Recent steroid therapy increases severity of varicella infections in children with acute lymphoblastic leukemia

The varicella-zoster virus (VZV) continues to be a dangerous pathogen to immunocompromised children. Children with acute lymphoblastic leukemia (ALL) are treated with intermittent steroid therapy. This study was undertaken to examine the relationship between steroid therapy for ALL and severity of varicella infection.

We performed a retrospective review of patients who were on Pediatric Oncology Group Protocol 9201 and had a history of varicella infection. Pediatric Oncology Group 9201 is a phase III study for the treatment of children with lesser risk ALL diagnosed between 1992 and 1999. Cases of varicella were coded 1 to 5 on the basis of severity: grade 1 caused minimal to no symptoms, grade 2 caused mild to moderate symptoms that did not require hospitalization, grade 3 caused symptoms severe enough to require hospitalization and intravenous acyclovir, grade 4 caused severe disease that had complications or that required intensive care, and grade 5 resulted in death.

Of 697 enrolled patients, 110 (15.8%) developed primary varicella; 59% of these were male. For analysis, disease grade was dichotomized into nonsevere (grades 1 and 2) and severe (grades 3, 4, and 5). Of the 110 patients, 56 had nonsevere disease; 54 had severe disease, including 2 deaths. Of the patients whose varicella was diagnosed within 3 weeks of receipt of prednisone, 70% had severe infection, whereas only 44% of those who had not received prednisone within 3 weeks had severe infection. The odds ratio for having a severe infection within 3 weeks of prednisone versus >3 weeks is 2.9 (95% confidence interval: 1.1-7.9). By multivariate analysis, older age at ALL diagnosis, years from ALL diagnosis to VZV diagnosis, and VZV diagnosis within the 4-week period of interest (during or within 3 weeks of prednisone therapy) all were independently associated with an increased risk for severe infection.

This study represents the largest study to date of varicella in children with ALL and provides convincing evidence that prednisone therapy during the VZV incubation period significantly increases the risk for developing severe varicella infection. In addition, older age is associated with more severe infection. Despite the varicella vaccine and a dropping incidence of primary infections, VZV remains a dangerous pathogen for pediatric patients with ALL. With the possible exception of induction therapy, patients who are on ALL therapy and are exposed to varicella should have steroid therapy delayed until after the VZV incubation period. These findings may have implications for other diseases that are treated with corticosteroids.