HISTOPLASMOSIS

HISTOPLASMOSIS - Robert P. Baughman, MD
BASICS
DESCRIPTION
Fungal infection with Histoplasma capsulatum, a dimorphic soil-dwelling saprophyte that has multiple clinical manifestations
• Initial infection is often asymptomatic.
• Other manifestations include a self-limited flu-like syndrome, mediastinal fibrosis, scar tissue residual, chronic cavitary disease in those with obstructive lung disease, and disseminated histoplasmosis, which is more frequent in the immunocompromised host and infants.
• Histoplasma capsulatum
- Worldwide distribution: Most endemic region in North America is central US
- Exists in mycelial form in nature and in yeast phase when exposed to mammalian temperatures
- Spores may remain active for up to 10 years
- Exposure to bird or bat excrement promotes growth of the fungus for unexplained reasons.
• Chronic pulmonary histoplasmosis: Usually occurs in white males with obstructive lung disease and apical bullous lung pathology. These patients exhibit evidence of an indolent infectious process.
• Disseminated histoplasmosis infection in the immunocompromised is a rare opportunistic infection, which may mimic sepsis syndrome and progress to multiple organ system failure.
• System(s) Affected: Gastrointestinal; Hemic/ Lymphatic/Immunologic; Pulmonary; Skin/Exocrine
ALERT
Geriatric Considerations
Increased incidence of disseminated histoplasmosis in males during 6th and 7th decades
Pediatric Considerations
One third of cases of disseminated histoplasmosis occur in infants 1 year old
GENERAL PREVENTION
Maintenance therapy is required in AIDS.
EPIDEMIOLOGY
Predominant sex: Acute histoplasmosis: Male = Female
Disseminated histoplasmosis: Male > Female (5-10:1)
Incidence
• Infection in endemic areas is virtually 100%.
• Few patients develop active disease.
• ~500,000 new infections in the US each year
• Occurrence in AIDS patients is 2-5%.
• Disseminated histoplasmosis occurs in 0.05% of infections.
Prevalence
Disseminated histoplasmosis
• Infants 1 year old are at higher risk for disseminated histoplasmosis (1/3 of all occurances).
• In adults there is an increased prevalence with age >60 years.
RISK FACTORS
• Spelunking
• Cleaning chicken coops
• Excavation near bird roosts
• Demolition or remodeling of old buildings
• Exposure to decayed wood or dead trees
• Performing routine activities in areas with high accumulation of bird droppings
• Immunosuppression
ETIOLOGY
Dimorphic fungus Histoplasma capsulatum
ASSOCIATED CONDITIONS
• Disseminated histoplasmosis is an opportunistic infection in the immunocompromised host
• HIV infection


DIAGNOSIS
SIGNS AND SYMPTOMS
• Primary infection is usually asymptomatic
• 1% immunocompetent individuals with low-level exposure develop symptoms
• 99% subclinical infection
• Arthralgiaerythema nodosumerythema multiforme is associated with acute infection
• Low-grade fever, anorexia, weight loss, night sweats, and productive cough are associated with chronic infections
TESTS
• Determine the presence of urinary H. capsulatum antigen.
• Bronchoscopy
• Liver and bone marrow biopsies
Lab
• For disseminated histoplasma antigen in AIDS patients, urinary and blood histoplasmosis
• Polysaccharide antigen detection is a rapid test for diagnosis and for monitoring relapse.
• Complement fixation may be negative in ~30% in acute histoplasmosis and 50% in disseminated histoplasmosis
• Immunodiffusion test may be negative in ~50% of patients with acute histoplasmosis. Maximum positivity of test occurs 4-6 weeks after exposure.
• Complement fixation antibodies at titers 1:8 or 1:16 are presumptive for diagnosis, >1:32 is strongly supportive as is an acute 4-fold titer rise. Determining the presence of H and M bands may be helpful.
• For chronic histoplasmosis and disseminated disease, cultures of sputum, bronchoalveolar lavage, bone marrow, lymph nodes, blood, liver, and cerebrospinal fluid may be positive. Demonstration of characteristic organisms by silver stain on biopsy and bronchoalveolar lavage and bronchial washing specimens is diagnostic.
• Disorders that may alter lab results
- Serologic tests may be falsely negative early in infection or in the immunocompromised.
- False-positive results may occur with tuberculosis and other fungal diseases.
- Slow clearance of antibodies may identify patients with past histoplasmosis infection who now present with a different disease.
- False-positive complement fixation titers may occur after histoplasmin skin antigen testing.
- False-positive H. capsulatum polysaccharide antigen test may occur with patients with disseminated blastomycosis and coccidioidomycosis.
Imaging
• Routine CXR may reveal focal mid-lung field infiltrates (27%), hilar or mediastinal adenopathy (25%) or both (30%). May see miliary or diffuse pattern with disseminated disease following large antigen load.
• If indicated, chest CT scan to differentiate mediastinal fibrosis from mediastinal granuloma
Diagnostic Procedures/Surgery
• Serologic blood work
• Bronchoscopy with bronchoalveolar lavage and transbronchial biopsy
• Liver and bone marrow biopsies for suspected disseminated disease
• Mediastinoscopy for lymph node biopsy
Pathological Findings
Poorly formed caseating granulomas on biopsy or bronchoscopy specimens with identification of characteristic yeast forms by methenamine silver stain
DIFFERENTIAL DIAGNOSIS
• Atypical pneumonia and viral pneumonitis
• Other fungal diseases such as blastomycosis, coccidioidomycosis
• Other granulomatous diseases such as M. tuberculosis
• Sarcoidosis
• Pneumoconiosis
• Lymphoma
• Malignancies associated with hilar lymphadenopathy
TREATMENT
GENERAL MEASURES
• Appropriate health care: Usually outpatient
• Disseminated histoplasmosis requires hospitalization for initial treatment.
• 99% of acute primary histoplasmosis resolve spontaneously; symptomatic treatment only
Activity
Avoid high-risk exposures.
MEDICATION (DRUGS)
First Line
• Disseminated histoplasmosis
- Amphotericin B: Test dose is 1mg followed by 0.25 mg/kg per dose, which may be slowly increased to 0.5 mg/kg per dose; cumulative dose to 1-2 g (at least 35 mg/kg is indicated).
- Itraconazole (induction therapy with 200 mg b.i.d. for 3 days, then 200 mg once or b.i.d.) for mild disease
- Ketoconazole (induction therapy with 400 mg/d for 3 days, then maintenance therapy 200 mg or 400 mg/d) for mild disease
• AIDS patients
- Itraconazole for mild disease: Induction therapy with 600 mg/d for 3 days, then 400 mg/d; drug of choice for primary and maintenance therapy is itraconazole; Ketoconazole is not effective in AIDS-related histoplasmosis; maintenance therapy with itraconazole 400 mg/d or amphotericin B 50-100 mg weekly (1 mg/kg)
• Chronic cavitary histoplasmosis
- Amphotericin B: For severe or moderately severe disease, 2.0-2.5 g cumulative
- Itraconazole (induction therapy with 200 mg b.i.d. for 3 days, then 200 mg once or b.i.d.) for mild disease
- Ketoconazole (induction therapy with 400 mg/d for 3 days, then maintenance therapy 200 mg or 400 mg/d) for mild disease
• Acute pulmonary histoplasmosis
- Amphotericin B for severe or moderately severe disease; test dose is 1 mg followed by 0.25 mg/kg per dose, which may be slowly increased to 0.5 mg/kg per dose; cumulative dose at least 35 mg/kg
- Ketoconazole (induction therapy with 400 mg/d for 3 days, then maintenance therapy 200 mg or 400 mg/d), or Itraconazole (induction therapy with 200 mg b.i.d. for 3 days, then 200 mg once or b.i.d.) for mild disease
• Duration of treatment
- Optimal duration of treatment with antifungals has not been established
- Disseminated histoplasmosis: 6 months course
- Chronic cavitary histoplasmosis: At least 12-months course with stable CXR findings over 3-6 months
- Acute pulmonary histoplasmosis: 2-3 month course
- AIDS-related or relapsed: Chronic, life-long, maintenance therapy
• Mediastinal granuloma
- Can mimic fibrosing mediastinitis, may respond to treatment with amphotericin B
• Fibrosing mediastinitis
- Has no active infection present and is not treatable
• No contraindications to treatment in patients with progressive cavitary disease or disseminated histoplasmosis. The latter has a mortality rate of 80%, if untreated.
• Precautions
- Amphotericin B: Dosage probably does not need to be adjusted for creatinine clearance. It is nephrotoxic. Renal function must be monitored closely. Monitor electrolytes, especially potassium and magnesium. Rigors can be prevented by pre-infusion meperidine. Fever and chills can be diminished by pre-infusion dose of acetaminophen plus diphenhydramine.
- Ketoconazole: Associated with gastrointestinal upset; may inhibit testosterone synthesis and should be used with caution in patients with underlying hepatic dysfunction.
• Significant possible interactions
- Expected benefits outweigh possible risks.
- Ketoconazole: Requires an acid environment for dissolution. If the patient requires antacid or H2 blockade, administer at least 2 hours after dose of ketoconazole. This may increase cyclosporine levels and decrease Rifampin and INH levels, as well as ketoconazole levels. Phenytoin levels may also be increased.
- Itraconazole: Rifampin levels may decrease itraconazole to undetectable levels. May increase digoxin levels; questionable effect on cyclosporine levels
- Fluconazole: May increase cyclosporine levels; may increase warfarin effect
Second Line
• Fluconazole has not been approved for histoplasmosis therapy.
- Fluconazole is undergoing investigational studies in its use for chronic pulmonary and disseminated histoplasmosis.
- Preliminarily, fluconazole doses of 400 mg/d or higher may be necessary for therapeutic outcome.
• Liposomal amphotericin may be used if amphotericin nephrotoxicity is encountered.
- Questionable effect of rifampin on fluconazole
FOLLOW-UP
PROGNOSIS
• Primary histoplasmosis: 99% resolve spontaneously
• The prognosis for chronic cavitary pulmonary histoplasmosis is determined by the loss of lung parenchyma and pulmonary function
• Treatment of disseminated disease in AIDS/non-AIDS cases does improve outcome with ketoconazole having >80% success rate and amphotericin B being 60-100% successful. Despite maintenance therapy, AIDS patients have a 10-50% relapse rate.
COMPLICATIONS
• Bronchial, tracheal or esophageal obstruction secondary to adenopathy, broncholithiasis
• Pulmonary, splenic and hepatic calcifications, rarely pericarditis, pleurisy, or effusion
• CNS histoplasmosis (rare): Chronic meningitis or intracranial histoplasmosis
• Endocarditis involving aortic or mitral valves
• Pericardial effusions (sterile exudates) not thought to be secondary to hematogenous spread
• Fibrosing mediastinitis can cause stenosis of vascular and bronchial structures within the mediastinum causing pulmonary hypertension, superior vena cava syndrome, and bronchial obstruction.
• Acute renal failure and hepatic dysfunction secondary to medications
• Amphotericin-induced hypokalemia
• Relapse occurring in the immunocompromised or inadequately treated patient with disseminated histoplasmosis
PATIENT MONITORING
• Renal function and liver chemistries every 1-2 months for chronic therapy patients
• Chest x-ray to evaluate therapy response at regular intervals
REFERENCES
1. Dismukes WE, Cloud G, Bowles C, et al. Treatment of blastomycosis and histoplasmosis with ketoconazole. Ann Intern Med. 1985;103:861-872.
2. Como JA, Dismukes WE. Oral azole drugs as systemic antifungal therapy. N Engl J Med. 1994;330:263-272.
3. Wheat JL, Connolly-Stringfield P, Kohler RB, et al. Histoplasma capsulatum polysaccharide antigen detection in diagnosis and management of disseminated histoplasmosis in patients with acquired immunodeficiency syndrome. Am J Med. 1989;87:396-400.
4. Wheat JL, Conces D, Allen SD, Blue-Hnidy D, Loyd J. Pulmonary histoplasmosis syndromes: recognition, diagnosis, and management. Se, Resp Crit Care Med. 2004;25:129-144.
5. Wheat J. Histoplasmosis: recognition and treatment. Clin Infect Dis. 1994;1(Suppl):S19-S27.