Treatment of Neonatal Enterovirus Infections

The human neonate is uniquely susceptible to serious, often fatal enterovirus infections in the first 2 weeks of life that are associated with acute maternal illness, premature delivery, male gender, and absence of maternal antibody against the infecting enterovirus serotype. Although the term “sepsis” is sometimes used to describe neonatal enterovirus disease, postmortem pathology confirms that severe myocarditis and/or hepatitis, often accompanied by encephalitis, adequately explain the spectrum of enterovirus disease in neonates. Less commonly, infants may present with pneumonitis, which may also be fatal [1]. These infections occur sporadically and in clusters with the emergence of newly evolving enterovirus serotypes [2, 3]. The overall population impact is not well understood because nonpolio enterovirus infections are generally not reportable. There is no approved treatment for enterovirus infections. Intravenous immune globulin (IVIG) is often administered to infected neonates, but without satisfactory evidence of efficacy [4–6]. Pleconaril was developed in the 1990s as a capsid-binding antiviral agent that prevents virion uncoating of all susceptible enteroviruses following cell entry, and also inhibits attachment to cells for a subset of enteroviruses. The drug exhibits potent in vitro activity against many enterovirus and human rhinovirus serotypes and a favorable pharmacokinetic profile when administered orally [7, 8]. In a clinical trial in adolescents and adults with enterovirus meningitis, pleconaril elicited few serious adverse events and reduced the duration of headache when given within 2 days of onset [9]. An uncontrolled study of patients given pleconaril under a treatment Investigational New Drug application (IND), including 6 neonates, suggested efficacy against serious enterovirus infections [10]. However, the developer chose to seek marketing approval for upper respiratory tract illness based on a 1-day reduction in symptoms in adults with rhinovirus and enterovirus colds [11]. At the recommendation of the Vaccines and Related Biological Products Advisory Committee, the application was disapproved by the U.S. Food and Drug Administration (FDA) in 2002 due to modest effectiveness for this indication, and because of breakthrough menstrual bleeding in some women taking oral contraceptives who took pleconaril for 6 weeks for upper respiratory infection prophylaxis. In 1999, prior to the FDA decision, a placebo-controlled trial of oral pleconaril for severe enterovirus infection in neonates was initiated by the NIH Collaborative Antiviral Study Group (CASG). The results of this study are reported by Abzug et al. in this issue of the Journal [12]. The study faced headwinds from the beginning due to the infrequent occurrence of disease in newborns and the difficulty in obtaining parental consent for a placebocontrolled study of a potentially fatal infectious disease. To encourage enrollment, the protocol was modified in 2000 to permit concurrent use of IVIG. In the end, the study was discontinued after 11 years with the expiration of the available drug supply and just short of reaching the accrual target of 45 laboratory-confirmed cases of enterovirus infection. The primary endpoint could not be assessed because oropharyngeal viral cultures were negative for all enrolled infants after 5 days of treatment, a mean of 10 days after onset of illness [12]. This result should not be surprising, because although data from newborns are lacking, enteroviruses can be isolated from the oropharynx in only a portion of older infants and children with primary infection, and then for brief periods, typically disappearing with the development of serum neutralizing antibody [13–15]. Nonetheless, the study produced substantial evidence of pleconaril effectiveness, as the mean time to a negative viral culture from all sites was 4 days in the pleconaril arm compared with 7 days in the placebo arm, a difference that not only approached statistical significance, Editorial Commentary