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BACKGROUND. Idiopathic CD4 lymphopenia (ICL) is defined by persistently low [CD4.sup.+] cell counts ( METHODS. We hybridized 34 and 51 ICL patients' sera to a 9,000-human-proteome array and to a 128-known-autoantigen array, respectively. Using a flow-based method, we characterized the presence of anti-lymphocyte Abs in the whole cohort of 72 patients, as well as the Ab functional capability of inducing Ab-dependent cell-mediated cytotoxicity (ADCC), complement deposition, and complement-dependent cytotoxicity (CDC). We tested ex vivo the activation of the classical complement pathway on ICL [CD4.sup.+] T cells. RESULTS. All ICL patients had a multitude of autoantibodies mostly directed against private (not shared) targets and unrelated quantitatively or qualitatively to the patients' autoimmune disease status. The targets included lymphocyte intracellular and membrane antigens, confirmed by the detection by flow of IgM and IgG (mostly [IgG.sub.1] and [IgG.sub.4]) anti-[CD4.sup.+] cell Abs in 50% of the patients, with half of these cases triggering lysis of [CD4.sup.+] T cells. We also detected in vivo classical complement activation on [CD4.sup.+] T cells in 14% of the whole cohort. CONCLUSION. Our data demonstrate that a high prevalence of autoantibodies in ICL, some of which are specific for [CD4.sup.+] T cells, may contribute to pathogenesis, and may represent a potentially novel therapeutic target. TRIAL REGISTRATION. ClinicalTrials.gov NCT00867269. FUNDING. NIAID and National Institute of Arthritis and Musculoskeletal and Skin Diseases of the NIH., Introduction Idiopathic CD4 lymphopenia (ICL) was initially described in the late 1980s when some patients presented with opportunistic infections and CD4 lymphopenia consistent with AIDS, but with negative HIV testing. [...]

Background People with HIV and mycobacterial infections can develop immune reconstitution inflammatory syndrome (IRIS) after starting antiretroviral therapy (ART). Severe mycobacterial IRIS has an overlapping clinical phenotype with hemophagocytic lymphohistiocytosis (HLH). We evaluated the pathophysiologic similarities between mycobacterial IRIS and HLH to identify clinical and immune predictors of mycobacterial IRIS severity. Methods HLH criteria were applied to a longitudinal cohort of 80 patients with HIV (CD4 <100 cells/µL) and mycobacterial infections. Participants were subdivided into IRIS meeting HLH criteria (HLH-IRIS), IRIS without HLH (IRIS), and those without IRIS (non-IRIS). Clinical outcomes were evaluated by regression analyses. Soluble biomarkers and T-cell subsets were assessed at baseline and IRIS-equivalent time points. Results HLH-IRIS patients required corticosteroids more frequently (OR: 21.5; 95%CI: 5.6–114.8) and for longer duration (21.2; 95%CI: 10.7–31.7 weeks) than those not meeting HLH criteria. Utilizing decision tree analyses, hemoglobin <9.2 g/dL was the best predictor of HLH-IRIS before ART, whereas ferritin, CXCL9 and sCD25 were most diagnostic for HLH at IRIS onset. At the IRIS timepoint, but not baseline, HLH-IRIS patients had lower regulatory and higher activated T cells along with greater production of IFNγ–IL-18 axis biomarkers compared with both IRIS and non-IRIS groups. Principal component analysis corroborated the distinct clustering of HLH-IRIS patients. Conclusions Severe mycobacterial IRIS and HLH have an overlapping pathogenesis involving IFNγ and unopposed T-cell activation causing severe inflammatory disease clinically distinguished by hyperferritinemia (hyperferritinemic IRIS [FIRIS]). Hemoglobin, ferritin, CXCL9, and sCD25 identify high-risk patients and may improve risk stratification and therapeutic strategies for mycobacterial IRIS. [ABSTRACT FROM AUTHOR]

In the combination antiretroviral era, there are limited data regarding the pathogenesis of histoplasmosis immune reconstitution inflammatory syndrome (IRIS) in people with human immunodeficiency virus (HIV). We immunologically characterized 10 cases of histoplasmosis, 4 of whom developed histoplasmosis IRIS. CD4+ T cells in histoplasmosis IRIS demonstrated a significant polyfunctional cytokine response to histoplasma antigen. [ABSTRACT FROM AUTHOR]

Chronic immune activation in HIV-infected individuals leads to accumulation of exhausted tissue-like memory B cells. Exhausted lymphocytes display increased expression of multiple inhibitory receptors, which may contribute to the inefficiency [...]

This study sought to elucidate methodological issues in adherence research by comparing multiple methods of assessing adherence to antiretroviral medication. From 2003 to 2004, 24 youths with vertically infected HIV disease (mean age = 14.0 years; range, 8-18) and their caregivers participated in a 6-month study. These children were all on highly active antiretroviral therapy (HAART) and were relatively healthy (mean CD4 absolute count= 711.8 [+ or -] 604.5). Adherence was assessed with the Medication Event Monitoring System (MEMS), pill counts, and interviews. Patients and caregivers completed the Perceptions of Adherence Study Participation (PASP) questionnaire. MEMS provided the most detailed adherence information, and good reliability was indicated by significant correlations with medical markers. Pill counts provided similar adherence rates, while patients and caregivers reported nearly perfect adherence in interviews. Problems were experienced with each method: MEMS were expensive, had cap malfunctions, and lack a consistent guiding principle for data interpretation. With pill counts, families forgot to bring all medication bottles to clinic, and interviews were compromised by social desirability and difficulty reaching families by telephone. Most patients and caregivers believed study participation improved the child's adherence, although PASP ratings were unrelated to adherence at the study endpoint. While MEMS may be most reliable, pill counts offer comparable data and are less costly, while interviews seemed least accurate in this study. Most participants reported positive perceptions of their research experience. A consensus among researchers is needed for defining and measuring adherence, and specific recommendations are offered for achieving this goal.

A novel method of quantifying regimen complexity using objective criteria addressing the factors that might complicate adherence to antiretroviral regimens is presented.

Background: People with human immunodeficiency virus (HIV) can present with new or worsening symptoms associated with Mycobacterium avium complex (MAC) infection shortly after antiretroviral therapy (ART) initiation as MAC immune reconstitution inflammatory syndrome (MAC-IRIS). In this study, we assessed the utility of several laboratory tests as predictors of MAC-IRIS.Methods: People with HIV with clinical and histologic and/or microbiologic evidence of MAC-IRIS were identified and followed up to 96 weeks post-ART initiation within a prospective study of 206 ART-naive patients with CD4 <100 cells/µL.Results: Fifteen (7.3%) patients presented with MAC-IRIS within a median interval of 26 days after ART initiation. Patients who developed MAC-IRIS had lower body mass index, lower hemoglobin levels, higher alkaline phosphatase (ALP), and increased CD38 frequency and mean fluorescence intensity on CD8+ T cells at the time of ART initiation compared with non-MAC IRIS patients. A decision tree inference model revealed that stratifying patients based on levels of ALP and D-dimer could predict the likelihood of MAC-IRIS. A binary logistic regression demonstrated that higher levels of ALP at baseline were associated with increased risk of MAC-IRIS development.Conclusions: High ALP levels and increased CD8+ T-cell activation with low CD4 counts at ART initiation should warrant suspicion for subsequent development of MAC-IRIS. [ABSTRACT FROM AUTHOR]

Background: Immune reconstitution inflammatory syndrome (IRIS) is a common cause of morbidity among people with human immunodeficiency virus (PWH) who initiate antiretroviral therapy (ART) with severe lymphopenia. Easily accessible tools that reliably predict emergence and elucidate pathogenesis of IRIS are needed to facilitate improved clinical management.Methods: Plasma levels of biomarkers were measured before ART initiation in a large multinational cohort of ART-naive PWH with severe immunosuppression (CD4+ count <100 cells/mm3) in United States, Kenya, and Thailand. We performed a series of multiparametric analyses of inflammatory and clinical biomarkers and developed a composite score merging relevant biomarkers for use in a prediction model.Results: We identified a distinct baseline inflammatory profile and changes in inflammatory networks among biomarkers in participants who subsequently developed mycobacterial or viral IRIS. We also developed a composite score incorporating biomarkers associated with IRIS (interleukin-6 [IL-6], IL-10, IL-27, sCD14, interferon-γ, tumor necrosis factor-α, hyaluronic acid, D-dimer, body mass index, and hemoglobin) that accurately predicted mycobacterial IRIS and death in this cohort.Conclusions: Systemic inflammatory profiles in PWH with severe immunosuppression are predictive of IRIS. Composite scores for the prediction of mycobacterial IRIS and death could be useful for risk stratification in PWH and lymphopenia initiating ART.Clinical Trials Registration: NCT00286767. [ABSTRACT FROM AUTHOR]

Mycobacterium   genavense is a challenging opportunistic pathogen to diagnose and manage in patients with human immunodeficiency virus (HIV). Persistent immunosuppression or protracted immune reconstitution inflammatory syndrome can lead to complicated clinical courses. We describe 3 cases of M. genavense in patients with HIV representing the spectrum between disease burden and strength of immune response. [ABSTRACT FROM AUTHOR]

Background Patients living with human immunodeficiency virus (PLWH) with low CD4 counts are at high risk for immune reconstitution inflammatory syndrome (IRIS) and death at antiretroviral therapy (ART) initiation. Methods We investigated the clinical impact of IRIS in PLWH and CD4 counts <100 cells/μL starting ART in an international, prospective study in the United States, Thailand, and Kenya. An independent review committee adjudicated IRIS events. We assessed associations between baseline biomarkers, IRIS, immune recovery at week 48, and death by week 48 with Cox models. Results We enrolled 506 participants (39.3% were women). Median age was 37 years, and CD4 count was 29 cells/μL. Within 6 months of ART, 97 (19.2%) participants developed IRIS and 31 (6.5%) died. Participants with lower hemoglobin at baseline were at higher IRIS risk (hazard ratio [HR], 1.2; P =.004). IRIS was independently associated with increased risk of death after adjustment for known risk factors (HR, 3.2; P =.031). Being female (P =.004) and having a lower body mass index (BMI; P =.003), higher white blood cell count (P =.005), and higher D-dimer levels (P =.044) were also significantly associated with increased risk of death. Decision-tree analysis identified hemoglobin <8.5 g/dL as predictive of IRIS and C-reactive protein (CRP) >106 μg/mL and BMI <15.6 kg/m2 as predictive of death. Conclusions For PLWH with severe immunosuppression initiating ART, baseline low BMI and hemoglobin and high CRP and D-dimer levels may be clinically useful predictors of IRIS and death risk. [ABSTRACT FROM AUTHOR]

Background Immune reconstitution inflammatory syndrome (IRIS) represents an unexpected inflammatory response shortly after initiation of antiretroviral therapy (ART) in some human immunodeficiency virus (HIV)–infected patients with underlying neoplasia or opportunistic infections, including tuberculosis. We hypothesized that IRIS is associated with increased glycolysis and that 18F-fluorodeoxyglucose (FDG) positron emission tomography–computed tomography (PET/CT) could help identify high-risk subjects. Methods In this prospective cohort study, 30 HIV-infected patients (CD4+ count <100 cells/µL) underwent FDG-PET/CT scans at baseline and 4–8 weeks after ART initiation. Ten patients developed IRIS (6 mycobacterial). Results At baseline, total glycolytic activity, total lesion volume, and maximum standardized uptake values (SUVs) of pathologic FDG uptake (reflective of opportunistic disease burden) were significantly higher in IRIS vs non-IRIS (P =.010,.017, and.029, respectively) and significantly correlated with soluble inflammatory biomarkers (interferon-γ, myeloperoxidase, tumor necrosis factor, interleukin 6, soluble CD14). Baseline bone marrow (BM) and spleen FDG uptake was higher in mycobacterial IRIS specifically. After ART initiation, BM and spleen mean SUV decreased in non-IRIS (P =.004,.013) but not IRIS subjects. Our results were supported by significantly higher glucose transporter 1 (Glut-1) expression of CD4+ cells and monocytes after ART initiation in IRIS/mycobacterial IRIS compared with non-IRIS patients. Conclusions We conclude that increased pathologic metabolic activity on FDG-PET/CT prior to ART initiation is associated with IRIS development and correlates with inflammatory biomarkers. Abnormally elevated BM and spleen metabolism is associated with mycobacterial IRIS, HIV viremia, and Glut-1 expression on CD4+ cells and monocytes. Clinical Trials Registration NCT02147405. [ABSTRACT FROM AUTHOR]