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The clinical pattern, prevalence, and factors associated with immune reconstitution inflammatory syndrome in Ugandan children
Global Health Sciences Literature Digest
Published November 1, 2010
Journal Article

Orikiiriza J, Bakeera-Kitaka S, Musiime V, Mworozi EA, Mugyenyi P, Boulware DR. The clinical pattern, prevalence, and factors associated with immune reconstitution inflammatory syndrome in Ugandan children. AIDS. 20;1024:2009-2017.

In Context

Immune reconstitution inflammatory syndrome (IRIS) refers to clinical deterioration following the initiation of ART and occurs as the immune system recovers from severe immunodeficiency. Paradoxical IRIS refers to the clinical recrudescence of a previously treated opportunistic illness (OI) while unmasking IRIS refers to the development of new OIs. It is estimated that between 5% and 45% of adults experience IRIS.(1, 2, 3) The prevalence of pediatric IRIS was measured in hospitalized Thai patients and found to be 23.4% and 20% in children evaluated in Lima, Peru. Little is known about the prevalence of IRIS in children in sub-Saharan Africa.(4, 5)

Objective

To determine clinical pattern, prevalence, and factors associated with pediatric IRIS in Uganda.

Setting

Clinical research centers in central, eastern, and western regions of Uganda.

Study Design

Cross-sectional study.

Participants

Children <18 years of age who were patients at one of the clinics between December 2006 and October 2007 and receiving ART for at least 2 weeks but no more than 24 weeks.

Outcome

The prevalence of and risk factors for pediatric IRIS.

Methods

Physicians screened and enrolled eligible patients during routine clinical visits. Patients underwent a detailed clinical history and examination. Laboratory tests included a complete blood count, Giemsa-stained blood smear for malaria, liver and renal function tests, CD4 count and percentages, HIV viral load, C-reactive protein, erythrocyte sedimentation rate, and skin test for tuberculosis (TB). Past medical records were reviewed and previous OIs and baseline laboratory values were recorded as part of the study. A case of IRIS was defined as the occurrence of at least one of clinical criteria plus a decrease in viral load by at least 1 log10 or at least one clinical criterion plus at least two minor clinical criteria.(6) Immunological success was defined as an increase in CD4 cell percentage of at least 15% from pre-ART and viral success was defined as a viral load of <50 copies/mL.

Results

There were 414 patients screened and 263 (64%) were eligible for the study of whom 162 (62%) enrolled. Ninety-three (57.4%) of participants were female and the median age was 6 years (range: 0.5-18). At the time of beginning ART, 73% met the WHO clinical criteria of stage III/IV but none had clinically active OIs and all patients were receiving prophylaxis with co-trimoxazole. The median time on ART at enrollment was 11.5 weeks (interquartile range [IQR]: (3.5-20)). None of the patients experienced treatment interruptions.

The prevalence of IRIS was 38% and was higher in males than females (48% vs. 31% (OR 2.20, 95% CI: 1.06, 3.86). Unmasking of OIs was more frequent than paradoxical IRIS OIs (77% compared to 23% respectively). Although IRIS was not associated with age, the prevalence of IRIS was highest in children aged 5-12 years (42%). The likelihood of developing IRIS was significantly greater among children who had received ART from 2-4 weeks (55%) compared with those on ART for longer duration and more frequent among those with lower CD4 percentages.

Sixty-two percent of children with IRIS had a history of an OI. TB was the most common IRIS presentation accounting for 25 (29%) of the patients with a prevalence of 15.4% (25/162). Of mycobacterial-IRIS, 20 (80%) had pulmonary TB, two had disseminated TB, and three had Bacille-Calmette-Gu�rin (BCG) lymphadenitis (BCG-IRIS). Fourteen patients (8.6% prevalence) had no prior TB diagnosis. Paradoxical TB-IRIS occurred in 11 children who had a prior TB diagnosis with an overall prevalence of 6.8%.

The independent predictors of IRIS were male sex (adjusted OR [AOR] =2.96, 95% CI: 1.30, 6.74), a pre-ART CD4 percent under 15 (AOR=4.39, 95% CI: 1.62, 11.08), CD8 cells <100/µl at the time of evaluation for IRIS (AOR: 4.56, 95% CI: 2.01,10.34), and a cough at time of IRIS evaluation (AOR =4.30, 95% CI: 1.84, 10.08).

Conclusions

This study suggests a high prevalence of pediatric IRIS among Ugandan children and demonstrates that severely immunocompromised children are at increased risk for IRIS.

Quality Rating

This study included what is likely to be a representative sample of HIV-infected children receiving ART in sub-Saharan Africa and the control population was drawn from the same population as cases. Ascertainment of risk factors for IRIS may have been limited because of variation in the number and frequency of clinic visits and the medical history and examination of patients prior to the start of the study. The greatest limitation of the study is its cross-sectional nature. A carefully designed and executed prospective study of pediatric IRIS in the region is warranted.

Programmatic Implications

Although there are important limitations to the study it does confirm studies in other countries(4, 5) that have identified pediatric IRIS. This study found that IRIS occurred most often within a month of beginning ART and as such, highlights the importance of careful observation for OIs and worsening disease after initiation of ART in children. Effort should be made to by both medical providers as well as caregivers to be alert to the development of OIs or any other indication of worsening disease after the initiation of ART. Additional studies of pediatric IRIS including clinical management of the condition are necessary.

References

  1. Hirsch HH, Kaufmann G, Sendi P, Battegay M. Immune reconstitution in HIV-infected patients. Clin Infect Dis. 2004; 38:1159-1166.
  2. Resino S, Resino R, Maria Bello'n J, Micheloud D, Gutie'rrez MD, de Jose' MI, et al. Long-term effects of highly active antiretroviral therapy in pretreated vertically HIV type 1 Infected children: 6yrs of follow up. Clin Infect Dis. 2006; 42:862-869.
  3. Michelet C, Arvieux C, François C, Besnier JM, Rogez JP, Breux JP, et al. Opportunistic infections occurring during highly active antiretroviral treatment. AIDS. 1998; 12:1815-1822.
  4. Puthanakit T, Oberdorfer P, Akarathum N, Wannarit P, Sirisanthana T, Sirisanthana V. Immune reconstitution syndrome after highly active antiretroviral therapy in human immunodeficiency virus-infected Thai children. Pediatr Infect Dis. J 2006; 25:53-58.
  5. Wang ME, Castillo ME, Montano SM, Zunt JR. Immune reconstitution inflammatory syndrome in human immunodeficiency virus-infected children in Peru. Pediatr Infect Dis J. 2009;28:900-903.
  6. French MA, Price P, Stone SF. Immune restoration disease after antiretroviral therapy. AIDS. 2004; 18:1615-1627.