Therapeutics for fulminant hepatitis caused by enteroviruses in neonates

Abstract

Neonatal infection with nonpolio enteroviruses (EVs) causes nonspecific febrile illnesses and even life-threatening multiorgan failure. Hepatitis, which often results in hepatic necrosis followed by disseminated intravascular coagulopathy, is one of the most severe and frequent fatal neonatal EV infection complications. Coxsackievirus B (CVB) 1–5 and many echoviruses have been most commonly identified. Neonatal EV infection treatment has usually involved initial supportive care. Studies for CVB and echovirus infection treatments were developed for more than thirty years. Intravenous immunoglobulin and pleconaril therapy was performed in some clinical trials. Additionally, other studies demonstrated antiviral and/or anti-inflammatory pathogenesis mechanisms of neonatal EV hepatitis in in vitro or in vivo models. These treatments represented promising options for the clinical practice of neonatal EV hepatitis. However, further investigation is needed to elucidate the whole therapeutic potential and safety problems.

Update on nonpolio enterovirus and parechovirus infections in neonates and young infants

“…Increased survival was seen among enterovirus-infected neonates who received pleconaril, but it did not reach statistical significance [49]. These results support potential efficacy, and further studies are needed to evaluate it in neonates [29 ▪ ] and young infants. Currently, pleconaril is not available even for compassionate use [1,36].…”

“…Most infections are asymptomatic or present as ‘fever without a source’ in a well appearing infant that often prompts a sepsis evaluation, including a lumbar puncture [13], hospitalization, and empiric antimicrobial agents. Some clinical syndromes are linked to specific types such as EVA71 and CVA16 to HFMD and CVB3 to myocarditis [5 ▪▪ ,29 ▪ ].…”

“…Immunoglobulin intravenous (IGIV) has been used therapeutically for severe neonatal infections because of enterovirus [29 ▪ ] but with only anecdotal evidence for PeV. The rationale for use is its relative safety, the fact that neutralizing antibody titers against the most prevalent circulating viruses are present in IGIV products, correlation of severe disease with lack of neutralizing antibody, and experience with its use in patients with hypogammaglobulinemia and chronic enterovirus disease.…”

“…However, randomized trials showed inconsistency in its benefits [47], mostly as enteroviral disease is usually self-limited in normal hosts. In addition, pleconaril may induce adverse effects by increasing cytochrome P-450 3A (CYP3A) activity [29 ▪ ]. These concerns resulted in the FDA-denying approval for clinical use.…”

“…Drugs that interfere with structural proteins are under investigation [29 ▪ ,52]. The high mutation rate of these viruses leads to inevitable resistance development, so combination therapies are being evaluated [53].…”