Histoplasma capsulatum

Background

Microbiology

Saprophytic environmental fungus withing the family Ascomycetes
Thermally dimorphic, existing as a mold <35ºC and a yeast at >37ºC
- Mold
  - Mold form is highly infectious, associated with lab-related outbreaks
  - Septate hyaline mold with aerial hyphae with macroconidia, which are its identifying feature
  - Two types of conidia: tuberculate macroconidia (ovoid bodies 8 to 15 μm with spikes), and microconidia (small, smooth oval bodies 2 to 5 μm)
  - Two colony types, brown (B) and albino (A)
- Yeast
  - Non-infectious, once hanging out in your body
  - Small, 2 to 5 μm
  - Demonstrates multipolar narrow-based budding
  - Does not look particularly different from other yeast, but may be intracellular
Three variants
- H. capsulatum var. capsulatum, which is the most common worldwide, and is further divided into various clades
- H. capsulatum var. duboisii which is only present in western Africa, and has larger yeast forms
  - Can take up to 7 days to grow
- H. capsulatum var. farciminosum

Epidemiology

Distribution of histoplasmosis

Endemic in many parts of the world
- Ohio and Mississippi River Valley systems (Central/Eastern US), where seroprevalence is as high as 80% in adults
- Probably up through St. Lawrence River as well
- Probably more broadly distributed, including Central and South America, South and East Asia, and Australia
- H. capsulatum var. duboisii in western Africa
Typically found in moist soil enriched with bat or bird droppings, which helps it to sporulate
- Disturbing the soil aerosolizes it, allowing the microconidia to be inhaled
- Microconidia can be transported for miles by air currents

Risk Factors

HIV, solid organ transplant, hematologic transplant
Primary immunodeficiencies: X-linked hypogammaglobulinemia

Pathophysiology

Inhaled microconidia reach the alveolii and are phagocytosed by alveolar macrophages
- Innoculum size can be smaller with immunodeficiency
- Size of innoculation affects disease severity and progression
Microconidia transform into budding yeasts, in a process that is dependent on intracellular macrophage calcium and iron
They multiply inside macrophages, and translocate through the lymphatics
Cellular immunity developed around 2 weeks later
- Response depends on IL-12 and TNF-α
- Organize to form granulomas to contain the infection
Latent infection can reactivate, but rare
- Most common with infliximab
In impaired cellular immunity, infection can become disseminated

Clinical Manifestations

Spectrum of illness, related to the size of the inoculum, strain-specific virulence, and host immunity
Often asymptomatic; in endemic areas, 50-80% of people skin-test positive or have radiographic evidence of previous infection
Can cross tissue planes

Acute Pulmonary Histoplasmosis

Fever, chill, malaise, headaches, myalgias, anorexia, cough, dyspnea, and chest pain
- Spectrum from mild to severe
- Usually self-limited, no need to treat unless longer than a month
Pneumonitis on chest x-ray, often with adenopathy
- "Buckshot" appearance? (Mandell)
Can have rheumatologic sequelae in 5-10%, with arthralgias, arthritis, and erythema nodosum
Can have pericarditis from the inflammatory response
Hilar adenopathy can necrotize

Progressive Disseminated Histoplasmosis

Usually, though not exclusively, in immunocompromised patients
- Risk factors include CD4 <200, very old or very young, and therapeutic immunosuppression (prednisone, MMF, tacrolimus, methotrexate, TNF-α inhibitors, other biologics)
Can be rapidly-progressing and acute, or more subacute

Acute Progressive Disseminated Histoplasmosis

Fever, weight loss, organomegaly, thrombocytopenia
Meningitis or focal brain lesions
Oral and GI mucosal ulcerations
Adrenal insufficiency

Chronic Progressive Disseminated Histoplasmosis

In normal hosts
Absent or low-grade fever
Longer course
Most common finding is oropharyngeal lesion: deep, well-circumscribed, unrated, and painless
- Mimics squamous cell carcinoma
Can also have hepatosplenomegaly, chronic meningitis, or chronic granulomatous hepatitis

Chronic Cavitary Histoplasmosis

Typically seen in bullous emphysema
Productive cough, dyspnea, low-grade fever, night sweats, weight loss
- Hemoptysis is rare
- Progressive without treatment
Chest x-ray shows upper-lobe infiltrations, vacitation, and pleural thickening, similar to tuberculosis

Fibrosing Mediastinitis

Histoplasmosis is the most common cause of fibrosing mediastinitis
Rare but serious
Progressive fibrosis around hilar/mediastinal lymphadenopathy, wither unilateral or bilateral
- Occludes central vessels and airways
Can present with a SVC syndrome, obstruction of pulmonary vessels, or airway obstruction
Can also present with recurrent pneumonias, hemoptysis, or respiratory failure
30% mortality

Other Complications

Ophthalmic posterior uveitis
Meningitis
Infective endocarditis

African Histoplasmosis

H. capsulatum vars. capsulatum and duboisii coexist in Africa
var. duboisii has more skin and skeletal manifestations
- Ulcers, nodules, or psoriaform lesions that can spontaneously resolve
  - Can cause a cold abscess, without inflammation
- Osteolytic bone lesions are common (50%) of cases
  - Skull and ribs most common
  - Can have sinus formation and cystic bone lesions
- May not have any evidence on CXR of prior pulmonary histoplasmosis
- Can also present with progressive disseminated disease, with fevers and multiorgan involvement
  - Combianation of granulomas and pus
  - Larger yeast is harder for macrophages to engulf

Diagnosis

Histopathology of biopsy specimens
- Caseating and non-caseating granulomas
- Mold and yeast forms depending on the temperature
  - Best stain is GMS (Gomori methenamine silver)
  - Seen within the macrophages
Fungal culture of sputum (chronic cavitary), or blood or bone marrow aspirate (disseminated), or CSF (CNS histo)
- Usually grows within 7 days, and almost always within 21 days
- Need to use lysis centrifugation system to release intracellular pathogens before culture
- Yield of 15% for acute pulmonary, but cavitary is 60% and up to 90% in advanced HIV with bronchoscopy
- Bone marrow and blood cultures are 50% sensitive
- Sensitivity increases with volume and number of samples
Serology can be done for antigen or antibody
- Serology for antibodies by complement fixation
- Serology for antibodies by agar gel precipitin test
  - Anti-H is uncommon (<10% of patients), but signifies active infection
  - Anti-M is common (up to 80% of patients), but signifies either active or recovered infection
- Serology may be negative in immunosuppressed patients
- Antigen of urine (best), BAL fluid, and serum if available
  - Urine is best, but only 40% sensitive in cavitary, up to 95% in AIDS patients
    - However, this may no longer be the case, with overall sensitivity of 80% and specificity of 90% regardless of sample source
  - Cross-reacts with other endemic fungi; false-positives with antithymocyte globulin
PCR is possible
- 16S PCR

Management

In general, mild infections are treated with itraconazole and severe infections with amphotericin B
- Give tablets of itraconazole with acidic drink, such as can of soda, and avoid antacids
- Itraconazole requires therapeutic drug monitoring
Voriconazole is an easier-to-prescribe alternative that is likely as effective as itraconazole
Indications for antifungal therapy
- Definitely: moderate to severe acute diffuse pulmonary infection, chronic cavitary pulmonary disease, disseminated disease, CNS infection
- Possibly/uncertain: asymptomatic, mild symptoms lasting longer than 1 month, acute focal pulmonary infection, mediastinal lymphadenitis, mediastinal granuloma
- Not recommended: mediastinal fibrosis, pulmonary nodule, broncholithiasis, presumed ocular histoplasmosis syndrome

Syndrome	Treatment
Acute pulmonary histoplasmosis
Mild, self-resolving	If resolves within a month, no need to treat
Mild, ongoing symptoms	Itraconazole 200 mg po TID x3d then itra 200 mg po daily or BID for 6-12 weeks
Moderate to severe	Liposomal amphotericin B 3-5 mg/kg/d for 1-2 weeks, followed by itraconazole 200 mg TID x3d then itraconazole 200 mg BID x12wk Methylprednisolone 0.5-1 mg/kg IV daily for first 1-2 weeks if respiratory complications
Chronic cavitary pulmonary histoplasmosis	Itraconazole 200 mg TID x3d then daily or BID for at least 1 year (18-24 months may have lower relapse)
Complications
Pericarditis	NSAIDs if mild Prednisone 0.5-1 mg/kg daily then taper over 1-2 weeks, plus itraconazole (as above) for 6-12 weeks if hemodynamic compromise May need therapeutic pericardiocentesis
Rheumatologic	NSAIDs if mild, prednisone and itraconazole (as for pericarditis) if severe
Mediastinal lymphadenitis	Usually no treatment. Follow guide for acute pulmonary histoplasmosis.
Mediastinal granuloma	Usually no treatment. Standard itraconazole protocol for 6-12 weeks if symptomatic.
Mediastinal fibrosis	Antifungals not recommended. Treat only if there is suspicion of mediastinal granuloma. May need stenting of obstructed pulmonary vessels.
Broncholithiasis	Antifungals not recommended. May need surgery.
Progressive disseminated histoplasmosis	Follow antigen levels during therapy and for 12 months after to monitor for relapse
Mild to moderate	Itraconazole for 12 months
Moderately severe to severe	Liposomal amphotericin B 3 mg/kg for 1-2 weeks then oral itraconazole for at least 12 months
Immunosuppressed	May need lifelong suppressive therapy with itraconazole 200 mg po daily
CNS histoplasmosis	Liposomal amphotericin B 5 mg/kg daily for 4-6 weeks (total 175 mg/kg) followed by itraconazole for at least 1 year, until resolution of CSF abnormalities
Pregnancy	Liposomal amphotericin B 3-5 mg/kg for 4-6 weeks
Children	As per above guidelines, with amphotericin B deoxycholate 1 mg/kg and itraconazole 2.5-5 mg/kg bid (max 400 mg daily)
Prophylaxis	Itraconazole 200 mg po daily recommended if HIV with CD4 <150 and more than 10 cases per 100 patient-years

Note: therapeutic drug level monitoring is recommended for itraconazole
Source: IDSA guidelines 2007

Prevention

Lab Safety

Biosafety risk group 3 organism, so needs BSL 3
Should be suspected with any white mold

Prophylaxis

May be indicated for endemic areas in patients with advanced HIV and low CD4 count