Description

• Histoplasmosis (a.k.a., Ohio Valley disease, spelunker’s lung, cave disease, Darling disease, Appalachian Mountain disease, and reticuloendothelial cytomycosis) is the most prevalent endemic mycosis in United States.
• Dimorphic fungus Histoplasma capsulatum var. capsulatum in United States (African var. is duboisii, which affects skin, lymph nodes, and bone)
• Forms include acute, chronic, primary, reactivation, and the affected disease areas (pulmonary, extrapulmonary, disseminated)

Epidemiology

• Endemic in central and southeastern states, classically Ohio and Mississippi River valleys; also prominent in Central America but occasionally in Europe, Asia, and Africa
• Mold form at <35°C (whereas yeast form in tissue above 37°C) grows best in soil environments: warm, moist, and rich in nitrogen (bird/bat guano); found in caves, under roosting trees, abandoned buildings
• Occasional cluster infections usually with soil disruptions (spelunking, building demolition)
• Sporadic cases with some activities: gardening, roofing, installing air-conditioning/heating, cleaning older homes, playing in hollow trees
• Only mammals can be infected (birds do not carry the organism).
• No human or animal-to-human transmission except for one case of vertical transmission in infant with co-HIV infection
• Incubation typically 3 to 17 days but up to 5 months
• Total infections: estimated 500,000 per year
  • Chronic pulmonary infection: 1:100,000 cases
  • Disseminated infection: 1:2,000 cases

Risk Factors

• Males slightly more at-risk than females
• Infections more common in 30s to 40s but all ages affected
• Disseminated disease risk factors: immature cellular immunity (<2 years of age), large inoculum, acquired immunodeficiency (including TNF-α inhibitors), malnutrition

General Prevention

• Avoid areas/dust with likely mold.
• Spray water, oil, or 3% formalin in areas with dust/dirt if work planned.
• Wear cover apparel and face mask able to filter particles >1 millimicron (e.g., N95).
• Prophylaxis for certain populations

Pathophysiology

• Inhaled mold spores germinate in lungs to yeast form; rarely enter via skin
• Once germinated, some lymphatic and hematologic dissemination even in self-limited disease
• Immune system takes several weeks to respond, involves T lymphocytes, IL-12, IFN-γ, and TNF-α; macrophages kill fungus.

Etiology

Infectious mold spores are microconidia of H. capsulatum.

History

• Of 5% who develop symptoms, most (60–90%) have pulmonary symptoms and/or flu-like illness lasting days to 2 weeks for acute.
  • Most common complaints: headache, fatigue, fever, cough, myalgias, chest pain, which can be pleuritic
  • Pharyngitis, rhinorrhea, and congestion are unusual.
• 5% of symptomatic patients have more prolonged course with additional anorexia, weight loss, arthralgia, and night sweats lasting >2 weeks.
  • “Severe” symptoms: dyspnea and hypoxemia
  • Cavitary form can have tuberculosis (TB)-like symptoms (e.g., hemoptysis) but rare in children.
• Progressive disseminated histoplasmosis (PDH) (usually <2 years of age or immunocompromised) symptoms: fever, weight loss, hepatosplenomegaly, failure to thrive (in infants) often without respiratory symptoms

Physical Exam

• For acute pulmonary disease, exam is usually normal, aside from fever and occasionally crackles or decreased breath sounds; wheezing has been reported.
• More severe or diffuse pulmonary disease can present with weight loss, hypoxia, and dyspnea.
• Erythema nodosum (especially adolescent patients)
• Disseminated findings: hepatosplenomegaly, extrapulmonary lymphadenopathy and/or granulomas, oral or skin lesions, adrenal or intestinal masses, multifocal choroiditis, meningitis (60% of PDH of infancy), endocarditis, parotitis, arthritis, signs of disseminated intravascular coagulation (DIC)
• Other findings could include the following:
  • Pericardial effusion (10% of symptomatic pediatric patients) with potential cardiac rub
  • Pleural effusion
  • Chylothorax
  • Biliary obstruction
  • Superior vena cava syndrome

Differential Diagnosis

• Pulmonary histoplasmosis
  • TB and other mycobacteria
  • Pneumonia (atypical)
  • Other fungal lung infections (blastomycosis, sporotrichosis, and coccidioidomycosis)
  • Pneumocystis jirovecii (can mimic PDH symptoms)
  • Nocardia and Actinomyces
• Mediastinal lymphadenopathy
  • Malignancy
  • Sarcoidosis
• PDH
  • Malignancy
  • Sepsis
  • Opportunistic infections (Coinfection is common in immunodeficiency.)
  • Hemophagocytic lymphohistiocytosis/macrophage activation syndrome (MAS) (can be sequelae of PDH as well)
  • Brucella, Q-fever, leishmaniasis

Diagnostic Tests and Interpretation

General Measures

Standard precautions adequate for hospital isolation

Medication (Drugs)

• Immunocompetent patients with primary acute uncomplicated (nonsevere) pulmonary histoplasmosis <4 weeks’ duration do not require treatment.
• Therapy indicated for severe/complicated pulmonary disease, after high inoculum, PDH, infection in immunocompromised
• When itraconazole used, oral liquid suspension preferred for more consistent absorption
• Pulmonary disease (moderate but >1 month)
  • PO itraconazole 5 to 10 mg/kg/24 h divided b.i.d. × 6 to 12 weeks (max 400 mg daily)
• Pulmonary disease (severe)
  • Amphotericin B lipid formulation (unless renal involvement) 3 to 5 mg/kg/24 h depending on formulation (lipid complex vs. liposomal) or deoxycholate 1 mg/kg daily IV × 1 to 2 weeks followed by PO itraconazole 5 to 10 mg/kg/24 h divided b.i.d. (max 400 mg daily) for 12 weeks
  • Methylprednisolone (controversial in children) 1 to 2 mg/kg daily IV during first 1 to 2 weeks for patients with worsened hypoxemia or distress
• Disseminated (without HIV infection)
  • Amphotericin B lipid formulation (as above) × 4 to 6 weeks. Alternative: lipid formulation of amphotericin B (as above) for 2 to 4 weeks followed by itraconazole PO 5 to 10 mg/kg/24 h divided b.i.d. for 3 to 6 months until urine antigen concentration <2 mcg/mL
• Disseminated (with HIV infection)
  • Liposomal amphotericin B 5 mg/kg/24 h IV × 2 to 6 weeks followed by oral itraconazole for at least 1 year to life 5 to 10 mg/kg/24 h divided b.i.d. (max of 400 mg/24 h)
  • If highly active antiretroviral therapy (HAART) given for 6 months, CD4 >150 cells/mm³, antifungal taken for 1 year, and antigen levels low, can consider stopping secondary prophylaxis
• Meningitis
  • Liposomal amphotericin B 5 mg/kg/24 h IV × 4 to 6 weeks then oral itraconazole 5 to 10 mg/kg/24 h divided b.i.d. × 12 months and then until resolution of CSF profile; monitor antigen levels.
• Mediastinitis (rare)
  • Amphotericin B × 1 to 2 weeks then oral itraconazole for 6 months
• Fibrosing mediastinitis (rare)
  • Itraconazole for 3 months
  • May not have any effect on fibrosis
• Pericarditis/rheumatologic manifestations
  • Pericardiocentesis if severe tamponade
  • NSAID (usually indomethacin) for 2 to 12 weeks
  • Consider oral prednisone (1 mg/kg/24 h).
• Compression by granulomatous disease
  • Consider surgery and corticosteroid with concurrent use of itraconazole.
• Vertical transmission in newborn
  • Amphotericin B (lipid formulation)
• Although the Infectious Diseases Society of America (2007) guidelines state that lipid preparations of amphotericin are “not preferred” in children (except HIV patients) as nonlipid preparations are well tolerated, lipid formulations are most often used due to overall favorable side effect profile.
• Salvage therapy can be done with posaconazole and/or voriconazole; fluconazole is inferior to itraconazole.
• Prophylaxis for CD4 <150 cells/μL, in hyperendemic areas or solid organ transplant recipients, those scheduled to receive TNF inhibitors, or those undergoing intensive chemotherapy with a history of histoplasmosis in the past 2 years: oral itraconazole 5 mg/kg/24 h divided b.i.d. (max 200 mg/24 h)

Inpatient Consideratons

Patients receiving amphotericin may need prolonged IV access.

Follow-Up Recommendations

Prognosis

• Overall good prognosis except for untreated PDH disease, which is highly fatal
• Self-limited pulmonary patients recover in 2 to 3 weeks.
• Most treated PDH patients have significant improvement after 2 weeks of IV antifungals.

Complications

• Lymphatic, GI, esophageal, vascular, and biliary obstruction
• Renal stones
• Multifocal choroiditis
• Calcified nodules
• Fibrosis
• Pleural effusion
• Pericarditis
• Chylothorax
• Superior vena cava syndrome
• Hydrocephalus
• MAS

ICD-9

• 115.90 Histoplasmosis, unspecified, without mention of manifestation
• 115.00 Infection by Histoplasma capsulatum, without mention of manifestation
• 115.05 Infection by Histoplasma capsulatum, pneumonia
• 115.09 Infection by Histoplasma capsulatum, other

ICD-10

• B39.9 Histoplasmosis, unspecified
• B39.4 Histoplasmosis capsulati, unspecified
• B39.2 Pulmonary histoplasmosis capsulati, unspecified
• B39.3 Disseminated histoplasmosis capsulati
• B39.1 Chronic pulmonary histoplasmosis capsulati
• B39.0 Acute pulmonary histoplasmosis capsulati

SNOMED

• 12962009 Histoplasmosis (disorder)
• 76255006 Infection by Histoplasma capsulatum (disorder)
• 187054003 Pulmonary histoplasmosis (disorder)
• 240730004 Acute disseminated classical histoplasmosis (disorder)
• 26427008 Chronic pulmonary histoplasmosis (disorder)
• 58524006 acute pulmonary histoplasmosis (disorder)