Abstract
In human immunodeficiency virus and acquired immune deficiency syndrome (HIV/AIDS) patients with very low CD4 cell counts, there is a temporal relationship between administration of antiretroviral therapy (ART) and an increased inflammatory response state known as the immune reconstitution inflammatory syndrome (IRIS). The predominant clinical presentation of IRIS is an infectious disease that can be life-threatening. IRIS-related infectious events are distributed similarly between adult males and females, albeit a few studies have shown a skewing toward the male sex in pediatric IRIS. Here, we assessed sex-specific differences in the causes and extent of IRIS infectious events in HIV-infected pediatric patients on ART. We carried out a prospective clinical analysis (from 2000 to 2018) of IRIS-related infectious events after ART in a cohort of 82 Brazilian children and adolescents infected with HIV-1 through mother-to-child transmission as well as a comprehensive cross-referencing with public records on IRIS-related infectious causes in pediatric HIV/AIDS. Twelve events fulfilling the criteria of IRIS occurred exclusively in 11 females in our cohort. The median age at IRIS events was 3.6 years. The infectious causes included Mycobacterium bovis, varicella-zoster virus, molluscum contagiosum virus, human papillomavirus, cytomegalovirus, and Mycobacterium tuberculosis. In one female, there was regional bacillus Calmette-Guérin dissemination and cytomegalovirus esophagitis. There was complete health recovery after 10 IRIS events without the use of corticosteroids or ART interruption. One case of IRIS-associated miliary tuberculosis was fatal. The biological female sex was a significant risk factor for IRIS events (odds ratio: 23.67; 95% confidence interval 95%: 1.341–417.7; P = 0.0016 and P < 0.01 by the multivariable analysis). We observed an effect of the advanced HIV/AIDS variable in IRIS females as compared with non-IRIS females (mean CD4+ T cell percentage 13.36 vs. 18.63%; P = 0.0489 and P < 0.05 by the multivariable analysis), underpinning the exclusively skewed distribution toward the female sex of this cohort. Moreover, the IRIS females in our cohort had higher mean CD4+ T cell percentages before (13.36%) and after IRIS (26.56%) than those of the IRIS females (before IRIS, 4.978%; after IRIS, 13.81%) in previous studies conducted worldwide. The exclusively skewed distribution of pediatric IRIS toward the female sex in the cohort was not linked to preferential X-chromosome inactivation rates. We concluded that the exclusively skewed distribution of pediatric IRIS toward females is associated with more advanced AIDS.
Highlights
Rigorous adherence to antiretroviral therapy (ART) leads to recovery from immunodeficiency and results in a rapid decrease in morbidity and mortality rates among human immunodeficiency virus (HIV)-1 infected patients
We identified an abnormal distribution, fully skewed toward the female sex, of immune reconstitution inflammatory syndrome (IRIS)-related infectious events in HIV-infected Brazilian children and adolescents on ART
The bulk of clinical data allowed us to suggest that the observed skewed distribution toward the female sex is due to more advanced HIV/AIDS in these females than in non-IRIS females
Summary
Rigorous adherence to antiretroviral therapy (ART) leads to recovery from immunodeficiency and results in a rapid decrease in morbidity and mortality rates among human immunodeficiency virus (HIV)-1 infected patients. The onset of IRIS involves clinical manifestations that can be life-threatening and coincides with an elevation in CD4% and a drop in HIV-1 loads [1,2,3]. In severely immunocompromised HIV-infected adults, the onset of IRIS-related TB ranges from 10 to 14 days after ART [6]. In pediatric HIV/AIDS, IRIS-related TB can occur up to 6 months after ART [7,8,9,10,11,12,13,14]. Grave’s autoimmune disease as a manifestation of late-onset IRIS (>12 months) has been reported in adults [15], but in only one pediatric patient [16]. When corticosteroid treatment of IRIS-associated infections is ineffective, and life is threatened [17], ART interruption must be considered [18]
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