with Penicillins
o Treats: G⊖ bacilli only, no activity against G⊕ bacilli or anaerobes, used in Penicillin-allergic patients and those with renal insufficiency who
cannot tolerate Aminoglycosides
 o Side Effects: occasional GI, usually nontoxic
o Aztreonam
• Vancomycin
o Mechanism: prevents peptidoglycan cross-linking by binding D-Ala-D-Ala portion of cell wall precursors, bactericidal against most bacteria
(bacteriostatic against C. Difficile)
o Treats: G⊕ only, esp. serious, multidrug-resistant organisms, including MRSA, S. epidermidis, sensitive Enterococcus species, and C. difficile (PO
for pseudomembranous colitis)
o Side Effects: generally well-tolerated, but NOT trouble free: Nephrotoxicity, Ototoxicity, Thrombophlebitis, diffuse flushing (Red Man Syndrome,
largely preventable by pretreatment with antihistamines and slow infusion rate)
o Resistance: not susceptible to β-lactamases, occurs (e.g. in Enterococcus) via amino acid modification of D-Ala-D-Ala to D-Ala-D-Lac

• Daptomycin
o Mechanism: lipopeptide that disrupts cell membranes of G⊕ cocci by creating transmembrane channels
o Treats: S. aureus skin infections (esp. MRSA), bacteremia, endocarditis, VRE, Note: not used for pneumonia, avidly binds surfactant and is
inactivated by it
o Side Effects: myopathies, rhabdomyolysis

Protein Synthesis Inhibitors

• Introduction – specifically target smaller bacteria ribosome (30S + 50S = 70S), leaving human ribosome (40S + 60S = 80S) unaffected, Mnemonic: Buy AT
30, CCEL (sell) at 50”: 1.) 30S Inhibitors: Aminoglycosides (bactericidal), Tetracyclines (bacteriostatic), 2.) 50S Inhibitors: Chloramphenicol, Clindamycin
(bacteriostatic), Erythromycin (Macrolides – bacteriostatic), Linezolid (variable)
• Aminoglycosides
o Mechanism: irreversible inhibition of initiation complex through binding of 30S ribosomal subunit, also causes misreading of mRNA and blocks
translocation, bactericidal
o Treats: severe G⊖ bacilli infections, ineffective against anaerobes (requires O2 for uptake), synergistic with β-lactam antibiotics, bowel surgery
(Neomycin)
o Side Effects: nephrotoxicity, neuromuscular blockade, ototoxicity (esp. with Loop Diuretics), teratogen
o Contraindicated: pregnancy
o Resistance: bacterial transferase enzymes inactivate drug by acetylation, phosphorylation, or adenylation, mutation of ribosomal binding sites,
or mutated porins
o Gentamicin, Neomycin, Amikacin, Tobramycin, Streptomycin
• Tetracyclines
o Mechanism: binds 30S ribosomal subunit and prevents attachment of aminoacyl-tRNA, bacteriostatic, limited CNS penetration, fecally
eliminated (can be used in patients with renal failure), chelating agent, so should not be taken with milk (Ca2+), antacids (Ca2+ or Mg2+), or iron-
containing preparations (inhibits GI absorption)
o Treats: B. burgdorferi, M. pneumoniae, Rickettsia and Chlamydia species (accumulates intracellularly), treats acne, effective against MRSA
o Side Effects: GI, discoloration of teeth and inhibition of bone growth in children, photosensitivity
o Contraindicated: pregnancy
o Resistance: decreased uptake or increased efflux via plasmid encoded transport pumps
o Tetracycline, Doxycycline, Minocycline
• Glycylcyclines
o Mechanism: Tetracycline derivative, binds 30S ribosomal subunit, generally bacteriostatic
o Treats: broad-spectrum anaerobic, G⊖, and G⊕ coverage, multidrug-resistant organisms (MRSA, VRE) or infections requiring deep tissue
penetration
o Side Effects: GI, nausea/vomiting
o Tigecycline
• Chloramphenicol
o Mechanism: blocks peptidyltransferase at 50S ribosomal subunit, bacteriostatic
o Treats: meningitis (H. influenzae, N. meningitis, S. pneumoniae), RMSF (R. rickettsii), limited use due to toxicity, but still used in developing
countries because it is cheap
o Side Effects: anemia (dose-dependent), aplastic anemia (dose independent), gray baby syndrome (premature infants who lack liver UDP-
glucuronyltransferase)
o Resistance: inactivated by plasmid-encoded acetyltransferase
• Clindamycin
o Mechanism: blocks peptide transfer (translocation) at 50S ribosomal subunit, bacteriostatic
o Treats: anaerobes above the diaphragm (esp. Bacteroides, C. perfringens) in aspiration pneumonia, lung abscesses, and oral infections, effective
against GAS (contrast Metronidazole, which treats anaerobes below the diaphragm)
o Side Effects: pseudomembranous colitis (C. difficile overgrowth), fever, diarrhea
 • Linezolid
o Mechanism: binds 50S ribosomal subunit preventing formation of initiation complex
o Treats: G⊕ including MRSA and VRE
o Side Effects: bone marrow suppression (esp. thrombocytopenia), peripheral neuropathy, Serotonin Syndrome (has MAOI activity)
o Resistance: point mutation of ribosomal RNA
• Macrolides
o Mechanism: binds 23S rRNA of 50S ribosomal subunit, preventing translocation (“macroslides”), bacteriostatic
o Treats: atypical pneumonias (Mycoplasma, Chlamydia, Legionella), STIs (Chlamydia), G⊕ cocci (Strep infection in patients allergic to Penicillins),
B. pertussis
o Side Effects: MACRO: GI Motility problems, Arrhythmia caused by prolonged QT interval, acute Cholestatic hepatitis, Rash, eOsinophilia,
increases serum concentration of Theophylline and oral anticoagulants, Clarithromycin and Erythromycin inhibit CYT-P450
o Resistance: methylation of 23S rRNA-binding site prevents Macrolide binding
o Azithromycin, Clarithromycin, Erythromycin

Folate Synthesis Inhibitors

• Sulfonamides
o Mechanism: inhibits dihydropteroate synthase, inhibiting folate synthesis, bacteriostatic (bactericidal when combined with Trimethoprim)
o Treats: G⊕, G⊖, Nocardia, SMX for uncomplicated UTI
o Side Effects: hypersensitivity, hemolysis in G6PD Deficiency, nephrotoxicity (tubulointerstitial nephritis), photosensitivity, Stevens-Johnson
Syndrome, kernicterus in infants, displaces other drugs from albumin (e.g. Warfarin), increasing their serum concentration
o Resistance: altered enzyme (bacterial dihydropteroate synthase), decreased uptake, increased PABA synthesis
o Sulfamethoxazole (SMX), Sulfisoxazole, Sulfadiazine
• Dapsone
o Mechanism: similar mechanism to Sulfonamides, though structurally distinct
o Treats: Leprosy (lepromatous and tuberculoid), Pneumocystis jirovecii prophylaxis in HIV patients (CD4 <200)
o Side Effects: hemolysis in G6PD Deficiency
• Trimethoprim
o Mechanism: inhibits bacterial dihydrofolate reductase, bacteriostatic (bactericidal when combined with Sulfonamides)
o Treats: used in combination with Sulfonamides (Trimethoprim-Sulfamethoxazole, TMP-SMX) to block sequential steps of folate synthesis,
exerting a synergistic effect, UTIs, Shigella, Salmonella, Pneumocystis jirovecii pneumonia treatment and prophylaxis
o Side Effects: megaloblastic anemia, leukopenia, granulocytopenia (may be alleviated with supplemental folinic acid) (“TMP Treats Marrow
Poorly”)
Topoisomerase Inhibitors, Metronidazole, and Fidaxomicin
• Fluoroquinolones
o Mechanism: inhibits prokaryotic topoisomerase 2 (DNA gyrase) and 4, bactericidal, must not be taken with antacids
o Treats: G⊖ bacilli of GI and GU tracts (including Pseudomonas), some G⊕, otitis externa, ineffective against anaerobes
o Side Effects: GI, superinfections, skin rashes, headache, dizziness, leg cramps and myalgias (less common), prolongs QT interval, tendonitis or
tendon rupture in elderly (>60) and in patients taking Prednisone, inhibits CYT-P450 (“Fluoroquinolones hurt attachments to bones”)
o Contraindicated: pregnant women, nursing mothers, children <18 (possible cartilage damage)
o Resistance: chromosome-encoded mutation in DNA gyrase, plasmid-mediated resistance, efflux pumps
o Ciprofloxacin, Norfloxacin, Levofloxacin, Ofloxacin, Moxifloxacin, Gemifloxacin, Enoxacin
• Metronidazole
o Mechanism: forms toxic free radical metabolites in bacterial cell that damage DNA, bactericidal, antiprotozoal
 o Treats: Giardia, Entamoeba, Trichomonas, Gardnerella vaginalis, anaerobes below the diaphragm (Bacteroides, C. difficile, contrast Clindamycin,
which treats anaerobes above the diaphragm), can substitute for Amoxicillin in H. pylori “triple therapy” in Penicillin allergy
o Side Effects: disulfiram-like reaction (severe flushing, tachycardia, hypotension) with alcohol, headache, metallic taste
• Fidaxomicin
o Mechanism: inhibits sigma subunit of RNA polymerase, leading to protein synthesis impairment and cell death (bacteriocidal in C. Difficile),
macrocyclic antibiotic (related to Macrolides), poorly absorbed orally, thus accumulates in gut lumen (high fecal concentrations)
o Treats: patients with recurrent C. difficile colitis at increased risk of recurrence (e.g. recent antibiotic use, gastric acid suppression), narrow
spectrum of activity and lesser effect on colonic flora than either Metronidazole or Vancomycin, lower recurrence rate and higher sustained
cure rate than Vancomycin

Antimycobacterial Drugs
• Overview of Treatment and Prophylaxis
 Mycobacterium Prophylaxis Treatment
M. tuberculosis Isoniazid Rifampin, Isoniazid, Pyrazinamide, Ethambutol (RIPE)
M. avium-intracellulare Azithromycin, Rifabutin More drug-resistant than M. tuberculosis, use Azithromycin or Clarithromycin + Ethambutol,
possibly add Rifabutin or Ciprofloxacin
M. leprae N/A Tuberculoid: Long-term treatment with Dapsone and Rifampin
Lepromatous: Long-term treatment with Dapsone and Rifampin + Clofazimine
• Rifamycins
o Mechanism: inhibits DNA-dependent RNA polymerase
o Treats: M. tuberculosis, delays resistance to Dapsone when used for leprosy, meningococcal prophylaxis, chemoprophylaxis in contacts of
children with H. influenzae type B (“4 R’s of Rifampin: RNA polymerase inhibitor, Ramps up CYT-P450, Red/orange body fluids, Rapid resistance if
used alone”)
o Side Effects: minor hepatotoxicity, induces CYT-P450 (less with Rifabutin, favored in HIV patients, “Rifampin ramps up CYT-P450, but Rifabutin
does not”), orange body fluids (nonhazardous)
o Resistance: mutations reduce drug binding to RNA polymerase, monotherapy rapidly leads to resistance
o Rifampin, Rifabutin
• Isoniazid
o Mechanism: decreases mycolic acid synthesis, bacterial catalase-peroxidase (encoded by KatG) needed to convert INH to active metabolite
(different INH half-lives in fast vs. slow acetylators)
o Treats: M. tuberculosis (only drug used as solo prophylaxis, also used as monotherapy for latent TB)
o Side Effects: hepatotoxicity, inhibits CYP-P450, drug induced SLE, anion gap metabolic acidosis, vitamin B6 deficiency (peripheral neuropathy,
sideroblastic anemia, administer with pyridoxine/B6) (“INH Injures Neurons and Hepatocytes”)
o Resistance: mutations leading to underexpression of KatG
• Pyrazinamide
 o Mechanism: uncertain, prodrug converted to active compound Pyrazinoic Acid, works best at acidic pH (e.g. in host phagolysosomes)
o Treats: M. tuberculosis
o Side Effects: hyperuricemia, hepatotoxicity
• Ethambutol
o Mechanism: decreases carbohydrate polymerization of mycobacterium cell wall by blocking arabinosyltranferase
o Treats: M. tuberculosis
o Side Effects: optic neuropathy (red-green colorblindness) (“eye-thambutol”)
• Streptomycin
o Mechanism: interferes with 30S ribosomal subunit
o Treats: M. tuberculosis (2nd line)
o Side Effects: tinnitus, vertigo, ataxia, nephrotoxicity

Prophylaxis and Highly Resistant Bacteria

• Antimicrobial Prophylaxis

Clinical Scenario Medication

High risk for endocarditis during surgical/dental procedures Amoxicillin
Exposure to gonorrhoea Ceftriaxone
History of recurrent UTIs TMP-SMX
Exposure to meningococcal infection Ceftriaxone, Ciprofloxacin, or Rifampin
Pregnant women who test ⊕ for S. agalactiae (GBS) Intrapartum Penicillin G or Ampicillin
Prevention of gonococcal conjunctivitis in newborn Erythromycin eye ointment
Prevention of postsurgical S. aureus infection Cefazolin
Prophylaxis of Strep pharyngitis in child with prior RF Benzathine Penicillin G or PO Penicillin V
Exposure to Syphilis Benzathine Penicillin G
• Prophylaxis in HIV Patients

CD4 count Prophylaxis Infection

CD4 <200 cells/mm 3
TMP-SMX Pneumocystis pneumonia
CD4 <100 cells/mm3 TMP-SMX Pneumocystis pneumonia and toxoplasmosis
CD4 <50 cells/mm 3
Azithromycin or Clarithromycin Mycobacterium avium complex
• Treatment of Highly Resistant Bacteria

Organism Treatment
MRSA Vancomycin, Daptomycin, Linezolid, Tigecycline, Ceftaroline, Doxycycline
VRE Linezolid and Streptogramins (Quinupristin, Dalfopristin)
Multidrug-resistant P. aeruginosa, Acinetobacter baumannii Polymyxin B and E (Colistin)
Antifungal Therapy

• Amphotericin B
o Mechanism: binds ergosterol (unique to fungus), forms membrane pores that allow electrolyte leakage (“Amphotericn “tears” holes in fungal
membrane”)
o Treats: serious, systemic mycoses, Cryptococcus (+ Flucytosine for cryptococcal meningitis), Blastomyces, Coccidioides, Histoplasma, Candida,
Mucor, given intrathecally for fungal meningitis, supplement K+ and Mg2+ due to altered renal tubule permeability
o Side Effects: fever/chills (“shake and bake”), hypotension, nephrotoxicity (decreased with hydration and liposomal administration), arrhythmias,
anemia, IV phlebitis (“amphoterrible”)
• Nystatin
o Mechanism: same as Amphotericin B, topical use only (too toxic for systemic use)
o Treats: “swish and/or swallow” for oral candidiasis (thrush), topical for diaper rash or vaginal candidiasis
• Flucytosine
o Mechanism: inhibits DNA and RNA synthesis via conversion of 5-fluorouracil by cytosine deaminase
o Treats: systemic fungal infections (esp. cryptococcal meningitis, given with Amphotericin B)
o Side Effects: bone marrow suppression
• Azoles
o Mechanism: inhibits ergosterol (unique to fungus) synthesis by inhibiting CYT-P450 enzyme that converts lanosterol to ergosterol
 o Treats: local and less serious systemic mycoses, Fluconazole for chronic suppression of cryptococcal meningitis in AIDS patients and candidal
infections of all types, Itraconazole for Blastomyces, Coccidioides, Histoplasma, Clotrimazole and Miconazole for topical fungal infections,
Voriconazole for Aspergillus and some Candida, Isavuconazole for serious Aspergillus and Mucorales infections
o Side Effects: gynecomastia (esp. Ketoconazole, testosterone synthesis inhibition), inhibits CYT-P450
o Clotrimazole, Fluconazole, Itraconazole, Ketoconazole, Miconazole, Voriconazole, Isavuconazole
• Terbinafine
o Mechanism: inhibits fungal squalene epoxidase
o Treats: dermatophytes (esp. onychomycosis, fungal infection of finger or toe nails)
o Side Effects: GI, headaches, hepatotoxicity, taste disturbances
• Echinocandins
o Mechanism: inhibits cell wall synthesis by inhibiting synthesis of β-glucan
o Treats: invasive Aspergillosis, Candida
o Side Effects: GI, flushing (histamine release)
o Anidulafungin, Caspofungin, Micafungin
• Griseofulvin
o Mechanism: interferes with microtubule function, disrupting mitosis, deposits in keratin-containing tissues (e.g. nails)
o Treats: PO treatment of superficial infections, inhibits dermatophyte growth (tinea, ringworm)
o Side Effects: teratogenic, carcinogenic, confusion, headaches, disulfiram-like reaction (severe flushing, tachycardia, hypotension), induces CYT-
P450 (interferes with Warfarin metabolism)
o Contraindicated: pregnancy
• Antiprotozoan Therapy
o Pyrimethamine: toxoplasmosis
o Suramin and Melarsoprol: Trypanosoma brucei
o Nifurtimox: Trypanosoma cruzi
o Sodium Stibogluconate: leishmaniasis
• Anti-Mite/Louse Therapy
o Mechanism: “treat PML (Pesky Mites and Lice) with PML (Permethrin, Malathion, Lindane) because the NAG you (Na, AChE, GABA blockade)”
 Permethrin: neuronal membrane depolarization via Na+ channels
 Malathion: acetylcholinesterase inhibitor
 Lindane: blocks GABA A channels (neurotoxic)
o Treats: scabies (Sarcoptes scabiei) and lice (Pediculus, Pthirus)
• Chloroquine
o Mechanism: blocks detoxification of heme into hemozoin, leading to heme accumulation (toxic to plasmodia)
o Treats: plasmodial species other than P. falciparum (resistance too high – treat with Artemether/Lumefantrine or Atovaquone/Proguanil), for
life-threatening malaria use Quinidine (US, elsewhere Quinine) or Artesunate
o Side Effects: retinopathy, pruritus (esp. in dark-skinned individuals)
o Resistance: due to membrane pump that decreases intracellular drug concentration
 • Antihelminthic Therapy
o Mebendazole: microtubule inhibitor
o Pyrantel Pamoate
o Ivermectin
o Diethylcarbamazine
o Praziquantel

Antivirals
• Introduction
• Oseltamivir, Zanamivir
o Mechanism: inhibits influenza neuraminidase thus inhibiting viral release
 o Treats: treatment and prevention of Influenza A and B, beginning therapy within 48 hours of symptom onset may shorten illness duration
• Acyclovir, Famciclovir, Valacyclovir
o Mechanism: Guanosine analogs, monophosphorylated by HSV/VZV thymidine kinase but not phosphorylated in uninfected cells, leading to
fewer adverse effects, triphosphate formed by cellular enzymes, preferentially inhibit DNA Polymerase via chain termination
o Treats: HSV and VZV, weak activity against EBV, no activity against CMV, used for HSV-induced mucocutaneous lesions, genital lesions, and
encephalitis, for prophylaxis in immunocompromised patients, no effect on latent HSV or VZV, Valacyclovir (prodrug of Acyclovir) has better
bioavailability, Famciclovir used for Herpes Zoster
o Side Effects: obstructive crystalline nephropathy and acute renal failure (prevent with adequate hydration, dosage adjustment, and slowing
infusion rate)
o Resistance: mutated viral thymidine kinase
• Ganciclovir
o Mechanism: Guanosine analogue, 5’-monophosphate formed by CMV viral kinase, triphosphate formed by cellular kinases, preferentially
inhibits viral DNA polymerase
o Treats: CMV, esp. in immunocompromised, Valganciclovir (prodrug of Ganciclovir), has better oral bioavailability
o Side Effects: bone marrow suppression (leukopenia, neutropenia, thrombocytopenia), renal toxicity, more toxic to host enzymes than Acyclovir
o Resistance: mutated viral kinase
• Foscarnet
o Mechanism: viral DNA/RNA polymerase inhibitor, HIV reverse transcriptase inhibitor, binds to pyrophosphate-binding site of enzyme (“Foscarnet
= pyroFOSphate analogue”), does not require kinase activation
o Treats: CMV retinitis in immunocompromised when Ganciclovir fails, Acyclovir-resistant HSV
o Side Effects: nephrotoxicity, electrolyte abnormalities (hypo/hypercalcemia, hypo/hyperphosphatemia, hypokalemia, hypomagnesemia) can
lead to seizures
o Resistance: mutated DNA polymerase
• Cidofovir
o Mechanism: preferentially inhibits viral DNA polymerase, does not require viral kinase phosphorylation
o Treats: CMV retinitis in immunocompromised, Acyclovir-resistant HSV, long half-life
o Side Effects: nephrotoxicity (coadminister with Probenecid and IV saline to reduce toxicity)

Antiretrovirals (HIV Therapy) and Other Miscellaneous Antimicrobials

• Introduction – Highly Active Antiretroviral Therapy (HAART), often initiated at time of HIV diagnosis, strongest indication for patients presenting with
AIDS-defining illness, low CD4 cells counts (<500), or high viral load, 3 drug regiment to prevent resistance, 2 NRTIs and preferably an integrase inhibitor
• NRTIs
o Mechanism: competitively inhibit nucleotide binding to reverse transcriptase and terminate DNA chain (lack 3’ OH group), Tenofovir is a
nucleoTide,, the others are nucleosides, all must be activated via phosphorylation
o Treats: Zidovudine prophylaxis during pregnancy to decrease risk of fetal transmission
o Side Effects: bone marrow suppression (reversible with Granulocyte Colony-Stimulating Factor – G-CSF and Erythropoietin), peripheral
neuropathy, lactic acidosis (nucleosides), anemia (Zidovudine), pancreatitis (Didanosine)
o Contraindicated: Abacavir if patient has HLA-B5701 mutation (increased hypersensitivity risk, Abacavir Hypersensitivity Reaction – ASR)
o DELTAS Z: Didanosine (ddl), Emtricitabine (FTC), Lamivudine (3TC), Tenofovir (TDF), Abacavir (ABC), Stavudine (d4T), Zidovudine (ZDV, AZT,
Azidothymidine)
• NNRTIs
o Mechanism: bind to reverse transcriptase at different site from NRTIs, do not require activation via phosphorylation
o Side Effects: rash, hepatotoxicity, vivid dreams and CNS symptoms (Efavirenz)
o Contraindicated: Delavirdine, Efavirenz
o ENDER: Efavirenz (EFV), Nevirapine (NVP), Delavirdine (DLV), Etravirine (ETR), Rilpivirine (RPV)
• Protease Inhibitors
o Mechanism: inhibits HIV proteases (assembly of virions depends on HIV-1 protease – pol gene, which cleaves polypeptide products of HIV mRNA
into their functional parts), may “boost” other drug concentrations by inhibiting CYT-P450
o Side Effects: hyperglycemia, GI (nausea, diarrhea), lipodystrophy (Cushing-like syndrome), nephropathy, hematuria, thrombocytopenia
(Indinavir), concentrations reduced by Rifampin (use Rifabutin instead)
o RAD LIFTS: Ritonavir (RTV), Atazanavir (ATV), Darunavir (DRV), Lopinavir (LPV), Indinavir (IDV), Fosamprenavir (FPV), Tipranavir (TPV),
Saquinavir (SQV)
• Integrase Inhibitors
o Mechanism: inhibits HIV genome integration into host cell chromosome by reversibly inhibiting HIV integrase
o Side Effects: increases creatine kinase
o RED: Raltegravir (RAL), Elvitegravir (EVG), Dolutegravir (DTG)
• CCR-5 Inhibitors
o Mechanism: binds CCR-5 on surface of T-cells/monocytes, inhibiting interaction with glp120 (inhibits docking)
o Maraviroc (MVC)
• Fusion Inhibitors
o Mechanism: binds gp41, inhibiting viral entry (inhibits fusion)
o Side Effects: injection site reactions
o Enfuvirtide (T-20)
• Interferons
o Mechanism: glycoproteins normally synthesized by virus-infected cells, exhibiting wide range of antiviral and antitumoral properties
 o Treats:
 IFN-α: chronic HBV and HCV, Kaposi sarcoma, hairy cell leukemia, condyloma acuminatum, renal cell carcinoma, malignant melanoma
 IFN-β: MS
 IFN-γ: CGD
o Side Effects: flu-like symptoms, depression, neutropenia, myopathy

Hepatitis C Drugs
• Ribavirin
o Mechanism:
 Hypermutation Induction: phosphorylated intracellularly by adenosine kinase to ribavirin mono-, di-, and tri- metabolites, pairs equally
well with C and U when incorporated into RNA, causing hypermutation
 RNA Polymerase Inhibition: ribavirin triphosphate form
 GTP Depletion: ribavirin monophosphate inhibits inosine monophosphate dehydrogenase
 Defective mRNA 5’-Cap Formation: inhibits RNA guanylyltransferase and methyltransferase, ultimately produces ineffective viral
translation
 Enhances Immunity: enhances TH1 response, inhibits TH2 response, enhancing the body’s viral immunity
 o Treats: chronic HCV, also used in RSV (Palivizumab preferred in children)
o Side Effects: hemolytic anemia, severe teratogen
o Contraindicated: pregnancy
• Sofosbuvir
o Mechanism: inhibits HCV RNA-dependent RNA polymerase acting as a chain terminator
o Treats: chronic HCV in combination with Ribavirin, Simeprevir, Ledipasvir (NS5A inhibitor) + Pegylated Interferon Alfa-2a (Peginterferon), do
not use as monotherapy
o Side Effects: fatigue, headache, nausea
• Simeprevir
o Mechanism: HCV protease inhibitor, prevents viral replication
o Treats: chronic HCV in combination with Ledipasvir (NS5A inhibitor), do not use as monotherapy
o Side Effects: photosensitivity reactions, rash

Disinfection and Sterilization

• Introduction – done to reduce pathogenic organism counts to safe levels (disinfection) and to inactivate self-propagating biological entities (sterilization)
• Autoclave – pressurized steam at >120°C, may be sporicidal
• Alcohols and Chlorhexidine – denatures proteins and disrupts cell membranes, not sporicidal
• Hydrogen Peroxide – free radical oxidation, sporicidal
• Iodine and Iodophors – halogenation of DNA, RNA, and proteins, may be sporicidal

Contraindicated in Pregnancy
Antimicrobial Adverse Effect
Sulfonamides Kernicterus
Aminoglycosides Ototoxicity
Fluoroquinolones Cartilage
Clarithromycin Embryotoxic
Tetracyclines Discolored teeth, inhibition of bone growth
Ribavirin Teratogenic
Griseofulvin Teratogenic
Chloramphenicol Gray Baby Syndrome
• “Safe Children Take Really Good Care”
General Pathology Homepage
Apoptosis

Introduction – ATP-dependent programmed cell death, intrinsic and extrinsic pathways, both activate caspases (cytosolic proteases) leading to cellular
breakdown, including cell shrinkage, chromatin condensation, membrane blebbing, and formation of apoptotic bodies, which are then phagocytosed,
histology: deeply eosinophilic cytoplasm and basophilic nucleus, pyknosis (nuclear shrinkage), and karyorrhexis (fragmentation caused by endonuclease-
mediated cleavage), cell membrane typically remains intact without significant inflammation (contrast necrosis), DNA laddering (fragments in multiples
of 180 bp) a sensitive indicator of apoptosis
• Intrinsic (Mitochondrial) Pathway – involved in tissue remodelling in embryogenesis, occurs when regulating factor withdrawn from proliferating cell
population (e.g. decreased IL-2 after completed immunologic reaction leads to apoptosis of proliferating effector cells), also occurs after exposure to
injurious stimuli (e.g. radiations, toxins, hypoxia), regulated by Bcl-2 protein family, BAX and BAK proapoptotic, Bcl-2 and Bcl-x antiapoptotic, Bcl-2 keeps
mitochondrial outer membrane impermeable, preventing cytochrome C release from inner mitochondrial matrix, overexpression in Follicular Lymphoma
with t(14;18) leads to decreased caspase activation and tumorigenesis, normally ribosomal binding to 5’ cap of mRNA facilitated by family of proteins
called eukaryotic initiation factors (eIFs), caspase activation results in degradation of these eIFs leading to interruption of translation, thus translation of
many proteins necessary for apoptosis occurs via alternative method known as internal ribosome entry, where distinct nucleotide sequence called
internal ribosome entry site (IRES) attracts ribosome to mRNA and allows translation to begin in middle of mRNA sequence, IRESs usually located in 5’
untranslated region directly upstream from translation start codon
• Extrinsic (Death Receptor) Pathway – 2 pathways: 1.) Ligand Receptor Interaction: Fas ligand (FasL) binds to FAS (CD95) or TNF-α binds to its receptor,
Fas-FasL interaction necessary in thymic medullary negative selection, mutations in Fas increase numbers of circulating self-reactive lymphocytes due to
 failure of clonal deletion, defective Fas-FasL interactions also cause autoimmune lymphoproliferative syndrome, 2.) Immune Cell Interaction: cytotoxic T-
cell release of perforin and granzyme B

Necrosis, Cell Injury, and Infarction

• Introduction – enzymatic degradation and protein denaturation of cell due to exogenous injury, produces leakage of intracellular components,
inflammatory process (contrast apoptosis)
• Coagulative Necrosis – seen in ischemia/infarcts in most tissues (except brain), proteins denature followed by enzymatic degradation, histology: cell
outlines preserved but nuclei disappear, increased cytoplasmic binding of eosin dyes
• Liquefactive Necrosis – seen in bacterial abscesses and brain infarcts, neutrophils release lysosomal enzymes that digest tissue, enzymatic degradation
first, then proteins denature, histology: cellular debris and macrophages early, cystic spaces and cavitation late, neutrophils and cell debris seen with
bacterial infection

• Caseous Necrosis – seen in TB, systemic fungal infections (e.g. Histoplasma capsulatum), Nocardia, macrophages wall off infecting organism producing
granular debris, histology: fragmented cells and debris surrounded by lymphocytes and macrophages

• Fat Necrosis – types: 1.) Enzymatic: seen in acute pancreatitis (saponification of peripancreatic fat), 2.) Nonenzymatic: seen in trauma (e.g. breast tissue
injury), damaged cells release lipase to break down triglycerides, liberating fatty acids to bind to calcium, which results in saponification, histology:
outlines of dead fat cells without peripheral nuclei, fat saponification (combined with Ca2+) appears dark blue on H&E
• Fibrinoid Necrosis – seen in immune reactions in vessels (e.g. Polyarteritis Nodosa), preeclampsia, malignant hypertension, immune complexes combine
with fibrin producing vessel wall damage (T3), histology: vessel walls thick and pink

• Gangrenous Necrosis – seen in distal extremity and GI tract, and after chronic ischemia, types: 1.) Dry: caused by ischemia, histology: coagulative
necrosis, 2.) Wet: caused by superinfection, histology: liquefactive necrosis superimposed on coagulative necrosis

• Cell Injury
• Ischemia – results when blood supply inadequate to meet demand, regions most vulnerable to hypoxia, ischemia, and subsequent infarct: 1.) Brain:
ACA/MCA/PCA boundary (“watershed”) areas, which receive blood supply from most distal branches of 2 arteries with limited collateral vascularity and
are susceptible to hypoperfusion-induced ischemia (e.g. ACA/MCA anterior and MCA/PCA posterior watershed areas), most vulnerable CNS neurons are
Purkinje cells of cerebellum, pyramidal cells of hippocampus, and neocortex (zones 2, 3, 6), 2.) Heart: subendocardium (LV), 3.) Kidney: straight segment
of proximal tubule in medulla, thick ascending limb in medulla, 4.) Liver: area around central vein (zone 3), 5.) Colon: splenic flexure, rectum
• Red Infarct – hemorrhagic infarct, occurs in venous occlusions and tissues with multiple blood supplies (liver, lung, intestine, testes) and in reperfusion
injury (e.g. after angioplasty), which is caused by free radical damage (“red = reperfusion”)

• Pale Infarct – anemic infarct, occurs in solid organs with single (end-arterial) blood supply (heart, kidney, spleen)
Inflammation
• Introduction – characterized by rubor (redness), dolor (pain), calor (heat), tumor (swelling), and functio laesa (loss of function), components: 1.) Vascular
Component: increased vascular permeability, vasodilation, endothelial injury, 2.) Cellular Component: neutrophils extravasate from circulation to injured
tissue to participate in inflammation through phagocytosis, degranulation, and inflammatory mediator release
• Acute Inflammation – mediated by neutrophils, eosinophils, antibodies (pre-existing), mast cells, and basophils, rapid onset (seconds to minutes), short
duration (minutes to days), outcomes include complete resolution, abscess formation, or progression to chronic inflammation
• Chronic Inflammation – mediated by mononuclear cells (monocytes/macrophages, lymphocytes, plasma cells) and fibroblasts, characterized by
persistent destruction and repair, associated with vascular proliferation, fibrosis, formation of granulomas (nodular collections of epithelioid
macrophages and giant cells), outcomes include scarring, amyloidosis, and neoplastic transformation
• Nuclear Factor-Kappa B (NF-κB) – transcription factor that performs critical role in immune response to infection and inflammation, in inflammatory
cells, NF-κB normally present in latent, inactive state bound to its inhibitor protein IκB, as part of classical activation pathway, extracellular signal (e.g.
binding of bacterial antigen like LPS to a toll-like receptor) causes activation of IκB kinase, which results in ubiquination and subsequent proteolytic
destruction of IκB, releasing NF-κB, which can then enter nucleus and promote synthesis of several inflammatory proteins such as cytokines, acute phase
reactants, cell adhesion molecules, and leukocyte-related growth factors, cascade self-limiting because NF-κB also stimulates transcription of more IκB,
ultimately rebinding free NF-κB
• Calcification

Dystrophic Calcification Metastatic Calcification

2+
Ca Deposition In abnormal tissues In normal tissues
Extent Typically localized (e.g. calcific aortic stenosis), shows Widespread (i.e. diffuse, metastatic), shows metastatic
dystrophic calcification and thick fibrotic walls calcifications of alveolar walls in acute pneumonitis
Associated Conditions TB (lung, pericardium) and other granulomatous infections, Predominantly in interstitial tissues of kidney, lung, and gastric
liquefactive necrosis of chronic abscesses, fat necrosis, mucosa (these tissues lose acid quickly, increased pH favors
infarcts, thrombi, Schistosomiasis, Congenital CMV, Ca2+ deposition), nephrocalcinosis of collecting ducts may lead
Toxoplasmosis, Rubella, psammoma bodies, CREST Syndrome to Nephrogenic DI and renal failure
Etiology Injury or necrosis Hypercalcemia (e.g. caused by Primary Hyperparathyroidism,
Sarcoidosis, Hypervitaminosis D) or high calcium-phosphate
product levels (e.g. chronic renal failure with Secondary
Hyperparathyroidism, long-term dialysis, calciphylaxis, Multiple
Myeloma)
Serum Ca2+ Levels Typically normal Typically abnormal

• Leukocyte Extravasation – occurs predominantly at postcapillary venules, WBCs exit blood vessels at sites of tissue injury and inflammation, steps: 1.)
Margination and Rolling: leukocyte Sialyl-LewisX binds to vasculature E-selectin (upregulated by TNF and IL-1) and P-selectin (released from Weibel-
Palade bodies), leukocyte L-selectin binds to vasculature GlyCAM-1 and CD34, defective in Leukocyte Adhesion Deficiency Type 2 (decreased Sialyl-
LewisX), 2.) Tight Binding (Adhesion): leukocyte CD11/18 integrins (LFA-1, Mac-1) bind to vasculature ICAM-1 (CD54), leukocyte VLA-4 integrin binds to
VCAM-1 (CD106), defective in Leukocyte Adhesion Deficiency Type 1 (decreased CD18 integrin subunit), 3.) Diapedesis: leukocyte travels between
endothelial cells and exits blood vessel, involves PECAM-1 (CD31), 4.) Migration: leukocyte responds to chemotactic factors released in response to
bacteria (C5a, IL-8, LTB4, kallikrein, platelet-activating factor) and travels through interstitium to site of injury or infection
• Free Radical Injury – free radicals damage cells via membrane lipid peroxidation, protein modification and DNA breakage, initiated via radiation
exposure (e.g. cancer therapy), metabolism of drugs (phase 1), redox reactions, nitric oxide (e.g. inflammation), transition metals, leukocyte oxidative
burst (macrophages, neutrophils), free radicals eliminated by scavenging enzymes (e.g. catalase, superoxide dismutase, glutathione peroxidase),
spontaneous decay, antioxidants (vitamins A, C, E), and certain metal carrier proteins (e.g. transferrin, ceruloplasmin)
• Examples of Free Radical Injury
o Oxygen Toxicity: Retinopathy of Prematurity (abnormal vascularization), bronchopulmonary dysplasia, reperfusion injury after thrombolytic
therapy
o Drug/Chemical Toxicity: carbon tetrachloride and acetaminophen overdose (hepatotoxicity)
 o Metal Storage Diseases: Hemochromatosis (iron), and Wilson Disease (copper)

Scar Formation and Wound Healing

• Scar Formation – 70-80% of tensile strength regained at 3 months, minimal additional tensile strength will be regained afterward

Hypertrophic Scar Keloid

Collagen Synthesis  (Type 3 collagen)  (disorganized Types 1 and 3 collagen)
Collagen Organization Parallel Disorganized
Extent of Scar Confined to original wound borders Extends beyond original wound borders with “claw-like”
projections, typically on earlobes, face, and upper extremities
Recurrence Infrequent Frequent
Predisposition None Increased incidence in ethnic groups with darker skin
• Tissue Mediators of Wound Healing

Mediator Role
PDGF Secreted by activated platelets and macrophages, induces vascular remodeling and smooth muscle cell migration, stimulates
fibroblast growth for collagen synthesis
FGF Stimulates angiogenesis
EGF Stimulates cell growth via tyrosine kinases (e.g. EGFR/ErbB1)
TGF-β Angiogenesis, fibrosis
Metalloproteinases Tissue remodelling
VEGF Stimulates angiogenesis
• Phases of Wound Healing – phases: 1.) Inflammatory: up to 3 days after wound, mediated by platelets, neutrophils, macrophages, characterized by clot
formation, increased vessel permeability and neutrophil migration into tissue, macrophages clear debris 2 days later, 2.) Proliferative: day 3 to weeks
after wound, mediated by fibroblasts, myofibroblasts, endothelial cells, keratinocytes, macrophages, deposition of granulation tissue and Type 3
collagen, angiogenesis, epithelial cell proliferation, clot dissolution, and wound contraction (mediated by myofibroblasts), delayed wound healing in
vitamin C and copper deficiencies, 3.) Remodeling/Maturation: 1 week to 6+ months after wound, mediated by fibroblasts, Type 1 collagen replaces
Type 3 collagen, increasing tensile strength of tissue, delayed wound healing in zinc deficiency, TGF-β typically decreases during this phase to limit the
buildup of collagenous scar tissue, hypertrophic scars may be caused by consistently elevated TGF-β levels, which leads to increased fibroblast
proliferation and activity, and to altered TGF-β signalling due to upregulation of its receptor
• Angiogenesis – stimulated by: 1.) Vascular Endothelial Growth Factor (VEGF): acts in normal, chronically inflamed, healing, or neoplastic tissues,
increases endothelial cell motility and proliferation, causing capillaries to sprout, 2.) Fibroblast Growth Factor 2 (FGF-2): produced by wide range of cells,
involved in endothelial cell proliferation, migration, and differentiation, also plays important role in embryogenesis by stimulating angioblast production,
contributes to angiogenesis, embryonic development, hematopoiesis, and wound repair (recruits macrophages, fibroblasts, and endothelial cells to
damaged tissues)
• Granulomatous Diseases – granulomas composed of epithelioid cells (macrophages with abundant pink cytoplasm) with surrounding multinucleated
giant cells and lymphocytes, TH1 cells secrete IFN-γ, activating macrophages, TNF-α from macrophages induces and maintains granuloma formation, anti-
TNF drugs may induce breakdown of sequestering granulomas leading to disseminated disease (e.g. TB), always test for latent TB before starting anti-
TNF therapy, granulomas associated with hypercalcemia due to calcitriol (1,25-(OH)2 vitamin D3) production, caseating necrosis more common with
infectious etiology (e.g. TB), noncaseating granulomas upon biopsy required for diagnosing sarcoidosis, causes: 1.) Bacterial: Mycobacteria (Tuberculosis,
Leprosy), Bartonella henselae (Cat Scratch Disease), Listeria monocytogenes (Granulomatosis Infantiseptica), Treponema pallidum (tertiary Syphilis), 2.)
Fungal: endemic mycoses (e.g. Histoplasmosis), 3.) Parasitic: Schistosomiasis, 4.) CGD, 5.) Autoinflammatory: Sarcoidosis, Crohn Disease, Primary Biliary
Cirrhosis, Subacute (de Quervain/Granulomatous) Thyroiditis, Granulomatosis with Polyangiitis (Wegener), Eosinophilic Granulomatosis with Polyangiitis
(Churg-Strauss Syndrome), Giant Cell (Temporal) Arteritis, Takayasu Arteritis, 6.) Foreign Material: Berylliosis, Talcosis, retained sutures, Hypersensitivity
Pneumonitis
Markers of Inflammation
• Exudate vs. Transudate

Exudate Transudate
Viscosity Cellular (cloudy) Hypocellular (clear)
Protein  (>2.9 g/dL)  (<2.5 g/dL)
LDH relative to serum  
Cause Lymphatic obstruction (chylous), inflammation/infection, Increased hydrostatic pressure (e.g. HF, Na+ retention) or
malignancy decreased oncotic pressure (cirrhosis, nephrotic syndrome)
• Light Criteria – diagnostic analysis comparing serum and pleural fluid protein and LDH levels, considered exudative if >1 of following criteria met: 1.)
Pleural Effusion/Serum Protein Ratio: >0.5, 2.) Pleural Effusion LDH/Serum LDH Ratio: >0.6, 3.) Pleural Effusion LDH: >2/3 upper limit of normal for serum
LDH
• Erythrocyte Sedimentation Rate (ESR) – products of inflammation (e.g. fibrinogen) coat RBCs and cause aggregation, denser RBC aggregates fall at faster
rate within pipette tube, often co-tested with C-Reactive Protein (CRP) levels, clinical associations: 1.) Increased ESR: most anemias, infections,
inflammation (e.g. Giant Cell Arteritis, Polymyalgia Rheumatica), cancer (e.g. metastases, Multiple Myeloma), renal disease (end-stage or nephrotic
syndrome), pregnancy, 2.) Decreased ESR: SCD (altered RBC shape), polycythemia (increased RBC number “dilutes” aggregation factors, heart failure,
microcytosis, Hypofibrinogenemia

Amyloidosis
• Introduction – abnormal aggregation of proteins (or protein fragments) into β-pleated linear sheets, producing insoluble fibrils, cellular damage, and
apoptosis, amyloid deposits visualized by Congo Red stain, polarized light (apple green birefringence), and H&E stain, types: 1.) AL (Primary): due to
deposition of proteins from Ig light chains, may occur as plasma cell disorder or associated with Multiple Myeloma, often affects multiple organ systems,
including renal (nephrotic syndrome), cardiac (restrictive cardiomyopathy, arrhythmia), hematologic (easy bruising, splenomegaly), GI (hepatomegaly),
and neurologic (neuropathy) (“AL caused by Ig Light chains”), 2.) AA (Secondary): seen in common inflammatory conditions like RA, IBD,
Spondyloarthropathy, Familial Mediterranean Fever, protracted infection, fibrils composed of serum amyloid A, often multisystem like AL form (“AA
caused by Amyloid A), 3.) Dialysis-Related: fibrils composed of β2-microglobulin in patients with ESRD and/or on long-term dialysis, may present as
 Carpal Tunnel Syndrome, 4.) Heritable: heterogeneous group of disorders, including familial amyloid polyneuropathies due to transthyretin gene
mutation, 5.) Age-Related (Senile) Systemic: due to deposition of normal (wild-type) transthyretin (TTR) predominantly in cardiac ventricles, slower
progression of cardiac dysfunction relative to AL amyloidosis, 6.) Organ-Specific: amyloid deposition localized to single organ, amyloidosis in Alzheimer
Disease due to deposition of β-amyloid protein cleaved from amyloid precursor protein (APP), islet amyloid polypeptide (IAPP) commonly seen in
Diabetes Mellitus Type 2 and is caused by amylin deposition in pancreatic islets, isolated atrial amyloidosis due to ANP common in normal aging and can
predispose to increased risk of AFIB, amyloid deposition to ventricular endomyocardium in restrictive cardiomyopathy, calcitonin deposition in tumor
cells in medullary carcinoma of thyroid

• Lipofuscin – yellow-brown “wear-and-tear” pigment associated with normal aging, formed by oxidation and polymerization of autophagocytosed
organellar membranes, autopsy of elderly person reveals deposits in heart, colon, liver, kidney, eye, and other organs

Cellular Response to Stress

• Hyperplasia – increase in cell number, possible risk factor for future malignancy (e.g. endometrial hyperplasia), but not considered premalignant
• Hypertrophy – increase in cell size
• Atrophy – decrease in tissue mass due to decrease in cell size or number, caused by disuse, denervation, loss of blood supply or hormonal stimulation,
malnutrition
• Dysplasia – disordered, non-neoplastic cell growth, term only used with epithelial cells, mild dysplasia usually reversible, severe dysplasia progresses to
carcinoma in situ
• Metaplasia – replacement of one cell type with another, usually due to irritant exposure, such as gastric acid or cigarette smoke, reversible if irritant
removed, but may undergo malignant transformation with persistent insult (e.g. Barrett esophagus leading to esophageal adenocarcinoma)
• Neoplasia – uncontrolled, clonal proliferation of cells, may be benign or malignant
• Anaplasia – complete lack of cell differentiation in malignant neoplasm
• Differentiation – degree to which a malignant tumor resembles its tissue of origin, well-differentiated tumors closely resemble their tissue of origin and
are often less aggressive, poorly-differentiated tumors look almost nothing like their tissue of origin and are often more aggressive
Neoplastic Progression
• Introduction – hallmarks of cancer include evasion of apoptosis, growth signal self-sufficiency, anti-growth signal insensitivity, sustained angiogenesis,
limitless replicative potential, tissue invasion, and metastasis
• Normal Cells – cells with basal to apical polarity

• Dysplasia – abnormal proliferation of cells with loss of size, shape, and orientation (e.g. koilocytic change, contrast hyperplasia, which is an increase in
cell number)

• Carcinoma in Situ/Preinvasive – neoplastic cells that have not invaded the basement membrane (which remains intact), increased nuclear/cytoplasmic
ratio and clumped chromatin, neoplastic cells encompass entire thickness of structure

• Invasive Carcinoma – neoplastic cells that have invaded basement membrane using collagenases and hydrolases (metalloproteinases), cell-cell contacts
lost by inactivation of E-cadherin
 • Metastasis – spread of neoplastic cells to distant sites via lymphatics or blood, “Seed and Soil” theory of metastasis states that seed is a tumor embolus,
soil is the target organ, which is not random, but has suitable microenvironment for cancerous growth (i.e. some cancers predisposed to metastasize to
particular areas because that area’s environment favorable for growth of that particular cancer)

Tumor Grades, Stages, Nomenclature, and Treatment

• Tumor Grade – degree of cellular differentiation and mitotic activity on histology, ranges from low grade (well differentiated) to high grade (poorly
differentiated, undifferentiated, or anaplastic)
• Tumor Stage – degree of localization/spread based on site and size of primary lesion, spread to regional lymph nodes, presence of metastasis, based on
clinical (c) or pathology (p) findings, stage generally has more prognostic value than grade (e.g. a high-stage yet low-grade tumor is usually worse than a
low-stage yet high-grade tumor), TNM staging system: T: tumor size/invasiveness, N: nodal involvement, M: metastasis, each TNM factor has
independent prognostic value, N and M often most important, Example: cT3N1M0
• Tumor Nomenclature – carcinoma implies epithelial origin, sarcoma designates mesenchymal origin, both terms imply malignancy, benign tumors
usually well differentiated, well demarcated, low mitotic activity, no metastasis, no necrosis, malignant tumors usually poorly differentiated, show
erratic growth, local invasion, metastasis, and decreased apoptosis, upregulation of telomerase prevents chromosome shortening and cell death, terms
for non-neoplastic malformations include hamartoma (disorganized overgrowth of tissues in their native location, e.g. Peutz-Jeghers polyps) and
choristoma (normal tissue in foreign location, e.g. gastric tissue in distal ileum in Meckel diverticulum)

Cell Type Benign Malignant

Epithelium
Adenoma, Papilloma Adenocarcinoma, Papillary Carcinoma
Mesenchyme
Blood Cells - Leukemia, Lymphoma
Blood Vessels Hemangioma Angiosarcoma
Smooth Muscle Leiomyoma Leiomyosarcoma
Striated Muscle Rhabdomyoma Rhabdomyosarcoma
Connective Tissue Fibroma Fibrosarcoma
 Bone Osteoma Osteosarcoma
Fat Lipoma Liposarcoma
Melanocyte Nevus/Mole Melanoma
• Cancer Epidemiology – skin cancer (most not included below) the most common cancer (basal > squamous >> melanoma)

Men Women Children (0-14) Notes

Cancer Incidence 1. Prostate 1. Breast 1. Leukemia Lung cancer incidence has
2. Lung 2. Lung 2. Brain and CNS dropped in men, but has not
3. Colorectal 3. Colorectal 3. Neuroblastoma changed in women
4. Bladder 4. Uterus
5. Melanoma 5. Thyroid
Cancer Mortality 1. Lung 1. Lung 1. Leukemia Cancer the 2nd leading cause
2. Prostate 2. Breast 2. Brain and CNS of death in the US (heart
3. Colorectal 3. Colorectal 3. Neuroblastoma disease is 1st)
4. Pancreas 4. Pancreas
5. Bladder 5. Ovary
• Ionizing Radiation – gamma rays and x-rays, commonly used to treat or palliate several types of cancer, causes cell death via 2 mechanisms: 1.) DNA
Double-Strand Breakage: generally required, as single strand breaks readily repaired by polymerases, 2.) Free Radical Formation: ROS formed by
ionization of water, oxygen free radicals then able to cause cellular and DNA damage, effect of radiation most pronounced in malignant cells since they
are rapidly dividing and consequently less able to repair DNA damage, epithelial surfaces (e.g. bowel mucosa, skin) also severely affected because they
also are rapidly dividing, characteristic cell death curve of exposure to radiation shows nearly flat line on initial exposure, followed by steep increase in
cell death (rapid decrease in number of organisms/cell survival) as radiation dose increases, reflecting sharp increase in double-stranded DNA fractures
and oxygen free radicals
Paraneoplastic Syndrome
Manifestation Description/Mechanism Most Commonly Associated Cancers
Cutaneous
Acanthosis Nigricans Hyperpigmented velvety plaques in axilla and neck Gastric adenocarcinomas and other visceral malignancies (but
more commonly associated with obesity and insulin
resistance)
Sign of Leser-Trélat Sudden onset of multiple seborrheic keratoses GI adenocarcinomas and other visceral malignancies
Endocrine
Hypercalcemia PTHrR SCC of lung, head, and neck, renal bladder, breast, ovarian
carcinoma
1,25-(OH)2 vitamin D3 (calcitriol) Lymphoma
Cushing Syndrome ACTH Small cell lung cancer
Hyponatremia (SIADH) ADH Small cell lung cancer
Hematologic
Polycythemia Erythropoietin Renal cell carcinoma, hepatocellular carcinoma,
hemangioblastoma, pheochromocytoma, leiomyoma
Pure Red Cell Aplasia Anemia with low reticulocytes Thymoma
Good Syndrome Hypogammaglobulinemia Thymoma
Trousseau Syndrome Migratory superficial thrombophlebitis Adenocarcinomas, esp. pancreatic
Nonbacterial Thrombotic Deposition of sterile platelet thrombi on heart valves Adenocarcinomas, esp. pancreatic
(Marantic) Endocarditis
 Neuromuscular
Anti-NMDA Receptor Psychiatric disturbances, memory deficits, seizures, Ovarian teratoma
Encephalitis dyskinesias, autonomic instability, language dysfunction
Opsoclonus-Myoclonus “Dancing eyes, dancing feet” Neuroblastoma (children), small cell lung cancer (adults)
Ataxia Syndrome
Paraneoplastic Cerebellar Antibodies against Purkinje cell antigens Small cell lung cancer (anti-Hu), gynecologic and breast
Degeneration cancers (anti-Yo), and Hodgkin lymphoma (anti-Tr)
Paraneoplastic Antibodies against neuronal Hu antigens Small cell lung cancer (anti-Hu)
Encephalomyelitis
Lambert-Eaton Myasthenic Antibodies against presynaptic (P/Q-type) Ca2+ channels Small cell lung cancer
Syndrome at NMJ
Myasthenia Gravis Antibodies against postsynaptic ACh receptors at NMJ Thymoma

Oncogenes, Tumor Suppressor Genes, Oncogenic Microbes, and Carcinogens

• Introduction
• Oncogenes – gain of function increases cancer risk, only requires damage to one allele of an oncogene

Gene Gene Product Associated Neoplasm

ALK Receptor tyrosine kinase Lung Adenocarcinoma
BRC-ABL Tyrosine kinase CML, ALL
Bcl-2 Antiapoptotic molecule (inhibits apoptosis) Follicular and Diffuse Large B-cell Lymphoma
BRAF Serine/threonine kinase Melanoma, non-Hodgkin lymphoma, Papillary Thyroid Carcinoma
c-KIT Cytokine receptor Gastrointestinal Stromal Tumor (GIST)
c-MYC Transcription factor Burkitt Lymphoma
HER2/neu (c-erbB2) Receptor tyrosine kinase Breast and gastric carcinomas
JAK2 Tyrosine kinase Chronic myeloproliferative disorders
KRAS GTPase Colon, lung, and pancreatic cancer
MYCL1 Transcription factor Lung tumor (“MYCL1 affects Lung”)
MYCN Transcription factor Neuroblastoma (“MYCN causes Neuroblastoma”)
RET Receptor tyrosine kinase MEN2A and 2B, medullary thyroid cancer
• Tumor Suppressor Genes – loss of function increases cancer risk, requires both (two) alleles to be lost before expression of disease

Gene Gene Product Associated Condition

APC Negative regulator of β-catenin/WNT pathway Colorectal cancer (associated with FAP)
BRCA1/BRCA2 DNA repair protein Breast, ovarian, and pancreatic cancer
CDKN2A p16, blocks progression of G1  S phase Melanoma, pancreatic cancer
DCC DCC (“Deleted in Colon Cancer”) Colon cancer
DPC4/SMAD4 DPC (“Deleted in Pancreatic Cancer”) Pancreatic cancer
MEN1 Menin MEN1
 NF1 Neurofibromin (Ras GTPase activating protein) NF1
NF2 Merlin (schwannomin) protein NF2
PTEN Tyrosine phosphatase of PIP3 (e.g. protein kinase B – AKT Breast, prostate, and endometrial cancer
activation)
RB Inhibits E2F, blocks progression of G1  S phase Retinoblastoma, osteosarcoma
TP53 p53, activates p21, blocks progression of G1  S phase Most human cancers, Li-Fraumeni Syndrome (multiple
malignancies at early age, aka SBLA cancer syndrome: Sarcoma,
Breast, Leukemia, Adrenal gland)
TSC1 Hamartin protein Tuberous sclerosis
TSC2 Tuberin protein Tuberous sclerosis
VHL Inhibits hypoxia inducible factor 1a Von Hippel-Lindau Disease
WT1 Transcription factor that regulates urogenital development Wilms Tumor (Nephroblastoma)
• Oncogenic Microbes

Organism Associated Cancer

EBV Burkitt Lymphoma, Hodgkin lymphoma, nasopharyngeal carcinoma, primary CNS lymphoma (immunocompromised)
HBV, HCV Hepatocellular carcinoma
HHV-8 Kaposi sarcoma
HPV Cervical and penile/anal carcinoma (16, 18), head and neck cancer
H. pylori Gastric adenocarcinoma, MALT Lymphoma
HTLV-1 Adult T-cell Leukemia/Lymphoma
Clonorchis Sinensis (liver fluke) Cholangiocarcinoma
Schistosoma haematobium Bladder cancer (SCC)
• Hereditary Cancer Syndromes
• Carcinogens

Toxin Organ Associated Condition

Aflatoxins (Aspergillus) Liver Hepatocellular Carcinoma
Alkylating agents Blood Leukemia/Lymphoma
Aromatic amines (e.g. Benzidine, 2-Naphthylamine) Bladder Transitional Cell Carcinoma
 Arsenic Liver Angiosarcoma
Lungs Lung cancer
Skin SCC
Asbestos Lungs Bronchogenic Carcinoma > Mesothelioma
Carbon tetrachloride Liver Centrilobular necrosis, fatty change
Cigarette smoke Bladder Transitional Cell Carcinoma
Cervix Cervical Carcinoma
Esophagus SCC/Adenocarcinoma
Kidney Renal Cell Carcinoma
Larynx SCC
Lungs SCC and Small Cell Carcinoma
Pancreas Pancreatic Adenocarcinoma
Ethanol Esophagus SCC
Liver Hepatocellular Carcinoma
Ionizing radiation Thyroid Papillary Thyroid Carcinoma
Nitrosamines (smoked foods) Stomach Gastric cancer
Radon Lungs Lung cancer (2nd leading cause after cigarette smoke)
Vinyl chloride Liver Angiosarcoma

Markers of Neoplasia
• Psammoma Bodies – laminated, concentric spherules with dystrophic calcification, PSaMMoma bodies seen in: Papillary Thyroid Carcinoma, Serous
Ovarian Papillary Cystadenocarcinoma, Meningioma, Malignant Mesothelioma
• Serum Tumor Markers – should not be used as primary tool for cancer diagnosis or screening (definitive diagnose made via biopsy), but may be used to
monitor tumor recurrence and response to therapy

Marker Associated Cancer Notes

Alkaline Metastases to bone or liver, Paget Disease, seminoma (placental ALP) Must exclude hepatic origin by checking LFTs and gamma-
phosphatase (ALP) glutamyltransferase (GGT) levels
α-fetoprotein Hepatocellular Carcinoma, Hepatoblastoma, Yolk Sac (Endodermal Normally made by fetus, transiently elevated in pregnancy,
Sinus) Tumor, Mixed Germ Cell Tumor high levels in utero associated with neural tube/abdominal
wall defects, low levels associated with Down Syndrome
β-hCG Hydatidiform moles and Choriocarcinomas (Gestational Trophoblastic Produced by placental syncytiotrophoblasts
Disease), testicular cancer, mixed germ cell tumor
CA 15-3/CA 27-29 Breast cancer
CA 19-9 Pancreatic Adenocarcinoma
CA 125 Ovarian cancer
Calcitonin Medullary Thyroid Carcinoma (alone and in MEN2A, 2B)
CEA Major Associations: colorectal and pancreatic cancers Carcinoembryonic antigen, very nonspecific
Minor Associations: gastric, breast, and medullary thyroid carcinomas
Chromogranin Neuroendocrine tumors
PSA Prostate cancer Prostate-specific antigen, may also be elevated in BPH and
prostatitis, questionable risk/benefit for screening,
surveillance marker for recurrent disease after
prostatectomy
• P-Glycoprotein – also known a multidrug resistance protein 1 (MDR1), classically seen in Adrenocortical Carcinoma, but also expressed by other cancer
cells (e.g. colon, liver), used to pump out toxins, including chemotherapeutic agents (esp. Anthracyclines), key mechanism of decreased
responsiveness/resistance to chemotherapy over time, drugs like Verapamil, Diltiazem, and Ketoconazole decrease action of MDR1
• Cachexia – weight loss, muscle atrophy, and fatigue that occur in chronic disease (e.g. cancer, AIDS, heart failure, COPD), mediated by TNF, IFN-γ, IL-1,
and IL-6
Metastasis
• Common Metastases – most sarcomas spread hematogenously, most carcinomas spread via lymphatics, however “Four Carcinomas Route
Hematogenously”: Follicular thyroid carcinoma, Choriocarcinoma, Renal cell carcinoma, and Hepatocellular carcinoma

Metastatic Site Primary Tumor Notes

Brain Lung > breast > melanoma, colon, kidney 50% of brain tumors are from metastases, commonly appear as multiple well-circumscribed
tumors at gray/white junction
Liver Colon >> stomach > pancreas Liver and lung the most commons metastatic sites after regional lymph nodes
Bone Prostate, breast > lung, thyroid, kidney Metastases much more common than primary bone tumors (e.g. Multiple Myeloma, lytic),
(dual/bilobed organs) common metastases to bone: breast (mixed), lung (lytic), thyroid (lytic), kidney (lytic),
prostate (blastic), predilection for axial skeleton
Cancer Drugs – Cell Cycle and Targets
Antimetabolites
• Azathioprine, 6-Mercaptopurine (6-MP)
o Mechanism: purine (thiol) analogs, decreases de novo purine synthesis, activated by HGPRT, Azathioprine metabolized to 6-MP, S-phase specific
o Treats: prevent organ rejection, RA, IBD, SLE, used to wean patients off steroids in chronic disease and to treat steroid-refractory chronic disease
o Side Effects: myelosuppression, GI, hepatotoxicity
o Drug Interactions: Allopurinol and Febuxostat (increased toxicity, both metabolized by xanthine oxidase)
• Cladribine
o Mechanism: purine analog, multiple mechanisms (e.g. DNA polymerase inhibition, causes DNA strand breaks), S-phase specific
o Treats: Hairy Cell Leukemia
o Side Effects: myelosuppression, nephrotoxicity, neurotoxicity
• Cytarabine (Arabinofuranosyl Cytidine)
o Mechanism: pyrimidine analog, leads to inhibition of DNA polymerase, S-phase specific
o Treats: leukemias (AML), lymphomas
o Side Effects: myelosuppression, palmar-plantar erythrodysesthesia (hand-foot syndrome)
• 5-Fluorouricil
o Mechanism: pyrimidine analog bioactivated to 5-FdUMP, which covalently complexes with thymidylate synthase and folic acid (Capecitabine a
prodrug with similar activity), complex inhibits thymidylate synthase leading to decreased dTMP and thus decreased DNA synthesis, S-phase
specific
o Treats: colon cancer, pancreatic cancer, Basal Cell Carcinoma (topical), effects enhanced with addition of Leucovorin
o Side Effects: myelosuppression, palmar-plantar erythrodysesthesia (hand-foot syndrome)
• Methotrexate
o Mechanism: folic acid analog that competitively inhibits dihydrofolate reductase leading to decreased dTMP and decreased DNA synthesis, S-
phase specific, inhibition of DHF reductase leads to accumulation of folic acid and DHF polyglutamate
o Treats:
 Cancers: leukemias (ALL), lymphomas, choriocarcinoma, sarcomas
 Non-Neoplastic: ectopic pregnancy, medical abortion (+Misoprostol), RA, psoriasis, IBD, vasculitis
o Side Effects: myelosuppression (reversible with Leucovorin “rescue”), hepatotoxicity, mucositis (e.g. mouth ulcers), pulmonary fibrosis
Antitumor Antibodies
• Bleomycin
o Mechanism: induces free radical formation leading to breaks in DNA strands
o Treats: testicular cancer, Hodgkin Lymphoma
o Side Effects: pulmonary fibrosis, skin hyperpigmentation, minimal myelosuppression
• Dactinomycin (Actinomycin D)
o Mechanism: intercalates in DNA
o Treats: Wilms Tumor, Ewing Sarcoma, rhabdomyosarcoma, used for childhood tumors
o Side Effects: myelosuppression
• Doxorubicin, Daunorubicin
o Mechanism: generates free radicals, intercalates in DNA leading to breaks and decreased replication
o Treats: solid tumors, leukemias, lymphomas
o Side Effects: cardiotoxicity (dilated cardiomyopathy, prevented with use of chelating agent Dexrazoxane), myelosuppression, alopecia

Alkylating Agents
• Busulfan
o Mechanism: cross-links DNA
o Treats: CML, also used to ablate bone marrow before bone marrow transplantation
o Side Effects: severe myelosuppression (in almost all cases), pulmonary fibrosis, hyperpigmentation
• Cyclophosphamide, Ifosfamide
o Mechanism: cross-links DNA at Guanine N-7, requires liver bioactivation, nitrogen mustard
o Treats: solid tumors, leukemia, lymphomas
o Side Effects: myelosuppression, hemorrhagic cystitis (prevented with Mesna – thiol group binds toxic metabolites, or N-Acetylcysteine)
• Nitrosoureas
o Mechanism: cross-links DNA, requires bioactivation, crosses blood-brain barrier
o Treats: brain tumors (including Glioblastoma Multiforme)
o Side Effects: CNS toxicity (convulsions, dizziness, ataxia)

Microtubule Inhibitors
• Paclitaxel (and other Taxanes)
o Mechanism: hyper-stabilizes polymerized microtubules in M phase so that mitotic spindle cannot break down (anaphase cannot occur)
o Treats: ovarian and breast carcinomas
o Side Effects: myelosuppression, neuropathy, hypersensitivity
• Vincristine, Vinblastine
 o Mechanism: vinca alkaloids that bind β-tubulin and inhibit its polymerization into microtubules, preventing mitotic spindle formation (M-phase
arrest)
o Treats: solid tumors, leukemias, Hodgkin (Vinblastine) and non-Hodgkin (Vincristine) lymphomas
o Side Effects (Vincristine): neurotoxicity (areflexia, peripheral neuritis), constipation (including paralytic ileus)

Miscellaneous Agents
• Cisplatin, Carboplatin
o Mechanism: cross-links DNA
o Treats: testicular, bladder, ovary, and lung carcinomas
o Side Effects: nephrotoxicity (prevented with Amifostine, a free radical scavenger, and chloride/saline diuresis), peripheral neuropathy,
ototoxicity
• Etoposide, Teniposide
o Mechanism: inhibits topoisomerase 2, leading to increased DNA degradation
o Treats: solid tumors (esp. testicular and small cell lung cancer), leukemias, lymphomas
o Side Effects: myelosuppression, alopecia
• Irinotecan, Topotecan
o Mechanism: inhibits topoisomerase 1, preventing DNA unwinding and replication
o Treats: colon cancer (Irinotecan), ovarian and small cell lung cancers (Topotecan)
o Side Effects: severe myelosuppression, diarrhea
• Hydroxyurea
o Mechanism: inhibits ribonucleotide reductase, decreasing DNA synthesis (S-phase specific)
o Treats: myeloproliferative disorders (e.g. CML, Polycythemia Vera), SCD (increases HbF), melanoma
o Side Effects: severe myelosuppression
• Bevacizumab
o Mechanism: monoclonal antibody against VEGF, inhibits angiogenesis (“BeVacizumab inhibits Blood Vessel formation”)
o Treats: solid tumors (esp. colorectal cancer, Renal Cell Carcinoma)
o Side Effects: hemorrhage, blood clots, impaired wound healing
• Erlotinib
o Mechanism: inhibits EGFR tyrosine kinase
o Treats: non-small cell lung carcinoma
o Side Effects: rash
• Cetuximab
o Mechanism: monoclonal antibody against EGFR
o Treats: stage 4 colorectal cancer (wild-type KRAS), head and neck cancer
o Side Effects: rash, elevated LFTs, diarrhea
• Imatinib (Gleevec)
 o Mechanism: inhibits tyrosine kinase BCR-ABL (Philadelphia chromosome fusion gene in CML) and c-kit (common in GI stromal tumors)
o Treats: CML, GI stromal tumors (GIST)
o Side Effects: fluid retention
• Rituximab
o Mechanism: monoclonal antibody against CD20, which is found on most B-cell neoplasms
o Treats: Non-Hodgkin Lymphoma, CLL, ITP, RA
o Side Effects: increased risk of Progressive Multifocal Leukoencephalopathy
• Bortezomib, Carfilzomib
o Mechanism: inhibits proteasomes, inducing arrest at G2-M phase and apoptosis
o Treats: Multiple Myeloma, Mantle Cell Lymphoma
o Side Effects: peripheral neuropathy, Herpes Zoster reactivation
• Trastuzumab (Herceptin)
o Mechanism: monoclonal antibody against HER-2 (c-erbB2), a tyrosine kinase receptor, kills cancer cells that overexpress HER-2 through
inhibition of HER-2-initiated cellular signalling and antibody-dependent cytotoxicity
o Treats: HER-2⊕ breast cancer and gastric cancer (“Tras2zumab”)
o Side Effects: cardiotoxicity (“Heartceptin damages the heart”)
• Vemurafenib
o Mechanism: small molecule inhibitor of BRAF⊕ Melanoma (“VEmuRAFenib for V600E-mutated BRAF inhibition”)
o Treats: metastatic Melanoma
• Rasburicase
o Mechanism: recombinant uricase that catalyzes metabolism of uric acid to allantoin
o Treats: prevention and treatment of Tumor Lysis Syndrome

Selective Estrogen Receptor Modulators (SERMs)

• Tamoxifen, Raloxifene
o Mechanism: estrogen receptor antagonists in breast, agonists in bone, block binding of estrogen to ER⊕ cells
o Treats: treatment (Tamoxifen only) and prevention of breast cancer, osteoporosis prevention (Raloxifene)
o Side Effects: both increase risk of thromboembolic events (e.g. DVT, PE)
 Tamoxifen: partial estrogen agonist in endometrium, thus increases risk of endometrial carcinoma and hot flashes
 Raloxifene: estrogen antagonist in endometrial tissue, thus no increased risk of endometrial carcinoma (“so you can relax/ralox!”)

Chemotoxicities
• Tumor Lysis Syndrome – oncologic emergency triggered by massive tumor cell lysis, most often in lymphomas/leukemias, release of K+ leads to
hyperkalemia, release of PO43- leads to hyperphosphatemia, hypocalcemia due to Ca2+ sequestration by PO43-, increased nucleic acid breakdown leads to
hyperuricemia, which produces acute kidney injury, treat with aggressive hydration, Allopurinol, Rasburicase
• Common Chemotoxicities
o Cisplatin/Carboplatin – ototoxicity and nephrotoxicity
o Vincristine – peripheral neuropathy
o Bleomycin, Busulfan – pulmonary fibrosis
o Doxorubicin – cardiotoxicity
o Trastuzumab (Herceptin) – cardiotoxicity
o Cyclophosphamide – hemorrhagic cystitis