IRIS most commonly presents with an infectious etiology, and has been well described after starting HAART.4
This is the first study to examine pediatric IRIS in Latin America. The 20% incidence found in this study is similar to the 19% prospective IRIS incidence reported among children in Thailand. The range of infectious causes encountered in this study is similar to those reported previously.12,13,19
The majority of IRIS cases (67%) were associated with unmasking of infection and only 33% were associated with recurrence of previously treated infection (paradoxical IRIS). Studies of adults in the developing world have noted 50% to 80% of cases resulted from paradoxical IRIS.3,11
Increased screening at HAART initiation can decrease the number of unmasking infections, as demonstrated by 1 Ugandan study that showed a 50% decrease in unmasking TB infections in children after initiating tuberculin skin test screening before starting the therapy.20
The rate of TB-IRIS cases we found was within the wide range reported in the literature for children and adults. Prospective studies have found 10% of IRIS cases associated with TB in children and 41% of IRIS cases associated with TB in adults.11,13
Herpes viruses have also been commonly implicated in IRIS in children and adults, with varicella zoster virus being one of the most commonly reported causes of IRIS in children.12,13
The first report of IRIS in children found an incidence of 22.9 cases of varicella zoster virus per 100 person-years in the first 6 months after HAART,12
and the Thai study found 22% of IRIS cases in children caused by varicella zoster virus.13
Regarding HSV infections, while they can potentially cause more serious disease such as HSV encephalitis, the cases observed in our study were mild and resolved with treatment. Less severe infection may have been due to easy recognition of HSV labialis and early initiation of treatment. The Thai study showed that 19% of pediatric IRIS cases were related to HSV, including 1 case of HSV encephalitis,13
and the only prospective study in adults reported 9.1% of IRIS cases associated with HSV infection.11
Our study detected an association between IRIS and malnutrition. In children, malnutrition can cause further immunosuppression,21
and refeeding alone can produce paradoxical IRIS-like reactions.22
Although we did not collect information regarding nutritional supplementation for each child in this study, all children received monthly groceries and were perhaps at lower risk for this complication. HIV infection can also cause malnutrition through gastrointestinal illness, cachexia, and anemia.21
Thus, it is plausible that HIV-infected children with underlying malnutrition may develop an exaggerated immune response upon starting HAART. As our study only examined height and weight as indicators of malnutrition, future studies should include more detailed examination of nutrition measures to further examine the relationship between malnutrition and IRIS, as well as the association of refeeding, focusing on children with moderate to extreme malnutrition.
The immunologic mechanism of IRIS is not well defined, but experts suggest it is an antigen-driven process occurring when the immune system becomes dysregulated during the early period of effective antiretroviral therapy. French23
proposed that immune reconstitution is due to an imbalanced cellular immune response against pathogen-specific antigens, and depending on the pathogen, produces a TH
1, Th17, or CD8+
response. Bonham et al24
postulated that IRIS occurs during antigen clearance when antigen-specific immunity and homeostatic T-regulatory function is recovering, and that specific cytokines may serve as biomarkers for different forms of IRIS. Given the high prevalence of tuberculosis in Peru, we are not surprised that tuberculosis was a common manifestation of IRIS. Additional research is needed to further elucidate the immunopathogenesis of IRIS in the developed and developing world—where endemic infections are often different.
The most significant limitation of our study is the lack of an objective definition of IRIS with objective biomarkers for diagnosis. Furthermore, because of the retrospective nature of this study, CD4 lymphocyte counts and HIV viral loads were not consistently available before and after HAART initiation and at the time of the IRIS event. The hospital did not measure CD4 and CD8 lymphocyte percentages so they were calculated from total lymphocyte counts from the nearest date, which provided an approximation of the true CD4 and CD8 lymphocyte percentage. Finally, the number of patients in the study was too small to make firm conclusions about specific risk factors, however, the incidence and clinical spectrum were similar to other publications.
In conclusion, IRIS was a common occurrence in Peruvian HIV-infected children during the first year after initiation of HAART therapy. Clinicians should be aware of both the unmasking of subclinical infections as well as the paradoxical recrudescence of successfully treated infections in children shortly after initiating HAART. Future research should examine specific risk factors associated with IRIS in children so that children who are at highest risk of IRIS can be identified and treated promptly.