Pediatric Immune Reconstitution Inflammatory Syndrome Common in HIV, TB Endemic Areas

Immune reconstitution inflammatory syndrome occurs commonly in infants and young children with HIV initiating ART in countries with a high prevalence of HIV and TB.

Immune reconstitution inflammatory syndrome (IRIS) occurs commonly in infants and young children with HIV who are initiating antiretroviral therapy (ART) in countries with a high prevalence of HIV and tuberculosis (TB), according to study results published in PLoS One.

In this case-controlled, prospective, observational study, researchers recruited children with HIV (<6 years of age) from 7 clinical research sites in Sub-Saharan Africa and India. Children were within 1 week of ART initiation and, if ≤12 months of age, had a Bacillus Calmette-Guérin (BCG) immunization. The aim of the study was to describe the incidence, severity, and clinical features of pediatric IRIS events related to BCG, and of paradoxical and unmasking IRIS events related to TB infection. The main diagnostic criterion for IRIS was a new or worsening inflammatory event after ART initiation. Blood samples were collected at enrollment and at 2 and 48 weeks post-ART to identify CD4+ T-cell count and percentage and plasma HIV RNA, and at all study visits for IRIS cases. 

Between December 2010 and September 2013, 198 children, with a median age of 1.15 years, were included in the study. The majority of the participants came from Stellenbosch University in Cape Town, South Africa (39.6%), and the University of Zimbabwe in Harare (25.2%).

Of the 198 children, 38 developed 45 IRIS episodes. Median time to first IRIS event was 21 days, with 16 episodes (35.6%) occurring in the first 14 days of ART and 7 (15.6%) after day 60. Paradoxical IRIS comprised 71% of IRIS episodes. The main causes were BCG-related (46.7%), followed by TB (22.2%) and dermatologic (17.8%). Apart from a child aged 16 months, BCG IRIS occurred in infants younger than a year of age, and resolved without pharmacologic intervention. Most TB IRIS (7/10) was unmasking and identified at Stellenbosch University (8/10). Four cases of TB-related IRIS had severe morbidity, including 1 fatality. Cytomegalovirus colitis and cryptococcal meningitis IRIS were also severe.

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In the multinomial logistic regression analysis, IRIS was most associated with elevated plasma HIV RNA (likelihood ratio [LR], 10.629; P =.0011) and recruitment at Stellenbosch University (LR, 4.01; P =.0452). Low CD4+ T-cell count and receiving anti-TB therapy approached significant association with IRIS (LR, 3.4 [P =.065] and LR, 3.674 [P =.055], respectively). For paradoxic IRIS, plasma HIV RNA was even more strongly associated (LR, 12.556; P =.0004); also significantly related were current TB treatment (LR, 6.244; P =.00125), age younger than a year (LR, 5.559; P =.0184), and a lower CD4+ T-cell count (LR, 5.35; P =.0207). Meanwhile, for unmasking IRIS, only being at Stellenbosch University was significantly associated (LR, 7.993; P =.0047).

Restricting the comparison to the first 17 days of ART when the frequency of study visits was the same between cases and controls, researchers noted significantly more non-IRIS infectious and inflammatory events in cases vs controls (35% vs 15.2%; P =.0007). They suggested that IRIS events were potentially missed, given that those with IRIS had more infectious and inflammatory events not regarded as IRIS.

“Although often benign and self-limiting, the consequences of IRIS can be severe,” noted the researchers. “A better understanding of pathogenesis and identification of biomarkers to predict IRIS risk and assist diagnosis are needed,” they concluded.


Cotton MF, Rabie H, Nemes E, et al; P1073 team. A prospective study of the immune reconstitution inflammatory syndrome (IRIS) in HIV-infected children from high prevalence countries. PLoS One. 2019;14(7):e0211155.