Pulmonary Histoplasmosis: A Clinical Update.

Histoplasma capsulatum, the etiological agent for histoplasmosis, is a dimorphic fungus that grows as a mold in the environment and as a yeast in human tissues. The areas of highest endemicity lie within the Mississippi and Ohio River Valleys of North America and parts of Central and South America. The most common clinical presentations include pulmonary histoplasmosis, which can resemble community-acquired pneumonia, tuberculosis, sarcoidosis, or malignancy; however, certain patients can develop mediastinal involvement or progression to disseminated disease. Understanding the epidemiology, pathology, clinical presentation, and diagnostic testing performance is pivotal for a successful diagnosis. While most immunocompetent patients with mild acute or subacute pulmonary histoplasmosis should receive therapy, all immunocompromised patients and those with chronic pulmonary disease or progressive disseminated disease should also receive therapy. Liposomal amphotericin B is the agent of choice for severe or disseminated disease, and itraconazole is recommended in milder cases or as "step-down" therapy after initial improvement with amphotericin B. In this review, we discuss the current epidemiology, pathology, diagnosis, clinical presentations, and management of pulmonary histoplasmosis.

Central Nervous System Histoplasma-Associated Post-infectious Inflammatory Response Syndrome (Histo-PIIRS).

We present a case of central nervous system (CNS) histoplasmosis in a previously healthy adult with hepatitis C (HCV) presenting with neurological symptoms refractory to antifungal therapy and ventriculoperitoneal (VP) shunting 4 months after initial diagnosis. Persistent symptoms were thought to be inflammatory rather than infectious given negative cerebrospinal fluid (CSF) and serum fungal antigens. The patient promptly improved after initiation of corticosteroid therapy. Elevated CSF cytokines and regional enhancement on brain MRI resolved with corticosteroid treatment. This is the first case of Histoplasma-associated post-infectious inflammatory response syndrome (Histo-PIIRS) documented by CSF cytokine reduction in response to corticosteroid therapy.

CD4+CTLs in Fibrosing Mediastinitis Linked to Histoplasma capsulatum.

Although fibrotic disorders are frequently assumed to be linked to TH2 cells, quantitative tissue interrogation studies have rarely been performed to establish this link and certainly many fibrotic diseases do not fall within the type 2/allergic disease spectrum. We have previously linked two human autoimmune fibrotic diseases, IgG4-related disease and systemic sclerosis, to the clonal expansion and lesional accumulation of CD4+CTLs. In both these diseases TH2 cell accumulation was found to be sparse. Fibrosing mediastinitis linked to Histoplasma capsulatum infection histologically resembles IgG4-related disease in terms of the inflammatory infiltrate and fibrosis, and it provides an example of a fibrotic disease of infectious origin in which the potentially profibrotic T cells may be induced and reactivated by fungal Ags. We show in this study that, in this human disease, CD4+CTLs accumulate in the blood, are clonally expanded, infiltrate into disease lesions, and can be reactivated in vitro by H. capsulatum Ags. TH2 cells are relatively sparse at lesional sites. These studies support a general role for CD4+CTLs in inflammatory fibrosis and suggest that fibrosing mediastinitis is an Ag-driven disease that may provide important mechanistic insights into the pathogenesis of idiopathic fibrotic diseases.

Central nervous system histoplasmosis: Multicenter retrospective study on clinical features, diagnostic approach and outcome of treatment.

Central nervous system (CNS) involvement occurs in 5 to 10% of individuals with disseminated histoplasmosis. Most experience has been derived from small single center case series, or case report literature reviews. Therefore, a larger study of central nervous system (CNS) histoplasmosis is needed in order to guide the approach to diagnosis, and treatment.A convenience sample of 77 patients with histoplasmosis infection of the CNS was evaluated. Data was collected that focused on recognition of infection, diagnostic techniques, and outcomes of treatment.Twenty nine percent of patients were not immunosuppressed. Histoplasma antigen, or anti-Histoplasma antibodies were detected in the cerebrospinal fluid (CSF) in 75% of patients. One year survival was 75% among patients treated initially with amphotericin B, and was highest with liposomal, or deoxycholate formulations. Mortality was higher in immunocompromised patients, and patients 54 years of age, or older. Six percent of patients relapsed, all of whom had the acquired immunodeficiency syndrome (AIDS), and were poorly adherent with treatment.While CNS histoplasmosis occurred most often in immunocompromised individuals, a significant proportion of patients were previously, healthy. The diagnosis can be established by antigen, and antibody testing of the CSF, and serum, and antigen testing of the urine in most patients. Treatment with liposomal amphotericin B (AMB-L) for at least 1 month; followed by itraconazole for at least 1 year, results in survival among the majority of individuals. Patients should be followed for relapse for at least 1 year, after stopping therapy.

From suspected Creutzfeldt-Jakob disease to confirmed histoplasma meningitis.

A 77-year-old man with chronic obstructive lung disease who was on steroids, presented to the hospital after a fall with subacute headaches and ataxia. During the patient's hospital course, his clinical condition deteriorated with myoclonic jerks, fevers and severe encephalopathy. An extensive workup, including EEG, brain MRI and lumbar puncture, revealed possible Creutzfeldt-Jakob disease. Unfortunately, the patient failed to improve and died 12 days after admission. A brain-only autopsy revealed he had acute histoplasma meningitis with patchy superficial cerebritis.

Sensitivity and Specificity of Histoplasma Antigen Detection by Enzyme Immunoassay.

The objective of this study was to evaluate the sensitivity and specificity of an antigen enzyme immunoassay (EIA) on urine samples for the diagnosis of histoplasmosis in dogs. This retrospective medical records review included canine cases with urine samples submitted for Histoplasma EIA antigen assay between 2007 and 2011 from three veterinary institutions. Cases for which urine samples were submitted for Histoplasma antigen testing were reviewed and compared to the gold standard of finding Histoplasma organisms or an alternative diagnosis on cytology or histopathology. Sensitivity, specificity, negative predictive value, positive predictive value, and the kappa coefficient and associated confidence interval were calculated for the EIA-based Histoplasma antigen assay. Sixty cases met the inclusion criteria. Seventeen cases were considered true positives based on identification of the organism, and 41 cases were considered true negatives with an alternative definitive diagnosis. Two cases were considered false negatives, and there were no false positives. Sensitivity was 89.47% and the negative predictive value was 95.35%. Specificity and the positive predictive value were both 100%. The kappa coefficient was 0.9207 (95% confidence interval, 0.8131-1). The Histoplasma antigen EIA test demonstrated high specificity and sensitivity for the diagnosis of histoplasmosis in dogs.

Measurement of antiretroviral drugs in the lungs of HIV-infected patients.

AIMS: Prior studies have shown that HAART is associated with decreased HIV viral load in the lungs. The correlation between antiretroviral exposure in bronchoalveolar lavage (BAL) fluid and virologic response was evaluated in patients starting HAART and enrolled in The AIDS Clinical Trial Group Protocol 723. MATERIALS #ENTITYSTARTX00026; METHODS: A total of 24 subjects underwent blood and BAL sampling prior to starting HAART, and after 4 and 24 weeks of HAART. Drug concentrations and HIV RNA were measured in paired plasma and BAL samples. RESULTS: Antiretroviral drugs, including efavirenz, were detectable in BAL fluid of HIV-infected subjects beginning HAART. Efavirenz was also associated with a higher likelihood of clearing HIV RNA from the lungs. CONCLUSION: These results suggest the excellent pulmonary virologic response to antiretroviral therapy may, in part, be due to penetration of antiretroviral drugs into the alveolar compartment.

False-negative Histoplasma antigen in acute pulmonary histoplasmosis: the value of urinary concentration by ultrafiltration and heat denaturation of serum proteins in detection of Histoplasma antigen.

We report an infant with localized pulmonary histoplasmosis in whom Histoplasma antibody assays, quantitative Histoplasma urine and serum antigen concentrations, and histopathologic findings of a mediastinal mass were nondiagnostic. A provisional diagnosis of histoplasmosis was established by using laboratory methods that increase the sensitivity of the antigen assay using ultrafiltration of urine and ethylenediaminetetraacetic acid/heat denaturation of serum proteins.

Effect of highly active antiretroviral therapy on viral burden in the lungs of HIV-infected subjects.

BACKGROUND: Human immunodeficiency virus (HIV) is readily detectable in the lungs of infected subjects and leads to an accumulation of CD8(+) lymphocytes in the alveolar space. Although highly active antiretroviral therapy (HAART) is effective in reducing viremia, less is known about its effect on tissue compartments. The AIDS Clinical Trials Group Protocol 723 Team evaluated the effect of HAART on lung viral load and cellular constituents. METHODS: Bronchoalveolar lavage (BAL) fluid and blood were collected before initiation of HAART and again at 4 and 24 weeks after initiation of therapy. The BAL cell differential was determined, lymphocyte phenotyping was performed, and acellular BAL fluid, plasma HIV RNA load, and BAL cell and peripheral blood mononuclear cell HIV RNA and DNA loads were measured. RESULTS: HAART induced a rapid decrease in HIV that was detectable in acellular BAL fluid and a slower decrease in the HIV RNA and DNA loads in BAL cells. HAART was associated with a significant decrease in the absolute number and percentage of CD8(+) alveolar lymphocytes. There was a significant correlation between residual BAL cell DNA at 24 weeks and the absolute number of CD4(+) lymphocytes in the alveolar space. CONCLUSION: HAART is associated with a significant decrease in the pulmonary HIV burden and a return of alveolar cellular constituents to normal.

Aspergillus galactomannan antigen in the bronchoalveolar lavage fluid for the diagnosis of invasive aspergillosis in lung transplant recipients.

BACKGROUND: The clinical utility of Platelia Aspergillus enzyme immunoassay (EIA) for galactomannan (GM) antigen detection in bronchoalveolar lavage (BAL) for the diagnosis of invasive aspergillosis (IA) in lung transplant recipients is not known. METHODS: BAL fluid samples from consecutive lung transplant recipients who underwent bronchoscopy were prospectively analyzed for GM. RESULTS: A total of 333 BAL samples from 116 patients were tested. Invasive aspergillosis was documented in 5.2% (6/116) of the patients. Samples analyzed included 9 BALs from two patients with proven IA, 19 BALs from four patients with probable IA, and 305 BALs from 110 patients without IA. At the index cutoff value of > or =0.5, the sensitivity was 60%; specificity was 95%, with positive and negative likelihood ratios of 14 and 0.41, respectively. Increasing the index cutoff value to > or =1.0 yielded a sensitivity of 60%, a specificity of 98%, and the positive and negative likelihood ratios of 28 and 0.40, respectively. Two of six patients with IA receiving antifungal prophylaxis had false-negative results. CONCLUSIONS: A Platelia EIA index cut-off > or =1.0 in the BAL fluid in a lung transplant recipient with a compatible clinical illness may be considered as suggestive of IA.

Safety, tolerability, and plasma pharmacokinetics of high-strength formulations of enfuvirtide (T-20) in treatment-experienced HIV-1-infected patients.

BACKGROUND: Enfuvirtide, a HIV-1 membrane fusion inhibitor, is the first viral entry inhibitor approved for the treatment of HIV-1 infected patients in the USA. Parenteral administration of enfuvirtide in clinical trials has been safe and has resulted in significant decreases in plasma viral load, even in the setting of extensive previous treatment and multi-drug resistance to conventional antiretroviral (ARV) therapy. Previous formulations have required two injections administered twice-daily (BID). OBJECTIVES: The primary objectives of this study were to evaluate the safety, tolerability, and pharmacokinetics of two high-strength 100 mg/ml formulations of enfuvirtide (carbonate [CO(3)] and tromethamine [TRIS] buffer) and of the current formulation (50 mg/ml CO(3) formulation) at doses of 90 mg (deliverable) BID and 67.5 mg (deliverable) BID in treatment-experienced patients. STUDY DESIGN: This was a phase II, multi-center, open-label, sequential cross-over pharmacokinetic, efficacy, and safety study. Study design included two treatment variables; dose (90 mg or 67.5 mg BID) and formulation (A: 50 mg/ml CO(3), B: 100 mg/ml CO(3) or C; 100 mg/ml TRIS). RESULTS: Forty-six treatment-experienced participants were sequentially enrolled into three treatment cohorts. All cohorts had similar safety profiles and only one patient discontinued due to an adverse event. Pharmacokinetic data indicated that the high-strength 100 mg/ml CO(3) formulation was bioequivalent to the 50 mg/ml CO(3) formulation whereas the TRIS formulation was not. At 48 weeks, 59.1%, 66.7% and 16.7% had <400 copies per milliliter HIV-1 RNA in the 90 MgCO(3), 67.5 MgCO(3) and 90 mg TRIS cohorts with median suppression of HIV-1 RNA of 2.97, 3.48, and 0.87 log(10)copies per milliliter, respectively. CONCLUSIONS: Based upon bioequivalence data and the convenience and similarity in safety and virological effect with the 50 mg/ml formulation, the 100 mg/ml CO(3) formulation was selected for use in clinical efficacy studies of enfuvirtide.