Chadi A. Hage

Differential Th17 CD4 T-cell depletion in pathogenic and nonpathogenic lentiviral infections

Acute HIV infection is characterized by massive loss of CD4 T cells from the gastrointestinal (GI) tract. Th17 cells are critical in the defense against microbes, particularly at mucosal surfaces. Here we analyzed Th17 cells in the blood, GI tract, and broncheoalveolar lavage of HIV-infected and uninfected humans, and SIV-infected and uninfected sooty mangabeys. We found that (1) human Th17 cells are specific for extracellular bacterial and fungal antigens, but not common viral antigens; (2) Th17 cells are infected by HIV in vivo, but not preferentially so; (3) CD4 T cells in blood of HIV-infected patients are skewed away from a Th17 phenotype toward a Th1 phenotype with cellular maturation; (4) there is significant loss of Th17 cells in the GI tract of HIV-infected patients; (5) Th17 cells are not preferentially lost from the broncheoalveolar lavage of HIV-infected patients; and (6) SIV-infected sooty mangabeys maintain healthy frequencies of Th17 cells in the blood and GI tract. These observations further elucidate the immunodeficiency of HIV disease and may provide a mechanistic basis for the mucosal barrier breakdown that characterizes HIV infection. Finally, these data may help account for the nonprogressive nature of nonpathogenic SIV infection in sooty mangabeys.

An Official American Thoracic Society Statement: Treatment of Fungal Infections in Adult Pulmonary and Critical Care Patients

With increasing numbers of immune-compromised patients with malignancy, hematologic disease, and HIV, as well as those receiving immunosupressive drug regimens for the management of organ transplantation or autoimmune inflammatory conditions, the incidence of fungal infections has dramatically increased over recent years. Definitive diagnosis of pulmonary fungal infections has also been substantially assisted by the development of newer diagnostic methods and techniques, including the use of antigen detection, polymerase chain reaction, serologies, computed tomography and positron emission tomography scans, bronchoscopy, mediastinoscopy, and video-assisted thorascopic biopsy. At the same time, the introduction of new treatment modalities has significantly broadened options available to physicians who treat these conditions. While traditionally antifungal therapy was limited to the use of amphotericin B, flucytosine, and a handful of clinically available azole agents, current pharmacologic treatment options include potent new azole compounds with extended antifungal activity, lipid forms of amphotericin B, and newer antifungal drugs, including the echinocandins. In view of the changing treatment of pulmonary fungal infections, the American Thoracic Society convened a working group of experts in fungal infections to develop a concise clinical statement of current therapeutic options for those fungal infections of particular relevance to pulmonary and critical care practice. This document focuses on three primary areas of concern: the endemic mycoses, including histoplasmosis, sporotrichosis, blastomycosis, and coccidioidomycosis; fungal infections of special concern for immune-compromised and critically ill patients, including cryptococcosis, aspergillosis, candidiasis, and Pneumocystis pneumonia; and rare and emerging fungal infections.

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.

Recognition, diagnosis, and treatment of histoplasmosis complicating tumor necrosis factor blocker therapy.

Life-threatening histoplasmosis is one of the most common opportunistic infections in patients receiving tumor necrosis factor (TNF) blockers. Delays in considering the diagnosis may lead to increased morbidity and mortality. Most affected patients present with pneumonitis, usually accompanied by additional signs of progressive dissemination, or with signs of progressive dissemination alone. The diagnosis often can be promptly established using antigen detection or direct examination of bronchoalveolar lavage specimens. If histoplasmosis is diagnosed promptly, antifungal therapy is highly effective. After a favorable clinical response, the safety of both discontinuation of antifungal therapy and the resumption of TNF blocker remains undetermined. The management of the immune reconstitution inflammatory syndrome that may follow discontinuation of TNF blockers also requires investigation. Prescribers should become aware of the recognition, diagnosis, and treatment of histoplasmosis and educate recipients about decreasing their risk of exposure and both recognizing and reporting signs of early infection.

Performance Characteristics of the Platelia Aspergillus Enzyme Immunoassay for Detection of Aspergillus Galactomannan Antigen in Bronchoalveolar Lavage Fluid

ABSTRACT We have evaluated the Platelia Aspergillus enzyme immunoassay for detection of galactomannan in bronchoalveolar lavage (BAL) specimens in solid organ transplant patients with aspergillosis. The precision and reproducibility in serum or BAL to which galactomannan was added were similar. Sensitivity was 81.8% in patients with aspergillosis, and specificity was 95.8% in lung transplant patients who underwent BAL for surveillance for infection or rejection. Among transplant controls, positive results were more common in patients (i) who underwent diagnostic BAL performed for evaluation of symptoms or chest computed tomographic abnormalities, (ii) who had undergone lung transplantation, or (iii) who were colonized with Aspergillus. Galactomannan testing in BAL is useful for diagnosis of aspergillosis in transplant patients. The significance of positive results in patients without confirmed aspergillosis requires further evaluation.

High frequencies of polyfunctional HIV-specific T cells are associated with preservation of mucosal CD4 T cells in bronchoalveolar lavage

The mechanisms underlying the massive gastrointestinal tract CD4 T-cell depletion in human immunodeficiency virus (HIV) infection are not well understood nor is it clear whether similar depletion is manifest at other mucosal surfaces. Studies of T-cell and virus dynamics in different anatomical sites have begun to illuminate the pathogenesis of HIV-associated disease. Here, we studied depletion and HIV infection frequencies of CD4 T cells from the gastrointestinal tract, bronchoalveolar lavage (BAL), and blood with the frequencies and functional profiles of HIV-specific T cells in these anatomically distinct sites in HIV-infected individuals. The major findings to emerge were as follows: (i) depletion of gastrointestinal CD4 T cells is associated with high frequencies of infected CD4 T cells; (ii) HIV-specific T cells are present at low frequencies in the gastrointestinal tract compared to blood; (iii) BAL CD4 T cells are not massively depleted during the chronic phase; (iv) infection frequencies of BAL CD4 T cells are similar to those in blood; (v) significantly higher frequencies and increased functionality of HIV-specific T cells were observed in BAL compared to blood. Taken together, these data suggest mechanisms for mucosal CD4 T-cell depletion and interventions that might circumvent global depletion of mucosal CD4 T cells.

Histoplasmosis After Solid Organ Transplant

BACKGROUND To improve our understanding of risk factors, management, diagnosis, and outcomes associated with histoplasmosis after solid organ transplant (SOT), we report a large series of histoplasmosis occurring after SOT. METHODS All cases of histoplasmosis in SOT recipients diagnosed between 1 January 2003 and 31 December 2010 at 24 institutions were identified. Demographic, clinical, and laboratory data were collected. RESULTS One hundred fifty-two cases were identified: kidney (51%), liver (16%), kidney/pancreas (14%), heart (9%), lung (5%), pancreas (2%), and other (2%). The median time from transplant to diagnosis was 27 months, but 34% were diagnosed in the first year after transplant. Twenty-eight percent of patients had severe disease (requiring intensive care unit admission); 81% had disseminated disease. Urine Histoplasma antigen detection was the most sensitive diagnostic method, positive in 132 of 142 patients (93%). An amphotericin formulation was administered initially to 73% of patients for a median duration of 2 weeks; step-down therapy with an azole was continued for a median duration of 12 months. Ten percent of patients died due to histoplasmosis with 72% of deaths occurring in the first month after diagnosis; older age and severe disease were risk factors for death from histoplasmosis. Relapse occurred in 6% of patients. CONCLUSIONS Although late cases occur, the first year after SOT is the period of highest risk for histoplasmosis. In patients who survive the first month after diagnosis, treatment with an amphotericin formulation followed by an azole for 12 months is usually successful, with only rare relapse.

Plasmalyte as a Cause of False-Positive Results for Aspergillus Galactomannan in Bronchoalveolar Lavage Fluid

The detection of galactomannan (GM) in the serum of immunocompromised patients is widely used for the early diagnosis of invasive aspergillosis ([6][1]). The test may also be useful when applied to bronchoalveolar lavage (BAL) fluid specimens for clinical diagnosis ([5][2]), though not FDA approved

Diagnosis of Histoplasmosis by Antigen Detection in BAL Fluid

BACKGROUND Detection of antigen in BAL is useful for diagnosis of histoplasmosis. The MVista Histoplasma antigen enzyme immunoassay has been modified to permit quantification. The purpose of this study is to compare the sensitivity of the quantitative antigen detection assay with cytopathology and culture of BAL specimens. METHODS BAL from patients with histoplasmosis who were evaluated at the Indiana University Medical Center and controls without histoplasmosis were studied. BAL fluid was tested in the quantitative Histoplasma antigen assay. RESULTS Antigen was detected in the BAL in 93.5% of patients with histoplasmosis, 80% with blastomycosis, and 0% of controls with nonfungal infections. Antigen was detected in the urine of 79% and serum in 65% of patients with histoplasmosis. Cytopathology was positive in 48% and culture in 48% of patients with histoplasmosis, and 40% and 60% of patients with blastomycosis, respectively. Serology was positive in 65%. Combining BAL antigen detection and BAL cytopathology, both methods for rapid diagnosis, the sensitivity was 96.8% in histoplasmosis and 80% in blastomycosis. CONCLUSIONS Detection of antigen in BAL complements antigen detection in serum and urine as an objective diagnostic test for histoplasmosis.

Blastomyces dermatitidis Antigen Detection by Quantitative Enzyme Immunoassay

ABSTRACT The second-generation MVista Blastomyces antigen enzyme immunoassay was not quantitative; therefore, specimens obtained previously were tested in the same assay as new specimens to assess the change in antigen levels. Furthermore, the sensitivity in serum had not been fully evaluated. The purpose of this study was to evaluate a quantitative Blastomyces antigen assay and detection of antigen in serum. Calibrators containing known concentrations of Blastomyces galactomannan were used to quantify antigen in urine and serum from patients with proven blastomycosis and from controls. Paired current and previously obtained urine specimens were tested to determine if quantification eliminated the need for concurrent testing to assess change in antigen. Pretreatment of serum with EDTA at 104°C was evaluated to determine if dissociation of immune complexes improved detection of antigenemia. Antigenuria was detected in 89.9% of patients with culture- or histopathology-proven blastomycosis. Specificity was 99.0% in patients with nonfungal infections and healthy subjects, but cross-reactions occurred in 95.6% of patients with histoplasmosis. Change in antigen level categorized as increase, no change, or decrease based on antigen units determined in the same assay agreed closely with the category of change in ng/ml determined from different assays. Pretreatment increased the sensitivity of detection of antigenemia from 35.7% to 57.1%. Quantification eliminated the need for concurrent testing of current and previously obtained specimens for assessment of changes in antigen concentration. Pretreatment increased the sensitivity for detection of antigenemia. Differentiation of histoplasmosis and blastomycosis is not possible by antigen detection.