Global emergence of enterovirus D68: a systematic review

Review

Global emergence of enterovirus D68: a systematic review Charlotte Carina Holm-Hansen, Sofie Elisabeth Midgley, Thea Kølsen Fischer

Since its discovery in California in 1962, reports of enterovirus D68 have been infrequent. Before 2014, infections were confirmed in only 699 people worldwide. In August, 2014, two paediatric hospitals in the USA reported increases in the number of patients with severe respiratory illness, with an over-representation in children with asthma. Shortly after, the authorities recognised a nationwide outbreak, which then spread to Canada, Europe, and Asia. In 2014, more than 2000 cases of enterovirus D68 were reported in 20 countries. Concurrently, clusters of children with acute flaccid paralysis of unknown cause were reported in several US states and in Europe. Enterovirus D68 infection was confirmed in some of the paralysed children, but not all. Complications in patients who were severely neurologically affected resemble those caused by poliomyelitis. In this paper we systematically review reports on enterovirus D68 to estimate its global epidemiology and its ability to cause respiratory infections and neurological damage in children. We extracted data from 70 papers to report on prevalence, symptoms, hospitalisation and mortality, and complications of enterovirus D68, both before and during the large outbreak of 2014. The magnitude and severity of the enterovirus D68 outbreak underscores a need for improved diagnostic work-up of paediatric respiratory illness, not only to prevent unnecessary use of antibiotics, but also to ensure better surveillance of diseases. Existing surveillance systems should be assessed in terms of capacity and ability to detect and report any upsurge of respiratory viruses such as enterovirus D68 in a timely manner, and focus should be paid to development of preventive measures against these emerging enteroviruses that have potential for severe disease.

Introduction Enterovirus D68 was first isolated in 1962 in Berkeley, CA, USA, from four children with severe respiratory tract infection and pneumonia.1 Since its initial identification, the virus has only been associated with sporadic cases of respiratory disease; only 26 cases were confirmed in the USA between 1970 and 2005.2 Minor outbreaks of enterovirus D68 were also described, with 699 cases confirmed in Europe, Africa, and southeast Asia between 1970 to 2013.1–32 In late summer of 2014 a large-scale outbreak of enterovirus D68 causing severe respiratory infection mainly in children was noted in the USA and Canada, with subsequent reports from other countries. So far, 2287 cases of enterovirus D68 infection in 2014 have been published.7,30–51 Enteroviruses are small single-stranded RNA viruses in the Picornaviridae family that share similar morphology, structure, molecular properties, and replication strategies.52,53 All viruses in the Picornaviridae family are small (18–30 nm), non-enveloped, and single-stranded positive-sense RNA viruses.54 Enteroviruses cause more than 10 million infections and several thousand hospital admissions every year in the USA alone and, together with human rhinoviruses, are among the most common pathogens associated with human disease.34,52,55 Enteroviruses are major contributors to disease worldwide, with a wide range of clinical features ranging from very mild to fatal infections.52 Enteroviruses are commonly involved in both acute and chronic cardiac disease; hand, foot, and mouth disease; respiratory infections; herpangina; myositis; pleurodynia; eye infections including acute haemorrhagic conjunctivitis; encephalitis; aseptic meningitis; and acute flaccid paralysis. Recently investigators have suggested that enterovirus infection combined with specific genetic host factors can trigger insulindependent diabetes in susceptible individuals.54 The

most well known enterovirus is poliovirus, the cause of poliomyelitis. Despite the eradication of poliovirus in most parts of the world, the disease remains of great concern because of its potential to spread and cause large outbreaks with high mortality and disability. In 2015, reported cases of wild poliovirus have been low with only 102 cases reported worldwide, 77 in endemic countries (Afghanistan and Pakistan) and 25 in non-endemic countries (Guinea, Laos, Madagascar, Myanmar, Nigeria, and Ukraine).56 Enterovirus D68 belongs to the species enterovirus D, which consists of four human genotypes: enterovirus D68, enterovirus D70, enterovirus D94, and enterovirus D111, as well as the genotype enterovirus D120 recently identified in the stool of apes.54,57,58 Human rhinovirus 87 was reclassified as a strain of enterovirus D68 in 2002, and is therefore of great importance when studying its historic emergence. Enterovirus D68 is a unique genotype that differs somewhat from most enteroviruses, sharing more physiochemical properties with human rhinoviruses.23,59,60 Furthermore, enterovirus D68 differs from other enteroviruses in temperature sensitivity, growing in cell culture at 33°C, which is the temperature of the nose, rather than at 37·0°C.59,61 Enterovirus D68 has mainly been isolated from respiratory samples, and has very rarely been reported in stools.3,7,37 Additionally, enterovirus D68 has a short C-terminal α helix in the VP3 protein not present in other enteroviruses.62 Three primary clades (A, B, and C) have been identified by Bayesian phylogenetic analysis of the VP1 region. Although all three clades are distributed globally, most of the observed diversity within enterovirus D68 has been reported from the USA.26 However, the enterovirus D68 phylogeny is characterised by the frequent presence of long branches throughout the tree, indicative of a general absence of global surveillance and detection of enterovirus D68, as well as the presence of in-situ evolution

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Lancet Infect Dis 2016 Published Online February 23, 2016 http://dx.doi.org/10.1016/ S1473-3099(15)00543-5 Virology Surveillance and Research Section, Department of Microbiological Diagnostics and Virology, Statens Serum Institut, Copenhagen, Denmark (C C Holm-Hansen MD, S E Midgley PhD, Prof T K Fischer DMSc); and Center for Global Health and Department of Infectious Diseases, Clinical Institute, University of Southern Denmark, Odense, Denmark (Prof T K Fischer) Correspondence to: Prof Thea Kølsen Fischer, Virology Surveillance and Research Section, Department of Microbiological Diagnostics and Virology, Statens Serum Institut, 2300 Copenhagen S, Denmark [email protected]

1

Review

in individual locations. Retrospective or broader sampling could reveal additional (and deeper) diversity.26 The unprecedented outbreak of enterovirus D68 in the autumn of 2014, which resulted in an upsurge of hospitalisations and admissions to intensive-care units, has prompted concern about a potential uncontrollable epidemic of severe lower respiratory diseases and neurological complications, including muscle weakness, polio-like acute flaccid paralysis, and cranial neuropathy.38,39,49,51,63–67 The 2014 outbreak was extensive; 1153 identified cases of severe respiratory disease and 107 cases of acute flaccid myelitis were reported in September to December, 2014, in the USA alone.7,30–49,51,68 Furthermore, nearly 700 cases were confirmed in Canada, including eight cases of acute flaccid paralysis and other neurological diseases, two cases in Chile, and 408 cases in Europe, including three children with complications of acute flaccid paralysis in France and Norway.32,35–38,40,41,43–49,51,67,69 25 cases have been reported in China, Taiwan, and Thailand.7,30,31,47 These cases have subsequently all been attributed to enterovirus D68 infection.7,30–49 Due to the testing practices of enteroviruses in respiratory material, which we detail in this Review, the cases presented are most probably a small proportion of actual cases that have occurred. In this systematic review we aimed to use the published work to investigate the potential of enterovirus D68 to

326 records identified through database searching

4 additional records identified through other sources

149 after duplicates removed

cause severe respiratory infection and neurological symptoms in children.

Methods Search strategy and selection criteria We used the 2009 PRISMA guidelines to systematically review the literature for enterovirus D68. We searched PubMed for reports published from 1962 to Aug 18, 2015, with the terms “enterovirus 68”, “enterovirus D68”, and “EV D68”, without MeSH terms. We reviewed all available published work. All studies were published in peer-reviewed journals, apart from data from the Canadian health authorities. We used no language restrictions, and data from abstracts from Spanish and Chinese studies were also included in the review. 62 papers were identified as eligible for inclusion in the Review (figure 1). We repeated the search on Dec 7, 2015, while revising the paper and included another eight articles published within these dates.

Study bias Most epidemiological studies included in this report were based on retrospective analyses of respiratory samples with small sample sizes and were done in paediatric inpatient hospital settings. These characteristics restrict the representativeness of reported data for age of patients, severity of disease, and geographical location. Furthermore, the scarcity of testing for enterovirus, particularly of enterovirus D68 specifically, in respiratory samples also provides a bias in the data available. Following the 2014 enterovirus D68 outbreak the US Centers for Disease Control and Prevention (CDC) have emphasised the importance of this virus in the aetiology of lower respiratory illness by recommending testing for enterovirus D68 in patients with an unclear cause of respiratory disease.

149 screened

Historical outbreaks from 1962 to January, 2014 87 excluded because they did not include original clinical data

62 eligible

62 included in first draft of systematic review

32 identified in second search during revisions 8 included 24 excluded

70 included in systematic review

Figure 1: Study selection procedure

2

Before 2014 enterovirus D68 was one of the rarest identified enteroviruses.26 After its first identification in 1962 cluster outbreaks of respiratory disease caused by enterovirus D68 were reported in the USA, Europe, southeast Asia, and Africa. 699 cases of enterovirus D68 were reported up to the beginning of 2014 (table 1).1–32 Most of these cases have been identified retrospectively in respiratory samples from patients with severe respiratory diseases with an unknown pathogen or an unspecified enterovirus diagnosis. Testing has only been done in a few centralised health centres with special expertise and interest in enterovirus D68 within some countries, which does not accurately reflect the burden of disease. Between June, 2007, and September, 2010, 66 sporadic cases of enterovirus D68 were reported in the USA, including one fatal case of acute flaccid paralysis in New Hampshire, which was reported in 2008.5,10,12,26,27 Cluster outbreaks were also been reported in France, Italy, the

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Review

Location

Period

Schneible1

Berkeley, CA, USA

October–December, 1962

Khetsuriani et al2

USA

1970–2005

Kreuter et al12

New Hampshire, USA

Fall 2008

MMWR5

Georgia, USA

MMWR5

Total samples (n)

Cases (n)

Samples used

Age range

Signs and symptoms

Deaths (n)

AFP (n)

4

4

Respiratory samples

10 months to 3 years

Acute lower respiratory tract illness, pneumonia, wheezing, and bronchiolitis

0

0

NA

26

Respiratory samples

10 months to 43 years

Bronchiolitis, pneumonia, wheezing, and respiratory distress

NA

NA

1

1

CSF

5 years

Headache, low-grade fever, sore throat, unilateral neck tenderness, myalgia, weakness in arms, bowel and bladder incontinence, and inability to walk

1

1

September, 2009–April, 2010

68

6

Respiratory samples

20 years or older

Fever and cough

0

0

Pennsylvania, USA

August–October, 2009

66

28

Respiratory samples

0–4 years

Respiratory infection

0

0

MMWR5

Arizona, USA

August–September, 2010

NA

5

Respiratory samples

Paediatric

Lower respiratory tract infection

0

0

Tokarz et al26

New York, NY, USA

May, 2009–May, 2010

940

14

Nasopharyngeal NA swabs

>37·7°C fever, respiratory illness

NA

NA

Wang et al27

San Diego, CA, USA 2007

202

7

Throat swab samples

Febrile respiratory illness, pneumonia, pharyngitis, and bronchitis

0

0

Meijer et al17

Netherlands

1994–2010

13 310

71

0–89 years Upper respiratory tract samples

Fever, malaise, headache, myalgia, sore throat, cough, dyspnoea, rhinorrhoea, bronchitis, and pneumonia

NA

NA

Meijer et al18

Netherlands

2011–14

NA

27

Respiratory samples

0–80 years

Acute respiratory infection, influenza-like NA illness

NA

Renois et al24

ChampagneArdenne, France

September, 2009–June, 2010

651

10

Respiratory samples

6 months to 10 years

Bronchitis, acute asthma, and bronchiolitis

0

0

Piralla et al21

San Matteo, Pavia, Italy

October, 2008–September, 2009

6211

9

Respiratory samples

Unknown

Acute respiratory infection

NA

NA

Lauinger13

London, UK

November, 2009–December, 2010

403

17

Respiratory samples

Mean 10·2 years Upper respiratory tract infection and lower respiratory tract infection

1

NA

Jacobson et al11

Indian Health Service, Albuquerque, NM, USA

August, 2010–September, 2010

7

5

Respiratory samples

6 months to 18 years

Pneumonia and wheezing

0

0

0–15 years

Acute lower respiratory tract infection, pneumonia, wheezing, and bronchiolitis

3

0

NA

Linsuwanon et al15 Bangkok, Thailand

February, 2006–November, 2011

1810

25

Respiratory samples

Ikeda et al8

2005–10

6307

55

Nasopharyngeal 5 months swabs to 15 years

Acute respiratory infection, fever, and rhinorrhoea

0

0

NA

88

NA

NA

NA

NA

2150

9

Nasopharyngeal 1 month to swabs 54 years

Fever, cough, wheezing, sputum production, respiratory failure, headache, fatigue, and myalgia

NA

NA

85

8

Respiratory samples

4–71 years

Sore throat and unexplained acute respiratory illness

0

0

816

21

asopharyngeal swabs

1 month to 9 years

Cough, difficulty breathing, wheeze, and chest indrawings

2

0

Yamagata, Japan

Infectious Japan Diseases Surveillance Report (data from Ikeda et al8)

2010

NA

Quing-Bin et al22

China

June, 2009–June, 2012

Ly et al16

Cambodia

2009–12

Imamura et al9

Viasayas region of Philippines

May, 2008–May, 2009

Todd et al25

New Zealand

March–August, 2010

NA

15

1 month to Throat swabs, nasopharyngeal 48 years swabs, and nasopharyngeal aspirate

Respiratory disease

0

0

Opanda et al20

Kenya

2008–11

NA

13

Nasopharyngeal 2 months to samples 6 years

Cough, runny and stuffy nose, fatigue, malaise, and neurological signs

0

0

Tokarz et al26

The Gambia

June, 2008

NA

5

Respiratory samples

Respiratory disease

NA

NA

0–2 years

(Table 1 continues on next page)

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Location

Period

Total samples (n)

Cases (n)

Samples used

Age range

Signs and symptoms

Deaths (n)

AFP (n)

(Continued from previous page) Tokarz et al26

South Africa

May, 2000–May, 2001

NA

8

Respiratory samples

5–23 months

Respiratory disease

NA

NA

Tokarz et al26

Senegal

February–March, 2010

NA

3

Respiratory samples

2–32 years

Respiratory disease

NA

NA

Rahamat et al23

Netherlands

January 2009–October, 2010

272

27

Respiratory samples

1 month to 72 years

Dyspnoea, cough, exacerbation of asthma or wheezing, pneumonia, and upper respiratory tract infection

0

0

Xiang et al29

Beijing, China

August, 2006–April, 2010

6942

13

Throat and nasal swabs

Adult patients (>15 years)

Pharyngeal congestion, headache, myalgia, chills, sore throat, rhinorrhoea, sneezing, cough, swelling of tonsils, rigors, and urinary tract infection

NA

NA

Hasegawa et al6

Yamaguchi, Japan

July–September, 2010

35

26

Nasopharyngeal Mean 3·5 years samples (SD 2·6)

Asthma attack

NA

NA

Kaida et al11

Osaka, Japan

October, 2009–October, 2010

448

14

Respiratory samples

7 months to 5 years

Respiratory tract infection and fever, bronchitis, wheezing, coughing, asthmatic bronchitis, pneumonia, pharyngitis, asthma, respiratory failure, febrile convulsions, and lower respiratory tract infection

NA

NA

Launes et al14

Spain

January, 2010–May, 2012

96

5

Respiratory samples

6 months to 18 years

Bronchospasm and bronchopneumonia

NA

NA

Ng et al19

Malaysia

March, 2012–May, 2014*

3935

12

Nasopharyngeal NA swabs

Acute upper respiratory tract infection

NA

NA

Carney et al4

Brazil

2009–10

594

2

NA

2 months to 4 years

Cough, runny nose, respiratory distress, low-grade fever, diarrhoea, and cardiopulmonary arrest

0

0

Huang et al7

Taiwan

2007–14

575

57

Throat swabs, rectal swabs, stool, serum samples, and CSF

0 years to adult

Fever, cough, rhinorrhoea, and sore throat

0

NA

Xiao et al30

China

January, 2012–November, 2013

1190

6

Cough, wheezing, fever, diarrhoea, and respiratory failure

0

0

Levy et al3

Australia

January, 2007–January, 2015†

NA

55

Lower respiratory tract infection, asthma, 0 wheezing, bronchiolitis, pneumonia, upper respiratory tract infection, fever, headache, malaise, rash, meningism, abdominal pain, and lethargy

2

Thongpan et al31

Thailand

September, 2013

NA

2

Fever, cough, runny nose, dyspnoea, wheezing, and respiratory failure

0

Nasopharyngeal 7 months to aspirate 4 years Respiratory samples, stool samples, rectal swabs, and CSF

10 days to 81 years

4 years Tracheal suction, nasopharyngeal suction

0

AFP=acute flaccid paralysis. MMWR=US Centers for Disease Control and Prevention’s Morbidity and Mortality Weekly Report. NA=not available. CSF=cerebrospinal fluid. *Enterovirus D68 cases detected in January, 2014, and therefore not identified as in the autumn 2014 outbreak. †Data from 2008–15, no cases were detected in 2014 and the one case from 2015 could not be separated from the other data.

Table 1: Reports of cases of enterovirus D68 before the 2014 outbreak

UK, and the Netherlands.13,17,20,22,23 24 (34%) of the 71 cases between 1994 and 2010 in the Netherlands occurred in 2010, suggesting an epidemic, which was confirmed with phylogenetic analyses of partial VP1 sequences showing increased genetic diversity.17 Between 2005 and January, 2014, southeast Asia also had an increased number of acute respiratory infections due to enterovirus D68 (table 1).6–9,15,16,18,21,28–30,49 However, little epidemiological data are available for countries in Asia and Oceania. The first cases from New Zealand were reported in 2010 in 15 patients aged from 1 month 4

to 48 years, and 55 patients have so far been diagnosed in Western Australia since 2007.3,24 Cases of enterovirus D68 have also been reported in The Gambia, South Africa, Senegal, and Kenya (table 1).19,25

The major enterovirus D68 outbreak in 2014 In the autumn of 2014 (between August and December; table 2), an unprecedented high number of people (almost all children) were admitted to hospitals across the USA, Canada, and Europe with severe lower respiratory disease. This outbreak was the largest since

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the identification of enterovirus D68, with 2287 cases confirmed worldwide in 2014.3,7,30–49,50,51 From the USA alone, 1153 cases were reported in 49 states from midAugust to Jan 15, 2015 (table 2).34,41 The CDC suggested that millions of people had mild infections, but did not require medical attention and so were not registered. Comparison of the genetic sequences from this outbreak to those from previous years show that they are genetically related to strains of enterovirus D68 that were detected in previous years in the USA, Europe, and Asia.11 Canada also reported an exceptionally high number (699) cases of enterovirus D68 in nine of its provinces (table 2).32,43,51 In British Columbia alone, 221 cases were reported between Sept 1 and Dec 31, 2014.32 Two cases in Santiago, Chile, were confirmed cases of enterovirus D68 (table 2).46 One patient was a father who had travelled to the USA within the past 3 months. Both cases in Chile were virologically and clinically related to the outbreak occurring in the USA.46

16 cases of enterovirus D68 were detected in northern Netherlands from February to September, 2014 (table 2); 11 of them in children, with a total of 56 cases recorded in the country in 2014.43,44 In Norway, an unexpectedly high number of severe respiratory infections were seen from Sept 1 until Oct 31, which resulted in screening of all paediatric (<15 years) patients at the Ullevål Hospital in Oslo.48 Enterovirus D68 was confirmed in 34 patients, including two with acute flaccid paralysis, and an additional 15 patients were identified at the Norwegian Institute of Public Health (NIPH) in Oslo and in Trondheim.44,48,49 In Spain, six patients with respiratory symptoms tested positive for enterovirus D68.37,44 In Germany, 41 patients, both children and adults, tested positive for enterovirus D68 from 325 outpatients with influenza-like illness or acute respiratory infection.44,45 In Denmark, 14 patients tested positive for enterovirus D68 from 1322 patients with respiratory diseases, and 11 were children younger

Cases Total samples (n) (n)

Samples used

Age range

Signs and symptoms

1153

Nose and throat samples

NA

Runny nose, cough, sneezing, body and muscle aches, wheezing, and difficulty breathing

NA

546

NA

NA

6

2

Nasopharyngeal samples

4267

56

354

Location

Period

CDC34,39,41,64,65,70

USA

Mid-August to December, 2014

NA

National Collaborating Centre for Infectious Diseases and BCCDC,32 Skowronski et al51

Canada

September–December, 2014

Torres et al46

Chile

September–October, 2014

Poelman et al43,44

Netherlands

Feb 1–Dec 1, 2014

Bragstad et al,48 Pfeiffer et al49

Ullevål, Norway

September–October, 2014

Poelman et al44

July 1–Dec 1, 2014 Norwegian Institute of Public Health, Norway, and Trondheim, Norway

Gimferrer et al,37 Poelman et al44

Spain

Reiche et al,45 Poelman et al44

Deaths AFP (n) (n) 14

107

NA

3

5

7–9 years

Upper respiratory symptoms, low-grade fever, respiratory distress, and breathing difficulty

0

0

Respiratory specimens

0 years to adult

Severe respiratory illness, bronchiolitis, mild cold symptoms, fatigue, cough, wheezing, pneumonia, and asthma exacerbation

0

0

34

Nasopharyngeal samples

0–15 years

Severe respiratory symptoms

0

2

223

15

Respiratory specimens

0 years to adult

Respiratory symptoms

0

0

July 1–Dec 1, 2014

1035

6

Respiratory specimens

0 years to adult

Respiratory symptoms

0

0

Germany

July 1–Dec 1, 2014

2509

41

Respiratory specimens

0 years to adult

Sudden onset, fever and shivers, cough, sore throat, and pneumonia

0

0

Midgley et al40

Denmark

September–November, 2014

130

14

Tracheal and nasopharyngeal secretions, expectorate

0–68 years

Pneumonia, respiratory failure, cough, fever, and wheezing

0

0

Zhang et al47

China

August–November, 2014

1478

1

Nasopharyngeal samples

5 years

Fever, cough, breathing difficulty, abdominal pain, and diarrhoea and vomiting

0

0

Lang et al38

France

September, 2014

1

1

Nasopharyngeal samples, stool

4 years

Headache, vomiting, febrile meningeal syndrome, bilateral pneumonia, and acute myocarditis

0

1

Dyrdak et al35

Sweden

July–October, 2014

30

7

Nasopharyngeal samples

2 months to 9 years

Respiratory symptoms

0

0

(Table 2 continues on next page)

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Location

Period

Cases Total samples (n) (n)

Samples used

Age range

Signs and symptoms

Deaths AFP (n) (n)

(Continued from previous page) Esposito et al36

Italy

June–December, 2014

Bal et al33

France

October, 2014

Peci et al42

Ontario, Canada

Huang et al7

176

4

Nasopharyngeal samples

8 months to 14 years

Severe respiratory symptoms, fever, cough

0

0

8

2

Nasal samples

79–101 years

Mild respiratory disease, cough, and rhinorrhoea

0

0

Sept 1–Oct 31, 2014

907

153

Nasopharyngeal swab, respiratory aspirate, throat swab or nasal swab

0 years to adult

Respiratory symptoms, fever, chills, and shortness of breath

0

0

Taiwan

2007–14*

NA

8

Throat swabs, rectal swabs, stools, sera, and CSF

0 years to adult

Fever, cough, rhinorrhoea, and sore throat

0

NA

Thongpan et al31

Thailand

2014

NA

3

Nasopharyngeal or nasal swabs

1–3 years

Fever, cough, vomiting, wheezing, chest retractions, runny nose, and dyspnoea

0

NA

Xiao et al30

China

September–October, 2014

686

13

Nasopharyngeal aspirate

1–6 years

Fever, cough, wheezing, respiratory failure, chest pain, expectoration, and diarrhoea

0

0

Poelman et al44

Pavia, Italy

July 1–Dec 1, 2014

195

9

Respiratory specimens

0 years to adult

Respiratory symptoms

0

0

Poelman et al44

Finland

July 1–Dec 1, 2014

900

17

Respiratory specimens

0 years to adult

Respiratory symptoms

0

0

Poelman et al44

Scotland

July 1–Dec 1, 2014

488

22

Respiratory specimens

0 years to adult

Respiratory symptoms

0

0

Poelman et al44

Ireland

July 1–Dec 1, 2014

1010

4

Respiratory specimens

0 years to adult

Respiratory symptoms

0

0

Poelman et al44

Wales

July 1–Dec 1, 2014

604

9

Respiratory specimens

0 years to adult

Respiratory symptoms

0

0

Poelman et al44

Austria

July 1–Dec 1, 2014

778

1

Respiratory specimens

0 years to adult

Respiratory symptoms

0

0

Poelman et al44

Slovenia

July 1–Dec 1, 2014

702

48

Respiratory specimens

0 years to adult

Respiratory symptoms

0

0

Poelman et al44

Luxembourg

July 1–Dec 1, 2014

19

1

Respiratory specimens

0 years to adult

Respiratory symptoms

0

0

Poelman et al44

France

July 1–Dec 1, 2014

3489

117

Respiratory samples

0 years to adult

Respiratory symptoms

0

0

AFP=acute flaccid paralysis. CDC=US Centers for Disease Control and Prevention. NA=not available. BCCDC=British Columbia Centre for Disease Control. CSF=cerebrospinal fluid. *Data from 2014.

Table 2: Reports of cases of enterovirus D68 during the 2014 outbreak

than 7 years.40 In France, a single case of acute flaccid paralysis was reported in a previously healthy 4 year old boy,38 and 117 additional cases have been identified through a multicentre study from a collaboration between the European Society of Clinical Virology (ESCV) and the European Centre for Disease Control (ECDC).38,44 In Sweden, seven children with enterovirus D68 were identified from July to October, 2014.35 In Milan, Italy, four children with community-acquired pneumonia tested positive for enterovirus D68, and nine cases were identified in Pavia.36,44 The ESCV and ECDC collaboration reports of an additional 17 patients in Finland, 22 in Scotland, four in Ireland, nine in Wales, one in Austria, 48 in Slovenia, and one in Luxembourg.44 25 cases were reported in 2014 in southeast Asia, with cases in China, Taiwan, and Thailand.7,30,31,47

Clinical presentation Enterovirus D68 can cause a wide range of respiratory disorders in children, from pharyngitis and bronchitis to the more severe pneumonia and respiratory failure (figure 2).1,13,59,62 Healthy adults can become infected with enterovirus D68 too, although they usually present with a milder range of respiratory symptoms. However, severe disease has been reported in adults including severe 6

acute respiratory distress syndrome in an otherwise healthy woman aged 25 years in whom mechanical ventilation was needed for longer than 30 days.28,71 Furthermore, enterovirus D68 has been associated with neurological features in both children and adults, including acute flaccid paralysis.12,32,36,49,63–66,68 Enterovirus D68 is associated with acute lower respiratory tract infection, which has mostly been reported in children,1,12,15,17,24 probably because of the lower amount of physical space in the airways than in adults. Although children are at higher risk for severe respiratory symptoms than are adults,1,6,8,10–12,15,20,21,24,35,38,46–50 cases of respiratory disease associated with enterovirus D68 have been reported in both healthy adults and adults with underlying respiratory diseases or immunosuppression.13,28 Wheezing, which is characteristic of bronchiolitis, together with radiograph-confirmed pneumonia were reported in all four children with enterovirus D68 when it was first identified in 1962.1 Little information is available on the clinical presentation of patients both in historic cases of enterovirus D68 and in most cases from 2014; specific data are available for 195 children (tables 1 and 2, figure 2).1,6,8,9,11,15,20–22,24,25,35,36,40,43,45,47,50 The most common symptom was coughing, which was reported in 74 children (38%), followed by wheezing in

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80

Number of patients (n=195)

70 60 50 40 30 20 10

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Figure 2: The most common symptoms due to enterovirus D68 infection Symptoms reported in 195 children in 19 papers with individual data available.1,6,8,9,11,15,20–22,24,25,35,36,40,43,45,47,50 Respiratory symptoms are shown first. Non-specified respiratory symptoms or symptoms reported for one to two children are grouped together as “other respiratory symptoms” and include respiratory distress or respiratory failure, bronchitis, and upper airway obstruction. Neurological symptoms other than acute flaccid paralysis are grouped together and include cerebral oedema, headache, and neck tenderness. Gastrointestinal symptoms include vomiting, diarrhoea, and abdominal pain.58

40 (21%), chest indrawing in 30 (15%), difficulties breathing in 25 (13%), and pneumonia (clinically or radiograph proven) in 25 (13%). Lower respiratory tract infection was reported in 62 (32%) children and influenza-like illness in 21 (11%). Of non-respiratory symptoms, fever was the most common symptom reported in 42 children (24%; figure 2), and eight (4%) reported vomiting and malaise.

Hospitalisations and deaths Patients who were severely affected by enterovirus D68 infection can need admission to hospital and further treatment in an intensive-care unit, including mechanical ventilation support.5,15,23,24,35,36,38,40,41,43,46,48,49,61,72 In 2014, 14 deaths in the USA were associated with enterovirus D68 infection, 1% of cases reported (table 2).34,41 The Cleveland Clinic reports that more than 45% of children identified with a respiratory enterovirus needed treatment and observation in an intensive-care unit.61 A focused review of all 1152 US cases describes that most children admitted to the hospital needed substantial amounts of respiratory support, including non-invasive ventilation, whereas only a few needed intensive-care treatment.41 Another study from the USA reports that 61 (18%) of 341 children needed to be admitted to a paediatric intensive-care unit, two for reasons other than respiratory ones.72 In Kansas all 19 children diagnosed were admitted to the intensivecare unit, and in Chicago ten of 11 were admitted to an intensive-care unit with respiratory distress, of whom two needed mechanical ventilation.70 Admission to an intensive-care unit has also been reported in the USA

before the 2014 outbreak: in 2009, of the 28 patients diagnosed with enterovirus D68 in Pennsylvania, PA, USA, 15 were admitted to an intensive-care unit.5 In 2014 in British Columbia, Canada, at least 140 patients needed hospitalisation with enterovirus D68 and three deaths were associated with infection with the virus.32 In Europe, several patients also needed hospital admission including five Dutch children with severe respiratory illness and a need for mechanical ventilation, one of whom was a previously healthy child who needed resuscitation before being admitted to an intensive-care unit.43 In Sweden, two of seven children were admitted to the intensive-care unit for up to 1 day.35 Most patients in the reports of enterovirus D68 in Norway were admitted to hospital but there were no fatalities, and none of the children with merely respiratory symptoms were admitted to an intensivecare unit, except for two with acute flaccid paralysis cases, one of whom needed mechanical ventilation and one needed continually positive airway pressure.48,49 The child with acute flaccid paralysis in France was admitted to an intensive-care unit.38 One of the children reported in Spain also needed admission into an intensive-care unit.37 In Milan, Italy, a 14-year-old girl with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS syndrome) died after 12 days in hospital, and the three other patients were in a paediatric intensive-care unit.36 In Chile, one child presented with respiratory distress and an oxygen saturation lower than 88% and needed admission to a paediatric intensive-care unit for non-invasive ventilation for 48 h.46

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Underlying disease Underlying disease is a risk factor for severe respiratory disease for both children and adults. Patients immunocompromised due to transplants, patients with chronic obstructive pulmonary disease, and underlying asthma are at increased risk.43 Of 195 children for whom specific data are available (figure 2), at least 60 (31%) had underlying disorders, but not all studies provided information on these diseases.1,6,8,9,11,15,20–22,24,25,35,36,40,43,45,47,50 Asthma was the most common underlying pulmonary disease, reported in six (10%) of 60 children with chronic underlying disease followed by recurrent wheezing in four (7%), and congenital pulmonary defect in three (5%). Malignancy was reported in four (7%) patients with chronic diseases. Rare underlying chronic disorders reported were gastro-oesophageal reflux, tracheomalacia, neuromuscular disease, dystrophy, MELAS syndrome, epilepsy, sickle-cell anaemia, and autism.10,53,59 The prevalence of asthma varied among published studies, as well as the total number of study participants. One study reported that seven (39%) of 18 patients with enterovirus D68 had a history of asthma, whereas another found an even higher proportion of underlying respiratory disease of 80% (eight of ten) of the paediatric patients.6,10,24 A study from Kansas found that 68% (13 of 19) of patients had a previous history of asthma or wheezing or both, which is similar to findings from Chicago in which 72% (eight of 11) of patients had a history of asthma or wheezing.70 In a Japanese study of hospitalised children with asthmatic attacks, enterovirus D68 was found in 26 (74%) of 35 children with asthmatic exacerbations.6 In a 2012 Dutch surveillance study of enterovirus D68, five of 16 samples positive for enterovirus D68 were from adults; all of whom had underlying disorders (heart transplant, lung transplant, kidney transplant, chronic obstructive pulmonary disease, and asthma).43 Patients with underlying chronic respiratory diseases are also at greater risk of infection, and in a UK study nine (56%) of 17 patients had underlying respiratory disorders and three (18%) had underlying chronic heart diseases.13 Both patients with enterovirus D68 detected in Chile had history of asthma.46 The study from ESCV and the ECDC in 14 European countries found that at least 131 (34%) of 389 patients had an underlying disease (data not available for 147 patients). 72 (19%) had underlying respiratory illnesses, 26 (7%) were immunocompromised, and 33 (8%) had non-respiratory illnesses; 111 had no underlying diseases.44 Published work suggests that immunosuppression is the greatest risk factor for severe illness with enterovirus D68.13,43 This preponderance has been shown previously in children with severe rhinoviral or enteroviral respiratory infections admitted to an intensive-care unit, suggesting substantial morbidity and mortality associated with pre-existing disorders, especially for immunocompromised children.73 Patients with an 8

underlying haematological disease have increased susceptibility to infections, especially those who are immunocompromised such as recipients of haemopoietic stem-cell transplants and patients with cancer receiving chemotherapy. Enterovirus D68 is often more complicated in these patients with increased risk of respiratory failure or death. Enterovirus D68 has been reported in people with underlying haematological malignancy such as Hodgkin’s lymphoma and leukaemia.74 In a case report from Seattle (WA, USA), enterovirus D68 was detected in eight patients with underlying haematological illness and hospital stays between 5 days and 55 days was needed.74

Acute flaccid paralysis Acute flaccid paralysis is a complex clinical syndrome with sudden onset of limb weakness in one or more limbs or the respiratory and bulbar muscles as a result of damage of the lower motor neurons.63,66 Acute flaccid paralysis is one of the most devastating and disabling complications of poliovirus and other non-polio enteroviruses, and surveillance for acute flaccid paralysis is the gold standard for monitoring of polio.75 Monitoring includes finding and reporting children with acute flaccid paralysis, collecting stool samples for analysis, and isolating and mapping wild poliovirus and vaccinederived poliovirus.75,76 60 231 cases of acute flaccid paralysis were reported to WHO in 2014 (data from Aug 26, 2015); the incidence of non-poliomyelitis acute flaccid paralysis is 5·0 cases per year per population younger than 15 years.77 Since the launch of The Global Polio Eradication Initiative in 1988, the annual reported incidence of poliomyelitis has decreased from an estimated 350 000 cases in 1988 to only 102 cases in 2015.56 Neurological complications caused by enterovirus A71 (one of the main pathogens responsible for outbreaks of hand, foot, and mouth disease in southeast Asia, the USA, and Europe), such as aseptic meningitis, encephalomyelitis, and acute flaccid paralysis have been well established for many years, but whether enterovirus D68 can cause these devastating complications has not yet been fully established.78 However, past cases of acute flaccid paralysis in which enterovirus D68 was detected in cerebrospinal fluid in 2005, and a fatal case of meningomyeloencephalitis with both respiratory symptoms and acute flaccid paralysis in a previously healthy 5-year-old boy with enterovirus D68 in his cerebrospinal fluid suggest that enterovirus D68 is associated with acute flaccid paralysis.12 Furthermore, several cases of acute flaccid paralysis and cranial neuropathy have been observed in the autumn 2014 outbreak, as well as several cases with samples positive for enterovirus D68; two cases of acute flaccid paralysis in Norway, one case in France, and 25 cases of acute flaccid paralysis in Colorado and California, of which 12 tested positive for enterovirus D68.12,38,49,63–66,68 At least

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107 paediatric cases of acute flaccid paralysis related to enterovirus D68 have been reported in the USA.68,79 The two Norwegian children with enterovirus-D68associated acute flaccid paralysis both have persisting neurological symptoms; one child walks steadily but has impaired head and motor control in their arms; the other child has severe paresis and atrophy in the left upper arm and shoulder.49 The status of the child with acute flaccid paralysis in France is unknown, however, 47 days after the initial presentation to health services the patient had only regained partial mobility.38 Five patients with neurological symptoms, three younger than 15 years, have been described in British Columbia, Canada. The initial diagnoses were two cases of acute flaccid paralysis, two cases of acute transverse myelitis, and one case of bulbar paresis; on follow-up three of the children had preceding head or neck pain.51,69 Another three cases of acute flaccid paralysis have been described in Alberta, Canada in children aged 5, 12, and 15 years, all with coexisting respiratory tract infection.67

Treatment No treatment is available for acute flaccid paralysis related to enterovirus D68. Three antiviral drugs— pleconaril (NCT00031512 and NCT00394914), pocapavir, and vapendavir (NCT02367313 and EUCTR2014-00178595-CZ)—are being clinically tested for enteroviral infections. Pleconaril inhibits enterovirus D68 by stabilising the capsid and preventing uncoating of the viral particle during cell entry.62 Other novel studies show that fluoxetine also might inhibit the replication of enterovirus D68.62,68

Discussion Enterovirus 68 was first identified in 1962 and up to 2014 few cases were reported. In the autumn of 2014 a large outbreak in the USA and Canada was reported, which led to an increased awareness and scaling up of surveillance in other parts of the world. At the time of publication, 2287 cases of enterovirus D68 have been reported to have occurred in 2014.7,30–49 The 2014 enterovirus D68 outbreak has led to an increased awareness of enterovirus D68 as a pathogen that can cause severe respiratory and neurological disease. Whether the outbreak of enterovirus D68 in the autumn of 2014 is due to an actual increase in the global incidence of enterovirus D68 or is an isolated occurrence remains to be seen. The increased awareness of viruses involved with respiratory symptoms that resulted from the enterovirus D68 outbreak might have contributed to increased characterisation of enteroviruses in respiratory sample materials, and might therefore be contributory to the perceived increase in incidence of enterovirus D68. Diagnostic methods continue to improve in sensitivity and specificity, especially as a result of the introduction of PCR-based methods, and this advance might have had a major role in the increased detection of enterovirus

D68 between 2005 and 2014. Furthermore, specific aminoacid changes in the VP1 protein of a subset of clade B strains of enterovirus D68, leading to altered immunogenicity, might partly explain the sudden increase in incidence of this enterovirus genotype.80 Severe lower respiratory disease that potentially needs treatment in an intensive-care unit and can cause acute flaccid paralysis is of serious concern to public health. Especially paralysis, which can lead to devastating disability in young children and associated decreases in disability-adjusted life-years. Outbreaks of enterovirus D68 have increased since the beginning of the 2000s, and the unprecedented outbreak of enterovirus D68 in the autumn of 2014 implicates it as an emerging infectious agent posing a serious threat to child health, particularly in children with underlying pulmonary disease.2,3,5,6,8–13,15–17,20–29,32,34–38,40,41,43–50 The only available treatment is symptomatic, and no preventive measures such as effective vaccines are available. The reported cases of enterovirus D68 in the autumn 2014 outbreak might only be the tip of the iceberg, with a potentially larger number of mild cases remaining undiagnosed, challenging the accuracy of estimates for severity and the burden of disease. The symptoms of enterovirus D68 are very similar to those of other respiratory viral infections, especially human rhinoviruses. Enterovirus D68 cannot be distinguished from rhinoviruses by its clinical presentation alone, and many cases of respiratory infection due to enterovirus D68 have therefore not been properly diagnosed. With inadequate clinical knowledge, this fact is a great challenge.51 No commercial clinical assay is available to detect enterovirus D68 specifically, which means that specimens need to be sent to a specialised centralised facility (eg, in Denmark to Statens Serum Institut, and in the USA to the CDC or large state reference laboratories), which increases the price and complexity of a correct diagnosis. Therefore, many cases of enterovirus D68 are probably undiagnosed.74 The issues about diagnosis of enterovirus D68 in respiratory samples also exist for other enterovirus genotypes; hence, the prevalence of respiratory infections due to enterovirus is neither reliable nor widely reported. Several rarely reported genotypes, such as enterovirus C105, have recently been detected in respiratory samples and have also been associated with a severe clinical presentation.81 Enhanced surveillance of enterovirus genotypes in this type of clinical specimen is necessary to evaluate the nature and magnitude of the health threat posed by these new emerging viruses. The data we derive from the published work has limitations. Historically, the most cases of enterovirus D68 identified in the published work have mainly been documented retrospectively in various nasopharyngeal swabs and respiratory specimens, and thus prevalence estimates are probably highly underestimated. Also, most documented cases of enterovirus D68 are probably

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not indicative of the national burden of disease, but representative of whether local health facilities test specimens retrospectively when no other pathogen was found to be the cause of severe respiratory disease. Generally, the tradition to identify and fully characterise bacteria-negative material from patients with respiratory illness is not prioritised even in many high-resource settings because of little consequences to treatment opportunities and scarce resources. Even when viruses are included in the diagnostic work-up, enterovirus as a cause of paediatric respiratory disease is probably grossly underestimated among paediatricians and clinicians. Other respiratory viral pathogens, such as influenza and respiratory syncytial viruses, which are associated with a much higher disease burden than enteroviruses and an explicit course of symptoms and disease, are more likely to be tested for. Furthermore, the established surveillance functions at the poliovirus national reference laboratories generally focus only on the exclusion of poliovirus as the agent in cases of aseptic meningitis. As a consequence, most characterisations of poliovirus are limited to tests of cerebrospinal fluid or stools, which in turn result in few national reference laboratories with the competence and capacity for testing and characterising enteroviruses in respiratory clinical material. Also the WHO Polio Eradication programme calls only for the screening of stools in acute flaccid paralysis, and so potential cases of acute flaccid paralysis due to enterovirus D68 are less likely to be identified. All of these factors challenge the estimate of the global burden of enterovirus D68 disease.

Conclusions and future actions Enterovirus D68 differs from other enteroviruses virologically, including physical and chemical properties, and epidemiologically.22,51,59,60 It is uncertain whether the increased incidence of enterovirus D68 in the autumn of 2014 was a one-time epidemic or whether the increased incidence in the past 10 years suggests that enterovirus D68 is establishing itself as an emerging pathogen. Either way, the recent epidemic and the potential for endemic transmission indicates the need for better surveillance for enterovirus D68 in respiratory specimens at community and hospital levels. Surveillance for enterovirus D68 during the coming enterovirus years will provide further clues to its prevalence. Considering the magnitude and severity of the 2014 outbreak and the number of severe neurological complications with acute flaccid paralysis in children, enterovirus D68 calls for increased attention. Existing surveillance systems should be assessed in terms of capacity and ability to detect and report any upsurge of respiratory viruses such as enterovirus D68 in a timely manner, and attention should be paid to development of preventive measures against these emerging enteroviruses that have potential for severe disease. 10

Surveillance of enterovirus in respiratory materials is not part of the global surveillance programme for poliovirus and so most laboratories specialised in enterovirus surveillance investigate mainly stool and spinal fluid samples. Emerging enterovirus subtypes targeting the respiratory tract might therefore go unnoticed for some time before more severe cases appear that need action from health-care providers and hospital admission. One obvious method would be to incorporate respiratory material in the already established and well functioning surveillance system for poliovirus. Increased testing for viruses in general for patients with nonbacterial respiratory disease would also reduce the use of antibiotics, which have little beneficial effect during viral pneumonia, but can lead to an increased incidence of subsequent infections with multidrug-resistant bacteria in adults.82 If enterovirus D68 becomes more prevalent, both healthy and ill individuals, particularly children with underlying respiratory disease, will be at risk for severe respiratory illness and devastating neurological disease. Enterovirus D68 disease surveillance is warranted to increase understanding about the mechanisms for the sudden upsurge in incidence and its unusual and severe complex disease manifestations. Contributors All authors developed the search strategy for this Review. CCH-H processed and analysed the data, interpreted the results, and drafted the manuscript. SEM and TKF contributed to the systematic review, the data extraction, and revision of the manuscript. TKF and SEM conceptualised the project. All authors approved the version of the paper for submission. Declaration of interests We declare no competing interests. References 1 Schieble JH, Fox VL, Lennette EH. A probable new human picornavirus associated with respiratory diseases. Am J Epidemiol 1967; 85: 297–310. 2 Khetsuriani N, Lamonte-Fowlkes A, Oberst S, Pallansch MA, for the Centers for Disease Control and Prevention. Enterovirus surveillance—United States, 1970-2005. MMWR Surveill Summ 2006; 55: 1–20. 3 Levy A, Roberts J, Lang J, et al. Enterovirus D68 disease and molecular epidemiology in Australia. J Clin Virol 2015; 69: 117–21. 4 Carney S, Brown D, Siqueira MM, Dias JP, da Silva EE. Enterovirus D68 detected in children with severe acute respiratory illness in Brazil. Emerg Microbes Infect 2015; 4: e66. 5 Centers for Disease Control and Prevention (CDC). Clusters of acute respiratory illness associated with human enterovirus 68--Asia, Europe, and United States, 2008–2010. MMWR Morb Mortal Wkly Rep 2011; 60: 1301–04. 6 Hasegawa S, Hirano R, Okamoto-Nakagawa R, Ichiyama T, Shirabe K. Enterovirus 68 infection in children with asthma attacks: virus-induced asthma in Japanese children. Allergy 2011; 66: 1618–20. 7 Huang YP, Lin TL, Lin TH, Wu HS. Molecular and epidemiological study of enterovirus D68 in Taiwan. J Microbiol Immunol Infect 2015; published online Sept 8. DOI:10.1016/j.jmii.2015.07.015. 8 Ikeda T, Mizuta K, Abiko C, et al. Acute respiratory infections due to enterovirus 68 in Yamagata, Japan between 2005 and 2010. Microbiol Immunol 2012; 56: 139–43. 9 Imamura T, Fuji N, Suzuki A, et al. Enterovirus 68 among children with severe acute respiratory infection, the Philippines. Emerg Infect Dis 2011; 17: 1430–35. 10 Jacobson LM, Redd JT, Schneider E, et al. Outbreak of lower respiratory tract illness associated with human enterovirus 68 among American Indian children. Pediatr Infect Dis J 2012; 31: 309–12.

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www.thelancet.com/infection Published online February 23, 2016 http://dx.doi.org/10.1016/S1473-3099(15)00543-5