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Delayed Bronchiolitis Epidemic in French Primary Care Setting Driven by Respiratory Syncytial Virus: Preliminary Data from the Oursyn Study, March 2021

Rybak, Alexis MD*,†,‡,§; Levy, Corinne MD*,†,¶,‖; Jung, Camille PhD§; Béchet, Stéphane MSc*; Batard, Christophe MD*,†; Hassid, Frédéric MD; Zouari, Morched MD; Cahn-Sellem, Fabienne MD; Bangert, Mathieu PhD**; Cohen, Robert MD*,†,¶,‖

Author Information
The Pediatric Infectious Disease Journal: December 2021 - Volume 40 - Issue 12 - p e511-e514
doi: 10.1097/INF.0000000000003270

Abstract

INTRODUCTION

Since March 2020, a range of nonpharmaceutical interventions (NPIs), including lockdowns, school closures, curfews, social distancing and face masks, have been deployed to reduce the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Europe.1 In France, a first stringent national lockdown with daycare centers (DCCs) and school closures was implemented between 17 March 2020 and 11 May 2020 (Fig. 1). DCCs and schools reopened partially on 11 May 2020 and fully on 22 June 2020. A “partial lockdown,” less stringent than the first one, with DCCs and schools remaining open, was implemented on 31 October 2020 and replaced by a national curfew on 15 December 2020.1

F1
FIGURE 1.:
Overview of nonpharmaceutical interventions (NPIs) for COVID-19 implemented in France and specific to schools and daycare.1 NPIs are presented until 31 March 2021. COVID-19 indicates coronavirus disease 2019.

As a result, the transmission of respiratory diseases that share similar transmission routes with the SARS-CoV-2 such as influenza was reduced, with very few cases reported in Europe in the 2020–2021 winter season.2 In France, bronchiolitis cases in primary care settings are regularly reported starting in October and ending in February,3 but since the beginning of the coronavirus disease 2019 (COVID-19) pandemic, a sharp decrease in bronchiolitis cases has been observed.4 During the same period, other national surveillance systems, such as in England5 or in Sweden,6 have not reported any cases in 2021.

In Australia, after a near-absence of respiratory syncytial virus (RSV) and influenza infections in the winter of 2020 in the southern hemisphere,7 a delayed bronchiolitis epidemic attributed to RSV infection was reported starting in New South Wales in September and October 2020.8 Similarly, in February 2021, the French national public health agency reported an unusually late increase in bronchiolitis cases in February 2021 (see Figure, Supplemental Digital Content 1; https://links.lww.com/INF/E482).4 This late outbreak was observed for pediatric emergency visits, hospitalizations and ambulatory visits suggesting a change in bronchiolitis epidemiology rather than a change in care-seeking behavior.3,4

In this context, we conducted a prospective surveillance of bronchiolitis cases in primary care and present early results from 8 February 2021 to 31 March 2021 in France.

MATERIALS AND METHODS

In total, 37 pediatricians from the “Pediatric and ambulatory research in infectious diseases” study group across France participated in the “OUt patients Respiratory SYNcytial virus” study (OURSYN).3 Children of <2 years old who presented a first episode of bronchiolitis, according to medical chart reviews and parental interview, in a primary care setting were prospectively enrolled. Bronchiolitis was defined as the association of one or more symptoms among fever, cough, otalgia, rhinopharyngitis or decrease in appetite with one or more symptoms among wheezing, crackles, diminished vesicular murmur and breathing difficulties. A single nasopharyngeal swab was taken for rapid diagnostic testing for RSV, SARS-CoV-2 and influenza with the Biosynex Combo COVID-FLU-RSV BSS test. An electronic case report form was completed prospectively by the pediatrician and included sociodemographic data, medical history, symptoms and additional positive laboratory tests.

Proportions were compared using chi-square test. Statistical tests were 2-sided, with P < 0.05 considered statistically significant. All statistical analyses involved STATA v15.1 (https://www.stata.com/).

All parents provided written informed consent. The study was approved by an ethics committee (Ile-de-France 1, 2020-A02876-33) and was registered at ClinicalTrials.gov (NCT04743609).

RESULTS

In 8 weeks of surveillance, 225 bronchiolitis cases were included; 123 (54.7%; 95% confidence interval [CI]: 47.9%–61.2%) were RSV-positive, 1 was SARS-CoV-2-positive (0.4%; 95% CI: 0.01%–2.4%) and 0 were influenza-positive (0%; 95% CI: 0%–1.6%). The median age of patients was 8.0 months (mean 9.3 ± 5.3); 60.6% of cases were boys. Overall, 89 (39.7%) children were in DCCs, 72 (32.1%) were at home, 61 (27.2%) had childminders and 2 were cared for in the grandparents’ house. Preterm-born children accounted for only 11.7% of cases. Five children (1 preterm) required hospitalization. The mean onset of bronchiolitis symptoms was 3.3 ± 2.6 days (median 3.0) before enrolment. RSV-positive and RSV-negative children did not differ in age (mean 9.2 ± 5.2, median 8 and 9.3 ± 5.6, median 8; P = 0.9), but significantly more children in DCCs were RSV-positive than RSV-negative (45.9% vs 32.7%, P = 0.045).

CONCLUSIONS

This primary-care study, through the point-of-care testing, allowed us to have a better description of the etiology of the unusually delayed bronchiolitis epidemic in France. The delayed RSV epidemic in France diverged from that reported in Australia.8 First, the 6-month lag of the epidemic was more prolonged in Australia than the 2-month delay in France. Second, the epidemic peak was less marked in France than Australia, with the number of cases reported not surpassing those historically reported (Supplemental Figure; Supplemental Digital Content 2; https://links.lww.com/INF/E482).4 These differences could be explained by the different approaches adopted in the 2 countries to respond to the COVID-19 pandemic over the last year. Australia aimed for elimination of COVID-19 whereas France chose mitigation.9 The delayed outbreak in France may have been reduced by the persistence of NPIs, contrary to Australia where the outbreak may have been facilitated by the stop of almost all NPIs. In addition, results from this study present findings for children with their first bronchiolitis episode and are derived from a primary care setting, whereas those reported in Australia are RSV infections in children <16 years old from public hospitals and emergency departments.7,8

The observation of a peak not surpassing those historically in France reported has raised question about whether this delayed outbreak was a delimited outbreak or a continuation of the season. Recent data showing a diminished peak and a sharp decrease of bronchiolitis in May 2021 are more consistent with an outbreak (see Figure, Supplemental Digital Content 1; https://links.lww.com/INF/E482). Therefore, our study managed to capture a delayed bronchiolitis outbreak rather than an inter-seasonal period.

The reasons for the delayed epidemic are likely the same as in Australia: stringent imposed NPIs have led to an important change in infectious disease transmission, including for RSV infection. This situation may have increased the proportion of RSV-naive children and therefore their susceptibility to an outbreak over time.8 Thus, the risk of an RSV outbreak, even with sustained mitigation strategies, and the negative impact of NPIs loosening may increase over time. This could explain why early schools and DCC opening, during a period where RSV protection was still high in children, was not followed by an earlier surge. This hypothesis is supported by modeled analysis showing that NPIs may lead to larger future RSV outbreak, especially for longer NPIs.10 Other countries reported an absence of RSV outbreak with less mitigation strategies. The difference may be explained by the total duration of school and DCC closures counterbalancing the less strict nature of the NPIs (10 weeks in France versus 23 weeks in Sweden or 47 weeks in the USA).11 Reasons explaining why epidemics start are not totally understood: the circulation of a “new virus,” population immunity against this virus and numerous other factors (seasonality, number of children at home, DCC and school attendance, NPIs, etc.). Furthermore, a viral infection might protect against other viruses through innate immunity and interferon release. Other factors such as the role of adults or the RSV off-season reservoir remain to be elucidated.

Of note, the French national surveillance for respiratory viruses reported low RSV positivity during the same time period (6.5% at week 9 in 2021 versus 20%–27% during the peaks in previous seasons), which suggests that testing policies may have changed during the SARS-CoV-2 outbreak.4 The national RSV surveillance network includes all RSV tests performed, separately from the bronchiolitis surveillance network, without any clinical information and concerns mainly hospital-based laboratories. In this study, of the 225 children with swabs for a first bronchiolitis episode, 54.9% had a positive RSV test result, 0 a positive influenza result and only one a positive result for SARS-CoV-2. From these results, the first bronchiolitis episode in children <2 years old remains an acceptable proxy to monitor RSV epidemics. To precise the role of other respiratory viruses on bronchiolitis in primary care, we are planning to test a subgroup of children using a multiplex PCR.

In the absence of an influenza epidemic in France and Europe, no influenza cases detected in children in primary care is not surprising. However, this is not the case for SARS-CoV-2, which was widely circulating during this period (incidence rate >200 of 100,000 population, Supplemental Figure; Supplemental Digital Content 2; https://links.lww.com/INF/E482). Therefore, bronchiolitis does not appear to be a frequent manifestation of SARS-CoV-2 infection in primary care. The basic reproduction number or R0 describes the transmission potential of a disease and explains the dynamics of epidemics. Initial data measured the R0 of SARS-CoV-2 between 2 and 3, which are comparable with the R0 of RSV. The apparition of more-contagious SARS-CoV-2 variants, with an R, between 3 and 5, are likely responsible of the COVID-19 outbreak observed during the study period despite NPIs.

Point-of-care testing is the most feasible approach in a primary care setting, with a unique antigenic test for influenza, RSV and SARS-CoV-2 used in this study demonstrating high specificity, >98%.12 However, the sensitivity of rapid detection tests is lower than the gold standard PCR. Antigenic tests may underestimate the role of RSV in bronchiolitis and not identify other respiratory viruses that are usually circulating during inter-seasonal periods.

This delayed RSV epidemic could have several implications, notably for the protection of vulnerable patients such as pre-term babies or those with congenital cardiopathy. Usually, in France, prescriptions of palivizumab to prevent severe forms of bronchiolitis are stopped at the beginning of March. In light of the changing seasonality of RSV infection in France in 2021, prescriptions may need to continue until the end of this current RSV epidemic.

ACKNOWLEDGMENTS

We are grateful to the investigators of the OURSYN study: Andre Jean-Marie, Ansoborlo Sophie, Auvrignon Anne, Bakhache Pierre, Batard Christophe, Bellemin Karine, Cahn Sellem Fabienne, Cheve Anne, Cohen Robert, Dagrenat Véronique, Desandes Roxane, D’ovidio Nadia, Dubreuil Barbara, Elbez Annie, Gebhard Françoise, Gelbert Nathalie, Gorde Grosjean Stéphanie, Grue-Fertin Pascaline, Hassid Frédéric, Kherbaoui Louisa, Kochert Fabienne, Langlais Sophie, Le Mouel Fanny, Lecailler Francine, Louvel Murielle, Michot Cottias Annesylvestre, Pressac Isabelle, Ravilly Sophie, Roques Gaëlle, Salaun Jean-François, Sellam Aurélie, Seror Elisa, Vie Le Sage François, Vigreux Jean-Christophe, Werner Andreas, Wollner Alain and Zouari Morched.

The authors are grateful to the Association Clinique Thérapeutique Infantile du Val de Marne (ACTIV) team for their technical assistance: Isabelle Ramay, Karin Lejeune, Aurore Prieur and Marine Borg.

REFERENCES

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Keywords:

respiratory syncytial virus; bronchiolitis; nonpharmaceutical intervention; COVID-19

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