Immunological profiling of tuberculosis-associated immune reconstitution inflammatory syndrome and non-immune reconstitution inflammatory syndrome death in HIV-infected adults with pulmonary tuberculosis starting antiretroviral therapy: a prospective observational cohort study

Abstract

Summary Background Patients co-infected with advanced HIV and tuberculosis are at risk of tuberculosis-associated immune reconstitution inflammatory syndrome (IRIS) and death soon after initiation of antiretroviral therapy (ART). Tuberculosis-associated IRIS has been associated with quicker recovery of cellular immune responses after ART initiation and early mortality with slower recovery of these responses. We aimed to assess whether patients who have these outcomes have distinct immunological profiles before and after ART initiation. Methods We undertook this prospective cohort study at 22 public clinics and the main public hospital in Gaborone, Botswana, in ART-naive adults (aged ≥21 years) with advanced HIV (CD4 cell counts ≤125 cells per μL) and pulmonary tuberculosis. We obtained data for clinical variables and for levels of 29 plasma biomarkers, quantified by Luminex assay. We classified patients as having tuberculosis-associated IRIS, early mortality, or survival without a diagnosis of tuberculosis-associated IRIS (controls), on the basis of outcomes recorded in the 6 months after ART initiation. We used rank-sum or χ² tests, and logistic regression with odds ratios (OR) and 95% CIs, to assess the association between variables measured before and 4 weeks after ART initiation with death and tuberculosis-associated IRIS, compared with controls. Findings Between Nov 12, 2009, and July 3, 2013, we enrolled 201 participants. 31 (15%) patients left the study before ART initiation, leaving 170 (85%) patients for analysis. Patients with tuberculosis-associated IRIS had reduced pre-ART concentrations of several pro-inflammatory biomarkers, including interleukin (IL)-6 (adjusted OR per 1 log10 increase 0·40 [95% CI 0·18–0·89]). However, patients with early death had increased pre-ART concentrations of inflammatory biomarkers, including monocyte chemoattractant protein-1 (adjusted OR 9·0 [95% CI 1·0–80·0]) and tumour necrosis factor (TNF)-α (7·8 [1·1–55·2]). At week 4 after ART initiation, tuberculosis-associated IRIS was independently associated with greater increases in several inflammatory biomarkers, including IL-6 (adjusted OR 1·7 [95% CI 1·2–2·5]) and TNF-α (1·5 [1·0–2·2]), versus controls. Death was likewise associated with greater increases in systemic inflammatory markers, including granulocyte colony-stimulating factor (adjusted OR 2·8 [95% CI 1·3–6·1]), IL-12p40 (1·8 [1·0–3·4]), and IL-15 (2·0 [1·1–3·7]), versus controls. However, changes in CD4 cell count during ART, which were similar between controls and patients with tuberculosis-associated IRIS (p=0·45), were substantially lower in patients who died (p=0·006). Interpretation Distinct immunologic profiles pre- and post-ART initiation characterize advanced HIV/TB patients who experience TB-IRIS and death. Interventions that decrease inflammation while promoting cellular immune recovery on ART among HIV/TB co-infected patients should be considered. Funding National Institutes of Health and the Penn Center for AIDS Research.

Neutrophil Activation and Enhanced Release of Granule Products in HIV-TB Immune Reconstitution Inflammatory Syndrome: Erratum

“…This is consistent with observations by others 14,37,38 that TB-IRIS may be heralded by lower cytokine concentrations at ART initiation but subsequent large magnitude changes.…”

Robust Reconstitution of Tuberculosis-Specific Polyfunctional CD4+T-Cell Responses and Rising Systemic Interleukin 6 in Paradoxical Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome

“…Patients were enrolled from public outpatient clinics and the main public hospital in Gaborone, Botswana, from November 2009 to July 2013, as described elsewhere [15]. Participants had to be HIV-infected, ART-naive adults with pre-ART CD4 counts ≤125 cells/µL who planned to initiate ART within 2 months of commencing antituberculosis therapy for a new diagnosis of WHO-defined smear-positive or smear-negative pulmonary tuberculosis [15,21,22].…”

“…Participants had to be HIV-infected, ART-naive adults with pre-ART CD4 counts ≤125 cells/µL who planned to initiate ART within 2 months of commencing antituberculosis therapy for a new diagnosis of WHO-defined smear-positive or smear-negative pulmonary tuberculosis [15,21,22]. Pregnant patients, those on immunomodulatory agents, and those with drug-resistant tuberculosis were excluded [15,21]. For the primary analysis, patients had to have clinical data and peripheral blood mononuclear cells (PBMCs) available from baseline and/or week 4 post-ART initiation.…”

“…Immunologically, higher pre-ART levels of immune activation and rapid increases in tuberculosis-specific interferon gamma (IFN-γ)-producing cells after ART initiation in HIV-infected adults have been associated with development of TB-IRIS [7,[9][10][11][12]. However, in several recent studies, levels of pre-ART immune activation were actually lower in TB-IRIS patients vs controls [13][14][15], and multiple reports have indicated that patients without TB-IRIS may also have robust increases in levels of pathogen-specific immune responses on ART [16,17]. Existing data are therefore inconclusive about whether higher levels of pre-ART immune activation predispose to TB-IRIS and whether tuberculosis-specific T-cells are involved in TB-IRIS pathogenesis.…”

Aberrant Inflammasome Activation Characterizes Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome

“…Prior studies have found multiple immunological abnormalities in association with TB-IRIS, including hyperactivation of M. tuberculosis Ag-specific T cells (6,10), leading to expansion of highly activated (11) polyfunctional CD4 + T cells (12), excessive production of proinflammatory cytokines (13)(14)(15)(16), dysfunction of NK cells (17,18), an increased frequency of neutrophils (19), or perturbation in NKT cells (20,21). The immunopathological mechanisms underlying the development of TB-IRIS are not fully understood, and the complex interplay between different arms of the immune system in TB-IRIS remains to be determined.…”