Severe enterovirus 68 respiratory illness in children requiring intensive care management

doi:10.1016/j.jcv.2015.07.298

Journal of Clinical Virology

Volume 70, September 2015, Pages 77-82

https://doi.org/10.1016/j.jcv.2015.07.298 Get rights and content

Highlights

•
Enterovirus 68 (EV-D68) causes severe respiratory disease.
•
EV-D68 infected children are older than those with other enteroviruses/rhinoviruses.
•
Children with asthma are at risk for severe EV-D68 disease.
•
Asthmatic EV-D68 infected children may require therapy for refractory bronchospasm.

Abstract

Background

Enterovirus 68 (EV-D68) causes acute respiratory tract illness in epidemic cycles, most recently in Fall 2014, but clinical characteristics of severe disease are not well reported.

Objectives

Children with EV-D68 severe respiratory disease requiring pediatric intensive care unit (PICU) management were compared with children with severe respiratory disease from other enteroviruses/rhinoviruses.

Study design

A retrospective review was performed of all children admitted to Children’s Mercy Hospital PICU from August 1-September 15, 2014 with positive PCR testing for enterovirus/rhinovirus. Specimens were subsequently tested for the presence of EV-D68. We evaluated baseline characteristics, symptomatology, lab values, therapeutics, and outcomes of children with EV-D68 viral infection compared with enterovirus/rhinovirus-positive, EV-D68-negative children.

Results

A total of 86 children with positive enterovirus/rhinovirus testing associated with respiratory symptoms were admitted to the PICU. Children with EV-D68 were older than their EV-D68-negative counterparts (7.1 vs. 3.5 years, P = 0.01). They were more likely to have a history of asthma or recurrent wheeze (68% vs. 42%, P = 0.03) and to present with cough (90% vs. 63%, P = 0.009). EV-D68 children were significantly more likely to receive albuterol (95% vs. 79%, P = 0.04), magnesium (75% vs. 42%, P = 0.004), and aminophylline (25% vs. 4%, P = 0.03). Other adjunctive medications used in EV-D68 children included corticosteroids, epinephrine, and heliox; 44% of EV-D68-positive children required non-invasive ventilatory support.

Conclusions

EV-D68 causes severe disease in the pediatric population, particularly in children with asthma and recurrent wheeze; children may require multiple adjunctive respiratory therapies.

Section snippets

Background

Enterovirus 68 (EV-D68) was identified from oropharyngeal swabs of 4 children hospitalized with acute lower respiratory tract illness (LRTI) in 1962 [1]. EV-D68 has features of both enteroviruses and rhinoviruses and is associated with respiratory symptoms [2], [3]. Many multiplex PCR assays used in clinical practice do not distinguish between the two species, so the manifestations and severity of EV-D68 have not been well characterized. Previous epidemiologic studies have been primarily

Objective

We aim to describe severe EV-D68 disease, including at-risk populations, presenting symptoms, and extent of intensive therapies used compared with children with severe disease from other enteroviruses/rhinoviruses. We report the largest cohort of pediatric EV-D68 disease to date, and the first to focus on children requiring pediatric ICU (PICU) stay.

Study subjects

An increase in emergency department visits and hospital admissions associated with severe respiratory disease was noted on August 15, 2014 at Children’s Mercy Hospital (CMH). A case definition was established on August 21, and respiratory pathogen panel (RPP) (Biofire Inc, Salt Lake City, Utah) testing was recommended for all inpatient children with increased work of breathing requiring supplemental oxygen or continuous albuterol. This assay does not distinguish between human enteroviruses and

Results

From August 1 to September 15, 2014, 562 children were admitted to CMH, had positive enterovirus/rhinovirus testing, and had specimens available for EV-D68 testing. 61/341 (17.9%) EV-D68 positive (EV-D68+) children required PICU management compared with 34/221 (15.4%) children with non-EV-D68 enteroviruses/rhinoviruses (EV-D68-). Of the 95 PICU children, 10 EV-D68- children and 2 EV-D68+ children were excluded because they required PICU management for non-respiratory reasons. Thus, 83 children

Discussion

In August 2014, we identified an outbreak of severe respiratory infection in children, which was confirmed to be caused by EV-D68 [18]. The need for ICU management of children was uncommonly reported in previous EV-D68 outbreaks, and descriptive literature provided little data to highlight specific clinical features, potential high-risk populations, or effective therapies. To our knowledge, this study is the largest pediatric cohort of EV-D68 disease and is the first to characterize severe

Competing interests

None declared.

Ethical approval

Children’s Mercy Hospital Institutional Review Board approved this study.

Funding

This work was funded in part by federal appropriations from the Emerging Infections line item to the Department of Health and Human Services.

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Cited by (49)

Enterovirus D68 vRNA induces type III IFN production via MDA5
2024, Virus Research
Enterovirus D68 (EV-D68) primarily spreads through the respiratory tract and causes respiratory symptoms in children and acute flaccid myelitis (AFM). Type III interferons (IFNs) play a critical role in inhibiting viral growth in respiratory epithelial cells. However, the mechanism by which EV-D68 induces type III IFN production is not yet fully understood. In this study, we show that EV-D68 infection stimulates Calu-3 cells to secrete IFN-λ. The transfection of EV-D68 viral RNA (vRNA) stimulated IFN-λ via MDA5. Furthermore, our findings provide evidence that EV-D68 infection also induces MDA5-IRF3/IRF7-mediated IFN-λ. In addition, we discovered that EV-D68 infection downregulated MDA5 expression. Knockdown of MDA5 increased EV-D68 replication in Calu-3 cells. Finally, we demonstrated that the IFN-λ1 and IFN-λ2/3 proteins effectively inhibit EV-D68 infection in respiratory epithelial cells. In summary, our study shows that EV-D68 induces type III IFN production via the activated MDA5-IRF3/IRF7 pathway and that type III IFNs inhibit EV-D68 replication in Calu-3 cells.
Prevalence and clinical presentation of EV-D68 infections in Kansas City children during the 2022 season
2023, Diagnostic Microbiology and Infectious Disease
Seasonal EV-D68 infections can strain medical care resources due to increased pediatric hospitalizations for respiratory illness. In this study, we examine Kansas City's 2022 EV-D68 season. Rhinovirus/enterovirus (RV/EV) positive respiratory specimens from standard of care testing were salvaged and tested by EV-D68 specific PCR. Of the 1412 respiratory specimens tested from July 1 to September 15, 2022, 346 (23%) were positive for RV/EV and EV-D68 was detected in 134/319 (42%) salvaged RV/EV positive specimens. The median age of children with EV-D68 infections was 35.2 months (IQR 16.1, 67.3), which was older than children with non-EV-D68 RV/EV infections (16 months, IQR 5, 47.8), but younger than children infected during the 2014 EV-D68 outbreak. EV-D68 infection was more likely to cause severe disease in children with asthma compared to those without asthma. Real-time EV-D68 monitoring for outbreaks could potentially improve resource utilization by hospitals and help prepare for surges of respiratory disease.
Likelihood of hospitalization for a chronic respiratory condition following pediatric infection with enterovirus and rhinovirus strains
2022, Infectious Medicine
Citation Excerpt :
However, there is conflicting evidence on the outcome of the emergent EV-D68 strain both in terms of acute complications of infections and longer-term prognosis. One study found that EV-D68 positive children admitted to intensive care were more likely to receive asthma or steroid medications and ventilatory support as part of their acute clinical management, as compared to enterovirus/rhinovirus positive, EV-D68 negative children [16]. Many studies have found EV-D68 to be associated with severe clinical respiratory disease in children [16–19,22,32].
Rhino-enteroviruses, particularly enterovirus strain D68 (EV-D68), have been associated with severe respiratory distress in children. The goal of this study was to compare the long-term outcomes of children with EV-D68 infection to that of children with other enterovirus / rhinovirus.
Nasopharyngeal swabs from 174 children presenting with respiratory distress were tested by PCR for respiratory viruses. The primary outcome was diagnosis of a chronic respiratory condition within the follow-up period. Admission to intensive care, and length of stay were recorded. Odds ratios were determined using multinomial logistic regression.
During 5 years of follow-up, the crude odds of diagnosis with a chronic respiratory condition were significantly more likely in EV-D68 cases (OR: 1.95, 95% CI: 1.02, 3.82), but failed to remain significant after adjusting for a past history of asthma. Upon admission for a primary concern of asthma, length of stay both in hospital and intensive care were significantly longer in EV-D68 cases (OR: 2.10 [95% CI: 1.56, 2.82, p < 0.001]) and (OR: 5.18 [95% CI: 1.90, 6.28, p < 0.001]), respectively. After adjustment for a history of asthma, EV-D68 cases had significantly longer length of stay in hospital, admitted for 1.94 days for each day that controls were admitted (95% CI: 1.40, 2.68). In admissions to intensive care, EV-D68 cases spent 2.74 days for each day of admission in controls (95% CI: 1.62, 4.97, p < 0.001).
Ours is first study to assess prognostic respiratory outcomes of patients infected with EV-D68 in childhood. Our study finds that EV-D68 cases were significantly more likely be hospitalized for longer than other enterovirus/rhinovirus controls in subsequent admissions for respiratory distress. Need for intensive care was significantly longer in EV-D68 infections. Our next steps will be validation in a larger sample size.
Respiratory presentation of patients infected with enterovirus D68 in Taiwan
2020, Pediatrics and Neonatology
Enterovirus-D68 (EV-D68) has been endemic in Taiwan for some years with a small number of positive cases. Detailed information about respiratory presentation is lacking. This study characterized the clinical course in children admitted to the medical center and regional hospital in Taichung during 2015.
Retrospective chart review of patients with confirmed EV-D68 infection admitted to the medical center and regional hospital in Taichung with respiratory symptoms in the second half of 2015. Past medical history, clinical presentation, management, and course in hospital were collected and analyzed. Simple demographic data and clinical symptoms were also collected from patients confirmed with EV-D68 infection who visited clinics in Taichung.
Six children were included. Two patients had a prior history of asthma or recurrent dyspnea, and one had other preexisting medical comorbidities. One child was admitted to the pediatric intensive care unit. All the patients were cured. Cough, rhinorrhea, tachypnea and fever were the most common clinical symptoms among inpatients, while influenza-like illness (ILI) was prevalent in outpatients.
EV-D68 infection resulted in respiratory presentations of asthma-like illness in the hospitalized pediatric population. Patients with a prior history of asthma or recurrent dyspnea appear to be more severely affected.
Enterovirus D68 outbreak detection through a syndromic disease epidemiology network
2020, Journal of Clinical Virology
Citation Excerpt :
EV-D68 respiratory illness in children typically presents with mild-to-severe clinical symptoms, such as runny nose, fever, cough, wheezing, and dyspnea, which may lead to hospitalization requiring intensive care [2,3]. Children with an underlying medical condition, such as asthma or recurrent wheezing, are at particular risk of severe EV-D68 infection [4]. In recent years, there is accumulating evidence to support that EV-D68 is associated with acute flaccid myelitis (AFM) in children [5–9].
In 2014, enterovirus D68 (EV-D68) was responsible for an outbreak of severe respiratory illness in children, with 1,153 EV-D68 cases reported across 49 states. Despite this, there is no commercial assay for its detection in routine clinical care. BioFire® Syndromic Trends (Trend) is an epidemiological network that collects, in near real-time, deidentified. BioFire test results worldwide, including data from the BioFire® Respiratory Panel (RP).
Using the RP version 1.7 (which was not explicitly designed to differentiate EV-D68 from other picornaviruses), we formulate a model, Pathogen Extended Resolution (PER), to distinguish EV-D68 from other human rhinoviruses/enteroviruses (RV/EV) tested for in the panel. Using PER in conjunction with Trend, we survey for historical evidence of EVD68 positivity and demonstrate a method for prospective real-time outbreak monitoring within the network.
PER incorporates real-time polymerase chain reaction metrics from the RPRV/EV assays. Six institutions in the United States and Europe contributed to the model creation, providing data from 1,619 samples spanning two years, confirmed by EV-D68 gold-standard molecular methods. We estimate outbreak periods by applying PER to over 600,000 historical Trend RP tests since 2014. Additionally, we used PER as a prospective monitoring tool during the 2018 outbreak.
The final PER algorithm demonstrated an overall sensitivity and specificity of 87.1% and 86.1%, respectively, among the gold-standard dataset. During the 2018 outbreak monitoring period, PER alerted the research network of EV-D68 emergence in July. One of the first sites to experience a significant increase, Nationwide Children's Hospital, confirmed the outbreak and implemented EV-D68 testing at the institution in response. Applying PER to the historical Trend dataset to determine rates among RP tests, we find three potential outbreaks with predicted regional EV-D68 rates as high as 37% in 2014, 16% in 2016, and 29% in 2018.
Using PER within the Trend network was shown to both accurately predict outbreaks of EV-D68 and to provide timely notifications of its circulation to participating clinical laboratories
Current status of enterovirus D68 worldwide and in Taiwan
2020, Pediatrics and Neonatology
Enterovirus D68 was first identified in 1962 and caused a worldwide outbreak starting from the North America in 2014. Enterovirus D68 has been in continuous circulation among many countries recently, including Taiwan. Reports also reveal high seroprevalence, which indicates that the disease burden of enterovirus D68 may be underestimated via viral culture or polymerase chain reaction results. Although most infected cases have mild respiratory illness, severe complications including acute flaccid myelitis and acute respiratory distress syndrome have also been reported. In the position of an emerging pathogen, enterovirus D68 poses a threat to public health and may cause devastating diseases. Diverse severity of neurological sequelae remains inevitable among acute flaccid myelitis patients, but no curable treatment is available currently. According to the management suggestions of the American Centers of Disease Control, uses of corticosteroids and plasmapheresis are either preferred or avoided and intravenous immunoglobulin also has no clear indication in the treatment for acute flaccid myelitis. In this review article, we provide information about the epidemiology, clinical recognition and treatment strategy of enterovirus D68. Better understanding of this disease is the foothold for advanced investigation and monitoring in the future.

View all citing articles on Scopus

¹: These authors contributed equally to this work.

View full text

Severe enterovirus 68 respiratory illness in children requiring intensive care management

Highlights

Abstract

Background

Objectives

Study design

Results

Conclusions

Section snippets

Background

Objective

Study subjects

Results

Discussion

Competing interests

Ethical approval

Funding

Virology

J. Clin. Virol.

J. Clin. Virol.

J. Clin. Virol.

J. Biomed. Inform.

Blood

J. Pediatr.

Pediatr. Neurol.

Lancet

J. Allergy Clin. Immunol.

A probable new human picornavirus associated with respiratory diseases

Am. J. Epidemiol.

Human rhinovirus 87 and enterovirus 68 represent a unique serotype with rhinovirus and enterovirus features

J. Clin. Microbiol.

Enterovirus 68 is associated with respiratory illness and shares biological features with both the enteroviruses and the rhinoviruses

J. Gen. Virol.

Enterovirus 68 among children with severe acute respiratory infection, the Philippines

Emerg. Infect. Dis.

Outbreak of lower respiratory tract illness associated with human enterovirus 68 among American Indian children

Pediatr. Infect. Dis. J.

Lineages, sub-lineages and variants of enterovirus 68 in recent outbreaks

PLoS One

Phylogenetic characterization of enterovirus 68 strains in patients with respiratory syndromes in Italy

J. Med. Virol.

Continued seasonal circulation of enterovirus D68 in the Netherlands, 2011–2014

Euro Surveillance

Enterovirus 68 in children with acute respiratory tract infections, Osaka, Japan

Emerg. Infect. Dis.

Enterovirus 68 in pediatric patients hospitalized for acute airway diseases

J. Clin. Microbiol.

Molecular epidemiology and evolution of human enterovirus serotype 68 in Thailand, 2006–2011

PLoS One