Enterovirus-Echovirus 11 Infection – the European Region

Situation at a glance

Since the Disease Outbreak News published on 31 May 2023 which reported enterovirus, Echovirus 11 (E-11) infection in France, additional Member States in the European Region have notified WHO of cases of E-11 among newborns.

As of 26 June 2023, Croatia, Italy, Spain, Sweden, and the United Kingdom of Great Britain and Northern Ireland have reported cases of E-11 infection confirmed in newborns. Further investigations and public health responses are being implemented in each of these Member States.

This Disease Outbreak News provides updates on the event and the public health response implemented in the reporting and non-reporting countries in the European Region.

Based on the limited information available, WHO assesses the public health risk for the general population to be low, while we continue to encourage countries to monitor for and report on cases. Health facilities caring for newborns should familiarize themselves with the signs and symptoms of echovirus and maintain vigilance for potential healthcare-associated infections and outbreaks.

Description of the cases

On 5 May 2023, France reported an increase in cases of severe neonatal sepsis associated with Enterovirus (Echovirus-11 (E-11)). A total of nine cases of neonatal sepsis with hepatic impairment and multi-organ failure with seven deaths were reported between July 2022 and April 2023 from four hospitals in three regions of France.

As of 26 June 2023, Croatia reported one confirmed case of E-11 infection from a cluster of enterovirus diseases in neonates detected in June 2023, Italy has reported seven cases of E-11 infection confirmed in neonates between April and June 2023, Spain reported two cases of E-11 infection in 2023, Sweden reported five E-11 cases with four cases of meningoencephalitis among infants due to E-11 infection between 2022 and 15 June 2023, and the United Kingdom of Great Britain and Northern Ireland (the UK) reported two cases in March 2023.

France:

As of 26 June 2023, France has reported nine cases of severe E-11 neonatal sepsis associated with hepatic impairment and multi-organ failure confirmed by enterovirus Reverse Transcription Polymerase Chain Reaction (RT-PCR) testing of blood samples, throat swabs, nasopharyngeal swabs, cerebrospinal fluid samples, and/or post-mortem biopsies from three French metropolitan regions between July 2022 and April 2023.  Six of the nine cases occurred in 2022 (July, October and December, n=2 each) and three cases in 2023 (January (n=1) and April (n=2)). Eight cases were preterm (born before 37 weeks gestation) in four pairs of twins born at 31 and 36 weeks. Of the nine cases, there were seven reported deaths (Case Fatality Ratio (CFR) = 78%), two have been discharged from the hospital and remain under follow-up. Detailed investigation of the cases was published in the Disease Outbreak News on 31 May 2023. No additional similar cases of severe neonatal E-11 infections have been reported so far.

Croatia:

Croatia reported one confirmed case of E-11 infection from a cluster of enterovirus disease in neonates detected in June 2023 from two separate maternity hospitals. Further investigations are ongoing with no additional cases reported so far. 

Italy:

As of 26 June 2023, seven cases of neonatal E-11 infection have been confirmed in Italy between April and June 2023. Three out of the seven cases were admitted to the Neonatal Intensive Care Unit (NICU). At the time of reporting, one case remains in the NICU, one is showing clinical improvement and one has been discharged. Two more cases, who tested positive at screening were without significant symptoms. Further investigation of the remaining two cases is ongoing with clinical and epidemiological data pending.

Spain:

Two cases of E-11 infection have been reported in Spain as of 26 June 2023. These cases were preterm twins born in January 2023. Both cases were admitted to the NICU after birth with one recorded death and a diagnosis of severe enterovirus infection with probable vertical transmission, while the second case was discharged from the hospital without sequelae.

Enterovirus infection was laboratory confirmed in blood samples in both cases, one case also tested positive in stool samples and nasopharyngeal aspirates. Further sequencing and phylogenetic analysis of the virus are awaited.

According to data available at the Spanish National Centre for Microbiology, E-11 has been in circulation in Spain in 2022 and 2023, but available E-11 data does not indicate an increase in incidence or severity in neonates.

Sweden:

Sweden reported four cases of infants with meningoencephalitis due to E-11 between the beginning of 2022 and 15 June 2023.  In addition to the four infant cases reported through the mandatory reporting of viral meningoencephalitis, one infant case of E-11 was detected in 2022 through enhanced enterovirus surveillance. None of the reported cases are twins.

Epidemiological analysis of trends in probable causative agents in cases reported with viral meningoencephalitis in 2022 did not indicate any findings beyond the expected.

The United Kingdom of Great Britain and Northern Ireland:

The United Kingdom reported two cases of E-11 infection in one pair of twins in March 2023. Both cases presented with several clinical conditions including hepatitis and multiorgan failure with rapid deterioration from the fourth day of birth to the tenth day when they were deceased.  Laboratory testing confirmed the presence of enterovirus, typed as E-11. Currently, the United Kingdom is not aware of new additional E-11 cases.

Other countries in WHO European region:

So far, Austria, Belgium, Denmark, Netherlands, and Norway have reported that in 2022 and 2023 no increase of E-11 associated with cases of neonatal sepsis has been observed.

Epidemiology of disease

Enteroviruses are a group of viruses that can cause various infectious illnesses and are responsible for annual epidemics. Illness is usually mild but has been found to affect neonates differently and sometimes more severely than older children and adults. There are multiple transmission routes, particularly in the neonatal period, including intrapartum by exposure to maternal blood, secretions, and/or stool, or postnatally from close contacts with infected caregivers.

Echovirus 11 (E-11) is a positive-strand RNA virus belonging to the genus Enterovirus of the family Picornaviridae. Like other enteroviruses, E-11 infections are associated with a wide spectrum of illnesses, ranging from mild nonspecific symptoms to systemic disorders such as rash, febrile illness to severe neurological disorders, including meningitis, encephalitis and acute flaccid paralysis (AFP).

Echovirus 11 (E-11) has been reported to cause severe illnesses in neonates and infants, with high morbidity and mortality. In addition, E-11 can be transmitted vertically from mother to child, increasing the difficulty of controlling infections. The infections can cause severe inflammatory illnesses in neonates, including severe acute hepatitis with coagulopathy. E-11 and other enteroviruses have been circulating continuously in the European region.

The European Centers for Disease Prevention and Control (ECDC) and WHO held a collaborative call with Member States to discuss the event and encourage both affected and non-affected Member States to collaborate with further information sharing.

France:

Continuous information sharing regarding this event among France and other Member States (through the European Non-Polio Enterovirus Network (ENPEN)), the European Centre for Disease Prevention and Control (ECDC) and WHO is ongoing.  Also, there are ongoing plans to publish the complete genome sequence of the virus on GenBank, the National Institutes of Health genetic sequence database.  Details of the reported cases (complete genome sequence available for the French cases) have been published in Eurosurveillance.

Croatia:

Isolation and typing of the enterovirus from the mentioned clusters detected in June 2023 are ongoing.

Italy

Details of two of the confirmed cases have also been published in Eurosurveillance. Further investigations of the confirmed cases and other probable cases are ongoing. The event is currently being monitored with response and prevention activities ongoing.

Spain:

Further investigations of the confirmed cases are ongoing.

The United Kingdom:

Further sequencing and phylogenetic analysis of the virus are awaited.

Sweden

The Public Health Agency of Sweden has sent an informational letter to all child clinics, microbiological laboratories and regional medical officers to enhance awareness and increase specimen collection suitable for enterovirus typing.

Between 2022 and June 2023, a few Member States in the European Region reported the detection of positive enterovirus, especially Echovirus 11 (E-11) cases. These include Croatia, France, Italy, Spain, Sweden and the UK. So far, Austria, Belgium, Denmark, the Netherlands, and Norway have reported no increase of E-11 associated with cases of neonatal sepsis has been observed in 2022 and 2023.

Based on the limited information available, WHO assesses the public health risk for the general population to be low. However, asymptomatic carriage and shedding of infectious viruses are a feature of enterovirus infection.

Although some countries have enterovirus surveillance, there is no systematic European-wide enterovirus surveillance in place in the European Region. It is therefore difficult to estimate the extent of the current severe neonatal E-11 infections or background rates for circulation of E-11 viruses in the population. Without enterovirus surveillance, only the most severe cases will probably be detected through active efforts to test and type specimens from such cases. As non-polio enterovirus infection is often not a notifiable disease in Member States, additional cases of severe neonatal enterovirus infection may have gone undiagnosed and/or unreported.

Non-polio enteroviruses are common and distributed worldwide. Although infections often are asymptomatic, some may present with respiratory tract infections. Some of the reported cases had fever and apnoea and progressed to hepatocellular and renal failure within the neonatal sepsis presentation. These viruses are also associated with occasional outbreaks in which an unusually high proportion of patients develop clinical disease, sometimes with serious and fatal consequences. Clinicians managing neonates and young infants presenting with circulatory shock should consider an underlying diagnosis of sepsis and perform appropriate diagnostic investigations, including testing for enteroviruses.

Health-care staff working with samples suspicious of non-polio enteroviruses should be properly trained to collect, store, and transport various samples. If samples are referred domestically and/or internationally for confirmation, typing, or sequencing purposes, appropriate national and international regulations on the transport of infectious substances should be strictly followed. Laboratories that perform sequencing should consider sharing genetic sequence data through publicly accessible databases.

No specific antiviral therapy for echovirus infection is available, and treatment focuses on preventing complications. Health facilities caring for obstetric and neonate populations should familiarize themselves with the signs and symptoms of echovirus infection and maintain vigilance for potential healthcare-associated infection cases and outbreaks in hospital units providing neonatal care. Health facilities and healthcare workers should implement infection prevention and control measures with a focus on adherence to WHO “Your 5 Moments for Hand Hygiene”, visitor restriction, re-enforcing the importance of cleaning and disinfecting the environment and use of contact precautions when caring for neonates suspected or confirmed to have E-11. For suspected and confirmed neonatal cases consider isolation, ensure utensils (e.g., cup, spoon, syringe) for supplemental feeding are not shared and educate mothers and caregivers on personal hygiene and handwashing during care of newborn including diaper change. WHO provides training for health and care workers on preventing maternal and neonatal infections in health facilities, which can be accessed on Open WHO.   

• World Health Organization. Transmission-based precautions for the prevention and control of infections: aide-memoire, 20 June 2022. Available at https://www.who.int/publications/i/item/WHO-UHL-IHS-IPC-2022.2
• World Health Organization, Open WHO. Infection Prevention and Control in Maternal and Neonatal Care. Available at https://openwho.org/courses/care-pregnant-woman-antenatal-clinic-en
• World Health Organization, Disease Outbreak News. Enterovirus Infection – France 31 May 2023. Available at https://www.who.int/emergencies/disease-outbreak-news/item/2023-DON469
• European Centre for Disease Control (ECDC). Echovirus 11 in newly born twins: case in Italy shows close genetic relation to strains found in France among neonates. Available on  https://www.eurekalert.org/news-releases/992726
• Bose CL, Gooch WM 3rd, Sanders GO, Bucciarelli RL. Dissimilar manifestations of intrauterine infection with echovirus 11 in premature twins. Arch Pathol Lab Med. 1983 Jul;107(7):361-3. PMID: 6344839. Available at https://pubmed.ncbi.nlm.nih.gov/6344839/
• James D. Cherry, Chapter 24 – Enterovirus and Parechovirus Infections, Infectious Diseases of the Fetus and Newborn Infant (Sixth Edition) 2006, Pages 783-822. Available at https://doi.org/10.1016/B0-72-160537-0/50026-8
• Gaelle Hennet. Severe neonates Echovirus-11 infections, July 2022-April 2023. Available at: https://www.sfm-microbiologie.org/2023/04/27/infections-neonatales-severes-a-echovirus-11-juillet-2022-avril-2023/
• Grapin M, Mirand A, Pinquier D, Basset A, Bendavid M, Bisseux M, Jeannoël M, Kireche B, Kossorotoff M, L’Honneur AS, Robin L, Ville Y, Renolleau S, Lemee V, Jarreau PH, Desguerre I, Lacaille F, Leruez-Ville M, Guillaume C, Henquell C, Lapillonne A, Schuffenecker I, Aubart M. Severe and fatal neonatal infections linked to a new variant of echovirus 11, France, July 2022 to April 2023. Euro Surveill. 2023 Jun;28(22):2300253. doi: 10.2807/1560-7917.ES.2023.28.22.2300253. PMID: 37261730; PMCID: PMC10236930.
• Piralla A, Borghesi A, Di Comite A, Giardina F, Ferrari G, Zanette S, Figar TA, Angelini M, Pisoni C, Pitrolo AMG, Paolucci S, Rovida F, Pellicioli I, Bonanomi E, Baldanti F, Ghirardello S. Fulminant echovirus 11 hepatitis in male non-identical twins in northern Italy, April 2023. Euro Surveill. 2023 Jun;28(24). doi: 10.2807/1560-7917.ES.2023.28.24.2300289. PMID: 37318763.
• Li, J., Yan, D., Chen, L. Zhang, Y., Song, Y., Zhu, S., Ji, T., Zhou, W., Gan, F., Wang, X., Hong, M., Guan, L., Shi, Y., Wu, G.  Multiple genotypes of Echovirus 11 circulated in mainland China between 1994 and 2017. Sci Rep 9, 10583 (2019). https://doi.org/10.1038/s41598-019-46870-w
• Chevaliez S, Szendröi A, Caro V, Balanant J, Guillot S, Berencsi G, Delpeyroux F. Molecular comparison of echovirus 11 strains circulating in Europe during an epidemic of multisystem hemorrhagic disease of infants indicates that evolution generally occurs by recombination. Virology. 2004 Jul 20;325(1):56-70. doi: 10.1016/j.virol.2004.04.026. PMID: 15231386.
• Tang JW, Bendig JW, Ossuetta I. Vertical transmission of human echovirus 11 at the time of Bornholm disease in late pregnancy. Pediatr Infect Dis J. 2005 Jan;24(1):88-9. doi: 10.1097/01.inf.0000148931.05186.99. PMID: 15665719.
• European Centre for Disease Control and Prevention. Communicable Disease Threat Report, Weekly Bulletin; Week 24, 2023. Available at https://www.ecdc.europa.eu/sites/default/files/documents/communicable-disease-threats-report-16-jun-2023.pdf
• World Health Organization recommendations for the care of preterm or low-birth-weight infants. Available at: https://www.who.int/publications/i/item/9789240058262

Citable reference: World Health Organization (07 July 2023). Disease Outbreak News; Enterovirus-Echovirus 11 Infection in the European Region. Available at https://www.who.int/emergencies/disease-outbreak-news/item/2023-DON474