Download CHAPTER 46 Cryptococcus, Histoplasma

CHAPTER 46
Cryptococcus, Histoplasma, Coccidioides, and Other
Systemic Fungal Pathogens
The fungi discussed in this group cause a variety of infections, each ranging in severity
from subclinical to progressive, debilitating disease. Most species are dimorphic, growing
in the infectious mold form in the environment but switching to a yeast form in tissues to
produce infection. They differ from the opportunistic fungi in their ability to cause
disease in previously healthy persons, but the most serious disease still occurs in
immunocompromised individuals. With the exception of Cryptococcus neoformans, each
of these species is restricted to a geographic niche corresponding to the environmental
habitat of the mold form of the species. None are transmitted from human to human.
Cryptococcus neoformans
I. Mycology
1. Cryptococcus neoformans (cryptococcus) is a yeast 4 to 6 µm in diameter that
produces a characteristic capsule
2. Various serotypes and varieties have same biology
3. Capsule is a polysaccharide polymer, the major component of which is
glucuronoxylomannan (GXM )
4. Urease, laccase and melanin produced
II. CRYPTOCOCCOSIS
A. EPIDEMIOLOGY
1. C. neoformans is ubiquitous throughout the world
2. Associated with soil contaminated with bird droppings
3. Yeasts or basidiospores inhaled
B. PATHOGENESIS
1. Following inhalation cryptococci reach the alveoli
2. Antiphagocytic capsule is prime factor in progression
3. Circulating GXM interferes with immune function
4. Melanin provides oxidative protection in CNS
5. Tissue reaction is often minimal
C. IMMUNITY
1. Antibody plays some role
2. TH1 responses are dominant
3. Dendritic cells present mannoproteins
III. CRYPTOCOCCOSIS: CLINICAL ASPECTS
A. MANIFESTATIONS
1. Meningitis is insidious and chronic
2. Intermittent headache, irritability, dizziness, and difficulty with complex
cerebral functions appear over weeks or months
3. Course is more rapid with AIDS
4. Cryptococcal pneumonia often asymptomatic
B DIAGNOSIS
1. Cells and glucose depression in CSF may be minimal
2. India ink prep demonstrates encapsulated yeast in 50% of cases
3. Few cryptococci may be present in CSF
4. GXM is detectable by latex agglutination or enzyme immunoassay in CSF and
serum
C. TREATMENT
1. Amphotericin, flucytosine and fluconazole used in combination
Histoplasma capsulatum
I. Mycology
1. Histoplasma capsulatum is a dimorphic fungus (Figure 46-3) that grows in the
yeast phase in tissue and in cultures incubated at 37°C
2. The mold phase grows in cultures incubated at 22 to 25°C and as a saprophyte
in soil
3. Yeast forms are small for fungi (2 to 4 µm) and reproduce by budding
(blastoconidia)
4. Mycelia are septate and produce the diagnostic tuberculate macroconidium
5. Growth may take many weeks
II. HISTOPLASMOSIS
A. EPIDEMIOLOGY
1. H. capsulatum grows in soil under humid climatic conditions, particularly soil
containing bird or bat droppings
2. Microconidia are infectious
3. High prevalence in United States regions drained by the Ohio and Mississippi
Rivers
B. PATHOGENESIS
1. Reticuloendothelial system is focus of infection
2. Grows in macrophages by controlling lysosomal pH
3. Lymphatic spread and reactivation are similar to tuberculosis
4. Granulomatous response seen in liver, spleen, and bone marrow
C. IMMUNITY
1. Skin test demonstrates DTH
2. Immunity is TH1 mediated
III. HISTOPLASMOSIS: CLINICAL ASPECTS
A. MANIFESTATIONS
1. Most cases are asymptomatic or with fever and cough
2. Progressive pulmonary disease shows cavities and weight loss
3. Dissemination involves reticuloendothelial organs, mucous membranes, and
adrenal glands
B. DIAGNOSIS
1. Blood and bone marrow examination require special stains
2. Immunodiffusion and probes used with cultures
3. Culture is required for firm diagnosis
4. Enzyme immunoassay (EIA)EIA detects circulating antigen
C. TREATMENT
1. For mild disease localized to the lung itraconazole is used
2. For more severe or disseminated disease a course of amphotericin B is followed
by the itraconazole regimen
Blastomyces dermatitidis
I. Mycology
1. Blastomyces dermatitidis is a dimorphic fungus with some characteristics
similar to those of Histoplasma
2. Large yeast cells have broad-based buds
3. Mold has small oval conidia-like Histoplasma
II. BLASTOMYCOSIS
A. EPIDEMIOLOGY
1. Geographic distribution similar to Histoplasma
B. PATHOGENESIS
1. The primary infection is pulmonary after inhalation of conidia, which develop
in soil
2. Surface adhesin binds to host cells
3. Large yeast are primarily outside cells
C. IMMUNITY
1. Complement, antibody, and cell-mediated immunity are involved
III. BLASTOMYCOSIS: CLINICAL ASPECTS
A. MANIFESTATIONS
1. Pulmonary blastomycosis is similar to other mycoses
2. Skin lesions are on exposed surfaces
B. DIAGNOSIS
1. KOH and biopsy show yeast with broad-based buds
2. Culture takes weeks and conidia not distinctive
3. DNA probe is useful in differentiating cultures from Histoplasma
C. TREATMENT
1. Itraconazole is used for mild to moderate disease and preceded by amphotericin
B for more serious or disseminated disease
Coccidioides immitis
I. Mycology
1. Coccidioides immitis is a dimorphic fungus
2. Instead of a yeast phase, a large (12-to 100-µm), distinctive, round-walled
spherule is produced in the invasive tissue form
3. Spherules differentiate to form and release endospores
4. In the environment C. immitis grows under harsh conditions in sandy alkaline
soil with high salinity
5. Barrel-shaped arthroconidia form in hyphae
6. Conidia are readily airborne and infectious
II. COCCIDIOIDOMYCOSIS
A. EPIDEMIOLOGY
1. Coccidioidomycosis is the most geographically restricted of the systemic
mycoses
2. C. immitis grows only in the alkaline soil of semiarid climates known as the
Lower Sonoran life zone
3. Primary endemic zones are in Arizona, Nevada, New Mexico, western Texas,
and the arid parts of central and southern California
4. High proportion of longtime residents of highly endemic areas have been
infected
5. Arthroconidia can spread long distances
6. Rainfall pattern influences C. immitis growth and subsequent attack rate
7. Considered a potential bioweapon
B. PATHOGENESIS
1. Inhaled arthroconidia are small enough (2 to 6 µm) to bypass the defenses of the
upper tracheobronchial tree and lodge in the terminal bronchioles
2. Arthroconidial wall resists phagocytosis
3. Surviving arthroconidia convert to the spherule stage, which begins its slow
growth to a size that makes effective phagocytosis difficult
4. Spherules produce endospores with extracellular matrix from the parent spherule
5. Proteases and Components of the spherule outer wall may be linked to virulence
C. IMMUNITY
1. Lifelong immunity to coccidioidomycosis clearly develops in the vast majority of
those who become infected
2. Immunity is associated with strong polymorphonuclear leukocyte and TH1
mediated responses to coccidioidal antigens
3. Cell-mediated immunity is of prime importance
4. Progressive disease develops in patients with AIDS or defects in cell-mediated
immunity
5. Endospores must be destroyed by cytokine-activated macrophages
6. Antibody production is inversely related to disease progress
III. COCCIDIOIDOMYCOSIS: CLINICAL ASPECTS
A. MANIFESTATIONS
1. More than one half of those infected with C. immitis suffer no symptoms, or the
disease is so mild that it cannot be recalled when evidence of infection (serology,
skin test) is discovered
2. Malaise, cough, chest pain, fever, and arthralgia lasting 2 to 6 weeks is called
valley fever
3. There are few objective findings and the chest x-ray is usually clear
4. Valley fever is self-limiting in >90%
5. Erythema nodosum common in women
6. Chronic and disseminated disease develops in less than 1%
7. Ethnicity and immune status are risk factors for dissemination
8. Chronic meningitis may be progressive
B. DIAGNOSIS
1. Detection of spherules in direct examination is diagnostic
2. Culture of C. immitis from sputum, visceral lesions, or skin lesions is not
difficult, but must be undertaken only by those with experience and proper
biohazard protection
3. Culture from CSF may be difficult
4. Coccidioidin DTH skin test remains positive for life
5. Precipitating IgM indicates acute infection
6. IgG antibody level correlates with extent of disease; High levels = bad
prognosis
C. TREATMENT
1. Primary disease is treated only with risk factors
2. Amphotericin B and azoles in progressive disease
PARACOCCIDIOIDES BRASILIENSIS
1. Paracoccidioides brasiliensis is the cause of paracoccidioidomycosis (South
American blastomycosis)
2. Disease limited to tropical and subtropical areas of Central and South America
3. Dimorphic fungus with production of multiple blastoconidia from the same cell
4. Manifests primarily as chronic mucocutaneous or cutaneous ulcers
5. Disease has a strong predilection for men