Tuberculosis-immune reconstitution inflammatory syndrome in HIV: from pathogenesis to prediction

Abstract

Tuberculosis-immune reconstitution inflammatory syndrome (TB-IRIS) is an exaggerated, dysregulated immune response against dead or viable antigens of Mycobacterium tuberculosis that frequently occurs after initiation of antiretroviral therapy despite an effective suppression of HIV viremia. Scientific advances in IRIS pathogenesis have led researchers and clinicians to postulate risk factors that could possibly predict this syndrome, in an attempt to reduce the incidence and the severity of IRIS, with appropriate anti-inflammatory therapy. This review is a summary of the available literature on pathogenic mechanisms involved from the macro to the micro level, the clinical spectrum, available predictors and the scope of these biomarkers to function as specific therapeutic targets, that could effectively modulate or ameliorate this syndrome in future.

Keywords::

• ART
• biomarkers for IRIS
• HAART
• HIV
• IRIS
• paradoxical reaction
• TB

Acknowledgements

The authors wish to thank I Sereti, L Antonelli, A Sher, BO Porter, T Nutman from the National Institute of Health, USA, S Babu ICER facility NIRT, C Chandrasekhar, Superintendant, OR Krishnarajasekar, Deputy Superintendant, S Kumar, K Raja, N Ravichandran, Government Hospital of Thoracic Medicine, Tambaram Sanatorium. R Sridhar, Prof. Chest medicine, Stanley Medical College, Chennai. K Bhanu, Professor of neurology, S Sekhar, ART Medical Officer, Government Rajiv Gandhi Hospital, Chennai, C Padmapriyadarsini, PA Menon, PK Bhavani, K Vijay, S Devarajulu Reddy, from the National Institute for Research in Tuberculosis Chennai for their valuable inputs, the staff of IRIS study team S Subramanyam, LE Hanna, S Anbalagan, S Rajasekaran, N Logeswaran, A Stella Mary, N Hariharan for their technical help and N Santhanakumar for his excellent secretarial assistance.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Early initiation of antiretroviral therapy (ART) with active Mycobacterium tuberculosis, a chronic infection with persisting antigens, sets an ideal stage for immune reconstitution inflammatory syndrome (IRIS).

• Dysregulated augmentation of immune responses after initiation of highly active ART (HAART) despite effective suppression of plasma viremia could lead to clinical deterioration.

• Restoration of pathogen-specific immune responses to either viable, active pathogens or residual antigens causes unmasking or paradoxical IRIS that usually occurs within 3 months after HAART initiation.

• Abrupt rise in CD4 T-cell count or rapid decline in viral load contributes to IRIS, but considerable variation exists in the reconstitution of CD4 lymphocytes upon HAART initiation questioning their role as reliable predictors.

• The abrupt rise in nonspecific mediators like IFN-γ levels in response to purified protein derivative and region of difference-1 is much more striking in unmasking than paradoxical IRIS.

• Increase in activated CD4 T cells induces an explosive exaggerated Th1 type of cytokine response overriding Th2 response, culminating in IRIS, justifying use of anti-inflammatory drugs.

• Matrix metalloproteinases have been recently implicated in tuberculosis (TB)-IRIS.

• Low CD4, low BMI, low hemoglobin, high viral load, disseminated TB, extra pulmonary foci and negative tuberculin skin testing pre-ART are useful clinical predictors, with the only modifiable risk factor being time to ART initiation.

• Our prospective TB-IRIS study in India, on a cohort of HIV-positive patients with culture-positive rifampicin-sensitive pulmonary TB, found the combined predictive value of IL-6 and CRP to be 92% in paradoxical IRIS.

• Specific molecular targets would be useful to precisely control the phenomenon without disturbing all the constituents of restored immunity.

Notes