Date Published: July 1, 2019
Publisher: Public Library of Science
Author(s): Mark F. Cotton, Helena Rabie, Elisa Nemes, Hilda Mujuru, Raziya Bobat, Boniface Njau, Avy Violari, Vidya Mave, Charles Mitchell, James Oleske, Bonnie Zimmer, George Varghese, Savita Pahwa, Esaki M. Shankar.
The immune reconstitution inflammatory syndrome (IRIS) in HIV-infected infants and young children is relatively understudied in regions endemic for HIV and TB. We aimed to describe incidence, clinical features and risk factors of pediatric IRIS in Sub-Saharan Africa and India.
We conducted an observational multi-centred prospective clinical study from December 2010 to September 2013 in children <72 months of age recruited from public antiretroviral programs. The main diagnostic criterion for IRIS was a new or worsening inflammatory event after initiating antiretroviral therapy (ART). Among 198 participants, median age 1.15 (0.48; 2.21) years, 38 children (18.8%) developed 45 episodes of IRIS. Five participants (13.2%) had two IRIS events and one (2.6%) had 3 events. Main causes of IRIS were BCG (n = 21; 46.7%), tuberculosis (n = 10; 22.2%) and dermatological, (n = 8, 17.8%). Four TB IRIS cases had severe morbidity including 1 fatality. Cytomegalovirus colitis and cryptococcal meningitis IRIS were also severe. BCG IRIS resolved without pharmacological intervention. On multivariate logistic regression, the most important baseline associations with IRIS were high HIV viral load (likelihood ratio [LR] 10.629; p = 0.0011), recruitment at 1 site (Stellenbosch University) (LR 4.01; p = 0.0452) and CD4 depletion (LR 3.4; p = 0.0654). Significantly more non-IRIS infectious and inflammatory events between days 4 and 17 of ART initiation were noted in cases versus controls (35% versus 15.2%: p = 0.0007). IRIS occurs commonly in HIV-infected children initiating ART and occasionally has severe morbidity. The incidence may be underestimated. Predictive, diagnostic and prognostic biomarkers are needed.
CD4+ T cell depletion from untreated HIV infection predisposes to severe opportunistic and intercurrent infections  . The first evidence that CD4 T cell recovery from antiretroviral medicines was associated with morbidity came from French et al who described unexpected Mycobacterium avium-intracellulare disease in immunosuppressed adults after commencing zidovudine . After combination antiretroviral (ART) was introduced, this phenomenon, labelled as ‘immune restoration disease’ was increasingly recognized and ascribed to recovering pathogen-specific immunity . Shelburne introduced the term “Immune Reconstitution Inflammatory Syndrome” (IRIS) recognizing that increased inflammation was a prominent feature . Two IRIS presentations were recognized: a) “Paradoxical’ for worsening of a known inflammatory condition and b) “unmasking’ for a previously unrecognized infection .
This is the first multi-centre study of IRIS in infants and young children from Sub-Saharan Africa and India that prospectively evaluated for both unmasking and paradoxical IRIS. We confirmed many findings noted individually in other paediatric studies and provided some new insights [7–9, 17, 18].
IRIS occurs commonly in HIV-infected infants and young children. It is commonly, but not exclusively, seen in those with advanced HIV disease. Adequate screening for TB and CMV infection is essential to minimise unmasking IRIS. Although often benign and self-limiting, the consequences of IRIS can be severe. A better understanding of pathogenesis and identification of biomarkers to predict IRIS risk and assist diagnosis are needed.