An off-season outbreak of human metapneumovirus infections after ending of a COVID-19 lockdown.

Dear editor,

We read with great interest the article by Lumley et al. who described changes in pediatric respiratory infections at a British hospital after ending of a national COVID-19 lockdown. They showed off-season increased infection rates with Respiratory Syncytial Virus (RSV), rhinovirus and adenovirus, whereas influenza virus infection rates remained low. Here, we report that in addition, also a change in human metapneumovirus (HMPV) epidemiology has been observed in our hospital. Normally, the peak incidence of HMPV infections is found in late winter and early spring in the northern hemisphere. In our hospital, this pattern has always been very stable with a peak incidence in March. Among 239 patients hospitalized with HMPV, we have previously observed only one infection in June. In contrast, in 2021, we observed an off-season outbreak of HMPV in June and July among both adults and children. The outbreak occurred just after national lockdown measures due to coronavirus disease 2019 (COVID-19) had been lifted. To characterize the outbreak further, clinical characteristics were studied of the patients and phylogenetic analysis of the viral samples was performed in order to investigate the relationship of the viruses.

Between June and July 2021, 28 patients were hospitalized with an HMPV infection in the Zuyderland Medical Center, which is a large teaching hospital situated in Heerlen in the south of The Netherlands. After exclusion of two patients who refused informed consent and three patients who were unable to communicate, 23 patients were analyzed. None of the patients had known relationships with each other. Twelve patients were children ranging from 0 to 4 years and the 11 adult patients were between 20 and 90 years old. None of the patients were immunocompromised. The most prominent comorbidity in adults was chronic obstructive pulmonary disease (COPD) in 5 (46%) of the patients. In general, the clinical disease severity at presentation and the course of disease was not different from that observed in other cohorts. Temperature in children and adults was 38.4 ± 1.1 °C and 37.9 ± 0.8 °C, respectively, heart rate 146 ± 17 and 100 ± 22 min−1 and respiratory rate 24 ± 12 and 23 ± 7 min−1. Antibiotics were administered to 3 (25%) children and 9 (82%) adults. No patient was admitted to the intensive care unit. Mean length of hospital stay was 4.0 ± 4.0 days for children and 4.4 ± 2.9 days for adults. One adult patient died after hospital dismissal but within 30 days after admission. This patient had severe comorbidity (end-stage neuroendocrine tumor and ileus).

For the purpose of this study, surplus samples initially tested for routine clinical care were obtained. For sequence analysis 14 samples were selected, in which HMPV could be detected by routine diagnostic qRT-PCR assays at a cycle threshold less than 27. For all samples, full length F sequences, and for 8 of these samples that of the attachment protein (G), were obtained with sanger sequencing as described previously. Phylogenetic analysis of complete F gene nucleotide sequences was performed using the MEGA 10 software with the best fit DNA model determined by the MEGA software with 1000 bootstraps. This phylogenetic analysis demonstrated that all viruses clustered in two smaller clusters within the A2.2.2 lineage (Fig. 1 ). All eight viruses, for which sequences were obtained for the G gene, had a 111 nt duplication in that gene.

Fig. 1

Maximum likelihood phylogenetic tree reconstructed from HMPV complete F gene sequences. The tree was reconstructed using the GTR +G + I substitution model with 1000 bootstraps. Fourteen complete F gene sequences (thirteen from GenBank, indicated with accession numbers, and one from) were included for the tree topology. Viruses sequenced in this study that contain a 111-nucleotide duplication in the G gene that was confirmed by Sanger sequencing of the G gene are underlined.

Taken together, this study described an off-season outbreak of infections with HMPV in both adults and children caused by viruses belonging to the HMPV A2.2.2 lineage. Because all 8 viruses for which sequences of the G gene could be obtained showed a 111-nt duplication in the G gene, it may be considered likely that this variant has been responsible for most infections during the outbreak. This variant was first described in 2016 and has gradually become the dominating strain worldwide but is not the only circulating variant. Some authors initially postulated that this strain may be more virulent; however, in time, HMPV incidence has not changed significantly. The cause of the unusual summer outbreak of HMPV infections is likely related to reopening of the society after a severe COVID-19 lockdown, thus enabling the spread of HMPV. During the first COVID-19 wave in 2020, both SARS-CoV-2 and HMPV had circulated independently, which suggested that there was no competition between the viruses at the time. During subsequent lockdowns HMPV incidence was very low, like that of RSV.. Together these data suggest that public health measures were probably more important drivers for the shift in HMPV incidence than viral interference. Whether the currently identified clusters of patients, all hospitalized with the same HMPV genotype, were limited to local transmission only or spread to the region, country or continent remains to be determined. However, because the cluster was further divided into two smaller clusters within the same A2.2.2 lineage and because the patients in our study did not have known relationships with each other, the HMPV outbreak probably did not occur locally only. Of note, whereas the incidence of HMPV in this cohort and the previously reported incidence of RSV in the study by Lumley et al. and others , both peaked after ending of the COVID-19 lockdown, the incidence of influenza viruses was not affected at that time. , Hence, different factors drive seasonal variation among different viruses and this concurrent outbreak of HMPV and RSV suggests that outbreaks of these viruses may be less depending on weather conditions.

CRediT authorship contribution statement

CMHJ Kivit: Methodology, Data curation, Formal analysis, Writing – original draft. K Groen: Methodology, Data curation, Formal analysis. M Jongbloed: Methodology, Writing – original draft. CFM Linssen: Resources, Methodology, Data curation. A van Loo: Writing – original draft. ECM van Gorp: Conceptualization, Supervision. S van Nieuwkoop: Methodology, Data curation, Formal analysis. BG van den Hoogen: Conceptualization, Resources, Writing – original draft. MD de Kruif: Conceptualization, Methodology, Writing – review & editing.

Declaration of Competing Interest

None