Clusters of Acute Respiratory Illness Associated with Human Enterovirus 68 --- Asia, Europe, and United States, 2008--2010

In the past 2 years, CDC has learned of several clusters of respiratory illness associated with human enterovirus 68 (HEV68), including severe disease. HEV68 is a unique enterovirus that shares epidemiologic and biologic features with human rhinoviruses (HRV) (1). First isolated in California in 1962 from four children with bronchiolitis and pneumonia (2), HEV68 has been reported rarely since that time and the full spectrum of illness that it can cause is unknown. The six clusters of respiratory illness associated with HEV68 described in this report occurred in Asia, Europe, and the United States during 2008--2010. HEV68 infection was associated with respiratory illness ranging from relatively mild illness that did not require hospitalization to severe illness requiring intensive care and mechanical ventilation. Three cases, two in the Philippines and one in Japan, were fatal. In these six clusters, HEV68 disproportionately occurred among children. CDC learned of clusters of HEV68 from public health agencies requesting consultation or diagnostic assistance and from reports presented at scientific conferences. In each cluster, HEV68 was diagnosed by reverse transcription--polymerase chain reaction (RT-PCR) testing targeting the 5'-nontranslated region, followed by partial sequencing of the structural protein genes, VP4-VP2, VP1, or both, to give definitive, enterovirus type-specific information. This report highlights HEV68 as an increasingly recognized cause of respiratory illness. Clinicians should be aware of HEV68 as one of many causes of viral respiratory disease and should report clusters of unexplained respiratory illness to the appropriate public health agency.

Philippines

During October 2008--March 2009, an outbreak of HEV68 was detected in the Eastern Visayas region of the Philippines among pediatric patients hospitalized with pneumonia (3). As part of a study of the etiology of pediatric viral respiratory illness, clinical samples from 816 patients hospitalized with pneumonia during May 2008--May 2009 were screened retrospectively for HEV68 by molecular methods (RT-PCR and partial sequencing); 21 (2.6%) were found to be positive. The virus was first detected in late October 2008, and cases peaked in early December. No cases of HEV68-related illness were found after March 2009. Among the 21 patients with HEV68 infection, 17 (81%) were aged 0--4 years (Table). Common signs and symptoms included cough, difficulty breathing, wheezing, and retractions. Two cases were fatal.

Japan

Japan's Infectious Agent Surveillance Report (IASR) system, which receives reports from local public health laboratories,* first received sporadic reports of HEV68 in 2005, with ≤10 cases identified each year until 2010. During 2010, an increase in HEV68 cases was observed, with more than 120 cases. Most HEV68 infections occurred during July--October 2010, with detections throughout Japan during this time. Clinical and demographic information was only available on a subset of 11 pediatric patients who were positive for HEV68. Of these 11 HEV68 cases, 10 were in patients diagnosed with acute respiratory illnesses, such as asthmatic bronchitis or pneumonia, and one in a patient with febrile convulsions (4). Of the 11 patients, 10 were aged 0--4 years (Table). One fatal case occurred, involving a boy aged 4 years in whom HEV68 was detected by nucleic acid amplification from a pharyngeal swab. The boy, who had been healthy with no underlying disease, arrived at the emergency department in cardiopulmonary arrest and could not be resuscitated (5).

Netherlands

During August--November 2010, HEV68 was detected within a prospective, hospital-based study of respiratory infections in the northern part of the Netherlands. All rhinovirus-positive samples obtained during September 2009--January 2011 were sequenced as part of a validation study. Specimens from 24 patients with acute respiratory illness, including pneumonia, asthma exacerbation, and wheezing, were positive for HEV68. Among the 24 patients, 23 were hospitalized during their illness, and five required intensive care. Three of the infections were acquired while in the hospital. Half of the 24 patients with HEV68 infection were aged ≥20 years (Table). Chronic underlying illness was present in approximately 80% of patients; no deaths were reported.

The National Institute for Public Health and the Environment also observed an increase in HEV68 infections among patients sampled in 2010 by the Netherlands sentinel general practice network for surveillance of acute respiratory infections among 42 practices. Samples have been collected in this network since 1994 and analyzed by RT-PCR for enteroviruses, allowing for a retrospective characterization of trends. As of the fall of 2010, a substantially greater number of HEV68 infections had occurred throughout the Netherlands that year than in previous years.

United States

Georgia. In September 2009, a hospital in Atlanta started using a new, multipathogen testing system (Luminex xTAG Respiratory Viral Panel [RVP], Luminex Corporation, Austin, Texas) for respiratory viral testing in its laboratory. The system can detect several respiratory viruses, including HRVs and enteroviruses, which are identified by the system only as "entero-rhinovirus." During the next respiratory illness season, September 2009--April 2010, adult patients at the Atlanta hospital facility who were diagnosed with "entero-rhinovirus" appeared to be more ill than those diagnosed with HRV in previous seasons. Nucleic acid sequencing of 68 specimens from the 2009--2010 season revealed that 62 (91.2%) contained HRV and six (8.8%) contained HEV68. Among the six patients with HEV68 (Table), three were aged >50 years and two were immunocompromised. Five patients had fever and four had cough. One patient had abnormal findings on chest radiography that were attributed to cryptococcosis. No other cases were associated with coinfections. Three patients were hospitalized for a median of 4 days. None of the patients required admission to an intensive-care unit (ICU), and none died.

Pennsylvania. In mid-September 2009, a pediatric hospital in Philadelphia noted more than twice the proportion of respiratory specimens testing positive for HRV by RT-PCR compared with those seen during previous fall HRV seasons. An investigation identified 390 children treated at the hospital during August--October 2009 from whom at least one respiratory specimen was positive for HRV. Respiratory specimens from 66 of these children were sent to CDC for further molecular characterization. HEV68 was identified in 28 (42%) of the specimens. Among the 28 patients with HEV68 infection, 15 (54%) were aged 0--4 years (Table), and 15 were admitted to the ICU. The median duration of hospitalization was 5 days, and none of the patients died.

Arizona. During August--September 2010, hospital officials at an isolated community hospital in rural Arizona noted an increase in pediatric admissions for lower respiratory tract illness. During this time, 43% of pediatric admissions were for respiratory illness, compared with a mean of 17% during the same period in the 3 previous years, a statistically significant difference. Similar illness, characterized by cough and tachypnea or hypoxemia, occurred in 18 patients. Abnormal lung examination result and wheezing, particularly new-onset wheezing, were noted. At least half of children with available chest radiographs had infiltrates. Hospitalization lasted a median of 1.5 days, and no deaths were reported. Despite viral testing and blood cultures performed at the Arizona Department of Health Services on patients with specimens available, no pathogen was detected. Nasopharyngeal specimens of seven patients were sent to CDC for further testing, and HEV68 was identified in five of the patients, one of whom also was positive by RT-PCR testing for Streptococcus pneumonia.

Reported by

Tadatsugu Imamura, Akira Suzuki, MD, PhD, Dept of Virology, Tohoku Univ Graduate School of Medicine, Japan. Adam Meijer, PhD, National Institute for Public Health and the Environment; Hubert G.M. Niesters, PhD, Janette C. Rahamat-Langendoen, MD, Univ Medical Center Groningen, Netherlands. Jose Lojo, MPH, Philadelphia Dept of Health; Richard L. Hodinka, PhD, Susan Coffin, MD, Children's Hospital of Philadelphia; Stephen M. Ostroff, MD, Pennsylvania Dept of Health. Colleen S. Kraft, MD, Emory Univ Hospital, Atlanta, Georgia. John T. Redd, MD, Indian Health Svc. Dean D. Erdman, DrPH, Xiaoyan Lu, Mark S. Oberste, PhD, Lauren J. Stockman, MPH, Gregory L. Armstrong, MD, Div of Viral Diseases, National Center for Immunization and Respiratory Diseases; Lara M. Jacobson, MD, Catherine Y. Yen, MD, EIS officers, CDC. Corresponding contributor: Lauren J. Stockman, lstockman@cdc.gov, 404-639-2553.

Editorial Note

Enteroviruses and HRV are common, closely related human pathogens in the Picornaviridae family. Most enterovirus infections are asymptomatic. When an enterovirus does cause disease, clinical manifestations vary widely and can include mild upper respiratory illness, febrile rash illness, and neurologic illness, such as aseptic meningitis and encephalitis. In contrast, HEV68 has been associated almost exclusively with respiratory disease (1,6). Since the early 1960s, only sporadic cases of infection with HEV68 have been reported (6,7). Identification of a large number of patients with HEV68 respiratory disease detected during a single season, such as described in this report, is a recent phenomenon.

Whether this increase in recognized cases is attributable to improved diagnostics or whether the clusters themselves represent an emergence of the pathogen is unknown. The technology for isolation of enteroviruses is not new. Viral culture has been available since the 1950s, although antisera for identifying an isolate as HEV68 were not widely available initially. The National Enterovirus Surveillance System, which has collected information on enterovirus isolates in the United States since 1961, recorded 26 isolates during 1987--2005; the highest number in a single year was 11 in 2003 (7).

During the past decade, improvements in nucleic acid amplification methods have increased the sensitivity of enterovirus detection and typing. In the clusters reported during 2008--2010, HEV68 was detected by real-time RT-PCR. Some sites used commercial, multipathogen detection systems that can detect enteroviruses. Two such systems, Luminex xTAG RVP and Idaho Technologies (Salt Lake City, Utah) FilmArray Respiratory Panel, are approved by the Food and Drug Administration for use in clinical settings in the United States. Both systems use broadly reactive primers that amplify RNA from either HRVs or enteroviruses (results are reported as "entero-rhinovirus" or "human rhinovirus/enterovirus").

Classic enteroviruses have prominent summer-fall seasonality in temperate climates (7,8), and outbreaks of enteroviruses tend to occur in several-year cycles. In the United States, echovirus 9 typically peaks every 3 to 5 years; echovirus 30 occurs irregularly and can remain active for several years (7). In France, HEV68 was associated with an autumnal peak of respiratory tract infections in 2008 (6). The seasonality of the HEV68 clusters described in this report typically fall within or later than the typical enterovirus season in the areas from which cases were reported (Figure) (7).

These recent clusters confirm that HEV68 is associated with outbreaks of respiratory illness severe enough to require hospitalization, and in some cases, might contribute to patient death. New-onset wheezing or asthma exacerbation were notable symptoms. However, in each cluster, respiratory specimens typically were collected from persons who had sought medical care or were hospitalized, which would have biased these reports toward more severe disease.

The spectrum of illness caused by HEV68 remains unclear. HEV68, like other enteroviruses, has been associated with central nervous system disease (9). Further investigation could help clarify the epidemiology and spectrum of disease caused by HEV68. Some diagnostic tests might not detect HEV68 or might misidentify it as an HRV. The gold standard test for HEV68 detection is partial sequencing of the structural protein genes, VP4-VP2 or VP1. Cases in this report were confirmed with this method. However, the sensitivity of multipathogen detection systems for HEV68 detection is unknown. Laboratories using the CDC rhinovirus real-time RT-PCR assay (10) as originally described and as recently modified (forward primer 5'-CPA_LNAGCCT_LNAGCGTGGY-3') should be aware that it might misidentify HEV68 as an HRV and lacks the sensitivity to detect all HEV68 cases.

Clinicians should be aware of HEV68 as one of many causes of viral respiratory disease. Clusters of unexplained respiratory illness should be reported to the appropriate public health agency. Local or state health departments may contact the CDC for assistance with laboratory diagnostics or consultation through the Unexplained Respiratory Disease Outbreak network (http://emergency.cdc.gov/urdo).

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