Abstract & Commentary
Enterovirus 68 Rumors, Realities, Research
By Philip R. Fischer, MD, DTM&H
Professor of Pediatrics, Department of Pediatric and Adolescent Medicine, Mayo Clinic.
Dr. Fischer reports no financial relationships in this field of study.
SYNOPSIS: A preliminary report from Missouri suggests that enterovirus 68 is responsible for a large outbreak of respiratory disease in children. Typically, there is a rapid onset of respiratory symptoms with wheezing, and intensive care is required for about 15% of affected patients.
SOURCES: Vesterling G. Respiratory illnesses due to enterovirus D68 (EV-D68) in Missouri. Missouri Department of Health and Senior Services, August 29, 2014, health.mo.gov/emergencies/ert/alertsadvisories/pdf.HA82914.pdf; Centers for Disease Control and Prevention. Severe respiratory illness associated with enterovirus d68 - Missouri and Illinois, 2014. MMWR 2014;63(36):798-9.
In recent months, a children’s hospital in Kansas City, MO, cared for over 300 children with respiratory illness, a surprisingly large number for the summer season. Approximately 15% of these children required intensive care, but no deaths have been reported. Samples from 22 affected children were tested by the Centers for Disease Control and Prevention (CDC); 19 (86%) were positive for enterovirus D68.
Similarly, St. Louis, MO is also experiencing an increase in pediatric respiratory illnesses. There, too, many samples have tested positive for enterovirus, and more detailed testing of virus type is pending. Cases have now also been reported from as far away as the northeastern U.S.
Professional emails and lay news services have been lighting up with reports of unseasonable outbreaks of pediatric respiratory illness. Even the September 8, 2014, issue of AMA Morning Rounds cited reports of a "mystery virus" and "a rare virus sending kids rushing to the hospital when they can’t breathe." Anecdotally, patients are usually children in the first decade of life with little or no history of asthma. They become very sick very quickly with mild upper respiratory symptoms, wheezing, and significant respiratory distress. When used, commercially available tests that identify RNA common to both enteroviruses and rhinoviruses are often positive. Many of these children, even without a prior history of asthma respond favorably to therapeutic trials of albuterol. Pressure and even ventilatory support are sometimes required for one to three days.
Most of these preliminary unconfirmed reports so far are from the central United States. The Missouri report cited above was the only semi-formal documentation of an outbreak as this issue went to press. Anecdotal discussions at a meeting of Midwestern pediatric residency program directors suggested that many centers are seeing unseasonably large numbers of children with respiratory illnesses. Internet and news reports suggest that this frightening "new" disease is common in Missouri, Colorado, Ohio, Illinois, and other states. Accurately but dramatically, reports often mention that there is no specific treatment available for enteroviral infections. Personal reports suggest that CDC staff are analyzing data in order to prepare a peer-reviewed paper about relevant findings.
There are over 100 different enteroviruses, and several of them cause mild illnesses in children, often during summer. (Polioviruses, echoviruses, and Coxsackie viruses are in subgroups of the larger enterovirus family.) Most enteroviruses spread through personal contact and manifest infection with upper respiratory symptoms, fever, rash, and, sometimes, meningitis.
Enterovirus 68 was isolated from four California children with bronchiolitis and pneumonia in 1962. [These isolates were further studied several decades later.1] In recent years, this enterovirus has been reported in Asia as well.
From October 2009 through October 2010, a laboratory in Japan evaluated 448 respiratory specimens from children with fever and respiratory tract infections.2 Fifteen of the children had enterovirus 68, all during illnesses occurring from June through September. Children were aged 3 months to 4 years 9 months. The majority of affected children wheezed. Retrospectively, only 14 patients were found to have enterovirus 68 during the preceding four years, so investigators believed that this represented an epidemic.
Clinical respiratory specimens collected from May 2008 to May 2009 in the Philippines were later retrospectively analyzed for enterovirus using polymerase chain reactions and genetic sequencing.3 Enterovirus 68 was identified in 21 samples, 2.6% of all samples evaluated in the study. Children were from Tacloban City and surrounding areas, and most all positive samples were from October through December. Ages of affected children ranged from 1 month to 9 years. All had cough, and two-thirds wheezed; all had retractions. Two patients did not survive the illness.
More recently, Chinese investigators studied 1565 samples obtained between 2009 and 2012; 41 (2.6%) were positive for enterovirus.4 Seven (17%) of the enterovirus positive samples tested positive for enterovirus 68, making it the predominant type of enterovirus in children with acute respiratory infection.
Most enterovirus 68-positive subjects were ill from August through December; two were adults. Most of the infected children also tested positive for other respiratory pathogens (human bocavirus, respiratory syncytial virus, Epstein Barr virus, cytomegalovirus, Chlamydia, Mycoplasma, and influenza A).
Genetic evaluation showed similarities between the Chinese strains and previously identified strains from the Netherlands and the USA, suggesting that the Chinese viruses might have migrated from Europe and North America to China.
In 2006, the CDC reviewed clinical data associated with 52,812 enterovirus infections in the US.5 There were only 26 cases of enterovirus 68 during the 36 studied years; most were associated with respiratory illness, but the virus was also identified from cerebrospinal fluid of a young adult with acute flaccid paralysis.
Different enteroviruses are known to be associated with acute flaccid paralysis,6 but there have been two paralyzed children in California since 2012 who were infected (or, at least, colonized) with enterovirus 68.7
Thus, the currently evolving outbreak of pediatric respiratory illness in the central United States seems similar to reported outbreaks of pediatric respiratory infections in Asia. However, associations and anecdotes do not prove causality. Especially as news agencies sound alarms over "mystery" illnesses that "rush" children to hospitals, we should show some restraint as we await the results of peer-reviewed studies.
Earlier this year, Swedish investigators reported on viral studies of 151 children with acute respiratory infections.8 They compared positive results in patients to positive results in controls. Interestingly, asymptomatic control children were as likely to test positive for enterovirus as were sick patients! As in the Chinese study noted above4, many sick children carry several potential pathogens, and it is not clear just which of multiple identified pathogens is etiologically related to their symptoms.
Rhinoviruses are commonly identified in both sick and asymptomatic children.8 The virus previously identified as rhinovirus 87 is actually the same virus as enterovirus 68.5 There is overlap between rhinovirus and enterovirus RNA, and current commercial polymerase chain reaction tests do not distinguish between rhinovirus and enterovirus. Thus, future studies will need to not only compare findings in symptomatic patients with controls but also to accurately identify strains of specific viruses.
While awaiting further research and peer-reviewed reports, however, clinicians should be aware that the current summer-fall viruses now circulating in the United States might include an enterovirus that can cause severe respiratory infections. While effective specific anti-viral therapy is not available, supportive care seems to be effective.
- Oberste MS, et al. Enterovirus 68 is associated with respiratory illness and shares biological features with both the enteroviruses and rhinoviruses. J Gen Virol 2004;85:2577-2584.
- Kaida A, et al. Enterovirus 68 in children with acute respiratory tract infections, Osaka, Japan. 2011 Emerg Infect Dis 17:1494-1497.
- Imamura T, et al. Enterovirus 68 among children with severe acute respiratory infection, the Philippines. Emerg Infect Dis 2011;17:1430-1435,
- Lu QB, et al. Detection of enterovirus 68 as one of the commonest types of enterovirus found in patients with acute respiratory tract infection in China. J Med Microbiol 2014;63:408-414.
- Khetsuriani N, et al. Enterovirus surveillance United States, 1970-2005. MMWR 2006;55:1-20,
- Laxmivandana R, et al. Characterization of the non-polio enterovirus infections associated with acute flaccid paralysis in south-western India. PLOS One 2013;8:e61650:1-9.
- Keuhn BM. Polio-like cases probed in California.JAMA 2014;311:1280-1281.
- Rhedin S, et al. Clinical utility of PCR for common viruses in acute respiratory illness. Pediatrics 2014;133:e538-e545.