Infecciones pediátricas por parechovirusEstudio prospectivo y multicéntrico de ámbito nacional. Comparación con infecciones por enterovirus

Resum

SUMMARY Background. Human parechoviruses (HPeV) are viruses of the Picornaviridae family described in the last 10 years. HPeV infections have been associated with mild respiratory or gastroenteritis disease but also with fever without source (FWS), sepsis-like illness, meningitis or encephalitis, these last pathologies mainly in young infants and neonates. Most studies about HPeV have been published recently and they use to be retrospective and quite heterogeneous, performed with different methodologies and without a systematic search for these infections. The knowledge of the epidemiological and clinical characteristics associated with HPeV infections is essential in order to be suspected, recognized, diagnosed and adequately treated. The aim of this doctoral thesis is to investigate HPeV infections in pediatric population in Spain, comparing with those of enterovirus (EV) infections detected in the same group of patients. Aims. 1) To study the prevalence of HPeV infections in infants under 3 years of age requiring hospitalization. 2) To determine the epidemiology and clinical caractheristics of HPeV infections. 3) To compare these characteristics with those of EV infections in the same age groups. 4) To analyze the medium-term neurologic outcome of the children who had suffered an HPeV infection. Patients and methods. A prospective multicenter study was conducted between 2013 and 2015, in 12 hospitals nationwide. Children under 3 years-old with suspected viral infection (FWS, aseptic meningitis, encephalitis or sepsis) were included. FSF was defined as axillary temperature above 37.9 °C with no apparent cause after complete physical examination and laboratory analysis. The diagnosis of aseptic meningitis was considered when there was pleocytosis greater than 30 cells/mm3 in neonates or greater than 5 cells/mm3 in children older than one month, with cultures of cerebrospinal fluid (CSF) being negative for bacteria. The diagnosis of encephalitis was made on the basis of clinical presentation of decreased level of consciousness, with other symptoms of neurological involvement. Clinical sepsis was defined as the presence of clinical data and biological markers of systemic inflammatory response syndrome, without bacteriological confirmation in the cultures. Samples of CSF, serum, pharyngeal exudate or faeces were collected. The samples were sent to the microbiology departments of the participating hospitals, where EV determination was performed using molecular methods. EV-positive samples were sent to the Enterovirus Unit (UE) of the National Center for Microbiology (CNM), where the type of EV was characterized by genomic amplification and subsequent sequencing. Some of the samples that were negative for EV were tested for HPeV in the CNM, and the genotype was characterized in positive cases. Clinical data were collected by the origin hospitals using a structured clinical record and they were analyzed using the SPSS 21.0 program. Results. A total of 849 samples from 843 patients were included, 574 of which were CSF, 141 serum, 89 pharyngeal swabs, 13 feces, and 4 biopsies. 43 cases of HPV infection (5.1%) and 403 cases of EV infection (47.5%) were identified. 88.6% of HPeV infections were caused by type 3, whereas in EV infections, up to 26 different serotypes were identified. For both EV and HPeV infections, May and July were the months in which more positive cases were detected. Furthermore, a biennial pattern was observed in HPeV-3 infections, being more frequently in years 2013 and 2015. The age of the HPeV-infected children was significantly lower than those infected with EV (median 23 days (IQR 12-42) vs. 36 days (IQR 18.5 to 91); p=,016). In the EV-positive patient group, meningism (28.3% vs. 4.7%, p=.004) and catarrhal symptoms (23% vs. 4.7%; p=.007) were more frequent, while clinical sepsis was more frequent in HPeV-positive patients (24.4% vs. 4.8%; p<.001). In EV-positive patients, a higher value of leukocytes in blood was observed (10,265 vs. 8,106 cells/mm3; p=.001), and CSF pleocytosis was also more frequent (51.4% vs. 6.1%; p<.001), while elevated transaminases were most common in the HPeV-positive group (11.9% vs. 2.95%; p=.007). There were no statistically significant differences in use of antibiotics in both groups of patients, but admission to PICU was more frequent in HPeV-infected children (34.5% vs. 10.6%; p=.004). Short-term outcome was favorable in both groups of patients. In HPeV infections group, only one patient had sequelae at discharge, compared to two in the EV-positive group. No patient died. It was possible to evaluate the neurological outcome of 15 patients with HPV infection, with 3 of them being altered in the motor scales, one of which presented hemiparesis. In addition, another patient had mild hypotonia. Conclusions. HPeV-3 is circulating in all regions included in this study, and is detected in 5% of patients under 3 years presenting with fever without source, sepsis-like illness, meningitis or meningoencephalitis. It seems to have a biennial distribution with predominance in spring and summer. HPeV-3 especially affects neonates and infants, presenting with different clinical characteristics of EV infections. Short-term prognosis is good but the long-term neurological outcome is uncertain, and psychomotor development involvement cannot be ruled out in patients with central nervous system disease. KEYWORDS Parechovirus. Enterovirus. Picornaviridae. Sepsis. Meningitis. Encephalitis. Fever without source. Psychomotor development. ASQ. Neonates. CSF