Vapendavir

We investigated the susceptibility of 10 enterovirus D68 (EV-D68) isolates (belonging to clusters A, B, and C) to (entero)virus inhibitors with different mechanisms of action. The 3C-protease inhibitors proved to be more efficient than enviroxime and pleconaril, which in turn were more effective than vapendavir and pirodavir. Favipiravir proved to be a weak inhibitor. Resistance to pleconaril maps to V69A in the VP1 protein, and resistance to rupintrivir maps to V104I in the 3C protease. A structural explanation of why both substitutions may cause resistance is provided.

In August 2014, the US Centers for Disease Control and Prevention (CDC) was alerted to a significant increase in cases of severe respiratory viral infections, some serious enough to require intensive care unit (ICU) level care and to cause death, in Kansas City and Chicago (1). Enterovirus 68 (EV-D68) was found to be the cause of the majority of these cases. Enteroviruses are small, nonenveloped positive-sense RNA viruses that are members of the picornavirus family (2). Although closely related to rhinoviruses, enteroviruses are characterized by their lack of acid lability in cell culture. Currently, there are more than 100 serotypes of enterovirus identified which infect humans. Enterovirus 68 was initially isolated in 1962 and has only rarely been reported in the United States until now (3). Historical surveillance data suggest that most infected patients were previously 19 years or younger, with the majority (64.7%) of infected individuals being 4 years or younger (3). Spread of virus is likely from contact with infected respiratory secretions, including saliva, nasal mucus, or sputum, and fomites that have come in contact with these respiratory secretions. During the current epidemic, patients have been between the ages of 6 weeks and 16 years (median is 4 years for Kansas cases and 5 years for Illinois cases); both sexes were equally affected (http://www.cdc.gov/non-polio-enterovirus/ about/EV-D68.html for current details) (1). Twenty-one (70%) of the initial cases had a history of asthma or wheezing. All patients have presented with difficulty breathing and hypoxia; wheezing is present in approximately 21%, and fever is present in approximately 23% on initial presentation for care. Admission chest radiographs showed perihilar infiltrates, often with atelectasis, and most documented cases have required admission to the ICU; a minority have required ventilator support (6 bilevel positive airway pressure ventilation, 2 mechanical ventilation, and 1 extracorporeal membrane oxygenation). Because there may be testing bias in favor of testing more severely ill patients, the full spectrum of disease, including milder cases, remains to be defined. Diagnosis can be made through viral culture or polymerase chain reaction (PCR). Many commercial respiratory viral PCR panels use a primer directed at the highly conserved 5¶-noncoding region of the genome of most picornaviruses; as a result, the assay cannot differentiate between an enterovirus or rhinovirus present in the material tested. Furthermore, not all commercial multiplex respiratory viral assays can detect EV-D68 with their current primers. Therefore, clinical knowledge about local assay capabilities is essential. Finally, in all cases, testing in a reference laboratory is currently required to determine that the detected virus is the D68 serotype because neither culture nor PCR can generally differentiate individual serotypes. There are currently no approved agents with activity against EV-D68, although several agents (ie, enteroviral protease inhibitor SG85 and capsid inhibitors vapendavir [Biota Pharmaceuticals, Alpharetta, Georgia] and pocapavir [ViroDefense Inc, Rockville, Maryland]) are currently being studied for the treatment of enteroviral infections (4Y6). Likewise, there are no vaccines approved to protect against EV-D68. Enterovirus 68 is an important pathogen that could affect transplant patients and transplant programs. Although most cases of EV-D68 have been in children, the full spectrum of EV-D68Ymediated disease in immunocompromised patients has not been studied. As a result, any pediatric or adult transplant patient with respiratory symptoms in regions with EV-D68 circulation should be tested with an assay that would detect EV-D68 with additional testing in an appropriate reference laboratory (ie, state health department or CDC) to determine if EV-D68 is the cause of the respiratory illness. All transplant recipients presenting with respiratory illness should be asked about recent contact with children with respiratory illness especially in regions where EV-D68 activity has been reported. Transplant programs should be in constant communication with hospital administration if their hospital is caring for a large number of patients with EV-D68 to ensure that there are sufficient SPECIAL FEATURE