The first line of defence is the innate system, made up of specialised cells that provide a rapid response that is

not tailored to the specific microbe that has infiltrated the body. Sometimes this can clear the infection alone but
usually the innate response will contain the infection long enough for the adaptive immune system to activate.
The adaptive response is the second line of defence and takes several days to assemble. The response is specific
to the microbe and leaves a lasting immune memory, which makes the response to future reinfection more
efficient (see here for more information). In a person with an immunodeficiency disorder, one or more
components of either the adaptive or innate immune response is impaired, resulting in the body being unable to
effectively resolve infections or disease. This leaves immunodeficient individuals at high risk of recurrent
infection

Examples of primary immunodeficiency disorders

B cell immunodeficiencies (adaptive) – B cells are one of two key cell types of the adaptive immune system.
Their main role is to produce antibodies, which are proteins that attach to microbes, making it easier for other
immune cells to detect and kill them. Mutations in the genes that control B cells can result in the loss of
antibody production. These patients are at risk of severe recurrent bacterial infections.

T cell immunodeficiencies (adaptive) – T cells are the second of two key cell types of the adaptive immune
system. One role of the T cell is to activate the B cell and pass on details of the microbe’s identity, so that the B
cell can produce the correct antibodies. Some T cells are also directly involved in microbe killing. T cells also
provide signals that activate other cells of the immune system. Mutations in the genes that control T cells can
result in fewer T cells or ones that do not function properly. This can lead to their killing ability being disrupted,
and can often cause problems with B cell function too. Therefore, T cell immunodeficiencies can often lead to
combined immunodeficiencies (CIDs), where both T and B cell function is defective. Some forms of CIDs are
more severe than others.

Severe combined immune deficiencies (SCID) (adaptive) – SCID disorders are very rare but extremely serious.
In SCID patients there is often a complete lack of T cells and variable numbers of B cells, resulting in little-to-
no immune function, so even a minor infection can be deadly. SCID patients are usually diagnosed in the first
year of life with symptoms such as recurrent infections and failure to thrive.

Phagocyte disorders (innate) - phagocytes include many white blood cells of the innate immune system, and
these cells patrol the body eating any pathogens they come across. Mutations typically affect the ability of
certain phagocytes to eat and destroy pathogens effectively. These patients have largely functional immune
systems but certain bacterial and fungal infections can cause very serious harm or death.

Complement defects (innate) – complement defects are some of the rarest of all the PIDs, and account for less
than 1% of diagnosed cases. Complement is the name given to specific proteins in the blood that help immune
cells clear infection. Some deficiencies in the complement system can result in the development of autoimmune
conditions such as systemic lupus erythematosus and rheumatoid arthritis (please see our autoimmune briefing
for more information). Patients who lack certain complement proteins are highly susceptible to meningitis.

Secondary immunodeficiency (SID)

SIDs are more common than PIDs and are the result of a primary illness, such as HIV, or other external factor
such as malnutrition or some drug regimens. Most SIDs can be resolved by treating the primary condition.

Examples of secondary immunodeficiency disorders

Malnutrition – Protein-calorie malnutrition is the biggest global cause of SIDs which can affect up to 50% of the
population in some communities in the developing world.vii T cell numbers and function decrease in proportion
to levels of protein deficiency, which leaves the patient particularly susceptible to diarrhoea and respiratory tract
infections. This form of immunodeficiency will usually resolve if the malnutrition is treated.

Drug regimens – There are several types of medication that can result in secondary immunodeficiencies, but
these drugs also perform critical roles in certain areas of healthcare. Immunosuppression is a common side-
effect of most chemotherapies used in cancer treatment. The immune system usually recovers once the
chemotherapy treatment has finished. Another common use forimmunosuppressive drugs is the prevention of
transplant rejection, where medication is required to suppress the transplant recipient’s immune system and
prevent it from targeting the transplanted tissue. These drugs can have significant side-effects and often suppress
more areas of the immune system than are required, leading to susceptibility to opportunistic infections. Use of a
new generation of medicines called biologics are becoming more widespread in treating transplant rejection.
These drugs are derived from biological sources like cells, rather than chemical structures. Monoclonal
antibodies are one such class of biologics and these drugs are made by farming antibodies from B cells that will
act against a specific part of the disease process. These agents are more specific in their action than traditional
drugs and have fewer side effects on non-target immune cells.

Chronic infections – There are a number of chronic infections which can lead to SID disorders, the most
common of which is acquired immune deficiency syndrome (AIDS), resulting from HIV infection. The virus
attacks CD4+ T cells, a type of white blood cell that plays a critical role in preventing infection, and gradually
depletes their numbers. Once the T cell count is less than 200 cells per ml of blood, symptoms of AIDS begin to
manifest and the patient is at high risk of recurrent infections that will eventually lead to death. Anti-viral
therapies, such as the HAART regimen (Highly Active Antiretroviral Therapy), allow the T cell population a
chance to recover and resume normal function

KONSEKUENSI DARI IMMUNODEFISIENSI

IMUNODEFISIENSI
Imunodefisiensi adalah penyakit yang disebabkan menurunya atau gagalnya salah satuatau lebih komponen
sistem imun. Imunodefisiensi spesifik dapat melibatkan kelainan pada sel T atau sel B yang merupakan
komponen sistem imun spesifik, sedangkan kelompok Imunodefisiensi lain adalah Imunodefisiensi non-spesifik
yang melibatkan komponen-komponen sistem imun yang terutama terdiri atas sistem fagosit dan komplemen.
Gejala klinis yangmenonjol pada Imunodefisiensi adalah infeksi berulang atau berkepanjangan atau oportunistik
atau infeksi yang tidak umum yang tidak memberikan respon yang adekuat terhadap terapiantimikroba. Telah
diketahui bahwa reaksi imunologi pada infeksi merupakan interaksi antara berbagai komponen dalam sistem
imun yang sangat komplek. Kelainan pada sistem fagosit,limfosit T dan limfosit B mapun dalam sistem
komplemen dapat menampilkan gejala klinik yangsama sehingga sulit dipastikan komponen mana dari sistem
imun yang mengalami gangguan.Penderita dengan defisiensi limfosit T biasanya menunjukan kepekaan
terhadap infeksi irus, proto!oa, dan jamur yang biasanya dapat diatasi dengan respon imun seluler.Gambaran
umum imunodefisiensi adalah sebagai berikut"
•

Konsekuensi utama imunodefisiensi adalah peningkatan kepekaan terhadap infeksi. #ifat infeksi pada indiidu
tertentu terutama bergantung pada komponen sistem imun mana yang mengalamidefek.
•

Pasien dengan imunodefisiensi biasanya juga mudah terkena kanker terutama kanker yangdisebabkan oleh irus.
$al ini sering terlihat pada imunodefisiensi sel T.
•

Imunodefisiensi merupakan penyakit yang sangat heterogen. Sebagian besar hal ini disebabkan defek komponen
sistem imun yang berbeda-beda dengan manifestasi klinis yang berbeda pula.dengan demikian, defek respon
imun dapat disebabkan kelainan imunitas spesifik maupun non spesifik, sedangkan defek imunitas spesifik
mungkin disebabkan kelainan dalam perkembangan sel-sel sistem imun, maupun aktivasi atau fungsi limfosit T
dan atau limfosit B Spesifik.

IMMUNOSUPRESS AND IMMUNODEPRESS

Imunosupresi adalah pasien dengan penurunan sistem kekebalan tubuh yang dapat disebabkan oleh berbagai hal
misalnya pengobatan dengan steroid dosis tinggi , sitostatika (kemo) dan lain-lain. Keadaan lainnya adalah
pasien yang mengalami penurunan daya tahan akibat penyakit misalnya Granulositopenia atau keadaan lain
termasuk AIDS. Kedua kelompok tersebut memiliki resiko infeksi dari petugas kesehatan lain atau
pengunjung.Kategori tersebut adalah sebagai Compromised Host Infection Precaution (CHIP). Tubuh Pasien
yang berada dalam kondisi imunosupresi rentan terhadap infeksi karena tidak mampu mengeluarkan respon
pertahanan terhadap pathogen. Maka dari itu untuk mencegah infeksi silang antara pasien yang
imucompromised dengan pasien lain dan petugas maka pasien diisolasi dalam kamar perawatan.

Yang disebut pasien imunosupresi adalah pasien dengan :

Kelainan darah dengan febril neutropeni

Kanker / keganasan dengan febril neutropeni
Penerima transplantasi organ
HIV /AIDS

. Neutropenia
Neutropenia didefinisikan apabila jumlah neutrofil absolut <500 sel/uL untuk pasien dengan tumor padat atau
<1000 sel/ul untuk pasien leukemia. Apabila jumlah neutrofil menurun secara bermakna dan masa neutropenia
cukup lama, maka risiko terjadinya infeksi oleh bakteri, jamur, virus atau mikroorganisme oportunistik akan
meningkat secara nyata. Khusus pasien yang sebelumnya telah mendapat kemoterapi atau radioterapi akan lebih
peka terhadap infeksi.
jumlah normal neutrofil : 2-8

Cryptococcus neoformans

Cryptococcus neoformans is a spherical, encapsulated, non-myceliated, non-fermenting fungal cell. Among

pathogenic fungi, C. neoformans is unique in that it possesses a mucinous capsule. Small-sized basidiospores
(1.8 to 3.0 μm) can turn into yeast cells, the form preferred at 37°C, or can form dikaryotic hyphae which are
favoured at 24°C. Cryptococcus neoformans causes fatal meningitis primarily in immunosuppressed humans

Infeksi C. neoformans sangat jarang pada orang yang sehat; kebanyakan kasus terjadi pada orang yang memiliki
sistem kekebalan yang lemah, terutama mereka yang memiliki HIV / AIDS tingkat lanjut.

Transmission
An environmental survey found that Cryptococcus neoformans was isolated from pigeon and other bird excreta
and less frequently in other environmental and veterinary (cat, dog, horse, sheep, cow) sources. The organism
exists as both free-living and in association with a variety of hosts. The primary mode of transmission is
inhalation of spores from the environment, affecting both humans and other domestic and wild animals.
Transmission from humans and other animals has not been documented.

Mechanism of action :
C. neoformans-mediated host damage at the molecular, cellular, tissue, and organism level. Direct mechanisms
of cytotoxicity include lytic exocytosis, organelle dysfunction, phagolysosomal membrane damage, and
cytoskeletal alterations. Cytotoxicity contributes to pathogenesis by interfering with immune effector cell
function and disrupting endothelial barriers thus allowing dissemination. When C. neoformans-mediated and
immune-mediated host damage is sufficient to affect homeostasis, cryptococcosis occurs at the organism level.
Pathogenesis

Infection is initiated by inhalation of the yeast cells. The primary pulmonary infection may be asymptomatic or
may mimic influenza like respiratory infection often resolving spontaneously. In immune-compromised patients
with impaired T cell immunity, the yeasts may multiply and disseminate to other parts of the body but
preferentially to the central nervous system (neurotropic), causing cryptococcal meningitis. Other common sites
of dissemination include the skin, adrenals, bone, eye and prostate gland. The inflammatory reaction is usually
minimal or granulomato

Lab result C neoformans :

Specimens: Common specimens include spinal fluid (CSF), tissue, exudates, sputum, blood and urine.
India ink preparation and cryptococcal antigen agglutination are commonly used diagnostic methods.
Cara Microscopy and staining: Cryptococcus neoformans appear as a spherical, single or multiple budding,
thick walled yeast that is 2-15 μm (wide variation in size) in diameter. It is usually surrounded by a wide
refractile capsule.
heavily capsulated yeast cells (see the image) in CSF, exudates and urine establishes the diagnosis.
Cara india ink preparation when positive in CSF is diagnostic of cryptococcal meningitis but its sensitivity is
low. Many diagnostic laboratories have replaced this test with more sensitive cryptococcal latex agglutination
test
Cryptococcus neoformans is sensitive to cycloheximide so media containing cycloheximide should be avoided.
Cryptococcus neoformans is identified by urease production and carbohydrate assimilation test, and confirmed
by direct immunoflurorescence using a fluorescein-labelled anti-neoformans antibody.

Detection of Antigen and/or Antibody

Detection of Antigen: Tests for capsular antigen can be performed on CSF and serum. Latex agglutination test is
most useful in detection of cryptococcal polysaccharide antigen. Slide latex agglutination test has sensitivity of
90% in the cases of cryptococcal meningitis.
Detection of Antibody: Serum antibodies can be detected by agglutination and immunofluorescence.

Di mana C. neoformans tumbuh?

C. neoformans hidup di lingkungan di seluruh dunia. Jamur ini biasanya ditemukan di tanah, pada kayu yang
membusuk, di lubang dalam pohon, atau di kotoran burung.

C. Neoformans mempengaruhi paru-paru atau sistem saraf pusat (otak dan sumsum tulang belakang), tetapi juga
dapat mempengaruhi bagian lain dari tubuh. Infeksi otak karena jamur Cryptococcus disebut meningitis
kriptokokal.

Life cycle Cryptococcus neoformans

Gejala Infeksi C. neoformans

Di paru-paru:
Infeksi C. neoformans di paru-paru dapat menyebabkan penyakit seperti pneumonia. Gejala-gejalanya sering
mirip dengan banyak penyakit lain, dan dapat meliputi:

Batuk
Sesak napas
Sakit dada
Demam

Di otak (meningitis cryptococcal):

Meningitis kriptokokus adalah infeksi yang disebabkan oleh jamur Cryptococcus setelah menyebar dari paru-
paru ke otak. Gejala meningitis kriptokokus meliputi:

Sakit kepala, demam, dan nyeri leher adalah gejala umum meningitis kriptokokal.
Sakit kepala
Demam
Sakit leher
Mual dan muntah
Sensitivitas terhadap cahaya
Kebingungan atau perubahan perilaku

Pemeriksaan CSF
Jika CSS keruh dan reaksi Nonne dan Pandy positif, pertimbangkan meningitis dan segera mulai berikan
pengobatan sambil menunggu hasil laboratorium. Pemeriksaan mikroskopik CSS pada sebagian besar
meningitis menunjukkan peningkatan jumlah sel darah putih (PMN) di atas 100/mm3. Selanjutnya dilakukan
pengecatan Gram.

Meningitis
Pertimbangkan meningitis tuberkulosis jika:
Demam berlangsung selama 14 hari
Demam timbul lebih dari 7 hari dan ada anggota keluarga yang menderita TB
Hasil foto dada menunjukkan TB
Pasien tetap tidak sadar
CSS tetap mempunyai jumlah sel darah putih yang tinggi (tipikal < 500 sel darah putih per ml, sebagian besar
berupa limfosit), kadar protein meningkat (0.8–4 g/l) dan kadar gula darah rendah (< 15 mmol/liter).

Pada pasien yang diketahui atau dicurigai menderita HIV-positif, perlu pula dipertimbangkan adanya TB atau
meningitis kriptokokal.
Bila ada konfirmasi epidemi meningitis meningokokal dan terdapat petekie atau purpura, yang merupakan
karakteristik infeksi meningokokal, tidak perlu dilakukan pungsi lumbal dan segera berikan Kloramfenikol.

Meningitis is an infection that causes inflammation of the membranes (meninges) that protect the brain and
spinal cord.

Normal Bacterial Meningitis Viral Meningitis* Fungal Meningitis**

Finding
Pressure (mm Increased Normal or mildly Normal or mildly
H2 O) increased increased in
tuberculous
50-150
meningitis; may be
increased in fungal;
AIDS patients with
cryptococcal
meningitis have
increased risk of
blindness and death
unless kept below
300 mm H2 O
Cell count No cell count result Cell count usually < Hundreds of
(mononuclear can exclude bacterial 500, nearly 100% mononuclear cells
cells/µL) meningitis; PMN mononuclear; up to
count typically in 48 hours, significant
Preterm: 0-25
1000s but may be PMN pleocytosis
Term: 0-22 less dramatic or even may be
normal (classically, indistinguishable
>6 months: 0-5 in very early from early bacterial
meningococcal meningitis; this is
meningitis and in particularly true with
extremely ill eastern equine
neonates); encephalitis;
lymphocytosis with presence of
normal CSF nontraumatic RBCs
chemistries seen in in 80% of HSV
15-25%, especially meningoencephalitis,
when cell counts < though 10% have
1000 or with partial normal CSF results
treatment; ~90% of
patients with
ventriculoperitoneal
shunts who have CSF
WBC count >100 are
infected; CSF
glucose is usually
normal, and
organisms are less
pathogenic; cell
count and chemistries
normalize slowly
(over days) with
antibiotics
Microscopy Gram stain 80% No organism India ink is 50%
sensitive; inadequate sensitive for fungi;
No organisms
decolorization may cryptococcal antigen
mistake Haemophilus is 95% sensitive;
influenzae for gram- AFB stain is 40%
positive cocci; sensitive for
pretreatment with tuberculosis
antibiotics may affect (increase yield by
stain uptake, causing staining supernatant
gram-positive from at least 5 mL
organisms to appear CSF)
gram-negative and
decrease culture yield
by average of 20%

Glucose Decreased Normal Sometimes

decreased; aside
Euglycemia:
from fulminant
>50% serum
bacterial meningitis,
Hyperglycemia lowest levels of CSF
: >30% serum glucose are seen in
tuberculous
Wait 4 hr after meningitis, primary
glucose load amebic
meningoencephalitis,
and
neurocysticercosis
Protein Usually >150, may Mildly increased Increased; >1000
(mg/dL) be >1000 with relatively
benign clinical
Preterm: 65-
presentation
150
suggestive of fungal
Term: 20-170 disease

>6 months: 15-

45

AFB = acid-fast bacillus; CSF = cerebrospinal fluid; HSV = herpes simplex virus; RBC = red blood cell;
PMN = polymorphonuclear leukocyte.

Agent Openin WBC Glucose Protein Microbiolog

g count (mg/dL) (mg/dL y
Pressur (cells/µL) )
e (mm
H2O)

Bacterial 200- 100-5000; < 40 >100 Specific

meningitis 300 >80% pathogen
PMNs demonstrate
d in 60% of
Gram stains
and 80% of
cultures
Viral 90-200 10-300; Normal, Normal Viral
meningitis lymphocyt reduced but isolation,
es in LCM may be PCR assays
and slightly
mumps elevate
d

Tuberculous 180- 100-500; Reduce Elevate Acid-fast

meningitis 300 lymphocyt d, < 40 d, >100 bacillus
es stain,
culture, PCR

Cryptococca 180- 10-200; Reduce 50-200 India ink,

l meningitis 300 lymphocyt d cryptococcal
es antigen,
culture

Aseptic 90-200 10-300; Normal Normal Negative

meningitis lymphocyt but findings on
es may be workup
slightly
elevate
d

Normal 80-200 0-5; 50-75 15-40

values lymphocyt
es

WO
4. The 5 classes of systemic antifungal medications include the polyenes, the azoles, a nucleoside analog, an
echinocandin, and an allylamine
Polyenes : There are 4 formulations of amphotericin B, the only polyene drug available for systemic use:
amphotericin B deoxycholate (Fungizone), amphotericin B colloidal dispersion (Amphotec), amphotericin B
lipid complex (Abelcet), and liposomal amphotericin B (AmBisome). Amphotericin B binds to ergosterol in the
fungal cell membrane, increases cell membrane permeability, and causes leakage of intracellular contents and
cell death.
Azole : The azole class includes 4 triazole agents: fluconazole, itraconazole, voriconazole, and ketoconazole.
The azoles inhibit C-14 a demethylation of lanosterol, thereby impairing synthesis of ergosterol in the fungal
cytoplasmic membrane

Nucleoside analog : Flucytosine (Ancobon), the only available nucleoside analog, disrupts pyrimidine
metabolism in the fungal cell nucleus.

Echinocandin : Caspofungin (Cancidas), an echinocandin, inhibits formation of b 1,3 glucan in the fungal cell
wall. Thus, there are 3 potential target sites for the antifungal drugs: ergosterol in the cell membrane, b 1,3
glucan in the cell wall, and nucleic acid synthesis in the cell nucleus.

Allylamine : Terbinafine is an allylamine compound that disrupts squalene oxidase in the fungal cell membrane.

6. Fungal infection in immunocompromised host and the opportunistic mycoses

Dalam keadaan normal relatif sedikit spesies jamur yang patogenik. Akan tetapi pada
beberapa keadaan tertentu seperti defisiensi imun (immunocompromised) beberapa spesies
jamur dapat menyebabkan infeksi, terutama pada pasien dengan keadaan defisiensi imun
(immunocompromised). Beberapa kondisi yang dapat menimbulkan keadaan
immunocompromised antara lain ialah neutropenia, adanya kerusakan pada imunitas
seluler dan humoral, perubahan pada sawar fisik, gizi buruk, adanya obstruksi dan
perubahan flora bakteri

7. Immunological intolerance and how does the body handle transplant

8. How immune response is organize