- 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)
- 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
Skin test reactivity as high as 50–80% by age 18 years in most highly endemic areas
- 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
- 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
- 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.
Infectious mold spores are microconidia of H. capsulatum.
- 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
- 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
- Biliary obstruction
- Superior vena cava syndrome
- 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
- 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
- Culture is the definitive method of diagnosis.
- Sterile site (blood, bone marrow, CSF, tissue biopsy) or nonsterile site (sputum/bronchoalveolar lavage [BAL])
- Can take from 1 to 6 weeks to grow
- Culture sensitivity varies with site and host (sputum 10% positive in acute pulmonary, 60% positive in cavitary disease, 90% in BAL from HIV patients).
- Antigen tests using quantitative enzyme immunoassay (often 1st-line test +/− serologic testing below)
- Urine along with blood most common sources for testing (less sensitive but can be done on BAL, CSF)
- 92% sensitivity: disseminated infection
- 80% sensitivity: severe pulmonary disease
- 34% sensitivity: self-limited pulmonary disease
- 14% sensitivity: chronic pulmonary disease
- Used to monitor fungal burden
- Cross-reactivity rarely with Paracoccidioides brasiliensis, Blastomyces dermatitidis, Coccidioides immitis, Coccidioides posadasii, and Penicillium marneffei
- Serologic: immunodiffusion (ID) and complement fixation (CF) antibody tests
- Most common test for localized pulmonary disease but often negative in acute period
- Best tests for chronic meningitis
- Less sensitive in immunocompromised patients
- Antibody appears 4 to 8 weeks after infection, can become negative after 12 to 18 months.
- ID usually 1st-line serologic test (specific test with only 5% cross-reactivity but only 80% sensitive)
- Tests for M and H bands; H bands more suggestive of acute infection
- H bands positive in 23%, M bands positive in 76% of acute pulmonary
- CF usually 2nd-line serologic test, as more sensitive but less specific (18% cross-reactivity)
- Cross-reacts with Blastomyces, Paracoccidioides, and Coccidioides
- 4-fold increase or single 1:32 or greater is presumptive of active/recent infection.
- Titers 1:8 and 1:16 unclear significance
- Molecular methods
- Presently used for confirmation or identification of culture isolates or histopathologic findings
- Histoplasma-specific polymerase chain reaction (PCR)
- Broad-range fungal PCRs/sequencing
- Presently used for confirmation or identification of culture isolates or histopathologic findings
- Noncaseating granulomas
- Intracellular yeast form in tissue, blood, bone marrow, or BAL
- Usually examined with silver stain
- Other lab findings:
- Mild anemia, elevated ferritin, hypercalcemia, elevated ESR/C-reactive protein
- PDH: pancytopenia, coagulopathy, elevated liver enzymes
- Meningitis: CSF lymphocytic pleocytosis, protein elevation, and low glucose
- Skin test: not clinically used; only used for epidemiologic studies
- Chest radiograph
- Majority are normal in self-limited disease, and 40–50% of cases of PDH are normal.
- Positive findings can include hilar adenopathy, infiltrates, pleural effusions (5% of children), pericarditis (10% of children), mediastinal granuloma, mediastinal fibrosis (rare in children), mass effect, calcifications.
- Chest CT
- Miliary nodules and calcifications more easily seen
- Can be diffuse parenchymal consolidation
- CNS imaging
- Leptomeningeal enhancement (often basilar), focal brain or spinal cord lesions, strokes, and encephalitis
- Most children will not require treatment for H. capsulatum pulmonary disease.
- Arthritis, pericarditis, and erythema nodosum do not necessitate antifungals.
- Children with PDH should be screened for HIV and immunodeficiency.
- Alert lab of any specimen suspected of Histoplasma (lab hazard if grown).
Standard precautions adequate for hospital isolation
- 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
- 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)
Patients receiving amphotericin may need prolonged IV access.
- In PDH, follow antigen levels monthly during therapy and 12 months posttherapy.
- Itraconazole blood levels should be measured after >2 weeks of therapy (goal serum level >1 mcg/mL but ideally 2 mcg/mL at steady state).
- On itraconazole measure liver function tests (LFTs) monthly
- On amphotericin, follow CBC, LFTs, BUN/Cr, and potassium and magnesium.
- 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.
- Lymphatic, GI, esophageal, vascular, and biliary obstruction
- Renal stones
- Multifocal choroiditis
- Calcified nodules
- Pleural effusion
- Superior vena cava syndrome
- Azar MM, Hage CA. Laboratory diagnostics for histoplasmosis. J Clin Microbiol. 2017;55(6):1612–1620. [PMID:28275076]
- Fischer GB, Mocelin H, Severo CB, et al. Histoplasmosis in children. Paediatr Respir Rev. 2009;10(4):172–177. [PMID:19879506]
- Hage CA, Knox KS, Wheat LJ. Endemic mycoses: overlooked causes of community acquired pneumonia. Respir Med. 2012;106(6):769–776. [PMID:22386326]
- Kauffman CA. Histoplasmosis: a clinical and laboratory update. Clin Microbiol Rev. 2007;20(1):115–132. [PMID:17223625]
- Montenegro BL, Arnold JC. North American dimorphic fungal infections in children. Pediatr Rev. 2010;31(6):e40–e48. [PMID:20516233]
- National Institute for Occupational Safety and Health, National Center for Infectious Diseases. Histoplasmosis: Protecting Workers at Risk. Washington, DC: U.S. Department of Health and Human Services. http://www.cdc.gov/niosh/docs/2005-109/pdfs/2005-109.pdf. Accessed September 1, 2017.
- Smith JA, Kauffman CA. Pulmonary fungal infections. Respirology. 2012;17(6):913–926. [PMID:22335254]
- Wheat LJ, Freifeld AG, Kleiman MB, et al. Clinical practice guidelines for the management of patients with histoplasmosis: 2007 update by the Infectious Diseases Society of America. Clin Infect Dis. 2007;45(7):807–825. [PMID:17806045]
- 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
- 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
- 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)
- Q: What are the most common clinical presentations of histoplasmosis?
- A: Asymptomatic, mild primary pulmonary disease. Moderate to severe pulmonary, disseminated, and cavitary are uncommon.
- Q: How is histoplasmosis best diagnosed?
- A: Isolation or identification of the organism is definitive. Antigen testing of urine or blood is used for acute infections, especially severe infections. Serologic testing can be helpful but lacks sensitivity and specificity. Skin tests are not useful.
- Q: Does histoplasmosis need to be treated with antifungal therapy?
- A: For mild primary disease in an immunocompetent patient, no treatment is necessary. More severe or disseminated disease is treated.
Dylan C. Kann, MD
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