Endemic mycosis caused by Histoplasma capsulatum, classically associated with Ohio and Mississippi River valleys and bird/bat guano exposure.
Also known as: Histoplasma capsulatum, Ohio Valley disease, spelunker's lung, cave disease
Overview
Systemic infection caused by the dimorphic fungus Histoplasma capsulatum, acquired by inhalation of microconidia from soil enriched with bird or bat guano. Clinical presentations range from asymptomatic infection to acute pulmonary, chronic cavitary pulmonary, and progressive disseminated disease.
Epidemiology
Endemic to the Ohio and Mississippi River valleys in the United States, parts of Central and South America, Africa, and Asia. Outbreaks linked to cave exploration, demolition of bird roosts, and excavation in contaminated soil. Severe disease is most common in immunocompromised patients (HIV with CD4 <150, solid organ transplant, TNF-alpha inhibitor therapy) and at the extremes of age.
🔒 Free preview limit reached
Keep reading — start your free trial
You've read your 2 free diagnosis previews. Create your free account to unlock the full Histoplasmosis outline — plus all 514 diagnoses, 3,500+ board-style questions, flashcards, and an AI tutor. Your 7-day free trial includes everything, and there's no credit card required.
Pre-existing structural lung disease (predisposes to chronic cavitary form)
Age <2 years or >55 years
Pathophysiology
Microconidia are inhaled and reach the alveoli, where they convert to the yeast phase at body temperature and are phagocytosed by alveolar macrophages. Inside macrophages, yeast replicate and disseminate via the lymphohematogenous route. Cell-mediated immunity (Th1, IFN-gamma) is required to contain infection; granulomas form within 2-3 weeks and typically calcify. Defective cell-mediated immunity allows uncontrolled replication and progressive disseminated disease.
Clinical presentation
Symptoms
Acute pulmonary: fever, dry cough, fatigue, chest pain, myalgias 1-3 weeks after heavy exposure; most immunocompetent infections are asymptomatic
Chronic cavitary pulmonary: productive cough, weight loss, night sweats, hemoptysis in patients with underlying COPD or emphysema
Mediastinal lymphadenopathy may cause cough, dysphagia, or superior vena cava syndrome
Signs / physical exam
Hepatosplenomegaly in disseminated disease
Oral or oropharyngeal ulcers (disseminated form)
Skin papules, nodules, or molluscum-like lesions in advanced HIV
Crackles or diminished breath sounds depending on form
Adrenal enlargement or evidence of adrenal insufficiency
Classic findings
Pancytopenia, hepatosplenomegaly, and oral ulcers in a patient with HIV/AIDS and exposure to the Ohio/Mississippi River valley. Calcified granulomas in lungs, spleen, or liver in patients with prior asymptomatic infection.
Differential diagnosis
Tuberculosis — Chronic cough, weight loss, upper-lobe cavitary disease, exposure history; AFB smear and culture, IGRA. Histoplasmosis and TB radiographically indistinguishable on chronic cavitary form
Sarcoidosis — Bilateral hilar adenopathy, non-caseating granulomas, elevated ACE; ethnic and geographic risk; biopsy and exclusion of fungi
Coccidioidomycosis — Southwestern US and parts of Central/South America; erythema nodosum, eosinophilia; serology and spherules on biopsy
Blastomycosis — Overlapping endemic areas; skin and bone disease more common; broad-based budding yeast on KOH or histopathology
Lung cancer — Solitary pulmonary nodule or mass; biopsy required to distinguish from histoplasmoma
Lymphoma — Mediastinal adenopathy, B symptoms; biopsy distinguishes
Community-acquired pneumonia — Acute onset, lobar consolidation; bacterial etiologies more common but exposure history should prompt fungal testing in endemic regions
Diagnostic workup
Diagnostic criteria
Definitive diagnosis by culture or histopathologic identification of yeast forms (2-4 microm narrow-based budding yeast within macrophages). Strong presumptive diagnosis from positive antigen testing in an appropriate clinical setting.
Labs
Histoplasma urine and serum antigen (sensitivity ~90% in disseminated disease, lower in localized pulmonary)
Histoplasma serology by immunodiffusion and complement fixation (limited utility in immunocompromised due to impaired antibody response)
Fungal blood cultures (positive in disseminated disease; may take 2-4 weeks)
Bone marrow biopsy with fungal stains and culture in suspected disseminated disease
Chest x-ray: patchy infiltrates, hilar/mediastinal adenopathy, or calcified granulomas; cavitary upper-lobe disease in chronic form
Chest CT for better characterization of nodules, adenopathy, and cavities
Abdominal imaging for hepatosplenomegaly or adrenal enlargement
Diagnostic algorithm
flowchart TD
A[Inhaled microconidia<br/>bird/bat guano exposure] --> B[Alveolar deposition]
B --> C[Yeast conversion in macrophages]
C --> D{Immune status}
D -->|Immunocompetent| E[Self-limited<br/>or asymptomatic]
D -->|Heavy inoculum| F[Acute pulmonary<br/>fever, cough, CXR infiltrates]
D -->|Structural lung dz| G[Chronic cavitary<br/>upper lobe]
D -->|HIV CD4 <150,<br/>transplant, TNF-i| H[Progressive disseminated<br/>HSM, pancytopenia, oral ulcers]
F --> I[Itraconazole if persistent]
G --> I
H --> J[Liposomal amphotericin B<br/>then itraconazole >=12 mo]
Histoplasmosis pathogenesis and treatment based on host immune status.
Treatment
First-line
Mild to moderate acute pulmonary in immunocompetent: often self-limited, observation reasonable; itraconazole 200 mg PO TID x 3 days then BID for 6-12 weeks if symptoms persist >1 month
Moderate to severe pulmonary or disseminated disease: liposomal amphotericin B 3-5 mg/kg/day IV for 1-2 weeks, then itraconazole 200 mg PO BID for at least 12 months (total)
Chronic cavitary pulmonary: itraconazole 200 mg PO BID-TID for at least 12 months
CNS histoplasmosis: liposomal amphotericin B 5 mg/kg/day for 4-6 weeks, then itraconazole for at least 12 months and until CSF abnormalities resolve
Second-line / adjunct
Alternative azole antifungal — voriconazole, posaconazole, fluconazole — for itraconazole intolerance or interaction
Therapeutic drug monitoring of itraconazole trough (target >1 microg/mL) — absorption is variable and pH-dependent
Lifelong suppressive itraconazole 200 mg daily in advanced HIV until immune reconstitution (CD4 >150 for >6 months on ART)
Complications
Progressive disseminated histoplasmosis with multiorgan failure
Adrenal insufficiency from bilateral adrenal involvement
Fibrosing mediastinitis (rare, late complication causing SVC syndrome, pulmonary vein or airway obstruction)
Broncholithiasis from calcified lymph nodes eroding into airways
CNS infection with chronic meningitis or focal lesions
Pericarditis from adjacent mediastinal inflammation
PANCE pearls
Think histoplasmosis in any HIV patient with CD4 <150, fever, pancytopenia, and exposure to Ohio/Mississippi River valley.
Urine antigen is the most useful single test for disseminated disease and is sensitive even when other tests fail.
Itraconazole capsule absorption requires gastric acidity — give with cola or food; solution is taken on empty stomach.
Avoid TNF-alpha inhibitor therapy in patients with active histoplasmosis; screen for latent infection in endemic areas before starting.
Fibrosing mediastinitis is a feared late complication that is not improved by antifungal therapy and may require stenting or surgery.
References
IDSA 2007 — Clinical Practice Guidelines for the Management of Patients with Histoplasmosis (Wheat et al., Clin Infect Dis 2007)
CDC — CDC — Histoplasmosis: epidemiology, diagnosis, and treatment
AIDSinfo — Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents with HIV — Histoplasmosis section
Practice Infectious Disease questions on FirstPassPA
Turn this outline into retention. 3,500+ board-style questions with an AI tutor that explains every answer — free to start, no card required.
Educational use only. This outline is a study aid for PA students and is not medical advice or a substitute for clinical judgment. FirstPassPA is an independent study tool and is not affiliated with, endorsed by, or sponsored by NCCPA. PANCE® and PANRE® are registered trademarks of the National Commission on Certification of Physician Assistants.