Enterovirus D68: a new threat to hematology patients?

In this issue of Blood, Waghmare et al report 8 patients with hematologic malignancies retrospectively diagnosed with enterovirus D68 (EV-D68) infections.¹ 

Enterovirus D68 is not a new virus, as it was identified in 1962, and small numbers of cases have been regularly reported to the US Centers for Disease Control and Prevention (CDC). However, during the summer of 2014, outbreaks of severe respiratory disease, especially in children and teenagers with a history of asthma, occurred in Missouri and Illinois.^2,3  EV-D68 was identified in a majority of these cases, and during the rest of 2014, more than 1100 cases with documented EV-D68 infections were diagnosed all over the United States and reported to the CDC, including a small number of fatal infections. It has been suggested that the diagnosed cases are only “the tip of the iceberg,” with a large number of undiagnosed mild infections occurring as well. Therefore, the proportion of severe infections is difficult to assess. Outbreaks with EV-D68 have also been documented in other countries, including Norway⁴  and the Netherlands.⁵  The latter report also included 3 cases occurring in solid organ transplant recipients.

For decades, viral infections have been recognized as threats to hematology patients, especially to hematopoietic stem cell transplant recipients. In the study by Waghmare et al, 6 patients were stem cell transplant recipients. Similarly to what is commonly seen with other respiratory viruses, the clinical manifestations varied greatly from mild upper respiratory symptoms to respiratory failure, with 2 of 8 patients requiring mechanical ventilation. All 8 diagnosed infections occurred in adults, and most patients had lymphopenia, a well-known risk factor for more severe disease in infections caused by other respiratory viruses such as respiratory syncytial virus and influenza virus.^6-8  Obviously, these observations are too limited to allow assessment of the pathogenic potential of EV-D68 in hematology and stem cell transplant patients, but if EV-D68 infections become more prevalent in the community, as recent epidemiology suggests, we will most likely get more information regarding the clinical importance of infections with this virus during the next couple of years.

With the development of molecular virology techniques, the number of “new” viruses is steadily increasing, and investigators need to address the impact of these new viruses in immunocompromised patients. The authors employed an interesting strategy by analyzing samples from patients with respiratory symptoms who had either tested negative for respiratory viruses by multiplex polymerase chain reaction (PCR) or tested positive for rhinoviruses. The latter group is interesting, because 10% of patients who tested positive for rhinovirus were in fact, after sequencing, proven to have EV-D68, showing that the rhinovirus primers used in the original multiplex PCR had limited specificity. This report illustrates a couple of important points. First, it shows the importance of having repositories of saved specimens allowing reanalysis when new technology becomes available. Second, this might explain some of the uncertainties about whether and how frequently rhinovirus causes severe lower respiratory tract disease, including respiratory failure.^9,10  Third, as discussed by the authors, there is no way to guarantee, even with negative diagnostic test results in patients with respiratory symptoms, that such patients are not contagious and cannot contribute to nosocomial spread of viral infections in hematology and stem cell transplant units. It is therefore important to include EV-D68 in the diagnostic strategy used in highly immunocompromised patients with upper or lower respiratory symptoms despite the fact that there is no available antiviral therapy for infections caused by EV-D68.