Since a severe outbreak of EV-A71 in Catalonia in 2016 that caused severe neurological involvement in children, Vall d'Hebron became a reference in the care of these patients and in the investigation of this infection and its consequences. The multidisciplinary work between different services, units and research groups of Vall d'Hebron Campus has allowed the publication of three new scientific articles, which have seen the light this 2021. In two of these published papers, both the outbreak of EV-A71-associated rhombencephalitis five years ago and the genetic characteristics of patients who could be prone to a greater severity of the infection are studied. The third publication describes the increase in cases of enterovirus D68 (EV-D68), typically respiratory but with potential to cause neurological complications in a low frequency of cases, following the relaxation of measures after the pandemic as a result of a surveillance of enteroviruses detected in our center.

2016: enterovirus A71-associated rhombencephalitis outbreak in Catalonia

Enterovirus infections are common among the pediatric population and usually give mild symptoms in symptomatic cases. Even so, EV-A71 is known to cause outbreaks of hand-mouth-foot disease with a high percentage of cases with neurological involvement especially in Asia, and in recent years and infrequently in some European countries. Specifically in our territory, between April and June 2016 there was an important outbreak of rhombencephalitis in children associated with EV-A71 infection in Catalonia. In these cases, inflammation of the brain stem and cerebellum occurs with symptoms such as fever, tremors, involuntary movements, lethargy, difficulty in speaking or swallowing, among others.

The article now published in The Pediatric Infectious Desease Journal, led by Vall d'Hebron, describes the characteristics of the outbreak and the actions of the different Pediatric services of the hospitals of the Institut Català de la Salut (ICS): Vall d'Hebron University Hospital, Germans Trias i Pujol University Hospital, Dr. Josep Trueta University Hospital, Joan XXIII University Hospital, Arnau de Vilanova University Hospital and Verge de la Cinta Hospital in Tortosa. "The aim of the work is to share the experience lived in 2016 to provide information that we did not have at the beginning of the outbreak so that it can be useful to establish priorities and criteria for care towards patients in future similar outbreaks," highlights Dr. Núria Wörner, pediatrician at the Pediatric Emergency Unit of Vall d'Hebron University Hospital, researcher of the Infection in Immunocompromised Pediatric Patients group at Vall d'Hebron Recerca and first author of the publication.   

To carry out the analysis, 123 patients with symptoms compatible with enterovirus infection and requiring hospitalization were studied. Of these, EV-A71 was detected in 64 and in the rest other types of enterovirus were detected or none were identified. Regarding treatment, 44 of the 64 patients received immunoglobulins to help fight the infection and 27 received corticosteroids to reduce inflammation.

Despite the numerous cases hospitalized and the need for admission to the pediatric ICU in six of them, the evolution was favorable in the vast majority of them without any sequelae after six months, with the exception of one patient with hypoxic ischemic encephalopathy. 

In this regard, as described by the researchers after the outbreak, the good subsequent evolution of the patients and the risk of complications of the infection derived from the use of corticosteroids reveal that in future cases it would be advisable to adjust the treatment according to each patient and his severity. This would make it possible to reduce unnecessary treatments, as well as diagnostic tests and monitoring of patients for whom no complications are expected.

The Vall d'Hebron Hospital's Pediatric Emergency Unit and the Microbiology, Pediatric Radiology and Preventive Medicine Departments participated in the study. 

Mutations that explain some severe cases

Among the questions addressed by the researchers is why some children infected with enteroviruses have very mild symptoms while others may end up in the pediatric ICU? A study published in the Journal of Experimental Medicine has provided evidence for the presence of mutations in human genes related to the immune system that could increase the risk of suffering complications from the infection. The study, led by the Rockefeller University in New York and the Institut National de la Santé et de la Reserche Médicale in Paris, involved the Translational Immunology group and the Infection in the Immunocompromised Pediatric Patient group at Vall d'Hebron Recerca.

The researchers describe the cases of two children admitted to Vall d'Hebron aged 3.5 years and 12 months who were infected by enterovirus EV-30 and EV-A71, respectively, and developed rhombencephalitis, although the evolution was finally good. In both cases mutations were found in genes involved in the immune response against the viruses. Specifically, the 3.5-year-old patient had mutations in the TLR3 gene and, in the case of the 12-month-old patient, the mutated gene was MDA5. "Both TLR3 and MDA5 are related to the initial immune response, which is carried out through type I interferons (IFN-I). These interferons play a relevant role in the response against enterovirus infections, preventing their uncontrolled replication." explains Dr. Roger Colobran, head of the Translational Immunology group at Vall d'Hebron Recerca. Therefore, alterations in this immune response would be related to an increased risk of suffering a serious disease.  

It should be noted that this greater severity occurs in the first infection by the virus, which would affect the immune memory and, therefore, these children would be equally protected against possible reinfections of the same virus. "But it is important to know these genetic variants that could be related to an insufficient immune response, not only for enterovirus, but also for other viruses such as herpesvirus or rhinovirus." Dr. Pere Soler-Palacín, head of the Pediatric Infectious Pathology and Immunodeficiency Unit at Vall d'Hebron University Hospital and of the Infection in Immunocompromised Pediatric Patients group at Vall d'Hebron Recerca, points out.

In fact, it is not the first time that mutations in these pathways related to IFN-I immunity are also associated with other viral infections. During the last year, the same research team has also found genetic and immunological defects related to severe cases of COVID-19.

2021: Surveillance of enterovirus D68

Vall d'Hebron's enterovirus research work is not limited to outbreak response, but since 2014 it has been monitoring the types of enteroviruses detected and the clinical features associated with infection, both in the inpatient and outpatient setting, in order to be able to take measures in advance, if necessary.

In recent months, for example, the focus has been on the monitoring of enterovirus D68 (EV-D68). This is a mostly respiratory virus that causes epidemics every two years, usually around autumn, and of which a greater number of cases are being detected this year than in previous years. "This increase in cases is consistent with the biennial seasonality of the virus according to data from 2014, but it is being especially important because of the relaxation of the measures derived from the pandemic, such as travel restrictions, school closures or social distance, and a non-circulation during 2020, which is when it was expected." says Dr. Andrés Antón, head of the Respiratory Virus Unit of the Microbiology Service of the Vall d'Hebron Hospital and researcher of the Microbiology group of Vall d'Hebron Recerca. In the last year, the transmission of respiratory viruses has been affected by the restrictions of the COVID-19 pandemic, and this has meant that children have not been exposed to this type of virus previously, favoring outbreaks during these months after the opening of the pandemic.

The study, published this fall in Eurosurveillance, involved 36 institutions from 18 European countries in response to the increase in EV-D68 infections in Europe, which have previously collaborated as active members of the European Non-Polio Enterovirus Network. Between July 31 and October 14, 139 cases were identified in 12 countries, including 10 cases from the state. "In the vast majority of cases in our center only mild respiratory symptoms appear that do not require hospitalization, although neurological involvement has been found in some of them. That is why it is necessary to do a continuous follow-up and be alert to the evolution of the virus", says Dr. Jorgina Vila, specialist of the Pediatric Hospitalization Unit of Vall d'Hebron and researcher of the group of Infection in Immunocompromised Pediatric Patients of Vall d'Hebron Recerca.

This has been an international study with the participation of the Pediatric Hospitalization Unit of the Pediatrics Service and the Respiratory Virus Unit of the Microbiology Service of Vall d'Hebron Hospital and the Microbiology and Infection in Immunocompromised Pediatric Patients groups of Vall d'Hebron Recerca, which is the continuation of a clinical and virological surveillance started in 2014.