Histoplasmosis
Also known as: Histoplasma capsulatum Infection, Darling Disease, Cave Disease
Histoplasmosis is a systemic infection caused by the thermally dimorphic fungus Histoplasma capsulatum (variety capsulatum), acquired by inhalation of microconidia from soil enriched with bird or bat droppings. It is the commonest endemic mycosis worldwide.
Most infections are asymptomatic or mild and self limited, and clinical disease ranges from acute pulmonary illness to chronic cavitary lung disease, mediastinal complications, and progressive disseminated infection in the immunocompromised. It is a major opportunistic infection in advanced HIV disease and in people on tumour necrosis factor inhibitors.
| Feature | Description |
|---|---|
| Dimorphism | Mould at 25 to 30 degrees Celsius in the environment and in culture; yeast at 37 degrees Celsius in tissue and on enriched media |
| Mould phase | Hyaline septate hyphae bearing microconidia (2 to 4 micrometres, the infectious form) and thick walled tuberculate macroconidia (8 to 14 micrometres), which are diagnostic |
| Yeast phase | Small oval yeasts 2 to 4 micrometres, with narrow based budding, inside macrophages of the reticuloendothelial system (the "capsule" is a halo artefact of fixation, and there is no capsule) |
| Culture | Slow growing: white or brown cottony colonies in 2 to 6 weeks (up to 8 weeks) on Sabouraud dextrose agar and enriched media such as brain heart infusion agar with blood; a high biosafety hazard in the laboratory, so cultures are handled in a class II or higher cabinet |
| Identification | Tuberculate macroconidia, conversion to yeast, DNA probes (AccuProbe), sequencing, and mass spectrometry; the mould phase is hazardous, so molecular identification is preferred |
| Genetics | A species complex with several phylogenetic clades; the variety duboisii causes African histoplasmosis |
| Aspect | Details |
|---|---|
| Geography | The Ohio and Mississippi river valleys in the United States (more than 80 percent seropositivity in some areas), Central and South America, the Caribbean, Africa, Asia (India, South East Asia, China), and parts of Australia and southern Europe |
| Reservoir | Soil with high nitrogen content from bird and bat guano, caves, chicken coops, starling roosts, bridges, old buildings, and decaying wood |
| Exposure | Cave exploring (speleology), demolition and construction, excavation, farming, bat and bird roost clearing, and tourism |
| Outbreaks | Point source outbreaks follow soil disturbance; attack rates are high (50 to 100 percent of those exposed, with a heavy inoculum) |
| Transmission | Inhalation only; not person to person; transplant transmission through the allograft is rare |
| Immunity | Infection confers partial immunity; reinfection is possible with heavy exposure |
| Group | Notes |
|---|---|
| Advanced HIV disease (CD4 count below 150 cells per microlitre) | Disseminated disease with high fungal burden, and in many endemic regions it is a leading cause of death |
| Tumour necrosis factor alpha inhibitors | Infliximab, adalimumab, and etanercept; granuloma formation fails, and disseminated disease occurs within months of starting |
| Solid organ and stem cell transplant | Reactivation or primary infection |
| Corticosteroids and other immunosuppressants | Rituximab, purine analogues, and Janus kinase inhibitors |
| Infancy and old age | Higher rates of disseminated disease; immature or senescent cellular immunity |
| Primary immunodeficiency | Interferon gamma pathway defects, STAT3 and CD40L deficiency, and GATA2 |
| Chronic lung disease | Emphysema predisposes to chronic cavitary histoplasmosis |
| Stage | Details |
|---|---|
| Inhalation and conversion | Microconidia reach the alveoli and convert to yeasts at body temperature through heat shock proteins and calcium binding protein |
| Intracellular survival | Yeasts bind CD18 integrins and are taken up by macrophages, and survive and multiply in phagosomes by raising the phagolysosome pH and by chelating iron and zinc |
| Dissemination | Silent spread in macrophages through lymphatics to the hilar and mediastinal nodes and then through blood to the liver, spleen, bone marrow, adrenals, and elsewhere |
| Cell mediated immunity | After 2 to 3 weeks, T helper 1 responses with interferon gamma and tumour necrosis factor alpha activate macrophages to kill yeasts; granulomas form and calcify |
| Failure of control | Defective cell mediated immunity leads to uncontrolled macrophage infection and progressive disseminated disease with a macrophage activation or haemophagocytic picture |
| Syndrome | Features |
|---|---|
| Asymptomatic infection | The commonest outcome; calcified lung and splenic granulomas on imaging years later |
| Acute pulmonary histoplasmosis | After an incubation of 3 to 17 days (about 14); fever, chills, headache, myalgia, dry cough, chest pain, and hilar and mediastinal lymphadenopathy; diffuse reticulonodular infiltrates after a heavy exposure (acute diffuse pulmonary disease, which can cause hypoxaemia and acute respiratory distress syndrome); resolves in weeks |
| Rheumatological syndrome | Arthralgia, arthritis, erythema nodosum, and erythema multiforme, with hilar adenopathy, as an immune reaction in about 5 to 10 percent of acute cases |
| Pericarditis | An inflammatory reaction to mediastinal nodes, with pericardial effusion and sometimes tamponade (about 5 to 10 percent of acute cases) |
| Chronic cavitary pulmonary histoplasmosis | Emphysematous lungs, middle aged smokers; apical cavitary disease similar to tuberculosis, with cough, weight loss, night sweats, and haemoptysis; progressive fibrosis |
| Mediastinal lymphadenitis and granuloma | Enlarged nodes with compression of the airway, oesophagus, and vessels; most often in children |
| Fibrosing mediastinitis | An uncommon late complication from an excessive fibrotic reaction, with encasement and obstruction of the superior vena cava, pulmonary arteries and veins, and bronchi, which causes dyspnoea, haemoptysis, and cor pulmonale; antifungal drugs have little effect |
| Histoplasmoma and broncholithiasis | Calcified nodules, and calcified nodes eroding into the bronchus, which cause cough, haemoptysis, and lithoptysis |
| Progressive disseminated histoplasmosis | Fever, weight loss, hepatosplenomegaly, lymphadenopathy, pancytopenia, raised lactate dehydrogenase, aminotransferases, alkaline phosphatase, and ferritin (often above 1000 micrograms per litre), and a sepsis like syndrome with shock, coagulopathy, and acute respiratory distress syndrome in advanced HIV; mucocutaneous lesions (oral ulcers, papules, nodules, ulcers), and adrenal involvement |
| Adrenal histoplasmosis | Bilateral adrenal enlargement and necrosis, with adrenal insufficiency |
| Central nervous system | About 5 to 20 percent of disseminated cases; subacute or chronic meningitis, parenchymal granulomas (histoplasmomas), stroke, and spinal lesions; low cerebrospinal fluid glucose with a raised protein |
| Gastrointestinal | Ileocaecal ulcers, mass lesions, and hepatic disease; weight loss, diarrhoea, and obstruction |
| Cardiovascular and other | Endocarditis (vegetations), vascular graft infection, osteoarticular disease, ocular histoplasmosis syndrome (a choroiditis that is considered an immune sequela, with no organism found) |
| Haemophagocytic lymphohistiocytosis | Fever, cytopenias, hyperferritinaemia, and hypertriglyceridaemia in severe disseminated disease |
| Immune reconstitution inflammatory syndrome | After antiretroviral therapy, usually within weeks, with fever and enlarging lesions |
| Condition | Points that separate it |
|---|---|
| Tuberculosis | Acid fast bacilli and culture; the two coexist in HIV; an adenosine deaminase is not specific |
| Sarcoidosis | Non caseating granulomas with no organism; a Histoplasma antigen is negative |
| Community acquired pneumonia and Pneumocystis jirovecii pneumonia | Antigen, cultures, and response to antibacterials |
| Other endemic mycoses (blastomycosis, coccidioidomycosis, paracoccidioidomycosis, talaromycosis, emergomycosis) | Microscopy, culture, and antigen cross reaction |
| Lymphoma and haemophagocytic lymphohistiocytosis from other causes | Tissue biopsy |
| Cryptococcosis and leishmaniasis | Yeast morphology, antigen, and amastigotes with kinetoplasts |
| Disseminated Mycobacterium avium complex | Blood culture |
| Sepsis and malaria in endemic regions | Targeted testing |
| Test | Details |
|---|---|
| Urine and serum Histoplasma antigen (enzyme immunoassay) | Detects galactomannan polysaccharide; sensitivity in urine is about 95 percent in progressive disseminated disease, 80 percent in acute pulmonary disease, and lower (about 30 to 90 percent) in chronic cavitary and localised disease; used to monitor therapy (antigen falls with response and rises on relapse); a point of care lateral flow assay is available. Cross reactivity is common with Blastomyces, Coccidioides, Paracoccidioides, Talaromyces, and Emergomyces |
| Serology | Immunodiffusion (the M band indicates acute or past infection, the H band active disease) and complement fixation (titre of 1 in 32 or higher or a fourfold rise indicates infection); antibodies appear 4 to 8 weeks after exposure, so early acute infection and the immunocompromised are often seronegative; cross reaction with other fungi |
| Culture | Blood (lysis centrifugation system), bone marrow, respiratory samples, and tissue; positive in 70 to 90 percent in disseminated disease but takes 2 to 6 weeks; sensitivity in acute and chronic pulmonary disease is lower |
| Microscopy and histology | Methenamine silver, periodic acid Schiff, or Giemsa show small narrow based budding yeasts inside macrophages; in the bone marrow, peripheral blood buffy coat, or tissue, giving rapid diagnosis in disseminated disease; granulomatous inflammation with necrosis |
| Molecular tests | Polymerase chain reaction on tissue, blood, and bronchoalveolar lavage, with variable availability; panfungal sequencing |
| Other tests | Full blood count (pancytopenia), ferritin, lactate dehydrogenase, liver function tests, adrenal function (cortisol and corticotrophin stimulation), chest and abdominal imaging (nodes, adrenal enlargement), brain imaging and lumbar puncture when neurological signs exist |
| Cerebrospinal fluid | Lymphocytic pleocytosis, low glucose, high protein; antigen and antibody in cerebrospinal fluid (antibodies are more sensitive in meningitis); culture is positive in a minority |
Principles
Therapy is based on severity, form, and host. Mild acute infection in a healthy host resolves without treatment, and severe, chronic, and disseminated forms need antifungal therapy.
| Form | Regimen |
|---|---|
| Mild to moderate acute pulmonary disease | No therapy if symptoms resolve within 4 weeks; if symptoms persist beyond 4 weeks, itraconazole 200 mg three times daily for 3 days, then 200 mg once or twice daily for 6 to 12 weeks |
| Moderately severe to severe acute pulmonary disease | Liposomal amphotericin B 3 to 5 mg per kg intravenously once daily for 1 to 2 weeks, then itraconazole 200 mg three times daily for 3 days, then 200 mg twice daily for a total of 12 weeks; methylprednisolone 0.5 to 1 mg per kg daily (intravenous) for the first 1 to 2 weeks in patients with hypoxaemia or acute respiratory distress syndrome, with limited trial evidence |
| Chronic cavitary pulmonary disease | Itraconazole 200 mg three times daily for 3 days, then 200 mg once or twice daily for at least 12 months (some for 18 to 24 months); relapse is up to 15 to 20 percent |
| Progressive disseminated disease, moderately severe to severe | Liposomal amphotericin B 3 mg per kg once daily for 1 to 2 weeks (2 weeks or until clinical improvement in HIV), then itraconazole 200 mg three times daily for 3 days, then 200 mg twice daily for at least 12 months |
| Progressive disseminated disease, mild to moderate | Itraconazole 200 mg three times daily for 3 days, then 200 mg twice daily for at least 12 months |
| Central nervous system | Liposomal amphotericin B 5 mg per kg once daily for a total of 175 mg per kg given over 4 to 6 weeks, then itraconazole 200 mg two to three times daily for at least 12 months and until resolution of cerebrospinal fluid abnormalities, including antigen |
| Pericarditis | Non steroidal anti-inflammatory drugs for 2 to 12 weeks; prednisone 0.5 to 1 mg per kg daily tapered over 1 to 2 weeks for haemodynamic compromise; drainage for tamponade; antifungal therapy is added for large effusions |
| Rheumatological syndrome | Non steroidal anti-inflammatory drugs, and prednisone (0.5 to 1 mg per kg daily) for severe disease, with itraconazole when a corticosteroid is used for more than 2 weeks |
| Mediastinal lymphadenitis | Antifungal therapy for severe symptoms, with a short course of corticosteroids |
| Fibrosing mediastinitis | Antifungal drugs are not effective; vascular and airway stenting, surgical release in selected cases; a corticosteroid trial is not proven |
| Histoplasmoma, broncholithiasis | Observation, with endoscopic or surgical removal of broncholiths |
| Adrenal insufficiency | Hydrocortisone replacement, with antifungal therapy |
| Haemophagocytic lymphohistiocytosis | Antifungal therapy, with corticosteroids or etoposide in selected cases |
Itraconazole details
- Capsules need food and gastric acid (take with a cola drink or fatty food, and avoid proton pump inhibitors and antacids); solution is taken on an empty stomach and is better absorbed.
- A serum concentration is checked after 2 weeks: a random level of at least 1 microgram per mL (and below 10 micrograms per mL by bioassay) of itraconazole plus hydroxy itraconazole.
- Interactions are many (cytochrome P450 3A4 inhibition, including with rifampicin, which reduces concentrations), negative inotropy (avoid in heart failure), hepatotoxicity, hypokalaemia, and oedema.
- Alternatives for itraconazole intolerance: voriconazole (200 mg twice daily after loading), posaconazole (delayed release 300 mg daily after loading), isavuconazole (372 mg daily after loading), with fluconazole (800 mg daily) the least effective option and used only when others cannot be used.
Special groups
| Group | Management |
|---|---|
| HIV | Amphotericin B induction for 2 weeks (or until improvement) then itraconazole 200 mg twice daily for at least 12 months; start antiretroviral therapy within 2 weeks of the start of antifungal therapy; maintenance itraconazole 200 mg daily is continued for at least 12 months and until CD4 above 150 cells per microlitre for 6 months with a suppressed viral load and falling antigen; lifelong suppression if immune recovery does not occur or the infection relapses |
| Transplant and tumour necrosis factor inhibitor use | Amphotericin B induction for severe disease, then itraconazole for 12 months or more; reduce immunosuppression; tumour necrosis factor inhibitors are stopped and are resumed after control (often after 12 months or longer, with itraconazole cover) |
| Pregnancy | Liposomal amphotericin B; azoles are avoided in the first trimester |
| Children | Liposomal amphotericin B 3 to 5 mg per kg daily, then itraconazole 5 to 10 mg per kg per day in two divided doses (maximum 400 mg per day), with levels |
| Immune reconstitution inflammatory syndrome | Continue antifungal and antiretroviral therapy; corticosteroids (prednisone 0.5 to 1 mg per kg daily) for severe reactions |
Monitoring
Antigen (urine and serum) at baseline, then every 3 months during therapy and for 12 months after it ends, to detect relapse; clinical review; itraconazole levels; liver tests; imaging; creatinine, potassium, and magnesium in those on amphotericin B.
| Group | Outcome |
|---|---|
| Acute pulmonary disease in healthy hosts | Excellent, with recovery in weeks |
| Chronic cavitary disease | Good with therapy; relapse and progressive lung damage without it |
| Progressive disseminated disease, untreated | 80 to 100 percent mortality |
| Treated disseminated disease | 7 to 23 percent mortality, with higher mortality in advanced HIV with shock and organ failure |
| Central nervous system disease | Mortality about 20 to 40 percent with relapse in up to 40 percent |
| Fibrosing mediastinitis | Poor, with progressive disease and 30 percent mortality in bilateral disease |
Avoid soil with guano and bat or bird roosts, and use respirators and dampen soil in dusty work in endemic areas. Primary prophylaxis with itraconazole 200 mg daily is considered in HIV with CD4 below 150 cells per microlitre in regions of very high incidence (above 10 cases per 100 patient years), and in selected transplant patients. Screening before tumour necrosis factor inhibitors in endemic regions is not routine, but antigen testing is used when symptoms occur.
