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Early infection of the thymus, an organ central to the ontogeny of the immune system, has been proposed as a cause of rapid progression in pediatric HIV disease.To test the hypothesis that small thymic volume is associated with rapid disease progression in HIV-infected children.Three pediatric radiologists established criteria for rating the size of the thymic profile on chest radiographs. All available baseline chest radiographs were reviewed in a random sequence, with radiologists blinded to study subjects’ clinical status. A consensus was reached on whether the thymus was normal or small for age.A prospective multicenter study of the natural history of HIV-1 infection in children, the Pediatric Pulmonary and Cardiovascular Complications of Vertically Transmitted Human Immunodeficiency Virus Infection (P2C2) Study.Fifty-eight HIV-infected children and 38 control children (uninfected but born to HIV-infected women) for whom chest radiographs in the first year of life were available.Rapid progression of HIV disease, defined as CDC Clinical Category C (severely symptomatic) or Immunologic Category 3 (severe immunosuppression) by 1 year of age.The mean age at the time of chest radiography was 3.5 months. Ten (17%) HIV-infected children had reduced thymic profile size, whereas no controls did (P = 0.006). Of the 58 (59%) HIV-infected children 34 were classified as rapid progressors, and 9 (26%) of them had reduced thymus size, compared with 1 (4%) of the non-rapid progressor children [odds ratio, 8.28; 95% confidence interval (CI), 1.0, 70.5;P = 0.035]. Baseline mean CD4+ count was 1642 (95% CI 1322 to 2009) cells/μl for those with normal thymus and 740 (95% CI 380 to 1275) cells/μl for those with reduced thymus (P = 0.007).Early thymic involution is associated with rapidly progressive disease in HIV-infected children.