Histoplasmosis (Histoplasma capsulatum)

Published on 22/03/2015 by admin

Filed under Pediatrics

Last modified 22/04/2025

Print this page

rate 1 star rate 2 star rate 3 star rate 4 star rate 5 star
Your rating: none, Average: 0 (0 votes)

This article have been viewed 1420 times

Chapter 230 Histoplasmosis (Histoplasma capsulatum)

Jane M. Gould, Stephen C. Aronoff

Etiology

Histoplasmosis is caused by Histoplasma capsulatum, a dimorphic fungus found in the environment as a saprophyte in the mycelial (mold) form and in tissues in the parasitic form as yeast.

Epidemiology

The saprophytic form is found in soil throughout the midwestern USA, primarily along the Ohio and Mississippi rivers. Sporadic cases of human and animal histoplasmosis have been reported from 31 of the 48 contiguous states. In parts of Kentucky and Tennessee, almost 90% of the population >20 yr of age have positive skin test results for histoplasmin. Histoplasma is endemic to parts of the Caribbean islands, Central and South America, certain areas of Southeast Asia, and the Mediterranean. H. capsulatum thrives in soil rich in nitrates such as areas that are heavily contaminated with bird or bat droppings or decayed wood. Fungal spores are often carried on the wings of birds. Focal outbreaks of histoplasmosis have been reported after aerosolization of microconidia resulting from construction in areas previously occupied by starling roosts or chicken coops or by chopping decayed wood. Unlike birds, bats are actively infected with Histoplasma. Focal outbreaks of histoplasmosis have also been reported after intense exposure to bat guano in caves and along bridges frequented by bats. Person-to-person transmission does not occur.

Pathogenesis

Inhalation of microconidia (fungal spores) is the initial stage of human infection. The conidia reach the alveoli, germinate, and proliferate as yeast. Alternatively, spores can remain as mold with the potential for activation. Most infections are asymptomatic or self-limited. When disseminated disease occurs, any organ system can be involved. The initial infection is a bronchopneumonia. As the initial pulmonary lesion ages, giant cells form, followed by formation of caseating or noncaseating granulomas and central necrosis. Granulomas contain viable yeast, and disease can relapse. At the time of spore germination, yeast cells are phagocytosed by alveolar macrophages, where they replicate and gain access to the reticuloendothelial system via the pulmonary lymphatic system and hilar lymph nodes. Dissemination with splenic involvement typically follows the primary pulmonary infection. In normal hosts, specific cell-mediated immunity follows in approximately 2 weeks, enabling sensitized T-cells to activate macrophages and kill the organism. The initial pulmonary lesion resolves within 2-4 mo but may undergo calcification resembling the Ghon complex of tuberculosis. Alternatively, “buckshot” calcifications involving the lung and spleen may be seen. Unlike tuberculosis, reinfection with H. capsulatum occurs and can lead to exaggerated host responses in some cases.

Clinical Manifestations

There are 3 forms of human histoplasmosis: acute pulmonary infection, chronic pulmonary histoplasmosis, and progressive disseminated histoplasmosis.

Acute pulmonary histoplasmosis follows initial or recurrent respiratory exposure to microconidia. The majority of patients are asymptomatic. Symptomatic disease occurs more often in young children; in older patients, symptoms follow exposure to large inocula in closed spaces (e.g., chicken coops or caves) or prolonged exposure (e.g., camping on contaminated soil, chopping decayed wood). The median incubation time is 14 days. The prodrome is not specific and usually consists of flulike symptoms including headache, fever, chest pain, cough, and myalgias. Hepatosplenomegaly occurs more often in infants and young children. Symptomatic infections may be associated with significant respiratory distress and hypoxia and can require intubation, ventilation, and steroid therapy. Acute pulmonary disease can also manifest with a prolonged illness (10 days to 3 wk) consisting of weight loss, dyspnea, high fever, asthenia, and fatigue. In 10% of patients, infection is a sarcoid-like disease with arthritis or arthralgia, erythema nodosum, keratoconjunctivitis, iridocyclitis, and pericarditis. Pericarditis, with effusions both pericardial and pleural, is a self-limited benign condition that develops as a result of an inflammatory reaction to adjacent mediastinal disease. The effusions are exudative, and the organism is rarely culturable from fluid. Most children with acute pulmonary disease have normal chest radiographs. Patients with symptomatic disease typically have a patchy bronchopneumonia; hilar lymphadenopathy is variably present. In young children, the pneumonia can coalesce. Focal or buckshot calcifications are convalescent findings in patients with acute pulmonary infection.

Exaggerated host responses to fungal antigens within the lung parenchyma or hilar lymph nodes produce thoracic complications of acute pulmonary histoplasmosis. Histoplasmomas are of parenchymal origin and are usually asymptomatic. These fibroma-like lesions are often concentrically calcified and single. Rarely, these lesions produce broncholithiasis associated with “stone spitting,” wheezing, and hemoptysis. In endemic regions, these lesions can mimic parenchymal tumors and are occasionally diagnosed at lung biopsy. Mediastinal granulomas form when reactive hilar lymph nodes coalesce and mat together. Although these lesions are usually asymptomatic, huge granulomas can compress the mediastinal structures, producing symptoms of esophageal, bronchial, or vena caval obstruction. Local extension and necrosis can produce pericarditis or pleural effusions. Mediastinal fibrosis is a rare complication of mediastinal granulomas and represents an uncontrolled fibrotic reaction arising from the hilar nodes. Structures within the mediastinum become encased within a fibrotic mass, producing obstructive symptomatology. Superior vena cava syndrome, pulmonary venous obstruction with a mitral stenosis–like syndrome, and pulmonary artery obstruction with congestive heart failure have been described. Dysphagia accompanies esophageal entrapment, and a syndrome of cough, wheeze, hemoptysis, and dyspnea accompanies bronchial obstruction.

Chronic pulmonary histoplasmosis is an opportunistic infection in adult patients with centrilobular emphysema. This entity is rare in children.

Progressive disseminated histoplasmosis accounts for 10% of histoplasmosis cases and affects infants and immunocompromised patients. Disseminated disease of childhood occurs almost exclusively in children <2 yr of age because of a relative immature cellular immune system and follows primary pulmonary infection. The mortality of progressive disseminated histoplasmosis without therapy is 100%. Fever is the most common finding and can persist for weeks to months before the condition is diagnosed. The majority of patients have hepatosplenomegaly, lymphadenopathy, anemia, and thrombocytopenia. Pneumonia and pancytopenia are variably present. Some patients develop mucous membrane ulcerations and skin findings such as nodules, ulcers, or molluscum-like papules. Half of the infected infants have transient T-cell deficiencies, and many experience transient hyperglobulinemia. Elevated acute phase reactants and hypercalcemia are typically seen but are not specific for disseminated histoplasmosis. Although chest radiographs are normal in more than half of these children, the yeast can often be identified on bone marrow examination.

Children who are immunosuppressed (cancer patients, organ transplant recipients, patients with HIV infection) are at increased risk for disseminated histoplasmosis. In children who are not infected with HIV, disseminated disease manifests with unexplained fevers, weight loss, lymphadenopathy, and interstitial pulmonary disease. Extrapulmonary infection is a characteristic of disseminated disease and can include destructive bony lesions, oropharyngeal ulcers, Addison disease, meningitis, multifocal chorioretinitis, cutaneous infection, and endocarditis. Elevated liver function test results and high serum concentrations of angiotensin-converting enzyme may be observed.

Disseminated histoplasmosis in an HIV-infected patient is an AIDS-defining illness. Disseminated disease is often preceded or followed by another opportunistic infection in this patient population. HIV-infected patients at greatest risk for acquiring disseminated histoplasmosis are those with a history of exposure to avian excreta or bat guano, no prior history of antiretroviral therapy, or no history of previous antifungal prophylaxis. Fever and weight loss occur in most patients. In the majority of patients, pulmonary disease develops; hepatosplenomegaly, lymphadenopathy, skin rashes, and meningoencephalitis are variably present. A sepsis-like syndrome has been identified in a small number of HIV-infected patients with disseminated histoplasmosis and is characterized by the rapid onset of shock, multiorgan failure, and coagulopathy. Reactive hemophagocytic syndrome has been described in immunocompromised patients with severe disseminated histoplasmosis. Transplacental transmission of H. capsulatum has been reported in immunocompromised mothers.

Diagnosis

Histoplasma typically grows within 6 wk on Sabouraud agar at 25 °C. Identification of tuberculate macroconidia allow for only a presumptive diagnosis, because Sepedonium also form similar structures. A confirmatory test using a chemiluminescent DNA probe for H. capsulatum is necessary to establish a definitive identification. Recovery of H. capsulatum by culture differs with the form of infection. In normal hosts with symptomatic or asymptomatic acute pulmonary histoplasmosis, sputum cultures are rarely obtained and are variably positive; cultures of bronchoalveolar lavage fluid appear to have a slightly higher yield than sputum cultures. Sputum cultures are positive in 60% of adults with chronic pulmonary histoplasmosis. The yeast can be recovered from blood or bone marrow in >90% of patients with progressive disseminated histoplasmosis. Blood cultures are sterile in patients with acute pulmonary histoplasmosis, and cultures from any source are typically sterile in patients with the sarcoid form of the disease. Yeast forms may be demonstrated histologically in tissue from patients with complicated forms of acute pulmonary disease (histoplasmoma, mediastinal granuloma, and mediastinal fibrosis). Tissue should be stained with methenamine silver or periodic acid–Schiff stains, and yeast can be found within or outside of macrophages. Wright stain of peripheral blood can demonstrate fungal elements within leukocytes. Polymerase chain reaction assay enables more accurate and early diagnosis but is not widely available.

Detection of fungal polysaccharide antigen by radioimmunoassay is the most widely available diagnostic study for patients with suspected progressive disseminated histoplasmosis. In HIV-infected patients as well as others at risk for disseminated disease, histoplasma-associated antigen can be demonstrated in the urine, blood, or bronchoalveolar lavage fluid in >90% of cases. False-positive results on urinary antigen testing can occur in patients with Blastomyces dermatitidis, Coccidioides immitis and posadasii, Paracoccidioides brasiliensis, and Penicillium marneffei. False-positive results on serum antigen testing can occur with rheumatoid factor and treatment with rabbit antithymocyte globulin. Antigen detection by enzyme immunoassay (EIA) has comparable sensitivity, improved specificity, but limited availability; however, both the radioimmunoassay and the EIA are more sensitive when urine is tested rather than serum. Serum, urine, and bronchoalveolar lavage fluid from patients with acute or chronic pulmonary infections are variably antigen positive. Sequential measurement of antigen in patients with disseminated disease is useful for monitoring response to therapy.

Seroconversion continues to be useful for the diagnosis of acute pulmonary histoplasmosis, its complications, and chronic pulmonary disease. Serum antibody to yeast and mycelium-associated antigens is classically measured by complement fixation. Although titers of >1 : 8 are found in >80% of patients with histoplasmosis, titers of ≥1 : 32 are most significant for the diagnosis of recent infection. Complement-fixation antibody titers are often not significant early in the infection and do not become positive until 4-6 wk after exposure. A 4-fold increase in either yeast or mycelial-phase titers or a single titer of ≥1 : 32 is presumptive evidence of active infection. Complement fixation titers may be falsely positive in patients with other systemic mycoses such as Blastomyces dermatitidis and Coccidioides immitis and may be falsely negative in immunocompromised patients. Antibody detection by immunodiffusion is less sensitive but more specific than complement fixation and is used to confirm questionably positive complement fixation titers. Skin testing is useful only for epidemiologic studies because cutaneous reactivity is lifelong, and intradermal injection can elicit an immune response in otherwise seronegative persons.

Treatment

Antifungal therapy is not warranted for persons with asymptomatic or mildly symptomatic acute pulmonary histoplasmosis. Oral itraconazole or fluconazole should be considered in patients with acute pulmonary infections who fail to improve clinically within 1 mo. Itraconazole is superior to fluconazole in treatment of histoplasmosis in adults. Patients with primary or re-exposure pulmonary histoplasmosis who become hypoxemic or require ventilatory support should receive amphotericin B (0.7-1.0 mg/kg/day) or amphotericin B lipid complex (3-5 mg/kg/day) until improved; continued therapy with oral itraconazole (5.0-10.0 mg/kg/day in 2 divided doses not to exceed 400 mg daily) for a minimum of 12 weeks is also recommended. The lipid preparations of amphotericin are not preferred. Patients with severe obstructive symptoms caused by granulomatous mediastinal disease may be treated sequentially with amphotericin B followed by itraconazole for 6-12 mo. Patients with milder mediastinal disease may be treated with oral itraconazole alone. Some experts recommend that surgery be reserved for patients who fail to improve after 1 mo of intensive amphotericin B therapy. Sarcoid-like disease with or without pericarditis may be treated with nonsteroidal anti-inflammatory agents for 2-12 wk.

Amphotericin B continues to be the cornerstone of therapy for infants with progressive disseminated histoplasmosis. In one study, sequential therapy with amphotericin B and oral ketoconazole for 3 mo was curative in 88% of patients. Alternatively, amphotericin B (1.0 mg/kg/day) or its lipid complex may be given acutely for 4-6 wk or amphotericin B (1.0 mg/kg/day) may be given for 2-4 wk followed by oral itraconazole (5.0-10.0 mg/kg/day in 2 divided doses) as maintenance therapy for 3 months, depending on histoplasma antigen status. Longer therapy may be needed in patients with severe disease, immunosuppression or primary immunodeficiency syndromes. It is recommended to monitor blood levels of itraconazole during treatment, aiming for a concentration of ≥1.0 µg/mL but <10 µg/mL to avoid potential drug toxicity. It is also recommended to monitor urine antigen levels during therapy and for 12 mo after therapy has ended to ensure cure. In general, amphotericin B lipid complex may be substituted in severely ill children who are intolerant of the classic drug preparation. The newer azoles (voriconzaole and posaconazole) have not been well studied in the treatment of histoplasmosis and are currently not recommended.

Relapses in HIV-infected patients with progressive disseminated histoplasmosis are common. Currently, induction therapy with amphotericin B or lipid complex amphotericin B is recommended. Lifelong suppressive therapy with daily itraconazole (5.0 mg/kg/day up to adult dose of 200 mg/day) is also required. For severely immunocompromised HIV-infected children living in endemic regions, itraconazole (2-5 mg/kg every 12-24 hr) may be used prophylactically. Care must be taken to avoid interactions between antifungal azoles and protease inhibitors.

Bibliography

Adderson EE. Histoplasmosis in a pediatric oncology center. J Pediatr. 2004;144:100-106.

Adderson EE. Histoplasmosis. Pediatr Infect Dis J. 2006;25:73-74.

Assi MA, Sandid MS, Baddour LM, et al. Systemic histoplasmosis a 15 year retrospective institutional review of 111 patients. Medicine. 2007;86(3):162-169.

Bracca A, Tosello ME, Girardini JE, et al. Molecular detection of Histoplasma capsulatum var. capsulatum in human clinical samples. J Clin Microbiol. 2003;41:1753-1755.

Centers for Disease Control and Prevention. Outbreak of histoplasmosis among travelers returning from El Salvador—Pennsylvania and Virginia, 2008. MMWR Morb Mortal Wkly Rep. 2008;57:1349-1352.

Goodwin RA, Loyd JE, Des Prez R. Histoplasmosis in normal hosts. Medicine. 1981;60:231-266.

Guedes HL, Guimaraes AJ, Muniz Mde M, et al. PCR assay for identification of Histoplasma capsulatum based on the nucleotide sequence of the M antigen. J Clin Microbiol. 2003;41:535-539.

Hajjeh RA, Pappas PG, Henderson H, et al. Multicenter case-control study of risk factors for histoplasmosis in HIV infected persons. HIV/AIDS. 2001;32:1215-1220.

Kauffman CA. Histoplasmosis: a clinical and laboratory update. Clin Microbiol Rev. 2007;20:115-132.

McLeod DSA, Mortimer RH, Perry-Keene DA, et al. Histoplasmosis in Australia. Medicine. 2011;90:61-68.

Mocheria S, Wheat LJ. Treatment of histoplasmosis. Semin Respir Infect. 2001;16:141.

Odio CM, Navarrete M, Carillo JM, et al. Disseminated histoplasmosis in infants. Pediatr Infect Dis J. 1999;18:1065-1068.

Swartzentruber S, Rhodes L, Kurkjian K, et al. Diagnosis of acute pulmonary histoplasmosis by antigen detection. Clin Infect Dis. 2009;49:1878-1882.

Tobon AM, Franco L, Espinal D, et al. Disseminated histoplasmosis in children: the role of itraconazole therapy. Pediatr Infect Dis J. 1996;15:1002-1008.

Walsh TJ, Seibel NL, Arndt C, et al. Amphotericin B lipid complex in pediatric patients with invasive fungal disease. Pediatr Infect Dis J. 1999;18:702-708.

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;45:807-825.

Wheat J, Hafner R, Wulfsohn M, et al. Prevention of relapse of histoplasmosis with itraconazole in patients with the acquired immunodeficiency syndrome. The NIAID Clinical Trials and Mycoses Study Group Collaborators. Ann Intern Med. 1993;118:610-616.

Wheat LJ, Kauffman CA. Histoplasmosis. Infect Dis Clin North Am. 2003;17:1-19.

Whitt SP, Koch GA, Fender B, et al. Histoplasmosis in pregnancy: case series and report of transplacental transmission. Arch Intern Med. 2004;164:454-458.

Woods JP, Heinecke EL, Leuke JW, et al. Pathogenesis of Histoplasma capsulatum infection. Semin Respir Infect. 2001;16:91-101.

Related posts:

Disorders of the Complement System Default ThumbnailGynecologic Care for Girls with Special Needs Cardiac Development Hypothyroidism Cystic Diseases of the Biliary Tract and Liver Vesicoureteral Reflux