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COCCIDIOIDOMYCOSIS
High-power view of coccidioidomycosis demonstrates a
large spore within a giant cell and a background of
chronic inflammation. (From DP: Nonneoplastic Derm.)
Fungal Infections: Morphological Diagnosis of Fungal Infections
TERMINOLOGY
Synonyms
Valley fever, San Joaquin Valley fever, desert
rheumatism
Definitions
Greek: "Coccidio" (little berry), "-ido" (resemblance)
Coccidioides immitis resembles Coccidia (protozoan
parasites)
ETIOLOGY/PATHOGENESIS
Infectious Agents
Cause by dimorphic fungi Coccidioides immitis and
Coccidioides posadasii
Although genetically distinct, the 2 species are
morphologically identical
Found in southwestern United States, and in parts of
Mexico, Central America, and South America
Also recently found in south-central Washington
CLINICAL ISSUES
Epidemiology
Incidence
Overall incidence in 2011 was 42.6 cases per
100,000 population
Immunocompromised individuals are at higher risk
for developing severe forms of coccidioidomycosis
HIV infection
Organ transplantation
Corticosteroid use
Pregnant women
Diabetics
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Age
Affects all ages
Most common in adults 60 years
1
Skin biopsy of coccidioidomycosis demonstrates
significant acanthosis and pseudoepitheliomatous
hyperplasia , with dense, diffuse granulomatous
inflammation . (From DP: Nonneoplastic Derm.)
Ethnicity
Risk of dissemination is common in Filipinos and
blacks
Presentation
Primary pulmonary disease is often self-limiting
Symptomatic persons (40% of cases) usually present
1-3 weeks after exposure with fatigue, cough, dyspnea,
headache, night sweats, myalgias, and rash
Disseminated disease occurs in an estimated 1% of
cases and commonly affects musculoskeletal, soft
tissues, and meninges in high-risk patients
Treatment
Oral azoles are popular first-line therapy
Amphotericin B: Severe disease
MICROBIOLOGY
Culture
Sabouraud dextrose agar
Brain heart infusion agar (5% sheep blood)
2-3 weeks for growth
Warning (select agent): Because of risk to laboratory
personnel from inhalation of organism during culture
process, specimens must be handled with extreme
caution and inside of an approved biological safety
hood or cabinet
Laboratory should be notified of suspected cases at
time of submission
MICROSCOPIC PATHOLOGY
Histologic Features
Granulomatous inflammation with large, thick-walled
spherules (100 m, containing endospores up to 5 m)
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COCCIDIOIDOMYCOSIS
Terminology
Caused by dimorphic fungi Coccidioides immitis and
Coccidioides posadasii
Found in soil in southwestern United States and parts
of Mexico and Central and South America
Clinical Issues
Immunocompromised individuals are at higher risk
for developing severe forms of coccidioidomycosis
Surrounding infiltrate is often rich in chronic
inflammatory cells, eosinophils, neutrophils, and giant
cell reactions
Pseudoepitheliomatous hyperplasia and
granulomatous dermal inflammation is common in
cutaneous disease
Key Facts
Microscopic Pathology
Granulomatous inflammation with large, thickwalled spherules (100 m, containing endospores up
to 5 m)
Top Differential Diagnoses
Rhinosporidiosis, adiaspiromycosis, histoplasmosis,
cryptococcosis, and blastomycosis
Histoplasmosis
Numerous 24 m fungal spores, narrow-based
budding, Fontana-Masson negative
Cryptococcosis
Numerous 5-10 m fungal spores, narrow-based
budding, Fontana-Masson positive
Fungal Infections: Morphological Diagnosis of Fungal Infections
ANCILLARY TESTS
Histochemistry
Gomori methenamine silver (GMS) highlights
coccidioidomycosis organisms
Endospores are PAS positive, but spherules are negative
Serologic Testing
Enzyme immunoassay (EIA): Very sensitive
and commonly used method for diagnosing
coccidioidomycosis
Immunodiffusion (ID) detects IgM and IgG
DIFFERENTIAL DIAGNOSIS
Rhinosporidiosis
Spherules are much larger (up to 300 m) with thicker
walls
Adiaspiromycosis
Spherules are much larger (200-400 m), refractile
walls, appear empty
IMAGE GALLERY
Blastomycosis
Larger organism (12 m), spherical, double-contoured
yeast with broad-based budding
SELECTED REFERENCES
1.
Muoz-Hernndez B et al: Parasitic polymorphism of
Coccidioides spp. BMC Infect Dis. 14:213, 2014
2. Shekhel TA et al: Surgical pathology of pleural
coccidioidomycosis: a clinicopathological study of 36
cases. Hum Pathol. 45(5):961-9, 2014
3. Nguyen C et al: Recent advances in our understanding of
the environmental, epidemiological, immunological, and
clinical dimensions of coccidioidomycosis. Clin Microbiol
Rev. 26(3):505-25, 2013
4. Welsh O et al: Coccidioidomycosis. Clin Dermatol.
30(6):573-91, 2012
5. Taljanovic MS et al: Musculoskeletal coccidioidomycosis.
Semin Musculoskelet Radiol. 15(5):511-26, 2011
(Left) Skin biopsy of coccidioidomycosis demonstrates several large fungal spores containing numerous small endospores amidst acute and
chronic inflammation in the dermis. (From DP: Nonneoplastic Derm.) (Center) H&E high magnification from a lung biopsy shows a single fungal
form with a distinctive refractile, "double-contour" membrane , consistent with Coccidioides infection. (Right) High-power view of lung
biopsy from an immunocompromised patient shows diffuse granulomatous inflammation and several large fungal spores .
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CRYPTOCOCCOSIS
High magnification of this lung section on H&E stain
shows variably sized round yeast cells with narrowbased budding and thick capsule around the cells,
consistent with Cryptococcus spp.
Fungal Infections: Morphological Diagnosis of Fungal Infections
TERMINOLOGY
Definitions
Greek: "Crypto" (hidden) + "kokkus" (berry, grain)
ETIOLOGY/PATHOGENESIS
Infectious Agents
Cryptococcus neoformans and Cryptococcus gattii
(formerly Cryptococcus neoformans var. gattii) produce
basidiomycetous encapsulated yeasts and are the main
pathogenic species causing human infections
C. neoformans: Corresponds to serotypes A and D
Found in association with rotting vegetation,
soil samples in roosting sites of pigeons, or areas
frequented by pigeons and chickens
Role of pigeon guano in pathogenesis is unclear;
direct transmission from pigeons to humans has not
been reported
Cryptococcus gattii: Corresponds to serotypes B and C
CLINICAL ISSUES
Epidemiology
Most cases are seen in immunocompromised patients
Risk factors
Most common: HIV infection
Other risk factors
Prolonged use of glucocorticoids or
immunosuppressants
Stem cell and organ transplant recipients
Malignancies
Underlying chronic lung disease, e.g., sarcoidosis
Infections caused by C. neoformans
Accounts for majority of infections found in
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1
immunocompromised individuals
Worldwide distribution
Infections caused by C. gattii
High magnification of a GMS-stained section shows
cryptococcal yeasts with narrow-based budding .
Tissue processing may have caused some of the yeast cells
to collapse and become crescent shaped.
Causes infection more often in immunocompetent
individuals than in immunocompromised patients;
however, testing for underlying HIV infection and
other causes of immunodeficiency is recommended
in patients with no apparent immunocompromise
Geographic distribution
Tropical and subtropical regions, including
Australia, Papua New Guinea, parts of Africa,
Mexico, and southern California
In 1999, outbreak of cryptococcosis due to C. gattii
was detected in British Columbia, with subsequent
spread to Pacific Northwest of United States
Sporadic cases also occur in various regions
around world
Presentation
Most common presentations: Pulmonary, central
nervous system, or skin disease
Lung is the primary site of infection caused by inhaled
yeasts or basidiospores of fungus
Cryptococci can disseminate via bloodstream to other
tissues
Central nervous system and skin are most common
secondary sites of infection
Involvement of other body sites have been reported,
e.g., osteomyelitis, hepatitis, pyelonephritis,
prostatitis, and peritonitis
Pulmonary involvement
Clinical course is determined by host immune
status, inoculum size of fungus, and innate virulence
of organism
Immunocompromised patients
Pulmonary involvement can be due to primary
infection in naive host, reactivation of latent
infection, or reinfection with new strain
More likely to have extrapulmonary disease than
immunocompetent patients
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CRYPTOCOCCOSIS
Etiology
Cryptococcus neoformans and Cryptococcus gattii are the
main pathogenic species causing human infections
C. neoformans accounts for majority of cases in
immunocompromised individuals
Clinical Issues
Most cases are seen in immunocompromised patients
Most common risk factors: HIV infection, prolonged
use of glucocorticoids or immunosuppressants,
history of stem cell and organ transplants,
malignancies
Lung is the primary site of infection caused by
inhaled yeasts or basidiospores of fungus
Central nervous system and skin are the most
common secondary sites of infection
Key Facts
Untreated disseminated Cryptococcus infection has a
mortality rate of up to 100%
Microscopic Pathology
Encapsulated, spherical to oval yeast cells (5-10
m in diameter) with narrow-based budding and
polysaccharide capsule
Ancillary Tests
Yeast cells are positive for GMS, PAS, Fontana-Masson
stains
Mucicarmine and Alcian blue stain polysaccharide
capsule
Top Differential Diagnoses
Candidiasis
Histoplasmosis
Blastomycosis
Fungal Infections: Morphological Diagnosis of Fungal Infections
CNS involvement should be ruled out in
immunocompromised patients presenting with
pulmonary cryptococcosis
CNS involvement
More commonly seen in immunocompromised
patients
Brain parenchyma is often involved in addition to
meningeal infection
Symptoms are nonspecific and clinical course can
vary from indolent, subacute to acute presentations
depending on the species causing infection and the
host immune status
HIV patients with CNS infection are likely to have
extraneural disease
Lumbar puncture criteria
Neurologic symptoms
High serum cryptococcal antigen titer
Underlying condition that predisposes to CNS
dissemination, e.g., immunosuppression
Cutaneous involvement
Due to secondary or primary infections
Manifestations are variable
Secondary infection due to cryptococcal
dissemination
Cutaneous signs of infection may be the 1st
indication of cryptococcosis and precede diagnosis
of disseminated disease
Factors suggesting secondary infection: Presence
of systemic symptoms, multicentric skin lesions,
deep dermal or subcutaneous lesions, lesions on
covered parts
Primary infection due to direct inoculation of
organisms
Less common than secondary infection
Factors suggesting primary infection: solitary
lesion, regional lymph node involvement,
lesions on uncovered parts, history of primary
inoculation
Cases of primary infection due to rarer species
such as Cryptococcus laurentii and Cryptococcus
albidus have been reported
Disseminated disease
Most commonly seen in immunocompromised
patients
Infection caused by C. gattii vs. infection caused by C.
neoformans
Large mass lesions, (i.e., cryptococcomas) of lungs
&/or brain are more likely to be caused by C. gattii
than C. neoformans
Infections due to C. gattii are more likely to be
associated with neurologic complications
Laboratory Tests
Direct examination of clinical specimens
Encapsulated yeast forms may be visualized in
sputum, bronchoalveolar lavage, CSF, or tissue
smears
Capsule highlighted by India ink in body fluid or
tissue smears as a halo against black background
Cryptococcal antigen (CRAG) testing
Latex agglutination or enzyme-linked
immunosorbent assay (ELISA) to detect cryptococcal
polysaccharide antigen
CSF: Sensitivity: 93-100%; specificity: 93-98%
Serum (immunocompromised patients)
Negative serum cryptococcal antigen result does
not exclude diagnosis of cryptococcosis
Positive serum cryptococcal antigen result should
prompt investigation for disseminated infection
Positive in essentially all patients with HIV
infection and pulmonary cryptococcosis, and
up to 84% of patients with other underlying
immunocompromising conditions
Antigen titer generally correlates with burden of
organisms
Limitations
False-positive results have been reported with
serologic assays in cases of fungal infection due to
Trichosporon asahii, and bacterial infections due to
Stomatococcus spp. or Capnocytophaga spp.
False-negative results can occur due to low fungal
burden or prozone effect
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Most serologic tests detect antigens present in
capsule; therefore, tests may not be helpful in
cases caused by capsule-deficient cryptococcal
organisms
Assays do not allow distinction of different
Cryptococcus spp.
No role for monitoring serum cryptococcal
antigen titers to determine duration of therapy in
either immunosuppressed or immunocompetent
hosts
CRAG lateral flow immunochromatographic assay
Semiquantitative
Can be used as a rapid point-of-care test with CSF,
serum and plasma samples
Compared with culture: 99.5% sensitivity and
98% specificity
Treatment
CNS disease
In general: Induction therapy with amphotericin
B plus flucytosine followed by consolidation and
maintenance therapy with fluconazole
Dosages and duration of treatments vary based on
Fungal Infections: Morphological Diagnosis of Fungal Infections
patient’s immune status and clinical conditions
Nonmeningeal pulmonary disease
Generally treated with fluconazole
Severe pulmonary disease presenting with
acute respiratory distress syndrome (ARDS) or
extrapulmonary manifestations should be treated
like CNS disease
Patients who have negative cultures and
undetectable cryptococcal antigen titers may not
require antifungal therapy
Nonmeningeal nonpulmonary disease
Single site: Generally treated with fluconazole
Multiple sites or high serum fungal titer: Treated like
CNS disease
Surgery may be considered for large, accessible lesions
with mass effect or for lesions not responding to
antifungal therapies
Prognosis
Untreated disseminated cryptococcal infection has a
mortality rate of up to 100%
ARDS is often associated with disseminated infection
and high mortality
High rate of extrapulmonary disease is seen among
immunocompromised patients with cryptococcal
pneumonia
Cerebral cryptococcomas are associated with delayed
or poor response to therapy and substantial neurologic
sequelae
IMAGE FINDINGS
Radiographic Findings
Chest
Features are variable and not specific
Most common findings: Solitary or few well-defined
III
nodules; cavitations within nodules/masses are more
commonly seen in immunocompromised patients
CRYPTOCOCCOSIS
Other findings: Lobar infiltrates, hilar and
mediastinal adenopathy, and pleural effusions
Brain
No abnormality or cerebral atrophy
Mass lesions &/or hydrocephalus have been reported
but are rare
Brain mass lesions seen in HIV or
immunocompromised patients should prompt
consideration of alternative diagnoses, such as
toxoplasmosis, lymphoma, tuberculosis
Cryptococcomas may mimic neoplasia or pyogenic
abscesses
MICROBIOLOGY
Culture
Sabouraud dextrose agar, bird seed agar, or creatinine
dextrose bromothymol blue thymine (CDBT) agar
(distinguishes cryptococcal species)
Provides a definitive diagnosis and differentiates
between C. neoformans and C. gattii
C. neoformans and C. gattii usually take 3-5 days to
grow in culture
Cultures are specific, but sensitivity can vary
depending on sample and fungal load
Blood, respiratory samples, CSF, and other body fluids
can be collected for cultures
MACROSCOPIC FEATURES
Brain Lesions
In patients with severe immunosuppression and
disseminated disease, classic "soap bubble" lesions
with clear gelatinous capsule can be present dissecting
through brain tissue without inflammation
MICROSCOPIC PATHOLOGY
Histologic Features
Encapsulated, spherical to oval yeast cells (5-10
m in diameter) with narrow-based budding and
polysaccharide capsule
Yeast cells vary in size
Organisms can be capsule deficient
Immunocompetent patients
Mixed suppurative and granulomatous reaction or
just granulomatous reaction
Granulomas and cryptococcomas can be seen in
chronic pulmonary infection; organisms may be
found inside macrophages and giant cells
Granulomatous inflammatory reaction may vary
from abundant fibrosis to abundant necrosis
Pseudotumoral spindle cell reactions to cryptococcal
organisms have been reported in rare cases
Immunocompromised patients
Inflammatory reaction may be minimal or absent
Proliferation of organisms forms cyst-like gelatinous
lesions packed with cryptococci that look like "soap
bubbles" (most commonly seen in brain)
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CRYPTOCOCCOSIS
Cases with autolysing human cells surrounded
by capsule-like vacuolated spaces mimicking
Cryptococcus spp. in inflammatory infiltrate have been
reported in patients with malignancies and immune
dysregulations
Special stains and cultures are needed to rule out
fungal infections in such cases
Different Cryptococcus spp. cannot be distinguished by
histologic features
ANCILLARY TESTS
Histochemistry
Yeast cells are positive by Gomori methenamine
silver (GMS) and periodic acid-Schiff (PAS) stains and
negative by Gram stain
Fontana-Masson stain highlights melanin contained
by yeast cells
Mucicarmine and Alcian blue stain polysaccharide
capsule, when present, of yeast cells
while Cryptococcus spp. are generally smaller (5-10 m
in diameter) with narrow-based budding
Cryptococcus spp. are positive for Fontana-Masson stain
while Blastomyces spp. are negative for melanin stains
DIAGNOSTIC CHECKLIST
Clinically Relevant Pathologic Features
Most cases are seen in immunocompromised patients
Clinical and radiographic presentations are
nonspecific
Pathologic Interpretation Pearls
Encapsulated, spherical to oval yeast cells (5-10
m in diameter) with narrow-based budding and
polysaccharide capsule which stains with mucicarmine
Yeast cells usually exhibit variability of sizes within
microscopic field
Capsule-deficient yeast forms can be present
Yeast cells are positive for Fontana-Masson stain
Fungal Infections: Morphological Diagnosis of Fungal Infections
Molecular Diagnostics
Molecular tests, such as DNA hybridization and PCRbased assays, are useful in cases when clinical isolates
do not grow in culture or when distinction among
Cryptococcus spp. is needed
DIFFERENTIAL DIAGNOSIS
Candidiasis
Yeast forms of Candida spp. can be confused with
capsule-deficient forms of Cryptococcus spp.
Positivity for Fontana-Masson stain differentiates
Cryptococcus spp. from Candida spp.
Candida spp. can be distinguished by positive Gram
stain and presence of pseudohyphae
Candida spp. commonly elicits a pyogenic tissue
reaction while Cryptococcus spp. generates a
granulomatous or mixed suppurative granulomatous
inflammation
Histoplasmosis
Histoplasma spp. can be mistaken with capsuledeficient forms of Cryptococcus spp.
Yeast cells of Cryptococcus spp. show a larger variety of
sizes, while Histoplasma yeast cells are more uniform in
size
Positive Fontana-Masson stain distinguishes
Cryptococcus spp. from Histoplasma spp., as the latter
are negative for melanin stains
Encapsulated forms of Cryptococcus spp. can be
differentiated from Histoplasma spp. by their capsular
material, which stains with mucicarmine
Blastomycosis
Mucicarmine stain can be positive for cell walls
of Blastomyces spp. and capsules of encapsulated
Cryptococcus spp.
Blastomyces spp. are larger in size (8-15 m in
diameter) and usually exhibit broad-based budding
SELECTED REFERENCES
1. Bernard C et al: Cryptococcosis in sarcoidosis: cryptOsarc, a
comparative study of 18 cases. QJM. 106(6):523-39, 2013
2. Hansen J et al: Large-scale evaluation of the immunomycologics lateral flow and enzyme-linked immunoassays
for detection of cryptococcal antigen in serum and
cerebrospinal fluid. Clin Vaccine Immunol. 20(1):52-5,
2013
3. Ko JS et al: Morphologic mimickers of Cryptococcus
occurring within inflammatory infiltrates in the setting of
neutrophilic dermatitis: a series of three cases highlighting
clinical dilemmas associated with a novel histopathologic
pitfall. J Cutan Pathol. 40(1):38-45, 2013
4. Kulkarni A et al: Primary cutaneous cryptococcosis due to
Cryptococcous laurentii in a renal transplant recipient.
Saudi J Kidney Dis Transpl. 23(1):102-5, 2012
5. Chaturvedi V et al: Cryptococcus gattii: a resurgent fungal
pathogen. Trends Microbiol. 19(11):564-71, 2011
6. Endo JO et al: Generalized Cryptococcus albidus in an
immunosuppressed patient with palmopustular psoriasis.
Cutis. 88(3):129-32, 2011
7. Guarner J et al: Histopathologic diagnosis of fungal
infections in the 21st century. Clin Microbiol Rev.
24(2):247-80, 2011
8. Perfect JR et al: Clinical practice guidelines for the
management of cryptococcal disease: 2010 update by the
infectious diseases society of america. Clin Infect Dis.
50(3):291-322, 2010
9. Sidrim JJ et al: Molecular methods for the diagnosis
and characterization of Cryptococcus: a review. Can J
Microbiol. 56(6):445-58, 2010
10. Dromer F et al: Determinants of disease presentation and
outcome during cryptococcosis: the CryptoA/D study. PLoS
Med. 4(2):e21, 2007
11. Sing Y et al: Cryptococcal inflammatory pseudotumors.
Am J Surg Pathol. 31(10):1521-7, 2007
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Gross and Microscopic Features
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g
g
p
(Left) Gross photo shows
a bisected mediastinal
mass consisting of enlarged
lymph node aggregates.
Microscopic examination
reveals cryptococcal
infection in association with
cryptococcal pneumonia,
confirmed by histology. (Right)
Low magnification of this tissue
section on H&E stain shows
necrotizing granulomatous
inflammation. Follow-up
GMS and PAS stains highlight
yeast forms consistent with
Cryptococcus spp. Acidfast stain is negative for
mycobacteria.
Fungal Infections: Morphological Diagnosis of Fungal Infections
(Left) Low magnification of
a lung section on H&E stain
shows prominent granulomata.
Necrosis is minimal. Followup GMS and Fontana-Masson
stains demonstrated the
resence of cryptococcal
yeast forms. (Right) High
magnification of this tissue
section on H&E stain shows
abundant multinucleated
iant cells in association with
ranulomatous inflammation
in a case of cryptococcosis.
Fungal organisms may be
resent inside giant cells and
can be best highlighted by
special stains.
CRYPTOCOCCOSIS
(Left) Medium magnification
of this liver section on
H&E stain shows focal
inflammation associated with
rare round yeast forms in
a patient with disseminated
cryptococcosis. (Right)
Fontana-Masson stain
highlights the cell walls of
Cryptococcus spp. in this
tissue section on medium
magnification.
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Microscopic Features
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p
Fungal Infections: Morphological Diagnosis of Fungal Infections
CRYPTOCOCCOSIS
(Left) High magnification
of this lymph node section
reveals multiple round yeast
forms with narrow-based
budding highlighted
by PAS stain. Culture
confirms the presence of C.
neoformans. (Right) High
magnification of this lung
section shows numerous
variably sized budding yeast
forms inside the alveoli.
Mucicarmine stains the yeast
capsule bright red/pink,
with a scalloped border. The
morphology is consistent
with Cryptococcus spp.
(Left) A large mount brain
section from a patient with
disseminated cryptococcosis
in the setting of severe
immunosuppression shows
classic "soap bubble" lesions
, which are large colonies
of cryptococci with thick
mucoid capsules. (Right)
Low magnification of a brain
section on H&E stain from
a patient with disseminated
Cryptococcus infection
shows classic "soap bubble"
lesions , which are large
colonies of encapsulated
yeast cells. No inflammation
is present.
(Left) High magnification
of this bronchial wash
specimen on ThinPrep shows
multiple intracellular yeasts
consistent with cryptococci
within the cytoplasm of
macrophages. The yeasts
vary from round to
teardrop shaped . Vague
clearing around the yeast
cells corresponds to the
resence of a capsule.
(Right) High magnification
of this bronchial brush
specimen on Diff-Quik stain
demonstrates numerous
round yeast forms
in a patient with known
ulmonary cryptococcosis.
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HISTOPLASMOSIS
High magnification of a lymph node section on H&E stain
shows numerous small round-to-oval yeast forms in
clusters. Follow-up Gram stain is negative, consistent with
Histoplasma spp.
Fungal Infections: Morphological Diagnosis of Fungal Infections
TERMINOLOGY
Synonyms
Cave disease, Darling disease, spelunker’s disease
Definitions
Greek: "Histos" (warp, web, from tissue) +
"plasma" (something molded or formed)
ETIOLOGY/PATHOGENESIS
Infectious Agents
2 strains of Histoplasma spp. are known to be
pathogenic to human beings: Histoplasma capsulatum
and Histoplasma duboisii
Thermally dimorphic fungus
Exists as a mold in environment (25C), and
converts into yeast phase in vitro and in tissues
(37C)
Pathogenesis
Infection acquired by inhaling fungal microconidia
Conidia are ingested by lung alveolar macrophages
Organisms then convert into yeast forms and exist
as intracellular pathogens until being eliminated by
specific cell-mediated immunity
Phagocytized organisms inside macrophages can
disseminate to other body sites, causing disease as
macrophages travel in reticulolymphatic system
Reactivation of latent histoplasmosis has been
reported in immunocompromised patients
There have been case reports showing transmission
of fungus from donor in cadaveric kidney
transplantation
Transplacental transmission of H. capsulatum has been
reported but is rare
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High magnification of this lung section on PAS stain
highlights multiple small round yeast clusters
inside pulmonary alveoli in a patient with pulmonary
histoplasmosis.
CLINICAL ISSUES
Epidemiology
Most prevalent endemic mycosis in United States
22% of population has positive skin test
50 million individuals infected
Infections caused by H. capsulatum
Most commonly in North America and Central
America, but cases have been reported around the
world
Endemic in Mississippi and Ohio River valleys;
also reported in localized foci in Maryland,
Pennsylvania, Delaware, West Virginia, Virginia, and
North Carolina
Organisms mostly found in soil or caves containing
bird or bat guano
Infections caused by H. duboisii (formerly named H.
capsulatum var. duboisii)
Occur in Africa but cases have also been reported in
Europe, where patients from Africa seek care
Risk factors for disseminated infection
HIV infection
Congenital T-cell immunodeficiencies
Hematopoietic stem cell or solid organ transplant
recipients on corticosteroids or tumor necrosis factor
antagonists
Use of other immunosuppressive drugs
Hematologic malignancies
Infants and elderly
Presentation
Depending on amount of fungus inhaled and immune
status of the individual, host may show no symptoms
or may develop pulmonary disease or disseminated
infection
Vast majority of infected persons have either no
symptoms or a mild self-limited illness; < 5% of
individuals who have low-level exposure to H.
capsulatum develop symptomatic disease
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HISTOPLASMOSIS
Etiology
Infections caused by dimorphic fungi: Histoplasma
capsulatum or Histoplasma duboisii
Fungus found in soil containing bird or bat guano
Infection acquired by inhaling fungal microconidia,
resulting in pulmonary infection
Phagocytized organisms inside macrophages can
disseminate to other body sites
Clinical Issues
Most prevalent endemic mycosis in United States:
Mississippi and Ohio River valleys
Most infections in immunocompetent patients are
asymptomatic or self-limited
Disseminated disease mostly occurs in
immunocompromised individuals
Key Facts
Microscopic Pathology
Oval small yeast cells (2-4 m in diameter) with
narrow-based budding
Yeasts tend to cluster within macrophages
Associated with granulomatous inflammation
Ancillary Tests
GMS(+); Gram and melanin stains (-)
Top Differential Diagnoses
Candidiasis
Cryptococcosis
Coccidioidomycosis
Blastomycosis
Pneumocystosis
Penicilliosis
Leishmaniasis, toxoplasmosis, Chagas disease
Fungal Infections: Morphological Diagnosis of Fungal Infections
Acute infection is mostly seen in infants and heavily
immunocompromised hosts
Pulmonary histoplasmosis
Acute disease
Hilar and mediastinal lymphadenopathy is
common
Severe infection occurs in cases with exposure to
a large fungal inoculum, or in immunosuppressed
patients
Chronic disease
Seen mostly in patients with underlying lung
disease
Pleural thickening and apical cavitary lesions are
common
Clinical and radiographic findings resemble those
seen in tuberculosis and sarcoidosis
Mycobacterial infection, aspergilloma,
blastomycosis, chronic or recurrent bacterial
pneumonia may develop in areas of lung damaged
by chronic pulmonary histoplasmosis and should
be excluded in work-up
Extrapulmonary manifestations
Granulomatous mediastinitis: Enlarged caseous
mediastinal lymph nodes
Fibrosing (sclerosing) mediastinitis: Following
infection of mediastinal lymph nodes, excessive
fibrosis progressively develops and envelops
structures of mediastinum
Broncholithiasis: Occurs when calcified node
erodes into bronchus, causing obstruction,
inflammation, and bronchial scarring
Disseminated histoplasmosis
Mostly in immunocompromised patients
Disseminated Histoplasma spp. can involve virtually
any organ system
Adrenal involvement: Relatively common (up to
80-90% in studies)
Patients with adrenal masses, adrenal
insufficiency, or electrolyte imbalances should
have disseminated histoplasmosis excluded in
work-up
Gastrointestinal involvement: Relatively common
(up to 70% in studies) but rarely produces clinical
symptoms
Skin involvement: Seen in up to 15% of cases in
studies
Occurs more commonly in patients with AIDS
Central nervous system (CNS) involvement: Seen in
5-20% of cases
Occurs more commonly in patients with
underlying immunosuppression
Laboratory Tests
Antigen detection
Enzyme immunoassays are available to detect
Histoplasma antigens in urine or serum
Sensitivity: 90% in disseminated disease and 75% in
acute pulmonary disease
False-positive results reported in urine infected
with other endemic mycoses, e.g., blastomycosis,
paracoccidioidomycosis, penicilliosis
Positive serum antigen assay but negative urine
assay are uncommon; false-positive serum assay has
been reported in transplant recipients who received
rabbit antithymocyte globulin
Serologic antibody detection
Antibodies may take 2-6 weeks to appear in
circulation; therefore, serologic assays are less
useful for detecting acute infection and in
immunosuppressed patients, who mount a poor
immune response
Useful in CSF specimens with negative culture, as
presence of antibodies allows one to make diagnosis
of Histoplasma meningitis in the proper clinical
context
Complement fixation test
Cross reactions had been reported in cases
caused by Blastomyces dermatitidis (up to 40%),
Coccidioides immitis (up to 16%), and Aspergillus
fumigatus (up to 2%)
Immunodiffusion assay
~ 80% sensitive
More specific than complement fixation assay
III
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