L. Joseph Wheat

Clinical practice guidelines for the management of patients with histoplasmosis: 2007 Update by the Infectious Diseases Society of America

Evidence-based guidelines for the management of patients with histoplasmosis were prepared by an Expert Panel of the Infectious Diseases Society of America. These updated guidelines replace the previous treatment guidelines published in 2000 (Clin Infect Dis 2000; 30:688-95). The guidelines are intended for use by health care providers who care for patients who either have these infections or may be at risk for them. Since 2000, several new antifungal agents have become available, and clinical trials and case series have increased our understanding of the management of histoplasmosis. Advances in immunosuppressive treatment for inflammatory disorders have created new questions about the approach to prevention and treatment of histoplasmosis. New information, based on publications from the period 1999-2006, are incorporated into this guideline document. In addition, the panel added recommendations for management of histoplasmosis in children for those aspects that differ from aspects in adults.

Defining responses to therapy and study outcomes in clinical trials of invasive fungal diseases: Mycoses Study Group and European Organization for Research and Treatment of Cancer consensus criteria.

Invasive fungal diseases (IFDs) have become major causes of morbidity and mortality among highly immunocompromised patients. Authoritative consensus criteria to diagnose IFD have been useful in establishing eligibility criteria for antifungal trials. There is an important need for generation of consensus definitions of outcomes of IFD that will form a standard for evaluating treatment success and failure in clinical trials. Therefore, an expert international panel consisting of the Mycoses Study Group and the European Organization for Research and Treatment of Cancer was convened to propose guidelines for assessing treatment responses in clinical trials of IFDs and for defining study outcomes. Major fungal diseases that are discussed include invasive disease due to Candida species, Aspergillus species and other molds, Cryptococcus neoformans, Histoplasma capsulatum, and Coccidioides immitis. We also discuss potential pitfalls in assessing outcome, such as conflicting clinical, radiological, and/or mycological data and gaps in knowledge.

Histoplasmosis in the acquired immune deficiency syndrome

This report describes the experience with disseminated histoplasmosis in seven of 15 patients with the acquired immune deficiency syndrome (AIDS) diagnosed in Indianapolis since 1981. Three were homosexual, two were intravenous drug addicts, one was the spouse of another patient with AIDS and disseminated histoplasmosis, and the seventh was a hemophiliac. Six had associated infections: candidiasis in three, Pneumocystis carinii pneumonia, recurrent mucocutaneous herpes simplex infection, and disseminated Mycobacterium avium infection in two each, and disseminated infection with an unidentified mycobacterium in one. Clinical diseases suggested sepsis in four. Histoplasma fungemia occurred in five, but the diagnosis was established first by visualization of organisms in blood or bone marrow in three. Results of Histoplasma serologic tests were positive in each. Three died before receiving 50 mg of amphotericin B, three had prompt improvement with amphotericin B, and one was treated with ketoconazole to prevent dissemination. However, two of the three patients treated with amphotericin B had relapses after a 35 mg/kg course, and the third died within a month following therapy. Disseminated histoplasmosis is a major opportunistic infection in patients with AIDS from endemic areas. AIDS should be strongly considered in otherwise healthy persons with disseminated histoplasmosis, especially if risk factors for AIDS are present. Amphotericin B is not curative in these patients.

Bronchoalveolar lavage galactomannan in diagnosis of invasive pulmonary aspergillosis among solid-organ transplant recipients.

ABSTRACT We review the experience at our institution with galactomannan (GM) testing of bronchoalveolar lavage (BAL) fluid in the diagnosis of invasive pulmonary aspergillosis (IPA) among solid-organ transplant recipients. Among 81 patients for whom BAL GM testing was ordered (heart, 24; kidney, 22; liver, 19; lung, 16), there were five cases of proven or probable IPA. All five patients had BAL GM of ≥2.1 and survived following antifungal therapy. The sensitivity, specificity, and positive and negative predictive values for BAL GM testing at a cutoff of ≥1.0 were 100%, 90.8%, 41.7%, and 100%, respectively. The sensitivity of BAL GM testing was better than that of conventional tests such as serum GM or BAL cytology and culture. Moreover, a positive BAL GM test diagnosed IPA several days to 4 weeks before other methods for three patients. Twelve patients had BAL GM of ≥0.5 but no evidence of IPA. Among these, lung transplant recipients accounted for 41.7% (5/12) of the false-positive results, reflecting frequent colonization of airways in this population. Excluding lung transplants, the specificity and positive predictive value for other solid-organ transplants increased to 92.9% and 62.5%, respectively (cutoff, ≥1.0). In conclusion, BAL GM testing facilitated more-rapid diagnoses of IPA and the institution of antifungal therapy among non-lung solid-organ transplant recipients and helped to rule out IPA.

Itraconazole Prophylaxis for Fungal Infections in Patients with Advanced Human Immunodeficiency Virus Infection: Randomized, Placebo-Controlled, Double-Blind Study

In a prospective, randomized, double-blind trial, 149 patients with advanced human immunodeficiency virus (HIV) infection were randomized to receive itraconazole capsules (200 mg daily) and 146 to receive a matched placebo. Both groups were monitored for evidence of fungal infections. Baseline characteristics of the two groups were similar. Failure of prophylaxis occurred in 29 (19%) of the itraconazole recipients and 42 (29%) of the placebo recipients (P = .004; log-rank test). There were 6 invasive fungal infections in the itraconazole group (4, histoplasmosis; 1, cryptococcosis; 1, aspergillosis) and 19 in the placebo group (10, histoplasmosis; 8, cryptococcosis; 1, aspergillosis) (P = .0007; log-rank test). Itraconazole significantly delayed time to onset of histoplasmosis (P = .03; log-rank test) and cryptococcosis (P = .0005; log-rank test). Prophylaxis failure due to recurrent or refractory mucosal candidiasis occurred with similar frequency in the two groups (itraconazole, 15%; placebo, 16%). A survival benefit was not demonstrated. Itraconazole generally was well tolerated. Primary prophylaxis with itraconazole capsules prevents histoplasmosis and cryptococcosis in patients with HIV infection.

Detection of Histoplasma Antigen by a Quantitative Enzyme Immunoassay

ABSTRACT The second-generation Histoplasma antigen immunoassay is semiquantitative, expressing results as a comparison to a negative control, which requires repeat testing of the prior specimen with the current specimen to accurately determine a change in antigen. Reporting results in this manner often is confusing to the ordering physician and laboratory. Development of a quantitative assay could improve accuracy, reduce interassay variability, and eliminate the need to test the prior sample with the current sample in the same assay. Calibrators with known concentrations of Histoplasma antigen were used to quantitate antigen in specimens from patients with histoplasmosis and from controls. Samples from cases of disseminated histoplasmosis or other mycoses and controls were tested to evaluate the performance characteristics of the quantitative assay. Paired specimens were evaluated to determine if quantitation eliminated the need to test the current and prior specimens in the same assay to assess a change in antigen. The sensitivity in samples from patients with AIDS and disseminated histoplasmosis was 100% in urine and 92.3% in serum. Cross-reactions occurred in 70% of other endemic mycoses, but not in aspergillosis. Specificity was 99% in controls with community-acquired pneumonia, medical conditions in which histoplasmosis was excluded, or healthy subjects. A change in antigen level categorized as an increase, no change, or decrease based on antigen units determined in the same assay agreed closely with the category of change in nanograms/milliliter determined from testing current and prior specimens in different assays. Sensitivity, specificity, and interassay precision are excellent in the new third-generation quantitative Histoplasma antigen immunoassay.

Improvements in diagnosis of histoplasmosis

Understanding the uses and limitations of a battery of laboratory methods is essential to diagnose histoplasmosis. Antigen detection and serology are valuable adjuncts to histopathology and culture. Improvements incorporated into the second-generation Histoplasma antigen assay have increased its sensitivity and specificity for diagnosis of histoplasmosis. More recently, the antigen assay has been modified to provide quantitation, which improves reproducibility and facilitates monitoring antigen clearance during treatment. Furthermore, detection of antigen in bronchoalveolar lavage fluid increases the sensitivity for diagnosis of pulmonary histoplasmosis. Serological tests for antibodies are also useful, but may be falsely negative in immunosuppressed patients. In addition, elevated antibody titres persist for several years following initial infection, complicating their interpretation. Although histopathology may provide for rapid diagnosis, its sensitivity is < 50% in patients with disseminated disease and even lower in pulmonary histoplasmosis. Polymerase chain reaction has been described, but sensitivity is less than that of histopathology. Culture, although highly specific, has notable limitations, including insensitivity, a need for invasive procedures and delayed growth. This review provides the background for understanding the role of a battery of diagnostic methods in histoplasmosis. Tests facilitating a rapid diagnosis are expected to improve the outcome in patients with severe disease.

Histoplasmosis-Associated Cross-Reactivity in the BioRad Platelia Aspergillus Enzyme Immunoassay

ABSTRACT We observed false-positive results in the Platelia Aspergillus enzyme-linked immunoassay (EIA) for specimens from patients with histoplasmosis and mice with experimental infection. Platelia Aspergillus EIA-positive specimens were negative in the second-generation Histoplasma antigen EIA. Care must be taken to exclude histoplasmosis for patients with positive Platelia Aspergillus EIA results.

Histoplasmosis: a review for clinicians from non-endemic areas

Histoplasmosis is an important systemic mycosis in the Americas, Asia, and Africa. Increasingly cases are recognised in nonendemic areas. Proper management requires recognition of the clinical syndromes caused by Histoplasma capsulatum infection, familiarity with the uses and limitations of the diagnostic tests, an understanding of the indications for treatment and role of specific antifungal agents. This review will address these issues with the goal of providing physicians in non‐endemic areas sufficient information to suspect, diagnose, and treat patients with histoplasmosis.

Safety of Discontinuation of Maintenance Therapy for Disseminated Histoplasmosis after Immunologic Response to Antiretroviral Therapy

We performed a prospective observational study to assess the safety of stopping maintenance therapy for disseminated histoplasmosis among human immunodeficiency virus infected patients after response to antiretroviral therapy. All subjects received at least 12 months of antifungal therapy and 6 months of antiretroviral therapy before entry. Negative results of fungal blood cultures, urine and serum Histoplasma antigen level of <4.1 units, and CD4+ T cell count of >150 cells/mm3 were required for eligibility. Thirty-two subjects were enrolled; the median CD4+ T cell count at study entry was 289 cells/mm3. No relapses of histoplasmosis occurred after a median duration of follow-up of 24 months. This corresponded to an observed relapse rate of 0 cases per 65 person-years. The median CD4+ T cell count at final study visit was 338 cells/mm3. Discontinuation of antifungal maintenance therapy appears to be safe for patients with acquired immunodeficiency syndrome with previously treated disseminated histoplasmosis and sustained immunologic improvement in response to antiretroviral therapy.