Safety and pharmacokinetics of ribavirin for the treatment of la crosse encephalitis.

BACKGROUND: La Crosse viral encephalitis (LACVE) is associated with residual epilepsy and neurocognitive deficits in survivors. This report summarizes 3 phases of clinical studies of children treated with intravenous (IV) ribavirin (RBV), each one exploring a different phase (I, IIA, IIB) of clinical trial development. METHODS: In phase I, 7 children with life-threatening LACVE were treated with emergency use RBV using a moderate IV dose (8.33 mg/kg/dose q 8 hours day 1, 5 mg/kg/dose q 8 hours days 2-10). In phase IIA, 12 children with severe LACVE were enrolled: 8 treated with RBV (same dose as phase I) and 4 with placebo. In phase IIB an escalated dose was used (33 mg/kg dose 1, then 16 mg/kg/dose q 6 hours for 4 days, and 8 mg/kg/dose q 8 hours for 3 days). RESULTS: In a group of 15 children treated in phase I and phase IIA, RBV appeared safe at moderate dose, but based on steady-state RBV levels of 9.3 µM, estimated cerebrospinal fluid levels were less than 20% of the EC50 of RBV for LACVE. At the escalated dose used in phase IIB, adverse events occurred, likely related to RBV, and therefore the trial was discontinued. Nevertheless, valuable pharmacokinetic (PK) and safety data were obtained at moderate dose, with potential treatment implications for other indications. CONCLUSIONS: Although the results do not support the use of RBV for LACVE, this nevertheless is the largest study of antiviral treatment for LACVE to date and the largest pharmacokinetic analysis of IV RBV in children for any indication.

Gastrointestinal norovirus infection associated with exacerbation of inflammatory bowel disease.

OBJECTIVE: In this study we aimed to determine, in pediatric patients, whether norovirus infection could be associated with exacerbations of inflammatory bowel disease (IBD) and ascertain whether the clinical expression of norovirus gastroenteritis was similar in patients with IBD compared with non-IBD controls. MATERIALS AND METHODS: We performed a case-control retrospective chart review, over a 10-month interval, of patients with IBD with an exacerbation of their disease. The presence of norovirus in stool and/or rectal swab samples, as determined by an enzyme-linked immunoassay, was assessed. In addition, sex, age, type of IBD, presence or absence of diarrhea, hematochezia, and the need for hospitalization were determined. A similar number of control patients who did not have IBD were used as controls. RESULTS: Nine patients with IBD (8 ulcerative colitis/1 Crohn disease) had exacerbations with diarrhea. Eight had norovirus antigen in at least 1 sample. All 9 patients with IBD presented with bloody diarrhea and 6 of the 8 norovirus-positive patients with IBD required hospitalization. All of the control patients experienced diarrhea; however, no hematochezia was noted and no hospitalization was required. Several patients with IBD and controls remained positive for norovirus months after the initial positive stool and/or rectal swab sample. The virus appeared to be more common during winter months. CONCLUSIONS: We conclude that norovirus may be associated with exacerbations of IBD. When norovirus accompanies IBD it is more likely to be associated with hematochezia than when the infection occurs in the absence of IBD.