4. Histoplasmosis By Anastassia Doutova R2 10/06/06

5. Background First described by a United States Army physician in Panama in 1906 Histoplasma capsulatum is a dimorphic fungus that remains in a mycelial form at ambient temperatures and grows as yeast at body temperature in mammals. Endemic to the Ohio, Missouri, and Mississippi River valleys (US) and river valleys between latitudes 45° north and 30° south in North and Central America.

6. Birds cannot be infected by the fungus and do not transmit the disease but their excretions enrich the growth medium for the mycelium; bats can become infected, and transmit the fungus through droppings. Contaminated soil can be potentially infectious for years. Background Cause

7. inhalation of aerosolized conidia and mycelial fragments from soil results in alveolar deposition Reactivation can occure Reinfection is possible although controversial Background Route

8. Epidemiology Most prevalent endemic mycosis in US 250-500K individuals are infected annually 50 million people infected in US Clinical illness occurs in <5% in people with underlying lung disease chronic pulmonary histoplasmosis occurs at a rate of 1 per 100,000 persons per year Clinical symptoms are more frequent in males than in females ratio of 4:1. Except for Rheumatologic manifestations which occur predominantly in females.

9. T lymphocytes are essential in limiting the extent of infection. Cytokines activate macrophages for fungistatic activity against intracellular yeasts. Organisms are confined to macrophages Delayed-type hypersensitivity to histoplasmal antigens occurs 3-6 wk after exposure 85-90% of immunocompetent individuals produce a positive response to skin antigen test calcified fibrinous granulomas with areas of caseous necrosis develope over weeks to months. Host Response

11. Course Can take form of acute or chronic pulmonary infection but may also hematogenously spread systemically spread may occur through the lymphatics to regional lymph nodes or the liver and spleen. Progressive disseminated histoplasmosis is rare in adult hosts who are immunocompetent.

12. Presentation Acute Most individuals are asymptomatic Those who develop clinical manifestation- usually immunocompromised - or exposed to a high quantity onset occurs 3-14 days after exposure

13. Common: Fever, headache, malaise, myalgia, abdominal pain, and chills, cough, hemoptysis, dyspnea, chest pain Large innoculum: severe dyspnea Uncomon: Joint pain=arthritis and skin lesions=erythema multiforme, and erythema nodosum (5-6%) mostly in females. Enlarged hilar and mediastinal lymph nodes are present in 5-10% of patients. SVC syndrome Pericarditis In 5% causing cardiac temponade in 40% Acute Presentation Symptoms/findings

14. occurs mostly in patients with underlying pulmonary disease Reccurent histoplasmosis - latent in healed granulomas Presentation Chronic

15. cough, weight loss, fevers, and malaise. ~ 90% of patients develop cavities that may enlarge and result in necrosis. cavitations may cause hemoptysis, sputum production, and increasing dyspnea formation of bronchopleural fistulae Broncholiths mediastinal granuloma and fibrosing mediastinitis Chronic Presentation Symptoms/findings

16. Presentation Dessiminated Histoplasmosis Occures in 1 out of 2000 acute cases but in patients with impaired cellular immunity it happens in 4-27% Can present as subacute, acute or Hyperacute syndrome typically involves CNS liver spleen rheumatologic ocular Lymphnodes Mucosal ulcers in 50-60%

17. Dessiminated Histoplasmosis Symptoms Subacute/chronic form: constitutional symptoms and GI: diarrhea and abdominal pain, abdominal mass or intestinal ulcers and lesions, Pancreatitis or cholecystitis Cards: valvular disease, cardiac insufficiency, vegetations causing dyspnea, edema, angina, and fever. CNS: headache, visual and gait disturbances, confusion, seizures, altered consciousness, and neck stiffness or pain (meningitis most common) Other: Hypercalcemia, Mediastinal fibrosis

18. Acute form: generalized symptoms Severe respiratory distress, DIC, Sepsis organomegaly CNS involvement (encephalopathy and meningitis) in 5-20% Cutaneous lesions in10% Accute Dessiminated Histoplasmosis Symptoms

19. Ocular histoplasmosis syndrome Macula involvement may result in blindness 10% of patients have bilateral involvement histo spots are Atrophic scars containing foci of lymphocytic cell infiltration Dessiminated Histoplasmosis OTHER

20. Differential diagnosis Penumonia Aspergillosis Blasto Carcinoid Lymphoma Ulcerative colitis PCP Sarcoidosis Mycoplasma TB Lung Cancer Chlamedial Pneumonitis

21. Diagnositc studies Acute pulm Sputum cult pos in 10-15% Fungal Stain (sens 10%) Complement-fixing Antibodies ( 1:8 exposure, 1:32 active dz) in 5-15% after 3 wks, 95% after 8wks Anti-M antibody is detected in 50-80% Anti-H antibody is detected in only 10-20% becomes undetectable in 6m Serum and urine antigen (sens 25-75%) Skin test becomes pos only after 1y CXR: normal, LA, Patchy infiltrates (lower lung fields), reticular nodular or miliary pattern in severe cases

23. Chronic pulm Mild anemia Alk Phosph elevated Sputum cult pos (sens 50-85%) Fungal stain (sens 40%) Complement-fixing Antibodies pos in 70-90% Anti-M antibody in nearly 100% Serum and urine antigen (sens 15%) CXR: Histoplasmomas, Cavitations (upper lobes) in 90%, fibrotic scarring in long-standing cases. Diagnositc studies

25. Acute disseminated Pancytopenia in 70-90% Blood cult pos in 50-90% Alk Phosph elevated Anti-H antibody Anti-M antibody Serum and urine antigen (pos in 90%) CXR hilar lymphadenopathy with diffuse nodular infiltrates in 50% of patients. Subacute Disseminated Pancytopenia rarely Complement-fixing Antibodies pos CXR has no acute findings OTHER: PFT’s, Serum angiotensin converting enzyme concentrations, CT (adrenal insufficiency), Bronchoscopy, biopsy Diagnositc studies

26. Treatment for symptomatic disease No treatment for asymptomatic immunocompetent individuals All chronic histo patients should be treated Mild forms can be treated with Itraconazole or Ketoconazole PO for 3-6wks Most cases may require 12-24m course PO meds effective 75-85%, high relapse rates Hospitalized Patients should be treated with amphoteracinB IV effective 59-100% given for total of 35 mg/kg Small cavitary lesions can be monitored, lesions that persist or develop thick walls>3mm should be treated medically /surgically

27. Disseminated histo not requiring hospitalization, immunocompetant host - Itraconazole alone 6-18m Severe dissemintated illness or failure of PO meds can be treated with amphoteracinB IV Steroids can be used in disseminated histo with respiratory compromise in immunocompetant host (prednisone 60 qd for 2wks) Patients with AIDS must be on life long therapy weakly amphoteracinB IV effective 81-97% Itroconazole effective 90% Fluconazole effective 88% high relapse Treatment for Disseminated disease

28. Outcome Acute pulmonary has excellent prognosis, mediastinal LA resolves over months, rarely diffuse fibrosis occures Chronic pulmonary Histo can cause cavities that may enlarge and result in necrosis. Untreated cases may lead to progressive pulmonary fibrosis that results in respiratory and cardiac failure and recurrent infections. Relapse chronic pulmonary 20% acute disseminated 50%, and decreases to 10-20% with life-long antifungal maintenance

29. subacute disseminated death occurs within 2-24 months in untreated cases 90% of cases resolve with treatment Hospitalization frequently required May be a problem for years with frequent relapse acute Disseminated death within weeks if untreated, 50% mortality despite treatment Almost always requires hospitalization DIC and sepsis are common Approximately 5-10% of patients, treated or not, develop adrenal insufficiency Approximately 10% of individuals develop hyperacute syndrome, which results in death. Outcome

30. Reinfection can occur Outcome

31. Summary Most prevalent endemic mycosis in US Majority of cases asymptomatic In immunocompromized host can become disseminated Diagnostics include serologies, antigen, cultures, radiological findings All chronic /disseminated cases should be treated Treatment depends on severity Great mimicker

32. Reference EMedicine Histoplasmosis Author: Ryan C. Chang M.D. Consulting Staff, Department of Internal Medicine, Divisions of Pulmonary and Critical Care, Kaiser Permanente UpToDate Pathogenesis and clinical manifestations of disseminated histoplasmosis Pathogenesis and clinical features of pulmonary histoplasmosis