Recent Steroid Therapy Increases Severity of Varicella Infections in Children with Lesser Risk Acute Lymphoblastic Leukemia.
Authors: Hill Garick , Chauvenet Allen R. , Lovato James , McLean Thomas W. 
Published: October 2019

Abstract
The varicella-zoster virus (VZV) is well recognized as a potential cause of morbidity and mortality in immunocompromised children. Small series and case reports have noted an association between steroid therapy and severe VZV infections. In children with acute lymphoblastic leukemia (ALL), steroid therapy and its relation to VZV severity has not been well studied. We hypothesized that patients who received recent (within 3 weeks) steroid therapy for ALL were at higher risk for severe varicella infection compared to those who had not been recently (>3 weeks) treated with steroids. We performed a retrospective review of patients on Pediatric Oncology Group (POG) Protocol 9201 with a history of varicella infection. POG 9201 is a phase III study for the treatment of children with lesser risk ALL diagnosed between 1992 and 1999. In addition to other chemotherapy agents, POG 9201 included a 4-week induction with prednisone at a dose of 40 mg/m2/day (max 60 mg/day) PO divided three times a day for 28 days, followed by one-week pulses of prednisone (same dose) at weeks 8, 17, and 25, then every 16 weeks until week 105. Vincristine (1.5 mg/m2/dose) was given on days 1 and 8 of each prednisone pulse. Cases of varicella were coded 1–5 based on severity: Grade 1 caused minimal to no symptoms, Grade 2 caused mild to moderate symptoms not requiring hospitalization, Grade 3 caused symptoms severe enough to require hospitalization and intravenous acyclovir, Grade 4 caused severe disease with complications or requiring 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 non-severe (grades 1 and 2) and severe (grades 3, 4, and 5). Of the 110 patients, 56 had non-severe disease, while 54 had severe disease, including 2 deaths. Comparing non-severe to severe cases, there were no significant differences in absolute neutrophil count at VZV diagnosis, VZV immune globulin administration, or acyclovir administration. The median number of days from prednisone treatment to varicella diagnosis was 49 for non-severe (grades 1 and 2) varicella while it was 42 days for grade 3, 21 days for grade 4, and 5 days for grade 5. Of the patients who were diagnosed with varicella within 3 weeks of receiving prednisone, 70% had severe infection, whereas only 44% of those who had not received prednisone within 3 weeks had severe infection (p=0.027). The odds ratio for having a severe infection within 3 weeks of prednisone versus > 3 weeks is 2.9 (94% CI: 1.1 – 7.9). Both deaths occurred in children recently treated with prednisone. 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 of developing severe varicella 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 on ALL therapy exposed to varicella should have steroid therapy delayed until after the VZV incubation period. In addition, the empiric use of oral acyclovir should be strongly considered in such circumstances.