FUNGAL INFECTIONS
FELISTUS
Learning Objectives
At the end of the lesson the learner should be
able to:-
Yeasts (e.g., Candida, Cryptococcus) appear
microscopically as round, budding forms; molds (e.g.,
Aspergillus, Rhizopus) appear as filamentous forms called
hyphae; and dimorphic fungi (e.g., Histoplasma) are
spherical in tissue but appear as molds in the
environment.
Endemic fungi (e.g., Coccidioides) are not part of the
normal human microbial flora and infect hosts
preferentially by inhalation.
Opportunistic fungi (e.g., Candida and Aspergillus) invade
the host from normal sites of colonization (e.g., mucous
membranes or the GI tract).
CANDIDIASIS
Epidemiology
Candida is a small, thin-walled, ovoid yeast that
reproduces by budding and occurs in three forms in
tissue: blastospores, pseudohyphae, and hyphae.
Candida is ubiquitous in nature and inhabits the GI
tract, the female genital tract, and the skin.
Dissemination probably results from fungal entry into
the bloodstream from mucosal surfaces after the
organisms have multiplied to large numbers as a
result of bacterial suppression by antibacterial drugs
C. albicans is common, but non-albicans
species (e.g., C. glabrata, C. krusei, C.
parapsilosis, C. tropicalis) now cause ~50% of
all cases of candidemia and disseminated
candidiasis.
Pts with a compromised immune system, pts
with indwelling catheters, pts with severe
burns, and neonates of low birth weight are at
risk for hematogenous dissemination
Clinical Manifestations
Mucocutaneous candidiasis: Thrush is characterized by
white, adherent, painless, discrete or confluent patches in
the mouth, tongue, or esophagus.
Vulvovaginal candidiasis presents with pruritus, pain, and a
vaginal discharge that may contain whitish “curds.”
Other cutaneous infections include paronychia, balanitis,
and intertrigo (erythematous irritation with pustules in skin
folds).
Chronic mucocutaneous candidiasis is a heterogeneous
infection of hair, nails, skin, and mucous membranes that
persists despite therapy and is associated with a
dysfunctional immune system
Deeply invasive candidiasis: These infections are
most commonly due to hematogenous seeding of
organs during candidemia, but they can also be due
to contiguous spread of organisms after disruption
of normal anatomic barriers (e.g., kidney infection
associated with an indwelling urinary catheter).
Nearly any organ can be infected, but the brain,
chorioretina, heart, and kidneys are most commonly
involved.
Skin involvement manifests as macronodular
lesions.
Diagnosis
The diagnosis of Candida infection is
established by visualization of pseudohyphae
or hyphae in the presence of inflammation in
appropriate clinical samples.
•The β-glucan test has a negative predictive
value of ~90% and can help exclude
disseminated disease.
TREATMENT Candidiasis
• Mucocutaneous Candida infection: Azoles
are the preferred agents; nystatin is an
alternative.
Oral therapy can be used for vulvovaginal
infections (fluconazole, 150 mg PO as a single
dose) and esophageal infections (fluconazole,
100–200 mg/d; or itraconazole, 200 mg/d)
Candidemia and suspected disseminated
candidiasis: should be treated with a systemic
antifungal agent for at least 2 weeks after the
last positive blood culture.
Lipid formulations of AmB, echinocandins, and
fluconazole or voriconazole are all effective
Neutropenic or hemodynamically unstable pts
should be treated with broader-spectrum
agents (e.g., AmB, echinocandins)
Fluconazole is the preferred agent for non neutropenic,
hemodynamically stable pts when azole resistance is not
considered likely.
When possible, foreign materials (e.g., catheters) should be
removed or replaced.
All pts with candidemia should undergo an ophthalmologic
exam because of high rates of Candida endophthalmitis, which
may require partial vitrectomy.
– Candida endocarditis should be treated with valve removal
and
long-term antifungal administration
– Candida meningitis is often treated with a polyene plus
flucytosine.
ASPERGILLOSIS
Epidemiology
Aspergillus is a mold with septate hyphae that
branch at 45° angles and have vast numbers of
conidia (spores).
It has a worldwide distribution and typically grows
in decomposing plant materials and in bedding.
A. fumigatus is responsible for most cases of
invasive aspergillosis, almost all cases of chronic
aspergillosis, and most allergic syndromes
Inhalation is common; only intense exposures
cause disease in healthy, immunocompetent
individuals.
The primary risk factors for invasive
aspergillosis are profound neutropenia and
glucocorticoid use.
Pts with chronic pulmonary aspergillosis have
a wide spectrum of underlying pulmonary
diseases (e.g., tuberculosis, sarcoidosis)
Clinical Manifestations
More than 80% of invasive disease cases involve the lungs; in pts who
are significantly immunocompromised, virtually any organ can be
affected.
Invasive pulmonary aspergillosis: Pts can be asymptomatic or can
present with fever, cough, chest discomfort, hemoptysis, and shortness
of breath.
Acute and subacute forms have courses of ≤1 month and 1–3 months,
respectively.
Early diagnosis requires a high index of suspicion, screening for
circulating antigen (in leukemia), and urgent CT of the chest.
Invasive sinusitis: Pts have fever, nasal or facial discomfort, and nasal
discharge.
The sinuses are involved in 5–10% of cases of invasive aspergillosis;
sinus involvement is especially likely in leukemic pts and hematopoietic
stem-cell transplant recipients
Disseminated aspergillosis: Aspergillus disseminates from lung to
brain, skin, thyroid, bone, and other organs, after which pts
develop skin lesions and deteriorate clinically over 1–3 days, with
fever and signs of mild sepsis. Blood cultures are usually
negative.
Cerebral aspergillosis: Single or multiple lesions, hemorrhagic
infarction, and cerebral abscess are common. The presentation
can be acute or subacute, with mood changes, focal signs,
seizures, and a decline in mental status. MRI is the most useful
investigation.
Cutaneous aspergillosis: Dissemination of Aspergillus occasionally
results in cutaneous features, usually an erythematous or
purplish nontender area that progresses to a necrotic eschar
Chronic pulmonary aspergillosis: Pts develop one or more cavities
that expand over months or years, with pulmonary symptoms,
fatigue, and weight loss.
Without treatment, pulmonary fibrosis can develop.
Aspergilloma: A fungal ball occurs in up to 20% of residual chest
cavities ≥2.5 cm in diameter. Life-threatening hemoptysis may
occur.
Chronic sinusitis: Pts develop one of three presentations: a sinus
aspergilloma in the maxillary sinus, chronic invasive sinusitis that
is slowly destructive, or chronic granulomatous sinusitis.
Allergic bronchopulmonary aspergillosis (ABPA): A hypersensitivity
reaction leads to bronchial plugging, coughing fits, and dyspnea,
primarily affecting asthmatics and pts with cystic fibrosis.
Diagnosis
Culture, molecular diagnosis, antigen
detection, and histopathology usually confirm
the diagnosis
Galactomannan antigen testing of serum
from high-risk pts is best done prospectively
• A halo sign on high-resolution thoracic CT
scan (a localized ground glass appearance
representing hemorrhagic infarction
surrounding a nodule) suggests the diagnosis
CRYPTOCOCCOSIS
Epidemiology
Cryptococcus is a yeast-like fungus. C. neoformans and C.
gattii are pathogenic for humans and can cause
cryptococcosis
Worldwide, there are ~1 million cases of cryptococcosis,
with >600,000 deaths annually.
Cryptococcosis is rare in the absence of impaired immunity.
• C. neoformans is found in soil contaminated with pigeon
droppings, whereas C. gattii is associated with eucalyptus
trees.
Most cases are acquired via inhalation, which results in
pulmonary infection
Clinical Manifestations
The clinical manifestations of cryptococcosis
reflect the site of fungal infection, which
usually involves the CNS and/or the lungs.
CNS involvement most commonly presents as
chronic meningoencephalitis, with headache,
fever, lethargy, sensory and memory deficits,
cranial nerve paresis, visual deficits, and
meningismus lasting for weeks.
Pulmonary cryptococcosis is generally
asymptomatic but can present as cough,
increased sputum production, and chest pain.
Skin lesions are common in pts with
disseminated cryptococcosis and can be
highly variable, including papules, plaques,
purpura, vesicles, tumor-like lesions, and
rashes.
Diagnosis
Diagnosis requires the demonstration of C.
neoformans in normally sterile tissue (e.g.,
positive cultures of CSF or blood).
India ink smear of CSF is a useful rapid
diagnostic technique, but may yield negative
results in pts with a low fungal burden.
Cryptococcal antigen testing of CSF and/or
serum provides strong presumptive evidence
for cryptococcosis; these tests are often
negative in pulmonary cryptococcosis
Treatment
Immunocompetent pts
Pulmonary cryptococcosis should be treated with
fluconazole (200–400 mg/d) for 3–6 months.
Extrapulmonary cryptococcosis may initially
require AmB (0.5–1.0 mg/kg daily for 4–6 weeks).
CNS disease should be treated with an induction
phase of AmB (0.5–1.0 mg/kg daily) followed by
prolonged consolidation therapy with fluconazole
(400 mg/d)
Meningoencephalitis is treated with AmB
(0.5–1.0 mg/kg) plus flucytosine (100 mg/kg)
daily for 6–10 weeks or with the same drugs
at the same dosages for 2 weeks followed by
fluconazole (400 mg/d) for 10 weeks.
Immunosuppressed pts are treated with the same initial
regimens except that maintenance therapy with fluconazole
is given for a prolonged period to prevent relapse.
HIV-infected pts with CNS involvement are typically treated
with AmB (0.7–1.0 mg/kg daily) plus flucytosine (100 mg/kg
qd) for at least 2 weeks followed by fluconazole (400 mg/d)
for 10 weeks and then by lifelong maintenance therapy with
fluconazole (200 mg/d).
An alternative regimen involves fluconazole (400–800
mg/d) plus flucytosine (100 mg/kg qd) for 6–10 weeks
followed by fluconazole (200 mg/d) as maintenance therapy
HISTOPLASMOSIS
Epidemiology
Histoplasma capsulatum, a dimorphic fungus, causes
histoplasmosis.
Microconidia are inhaled, reach the alveoli, and are transformed
into yeasts with occasional narrow budding.
A granulomatous reaction results; in pts with impaired cellular
immunity, infection may disseminate.
Histoplasmosis is the most prevalent endemic mycosis in North
America and is also found in Central and South America, Africa,
and Asia. In the United States, histoplasmosis is endemic in the
Ohio and Mississippi river valleys.
The fungus is found in soil, particularly that enriched by
droppings of birds and bats
Clinical Manifestations
Depending on the intensity of exposure, the immune status of
the exposed individual, and the underlying lung architecture of
the host, disease can range from asymptomatic to life-
threatening.
Immunocompetent pts usually have asymptomatic or mild and
selflimited disease.
1–4 weeks after exposure, some pts develop a flu-like illness
with fever, chills, sweats, headache, myalgia, anorexia, cough,
dyspnea, and chest pain.
5–10% of pts with acute histoplasmosis develop arthralgia or
arthritis, often associated with erythema nodosum.
Hilar or mediastinal lymphadenopathy may occur and can cause
vascular or tracheoesophageal compression
Immunocompromised pts are more likely to develop
progressive disseminated histoplasmosis (PDH).
The clinical spectrum ranges from a rapidly fatal course with
diffuse interstitial or reticulonodular lung infiltrates, shock,
and multiorgan failure to a subacute course with focal organ
involvement, hepatosplenomegaly, fever, and weight loss.
Meningitis, oral mucosal ulcerations, GI ulcerations, and
adrenal insufficiency can occur.
Chronic cavitary histoplasmosis most often affects smokers
with structural lung disease (e.g., emphysema) and presents
as productive cough, dyspnea, low-grade fever, night sweats,
and weight loss.
Diagnosis
Fungal culture remains the gold standard, but cultures
In PDH, the culture yield is highest for BAL fluid, bone
marrow aspirate, and blood; cultures of sputum or
bronchial washings are usually positive in chronic
pulmonary histoplasmosis.
Fungal stains of cytopathology or biopsy materials may be
helpful in diagnosing PDH.
Histoplasma antigen assay of body fluids (e.g., blood,
urine, CSF, BAL fluid) is useful in diagnosing PDH or acute
disease and in monitoring the response to treatment.
Serology can be helpful in diagnosis but requires ≥1
month for antibody production
Treatment
Acute pulmonary, moderate to severe illness
with diffuse infiltrates and/or hypoxemia
Lipid AmB (3–5 mg/kg per day) ±
glucocorticoids for 1–2 weeks; then
itraconazole (200 mg bid) for 12 weeks.
Monitor renal and hepatic function
Chronic/cavitary pulmonary
Itraconazole (200 mg qd or bid) for at least
12 months.
Monitor hepatic function
Progressive disseminated
Lipid AmB (3–5 mg/kg per day) for 1–2 weeks;
then itraconazole (200 mg bid) for at least 12
months.
Monitor renal and hepatic function
CNS Liposomal AmB (5 mg/kg per day) for 4–6
weeks; then itraconazole (200 mg bid or tid)
for at least 12 months.
Monitor renal and hepatic function
COCCIDIOIDOMYCOSIS
Epidemiology
Coccidioidomycosis is caused by the two species of the
dimorphic soil dwelling fungus Coccidioides: C. immitis
and C. posadasii.
These organisms exist as branching, filamentous molds.
Direct exposure to soil harboring Coccidioides increases
risk, but infection, which results from inhalation of
airborne arthroconidia, can occur without overt soil
exposure and may be related to other climatic factors
e.g., periods of dryness after rainy seasons)
Clinical Manifestations
60% of infected pts are asymptomatic;
the remaining 40% have primarily
pulmonary disease characterized by
fever, cough, and pleuritic chest pain
Primary pulmonary infection is sometimes associated
with erythema nodosum, erythema multiforme,
arthralgias, and arthritis.
A history of night sweats, profound fatigue,
eosinophilia, and hilar or mediastinal
lymphadenopathy suggests the disease.
Pneumonic complications include pulmonary nodules
(resembling pulmonary malignancies) and pulmonary
cavities (a thin-walled lesion in a bronchus that is
associated with cough, hemoptysis, and pleuritic
chest pain)
Disseminated infection affects <1% of infected
pts, most commonly pts with depressed cellular
immunity and pregnant women.
Common sites for dissemination include bone,
skin, joint, soft tissue, and meninges.
Pts with meningitis present with persistent
headache, lethargy, confusion, mild to moderate
nuchal rigidity, and CSF with lymphocytic
pleocytosis and profound hypoglycorrhachia.
The mortality rate is 100% without treatment.
Diagnosis
Serology and culture are the primary means of diagnosis
Tube-precipitin (TP) and complement-fixation (CF)
assays, immunodiffusion, and an EIA are available to
detect IgM and IgG antibodies.
TP antibody does not gauge disease progression and is
not found in CSF.
Rising CF titers in serum are associated with clinical
progression, and CF antibody in CSF indicates meningitis.
Examination of sputum or other respiratory fluids after
Papanicolaou or Gomori methenamine silver staining
reveals spherules in many pts with pulmonary disease
TREATMENT Coccidioidomycosis
The vast majority of pts with coccidioidomycosis do
not require treatment.
Exceptions include the following:
– Pts with focal primary pneumonia and underlying
cellular immunodeficiency or prolonged symptoms
(symptoms persisting for ≥2 months, night sweats
occurring for >3 weeks, weight loss of >10%
A serum CF antibody titer of >1:16, and extensive
pulmonary involvement apparent on CXR) should be
treated with fluconazole (≥400 mg/d) or itraconazole
(400–600 mg/d)
Pts with diffuse pulmonary disease are often treated initially
with AmB (deoxycholate, 0.7–1 mg/kg IV qd; liposomal, 5
mg/kg IV qd), with a switch to prolonged therapy with a triazole
Pts with chronic pulmonary disease or disseminated infection
are treated with prolonged triazole therapy (i.e., for ≥1 year).
Relapse occurs in 15–30% of individuals once therapy is
discontinued.
Pts with meningitis require lifelong triazole therapy; fluconazole
is the drug of choice.
If triazole therapy fails, intrathecal or intraventricular AmB may
be used.
Relapse occurs in 80% of pts when therapy is stopped.
BLASTOMYCOSIS
Microbiology and Epidemiology
Blastomyces dermatitidis is a dimorphic fungus
that is found in the south eastern and south-
central states bordering the Mississippi and Ohio
river basins, in areas of the United States and
Canada bordering the Great Lakes Fungal
Infections and the St. Lawrence River, and in
Africa.
Infection is caused by inhalation of Blastomyces
from moist soil rich in organic debris.
Clinical Manifestations
Acute pulmonary infection can present as abrupt-
onset fever, chills, pleuritic chest pain, myalgias, and
arthralgias.
However, most pts with pulmonary blastomycosis
have chronic indolent pneumonia with fever, weight
loss, productive cough, and hemoptysis.
Skin disease is common and can present as verrucous
(more common) or ulcerative lesions.
Blastomycosis can include osteomyelitis in one-fourth
of infections and CNS disease in ~40% of pts with
AIDS.
Diagnosis
Smears of clinical samples or cultures of
sputum, pus, or tissue are required for
diagnosis.
Antigen detection in urine and serum may
assist in diagnosing infection and in
monitoring pts during therapy.
TREATMENT Blastomycosis
Every pt should be treated because of the high risk of
dissemination.
– For immunocompetent pts with nonsevere disease that does not
involve the CNS, itraconazole (200–400 mg/d for 6–12 months) is
recommended.
– Immunocompetent pts with severe disease or CNS manifestations
should be treated initially with AmB (deoxycholate, 0.7–1 mg/kg
IV qd; liposomal, 3–5 mg/kg IV qd); once their clinical condition
improves, they can be switched to itraconazole (or, for those with
CNS disease, fluconazole, 800 mg/d).
– Immunocompromised pts with any form of infection should be
treated initially with AmB, with a switch to a triazole, as above, once
clinical improvement has occurred.
