Thursday 1 June 2023

Neonatal Enterovirus infection leads to seven deaths in France.

France has reported an increase in cases of severe neonatal sepsis associated with the Echovirus-11 Enterovirus, according to a press release issued by the World Health Organization on 31 May 2023. A total of nine cases of neonatal sepsis with hepatic impairment and multi-organ failure were reported between July 2022 and April 2023 from four hospitals in three regions of France. As of 5 May 2023, seven cases have died and two were still hospitalized in neonatal unit.

The current increase in incidence and severity in neonates, associated with a recombinant lineage of Echovirus-11 that previously was not detected in France, and is considered unusual due to the extremely rapid deterioration and associated case fatality rate amongst the affected babies. 

Based on the limited information available, the World Health Organization assesses the public health risk for the general population to be low, despite the concerning nature of the increase.

Of the nine cases of severe neonatal sepsis reported, eight were preterm (born before 38 weeks of gestation). Four pairs of twins were affected and presented with late-onset neonatal sepsis (occurring after one week of birth to three months).

The cases were reported from four hospitals in three regions between July 2022 and April 2023. Of the nine reported cases, six were reported in 2022 (two cases each in July, October, and December) and three were reported in 2023 (one case in January and two cases in April).

All cases presented with one or more clinical signs less than seven days after birth, suggesting a mother-to-child transmission route. The clinical presentation of these cases was considered to be atypical due to their extremely rapid deterioration and the associated case fatality rate. As of 5 May 2023, seven cases have died and two were still hospitalized in the neonatal unit; their short-term prognosis is no longer threatened.

Enterovirus reverse transcription polymerase chain reaction testing of all nine cases (including blood samples, throat swabs, nasopharyngeal swabs, cerebrospinal fluid samples, and/or post-mortem biopsies) confirmed the presence of Enterovirus, typed as Echovirus-11. Echovirus-11 maternal infection was confirmed by reverse transcription polymerase chain reaction testing and enterovirus genotyping by analyzing blood samples from four out of five mothers. All tested mothers presented with gastrointestinal signs or fever within the three days before or at delivery.

Sequence analyses of all typed Enterovirus infections in 2022 showed the circulation of at least two lineages of recombinant origin, of which the predominant one included all the sequences associated with the nine cases together with sequences associated with non-neonatal or non-severe neonatal infections. Further genetic analyses are ongoing.

According to historical data from 2016 to 2021, Echovirus-11 represented 6.2% (3 of 48) of reported severe neonatal infections with known Enterovirus type while this proportion increased to 55% (11 of 20) in 2022.

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 is a positive-strand RNA Virus belonging to the Genus Enterovirus of the Family Picornaviridae.

Structure of an Echovirus. Wang et al. (2020).

Echovirus 11 infections can cause severe inflammatory illnesses in neonates, including severe acute hepatitis with coagulopathy. 

On 28 April 2023, the French National Reference Centre for Enteroviruses and Parechoviruses informed clinicians and virologists involved in the care of newborns, to reinforce the diagnosis and surveillance of Enterovirus infection in neonates with severe sepsis through a professional network. In particular, the message focused on what to do in newborns with a picture of severe sepsis of indeterminate aetiology to sensitize about the risk of transmission. Clinicians were invited to systematically consider Enterovirus infection in neonates with severe liver failure, enterocolitis, meningoencephalitis, or myocarditis. Close monitoring of liver function, cardiac function, neurological function, and risk of enterocolitis were recommended in neonates with severe neonatal sepsis of undetermined cause.  Clinicians were also invited to undertake an early notification of referral hospitals in order to discuss potential therapeutic options. The risk of maternal transmission of Echovirus 11 was raised and recommendations made to monitor the infant closely for at least 7 days if the mother was known to have had an infection before or during childbirth. Emphasis was placed on importance of collecting additional samples (blood, stool, and nasopharyngeal samples) in newborns and mothers for Enterovirus, as was the importance of genotyping Enterovirus-positive samples: Clinical virologists were invited to send Enterovirus-positive samples in a prospective manner, especially from patients presenting with severe clinical signs. Samples are sent to the National Reference Laboratories for genotyping and genome studies.

Continuous information sharing regarding this event among France and other Member States (through the European Non-Polio Enterovirus Network), the European Centre for Disease Prevention and Control and World Health Organization is ongoing. To date, no comparable increase of Echovirus 11 cases associated with neonatal sepsis has been observed in countries that have reported to the European Centre for Disease Prevention and Control (Belgium, Denmark, Netherlands, Norway, and Spain) in 2022 and 2023.

A review of the epidemiological data collected from 2016 to 2022 in France through routine surveillance of Enterovirus infections among hospitalized patients showed a significant increase in incidence and mortality for all severe neonatal infections associated with Echovirus 11, defined as infections with at least one organ failure and/or requiring admission to intensive care.

A total of 443 Enterovirus neonatal infections (severe and non-severe types) including seven deaths (a case fatality rate of 1.6%) were reported in France in 2022. Of these, 72% (317 cases) had a known Enterovirus type. Echovirus 11 was the predominant circulating Enterovirus type (all ages included) and was identified in 30.3% (96 of 317) of neonatal infections (severe and non-severe) with known Enterovirus type. It has been continuously detected since June 2022.

Of the reported neonatal infections in 2022, 4.5% (22 of 443) were classified as severe. Of these 20 had known Enterovirus types. Echovirus 11 represented 55% (11 of 20) of these cases as compared to 6.2% (3 of 48) of cases with known Enterovirus type out of the total reported severe neonatal infections (62 cases) between 2016 to 2021. 

In 2022, there were seven deaths (case fatality rate, a case fatality ratio of 1.6%) out of the cumulative 443 Enterovirus neonatal infections recorded in 2022 (six associated with Echovirus 11), compared to seven deaths (a case fatality ratio of 0.4%), out of 1774 neonatal infections from 2016 to 2021 (none associated with Echovirus 11). There have also been seven deaths so far in 2023.

Sequence analyses showed the circulation of at least two lineages of recombinant origin, of which the predominant one included all the sequences associated with the nine severe cases together with sequences associated with non-neonatal or non-severe neonatal infections. This new variant of Echovirus 11 had not been observed in France before July 2022, nor elsewhere based on available sequences on the GenBank database, as of 28 April 2023. As of 5 May 2023, Echovirus 11 sequences retrieved from samples collected in 2023 all belong to this predominant lineage. Although higher pathogenicity of this new lineage cannot be excluded, the severity of infections may also be explained by the young age, prematurity, and the absence of maternal immunity. Further analyses are warranted to delineate the characteristics of this recombinant Virus.

Based on the limited information available, the World Health Organization 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. Echovirus infection was confirmed in four out of five mothers by analyzing blood samples three days before or at delivery. There have been previous reports of severe Echovirus 11 infection in twin neonates, however, the observation of four sets of twins amongst nine cases is more than expected. 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. Symptoms include fever, runny nose, and body weakness. 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. The World Health Organization recommends that 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.

The World Health organization further recommends that health and care workers 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 neonate populations in France should familiarize themselves with the signs and symptoms of Enterovirus and maintain vigilance for potential healthcare-associated infection cases and outbreaks in wards providing neonatal care. 

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