Fungal and Viral Infections of the

Pulmonary System
April 17, 2018

Joseph L. Alcorn, Ph.D.

Office: Rm MSB3.222
Phone: 713-500-5641
E-mail: Joseph.L.Alcorn@uth.tmc.edu
The incidence and severity of pulmonary fungal
infections have dramatically increased :

1. Increased numbers of immunocompromised patients

with malignancy, hematologic disease, and HIV.

2. Increased numbers of individuals receiving

immunosuppressive drug regimens for the
management of organ transplantation or autoimmune
inflammatory conditions.
 RESPIRATORY FUNGAL INFECTIONS

Fungal infections typically :

• cause localized disease in immunocompetent individuals
• can cause disseminated disease in immunocompromised
individuals

Initial exposure: “flu”-like symptoms may develop with histology

similar to primary TB.
• In the vulnerable host -- cavitary lesions similar to secondary TB
is seen.
• In immunocompromised host -- disseminated disease, with little
granuloma formation takes place.
Grocott-Gomori's methenamine stain (GMS):
silver based stain useful in fungi detection

Stains carbohydrates, making cell walls dark

 ASPERGILLOSIS

Caused by fungal spores from the

mold Aspergillus inhaled into lungs
and sinuses

Lives in soil, plants and rotting

material

Found in:
• Household dust (carpeting, heating
and A/C ducts)
• Certain foods including dried fish
• Marijuana

Leading cause of death from

invasive fungal infections in the US
 DIAGNOSIS
Generally starts out as a spot in lung (lung “nodule”)
Can be mistaken for lung cancer or tuberculosis

• Just a nodule --- generally no symptoms

• May develop into pneumonia or a fungus ball

• Examine sputum or take specimens by bronchoscopy for culture

--- may miss infection

• Tissue biopsy only way to diagnose with certainty

Serum galactomannan test: detect fungal parts in blood

A positive test + risk factors + a chest X-ray or CT scan increases the
chance of detecting infection

• A weak immune system or chronic lung disease allows the

Aspergillus to grow, invade the lungs and spread throughout the
body (Invasive Aspergillosis)
 PREVENTION AND TREATMENT
Aspergillosis is not Difficult to avoid being exposed
contagious! • avoid dusty areas and gardening
• wear a surgical mask

Anti-fungal drugs used to treat aspergillosis:

Polyenes: amphotericin B
Triazoles: fluconazole, caspofungin, itraconazole, and posaconazole.

Aspergilloma (a fungus ball)

requires surgery for removal
(drugs are ineffective). Common
with other conditions like TB.

Allergic bronchopulmonary aspergillosis (ABPA): asthma-like,

treated with steroids and an anti-fungal drug.
 PNEUMOCYSTIS PNEUMONIA (PCP)
Caused by inhaling Pneumocystis jirovecii (previously P. carinii)

Spreads from person to person through the air:

• Up to 20% of adults might carry P. jirovecii at any time, the immune
system removes after several months
• Infected can be asymptomatic

Most who get PCP have a medical condition or takes medication that
weakens their immune system, like HIV/AIDS.
Much of the information we have about PCP and its treatment comes
from caring for patients with HIV/AIDS
 SYMPTOMS

In people with HIV/AIDS, PCP symptoms

usually develop over several weeks and
• Fever include a mild fever.
• Cough
• Difficulty breathing
• Chest pain
In people who have weakened immune
• Chills
systems (not HIV/AIDS), PCP symptoms
• Fatigue
usually develop over a few days, often
with a high fever

• PCP is the most common opportunistic infection in persons with HIV

 DIAGNOSIS
• Analysis of sputum • Histological analysis
• Bronchoalveolar lavage • PCR of DNA
• Biopsy (bronchoscopy) • Serum testing for β-D-glucan
 PREVENTION AND TREATMENT

No Vaccine

Most commonly used drugs to prevent and treat PCP:

trimethoprim/sulfamethoxazole (TMP/SMX)
(Interferes with folate biosynthesis)

Without treatment, PCP can cause death

Corticosteroids are used as an agent in hypoxic

respiratory failure due to Pneumocystis pneumonia
 Dimorphic fungi are fungi that can exist in
the form of both mold and yeast

In soil, they that exist in the mold form

In humans they are in the yeast form.

In culture we identify the mold form.

In tissue or body fluids we identify the yeast form.
 HISTOPLASMOSIS

Caused by inhaling Histoplasma capsulatum

(spores again)
Found in:
• Bird and bat droppings (chicken coops)
• Damp soil rich in decayed material
(abandoned buildings and around large
trees and shrubs)

Most common endemic fungal infection in

North America that affects the lungs (up to
250,000 people in US)
Most often associated with river valleys

Common cause of chronic pneumonia

in the USA (4 wk – 65 yr)
 DIAGNOSIS
Anywhere from a few days to a couple of weeks after exposure

Symptoms vary, often flu-like: fever, chills, a dry cough, a cough

that brings up sputum (phlegm), sharp chest pain, muscle pain,
swollen joints, joint pain, headache and loss of appetite.

• Presence of histoplasma antigens in

blood or urine
• Culture of blood and sputum (4 wks)
• Biopsy if symptoms severe
(bronchoscopy)
• Macrophages containing Histoplasma

Even without symptoms, infection may result in small spots

(scars) on lungs or calcium in chest lymph nodes
 PREVENTION AND TREATMENT

Histoplasmosis is not contagious!

Mild symptoms: No treatment, infection may go away in a few weeks

Worse symptoms or last more than a month: anti-fungal drug (i.e.,

itraconazole or Aphotericin-B

Weakened immune system may mean “disseminated histoplasmosis”

Spread throughout your body and may infect the brain, liver or bone
marrow. Treated using intravenous Amphotericin-B and other drugs
for many months

Difficult to avoid exposure to histoplasmosis:

Control dust around gardens or when cleaning bird droppings,
wear a mask.
 BLASTOMYCOSIS

Caused by inhaling Blastomyces dermatidis

(spores again) that deposit deeply in the lungs

Found in:
• moist soil of rotting plants or wood

A rare disease that more commonly affects

people involved with outdoor activities

Symptoms are usually more severe in

people with a weakened immune system

The most common problem with Blastomycosis is pneumonia

 SYMPTOMS
Symptoms vary and may occur from 3 to 15 weeks after inhalation
Similar to many other problems (like the common cold): fever,
cough, cough with blood, shortness of breath, muscle aches, chest
pain, fatigue.

Can be slow growing and resemble a lung tumor

May spread to other organs:

• Skin problems can include a rash, sores or nodules (small
elevated areas on the skin)
• Bone and joint problems can include joint swelling or infected
bone (osteomyelitis) which cause joint or bone pain.
• Blastomycosis of the central nervous system can cause
meningitis

Immunocompromised are more likely to develop meningitis

 DIAGNOSIS
Culture fungus from sputum/phlegm, fluid from an infected joint, or
tissue from an infected area (sputum is not as reliable as the others).

Takes several weeks

B. dermatidis: broad based budding yeast; thick double

contoured wall with visible nuclei

PREVENTION AND TREATMENT

Blastomycosis is not contagious!

Treatment and prevention are the same as with H. capsulatum

Blastomycosis is readily treatable with antifungals once it is correctly

diagnosed; delayed diagnosis is common except in highly endemic areas.
 Coccidioidomycosis
also known as San Joaquin Valley Fever

Caused by inhaling Coccidioides immitis

(spores again)

Found in:
• In the soil of endemic areas and gets
into the air when the soil is disturbed
(i.e., construction, gardening,
farming, windy weather, dirt biking
or driving ATV’s AND
EARTHQUAKES)

100,000 people are infected with

Coccidioides spores, over 60% never
develop symptoms or mistake their
symptoms for a mild flu that goes away
 Three forms of Coccidioidomycosis;

Acute pulmonary coccidioidomycosis: starts one to three weeks

after exposure and is usually mild and goes away without treatment

Chronic pulmonary coccidioidomycosis: develops years after first

getting infected

Disseminated coccidioidomycosis: occurs in about 1% of all cases,

usually in people who have a poor immune system or pregnant
women
 DIAGNOSIS
Symptoms are varied and non-specific:
• cough (sometimes producing phlegm/mucus or blood), fatigue, fever,
headache, muscle aches, rash, joint pain and/or swelling (tender bumps
usually on leg)
• Severe forms can cause confusion, neck stiffness, or sensitivity to light
• frequent pneumonias
• nodules in your lungs that can be mistaken for lung cancer or TB

Diagnosis like the other dimorphic fungi: culture sputum, biopsy

lung tissue, X-ray

C. immitis: thick walled non budding spherules with endospores

 PREVENTION AND TREATMENT
Coccidioidomycosis is not contagious!
Risks:
• Anyone who visited endemic areas
• Older individuals
• Immunocompromised
• Steroids or anti-arthritic medication
• Pregnancy
• Filipinos, African Americans

Treatment and prevention are the same as with

Histoplasma capsulatum
 RESPIRATORY VIRAL INFECTIONS
General Overview
• Treatment is usually supportive.

• Antibacterial drugs are ineffective; prophylaxis against

secondary bacterial infections is not recommended.

• Antibiotics should be given only when secondary

bacterial infections develop.
 Adenovirus

• DNA viruses classified according

to 3 major capsid antigens (hexon,
penton, and fiber).

• Adenoviruses are commonly

acquired by aerosol droplets, feco-
oral route and by contact with
contaminated objects.

• Asymptomatic respiratory or GI viral shedding may continue

for months, or even years.
 Symptoms

• An important cause of febrile illnesses in young children

• Most often associated with upper respiratory tract infections

• Sore throat, cough, rhinorrhea, or other respiratory symptoms may

occur.
• Rare adenoviral syndromes in infants include severe bronchiolitis
and pneumonia.
• In adults, symptoms include fever and lower respiratory tract
symptoms, usually tracheobronchitis but occasionally pneumonia.

• Most infections are self limiting (immune response)

• Shedding in stool for weeks following an acute infection

• Shedding may be months in immunocompromised
• Immunocompromised individuals are at risk of fatal infections.
Diagnosis

• Clinical evaluation; laboratory diagnosis rarely affects management

• Viral culture, viral antigen assays and PCR of DNA

Treatment

• Treatment is symptomatic and supportive

• Ribavirin and cidofovir have been used in immunocompromised
patients

• Ribavirin depletes intracellular pools of GTP

(Ribavirin 5'-monophosphate inhibits cellular inosine monophosphate dehydrogenase)

• Cidofovir inhibits viral DNA polymerase 600X more than human

polymerase
 Rhinoviruses
• small (30 nm), non-enveloped viruses that contain a single-
strand RNA genome within an icosahedral (20-sided) capsid.

• Nasal mucosa is primary

site of infection
• Attaches to the
respiratory epithelium
and spreads locally.

• Does not replicate efficiently at 37°C, optimum temp 33-35°C.

• Could be the major reason why RV does well in the nasal passages
and upper tracheobronchial tree, but not so well in the lower
respiratory tract
• About 50% of all colds are caused by one of the >100 serotypes of
rhinoviruses.

• Most common during fall and spring and are less common during
winter.

• Most efficiently spread by direct person-to-person contact, although

spread may also occur via large-particle aerosols.
• The common cold is an acute, usually afebrile, self-limited with
viral infection causing upper respiratory symptoms.

• Susceptibility is not affected by exposure to cold temperature,

host health and nutrition, or upper respiratory tract abnormalities
(eg, enlarged tonsils or adenoids).

Diagnosis
• Diagnosis is generally made clinically and presumptively, without
diagnostic tests.
• Allergic rhinitis is the most important consideration in differential
diagnosis.

Treatment

• Symptomatic treatment, as no specific treatment exists.

 Respiratory Syncytial Virus (RSV)
• Medium-sized (120-200 nm) negative-
sense, single-stranded RNA enveloped
virus of the family Pneumoviridae

• The envelope contains fusion (F),

attachment (G) and small hydrophobic
(SH) glycoproteins and lipids.

• The F and G lipoproteins target the cell

membrane and are highly conserved
among RSV isolates.
• The activity of the F proteins on the surface of the virus cause
the cell membranes on nearby cells to merge, forming syncytia.
• RSV infections cause seasonal lower respiratory tract disease,
particularly in infants and young children

• Ubiquitous; almost all children are infected by age 4 yr.

• Outbreaks occur annually in winter or early spring in temperate

climates.

• Most common cause of lower respiratory tract illness in young

infants and is responsible for >50,000 hospitalizations annually in
the US in children under the age of 5 yr.

• Disease may be asymptomatic, mild, or severe, including

bronchiolitis and pneumonia.

• The immune response to RSV does not protect against reinfection,

the attack rate is about 40% for all exposed people. However,
antibody to RSV decreases illness severity.
 Diagnosis
 Clinical evaluation
 Rapid antigen tests of nasal washings or swabs
 reverse-transcription–PCR (RT-PCR), or viral culture

Treatment
Treatment of RSV infections is supportive and includes
supplemental O2 and hydration as needed.
 Corticosteroids and bronchodilators are generally not helpful.
 Antibiotics are reserved for patients with fever, evidence of
pneumonia on chest x-ray, and clinical suspicion of a bacterial
coinfection.
 Palivizumab (monoclonal antibody to RSV) is not effective for
treatment.
 Inhaled ribavirin, an antiviral drug with activity against RSV, has
marginal efficacy and is only recommended for severely
immunocompromised patients.
Prevention
Passive prophylaxis with palivizumab decreases the frequency of
hospitalization for RSV in high-risk infants. It is cost-effective only
for infants at high risk of hospitalization, such as prematurity,
chronic lung disease, congenital heart disease.

Palivizumab is a monoclonal
antibody that targets the F
protein of RSV, inhibiting its
entry into the cell and thereby
preventing infection.
 Human Parainfluenza Virus
• Common respiratory tract pathogens
that can infect persons of any age.

• Enveloped, negative-sense RNA

viruses that belong to the subfamily
Paramyxovirinae of the family
Paramyxoviridae.

• Four genetically and antigenically

different types, HPIV types; 1, 2, 3, and 4.

• They share antigenic cross-reactivity but tend to cause diseases of

different severity. Type 4 has antigenic cross-reactivity with the
mumps virus and appears to be an uncommon cause of respiratory
disease.
• Parainfluenza virus cause many respiratory illnesses varying from
the common cold to an influenza-like syndrome or pneumonia.

• Croup is the most common severe

manifestation.
• Diagnosis is usually clinical.
Treatment is supportive.

• Can cause repeated infections, generally milder illness upon re-

infection.
• In immunocompetent adults, most infections are asymptomatic or
mild.
• The most common illness in children is an upper respiratory illness
with no or low-grade fever
 • Parainfluenza type 1 commonly causes croup
(laryngotracheobronchitis), primarily in infants aged 6 to 36 mo.
• Croup begins with common cold symptoms. Later, fever, a barking
cough, hoarseness, and stridor develop

• Parainfluenza virus type 3 may cause pneumonia and bronchiolitis in

young infants.
• These illnesses are generally indistinguishable from disease caused
by respiratory syncytial virus but are often less severe.

• A specific viral diagnosis is unnecessary. Treatment is symptomatic.

Treatment for croup includes antipyretics, hydration, nebulized
racemic epinephrine, and corticosteroids.
 Influenza
• Influenza refers to illness caused by the influenza viruses, but
the term is commonly and incorrectly used to refer to similar
illnesses caused by other viral respiratory pathogens.

• Influenza is a viral respiratory infection causing fever, coryza,

cough, headache, and malaise.

• Influenza A is a 80–120 nm virus

with a roughly spherical shape. The
genome is not a single piece of
nucleic acid; but contains 8 pieces
of segmented negative-sense RNA
encode 11 proteins. The best
characterized of these proteins are
hemagglutinin and neuraminidase.
• Hemagglutinin (H) is a glycoprotein on the influenza viral
surface that allows the virus to bind to cellular sialic acid and
fuse with the host cell membrane.

• Neuraminidase (NA),
another surface
glycoprotein, enzymatically
removes sialic acid,
promoting viral release from
the infected host cell.

• There are 18 H types and 11 NA types, giving 198 possible

combinations, but only a few are human pathogens.

• These proteins are the antigenic determinants that allows

classification of virus serotypes, provide for antigenic drift and
shift, and are targets for antiviral drugs.
 Antigenic drift?
• Relatively minor, progressive mutations in preexisting combinations
of H and NA antigens, resulting in the frequent emergence of new
viral strains.

• Relatively rare development of new combinations of H and/or NA

antigens, which result from reassortment of subunits of the viral
genome.

• New strains may cause seasonal epidemics because protection by

antibody generated to the previous strain is decreased.

• Pandemics can result from antigenic shift because antibodies

against other strains (resulting from vaccination or native
infection) provide little or no protection against the new strain.
 Epidemiology
• Influenza causes widespread sporadic illness yearly during fall and
winter in temperate climates (seasonal epidemics).

• Seasonal often occur in 2 waves—the first in schoolchildren and their

household contacts (generally younger people) and the 2nd mostly in
housebound or institutionalized people, particularly the elderly.

• Most influenza epidemics are caused by a predominant serotype, but

different influenza viruses may appear sequentially in one location or
may appear simultaneously, with one virus predominating in one
location and another virus predominating elsewhere.
As of 2013, there have been 6 major pandemics, typically named
after the presumed location of origin:

• 1889: Russian influenza (H2N2)

• 1900: Old Hong Kong influenza (H3N8)
• 1918: Spanish influenza (H1N1)
• 1957: Asian influenza (H2N2)
• 1968: Hong Kong influenza (H3N2)
• 2009: Swine influenza (influenza A [H1N1]pdm09)
 • Influenza viruses can be spread by airborne droplets, person-
to-person contact, or contact with contaminated items.
• Airborne spread appears to be the most important mechanism.

At-risk groups
Certain patients are at high risk of complications from influenza:
 Children < 4 yr

 Adults > 65 yr

 People with chronic medical disorders (eg, cardiopulmonary disease, diabetes

mellitus, renal or hepatic insufficiency, hemoglobinopathies, immuodeficiency)

 Women in the 2nd or 3rd trimester of pregnancy

 Patients with disorders that impair handling of respiratory secretions (eg, cognitive
dysfunction, neuromuscular disorders, stroke, seizure disorders)

 Morbidity and mortality in these patients may be due to exacerbation of underlying

illness, acute respiratory distress syndrome, primary influenza pneumonia, or
secondary bacterial pneumonia.
Diagnosis
Generally made clinically in patients with a typical syndrome when
influenza is known to be present in the community.
 Rapid diagnostic tests are available with good specificity, but
sensitivities vary widely, and usually add little to patient
management.
 Diagnostic tests should be done when results will affect clinical
decisions. Reverse transcriptase–PCR (RT-PCR) assays are sensitive
and specific and can differentiate influenza types and subtypes.
 Tests can determine whether outbreaks of respiratory disease are
due to influenza.
 If patients have lower respiratory tract symptoms and signs (eg,
dyspnea, rales noted during lung examination), pulse oximetry to
detect hypoxemia and a chest x-ray to detect pneumonia should be
done.
Treatment
Treatment for most patients is symptomatic, including rest,
hydration, and antipyretics as needed. Complicating bacterial
infections require appropriate antibiotics.
Drugs for influenza include the following:
 Oseltamivir and zanamivir are neuraminidase inhibitors that
interfere with release of influenza virus from infected cells and
thus halt spread of infection.
 Amantadine and rimantadine (adamantanes) that block the M2
ion channel and thus interfere with viral uncoating inside the
cell. They are effective only against influenza A viruses
(influenza B viruses lack the M2 protein).

Prevention
Influenza infections can largely be prevented by
 Annual vaccination
 Sometimes chemoprophylaxis (ie, with antiviral drugs)
 Avian Influenza (Bird Flu)
• Caused by strains of influenza A that normally infect only wild
birds and domestic poultry (and sometimes pigs).

• The virus acquires mutations enabling

it to attach to human-specific receptor
sites in the respiratory tract.

• If these strains acquire the ability to

spread efficiently from person to
person, an influenza pandemic could
result.

• Avian influenza H5N1 strains can cause severe respiratory

symptoms. Mortality was 33% in the 1997 outbreak and has
been >60% in subsequent infections.
 • In early 2013, an extensive outbreak of H7N9 avian influenza
occurred in several provinces of southeastern China.

• About one third of cases were fatal, but significant illness

typically occurred only in the elderly.

• Human infection appeared to result from direct exposure to

infected birds in live poultry markets, therefore avoidance of live,
dead and uncooked poultry in areas of outbreak is key in
preventing infection.
Diagnosis
• Reverse transcriptase–PCR (RT-PCR)
• Exposure to a person known to be infected or to birds in an
area with an ongoing avian influenza outbreak.
• History of recent travel to regions with ongoing transmission of
virus from domestic poultry to humans (eg, for H5N1, Egypt,
Indonesia, and Vietnam) plus exposure to birds or infected
people should prompt testing for influenza A by RT–PCR.
• Culture of the organism should not be attempted. Suspected
and confirmed cases are reported to the Centers for Disease
Control and Prevention (CDC).
Treatment
 Treatment with neuraminidase inhibitors, such as oseltamivir or
zanamivir at usual doses.
 The H5N1 virus is resistant to amantadine and rimantadine;
resistance to oseltamivir has also been reported.
 Pandemic 2009 H1N1 Influenza (Swine Flu)

• Pigs infected by strains of influenza that are slightly different from

those that infect people.
• These strains very rarely spread to people, and when they do, they
very rarely then spread from person to person.

• The infection is not acquired through ingestion of pork and is

acquired very rarely by contact with infected pigs.
• Pandemic 2009 H1N1 influenza was caused by a new strain of
H1N1 influenza A virus, which genetically is a combination of
swine, avian, and human influenza viruses and spreads easily from
person to person.

• The attack rate and mortality for H1N1 swine flu are higher in
young and middle-aged adults and lower in the elderly than they
are for seasonal flu.
Diagnosis
• A(H1N1)pdm09 swine flu is the predominant strain of influenza
currently circulating worldwide. This diagnosis should be
considered in any patient with influenza-like symptoms.
• PCR can detect the virus in respiratory tract samples. Rapid
antigen detection tests have decreased sensitivity and generally
are clinically useful in diagnosis only if results are positive.

Treatment
• Symptom relief (eg, ibuprofen for fever and aches).
• Antiviral drugs, particularly for high-risk patients and those who
are seriously ill.
• Oseltamivir and zanamivir appear to be effective. Most patients
recover fully without taking these drugs.

Prevention
The current seasonal influenza vaccines are effective against the
A(H1N1)pdm09 virus.
 Coronaviruses and Acute Respiratory Syndromes
(MERS and SARS)

• Coronaviruses are enveloped RNA viruses

and that most frequently cause common
cold.

• In 2012, coronavirus MERS-CoV was found

to cause of Middle East respiratory
syndrome (MERS).
• In late 2002, SARS-CoV was found to
cause severe acute respiratory syndrome
(SARS).
 MERS and SARS

• Transmission is by person to person.

• More than half of cases of MERS have been fatal.

• In the only SARS epidemic, the mortality rate was only 10% despite
rapid person-to-person spread worldwide. During the 8-mo
outbreak, there were >8000 cases worldwide.

• Diagnosis is made clinically, and treatment is supportive.

• For suspected MERS real-time reverse-transcriptase PCR (RT-PCR)

testing of lower respiratory secretions may be considered.

• Eradication depends on rigidly maintained isolation

 Thanks!

Questions will be coming on Friday during review

session