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\begin{document}

\title{COVID-19 pandemic-altered epidemiology of respiratory syncytial virus
and human metapneumovirus infections in young children}



\author[1]{Masayuki  Nagasawa}%
\author[1]{Tomohiro Udagawa}%
\author[1]{Mari Okada}%
\author[1]{Ryuichi Nakagawa}%
\author[1]{Haruna Yokoyama}%
\author[1]{Tomoyuki Kato}%
\author[1]{Maki Furuya}%
\author[1]{Hayato Sakaguchi}%
\affil[1]{Musashino Sekijuji Byoin}%


\vspace{-1em}



  
  \date{May 22, 2024}


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COVID-19 pandemic-altered epidemiology of respiratory syncytial virus
and human metapneumovirus infections in young children

Tomohiro Udagawa\textsuperscript{1}, Mari Okada\textsuperscript{1},
Ryuichi Nakagawa\textsuperscript{1}, Haruna Yokoyama\textsuperscript{1},
Tomoyuki Kato\textsuperscript{2,4}, Maki Furuya\textsuperscript{3},
Hayato Sakaguchi\textsuperscript{3,4}, Masayuki
Nagasawa\textsuperscript{1,4}*

Department of Pediatrics\textsuperscript{1}, Department of
Pharmacy\textsuperscript{2}, Department of
Laboratory\textsuperscript{3}, Department of Infection
Control\textsuperscript{4},

Musashino Red Cross Hospital, 1-26-1, Kyonan-cho Musashino-city, Tokyo,
180-8610, Japan

Key word:

COVID-19, viral interference, respiratory syncytial virus,
metapneumovirus,

*Author for correspondence

Masayuki Nagasawa, PhD., MD.

Department of Pediatrics, Musashino Red Cross Hospital

1-26-1, Kyonan-cho, Musashino-city, Tokyo 180-8610, Japan

Tel: +81 422 32 3111

Fax: +81 422 32 9551

E-mail: masayukin@musashino.jrc.or.jp

Correspondence:

Respiratory syncytial virus (RSV) and human metapneumovirus (hMPV) are
closely related viruses belonging to pneumovirinae subfamily and cause
bronchiolitis and pneumoniae in infants and young children, resulting in
hospitalization, which becomes a major health problem in pediatric
care.\textsuperscript{1, 2} To evaluate the impact of the COVID-19
pandemic on the epidemiology of these viral infections, we investigated
and compared the epidemic patterns of RSV and hMPV infections in
children admitted and diagnosed at our hospital before and after
COVID-19 pandemic. The pathogenic diagnosis was made by antigen test
before 2020 and by Filmarray respiratory panel\selectlanguage{ngerman}® (ver2.1) test
thereafter.

In the reports so far, the epidemics of both virus infections have not
completely overlapped in Japan\textsuperscript{3, 4}, and the epidemic
peaks of both infections in our hospital from 2015 to 2019 did not
overlap as well as shown in Figure 1. These phenomena are referred to as
social viral interference and have been mentioned in several viral
infections.\textsuperscript{5-7} COVID-19, which emerged at the end of
2019, quickly spread around the world and became a
pandemic.\textsuperscript{8, 9} Japan also implemented a social lockdown
from April to May 2020. As a result, social activity restrictions
continued, and no epidemics of RSV or hMPV were observed in 2020. After
that, a large-scale epidemic of RSV was seen in the summer of 2021 due
to the easing of restrictions on social activities and movements and the
reopening of nursery schools, but no hMPV epidemic was observed. In 2022
and 2023, epidemics of both RSV and hMPV were seen. Interestingly, both
outbreaks occurred around the same time, unlike before the COVID-19
pandemic (Figure1). More interestingly, when comparing the age
distribution of infected children, the age distribution in post-COVID-19
epidemic shifted nearly 2 years older than that before COVID-19 epidemic
(figure 2). Prior to the COVID-19 pandemic, the age distribution during
the epidemic of both viral infections was almost similar from year to
year (data not shown).

The periodic prevalence of epidemic respiratory viral infections in
children can be attributed to several factors.

First is viral evolution. Viruses have the ability to mutate and evolve
rapidly. These new strains can lead to recurrent outbreaks as the
population lacks immunity to the modified virus. Second is host
susceptibility. In a population, individuals may gain immunity to a
specific viral infection through prior exposure or vaccination. However,
over time, the immunity acquired through natural infection or
vaccination can wane. Third are changes in population density and
mobility. Population dynamics, including changes in population density
and mobility, can influence the transmission of viral infections.
Increased travel, urbanization, and global connectivity facilitate the
rapid spread of viruses across regions and continents. Fourth are
environmental factors. Certain viral infections exhibit seasonal
patterns due to environmental factors. For instance, respiratory viruses
like influenza tend to peak during the colder months when people spend
more time indoors in close proximity, providing favorable conditions for
viral transmission. Additionally, changes in climate patterns or
ecological disturbances can affect the distribution and prevalence of
vector-borne infections such as dengue or Zika virus. Fifth is lack of
universal vaccination or treatment. The absence of effective vaccines or
treatments against a particular viral infection can contribute to its
periodic prevalence.

RSV and hMPV spread through similar routes of severe acute respiratory
syndrome coronavirus 2 (SARS-CoV-2), the measures taken to control
COVID-19 have inevitably limited the transmission of both respiratory
viruses among children. Furthermore, the reduced exposure to common
respiratory viruses during the pandemic may affect the development of
natural immunity in children, potentially leading to a susceptible
population when restrictions ease and social interactions increase. One
of the reasons why children aged 3 to 4 years became more susceptible to
RSV and hMPV after the COVID-19 pandemic may be that immunity was not
stimulated due to the decrease in epidemic viral diseases during the
COVID-19 pandemic. Also, the possibility that the virus mutated during
the COVID-19 pandemic cannot be completely ruled out.

Viral interference at the individual level has been verified in animal
experiments.\textsuperscript{10, 11} However, virus interference at the
population level is observed as an indirect phenomenon and its causes
are complicated. From this perspective, a detailed examination of the
trends in infectious diseases, especially in children before and after
the rare COVID-19 pandemic will provide very important suggestions for
considering the mode of transmission of viral infections in society, the
maturation process of immunity to viruses, and countermeasures against
acute viral infection epidemics.

\textbf{Declarations}

\textbf{AUTHOR CONTRIBUTIONS}

Tomohiro Udagawa: writing, data analysis, patient-care, Ryuichi
Nakagawa: patient-care, Mari Okada: patient-care, Haruna Yokoyama:
patient-care, Tomoyuki Kato: data curation. Maki Furuya: data curation.
Hayato Sakaguchi: data curation. Masayuki Nagasawa: conceptualization,
writing--original draft, review and editing, data analysis.

\textbf{FUNDING}

The authors received no funding in relation to this work.

\textbf{CONFLICTS OF INTEREST}

The authors declare no conflicts of interest.

\textbf{DATA AVAILABILITY STATEMENT}

Data available on request due to privacy/ethical restrictions.

\textbf{ETHICS STATEMENT}

This study was performed in compliance with the ethical treatment policy
of human and animal research participants and the Declaration of
Helsinki.

This observational study was approved by the Ethical Committee of
Musashino Red Cross Hospital (approval number 4061). Informed consent
was secured by opt\selectlanguage{english}-out method.

\textbf{References:}

1. Diez-Domingo J, Perez-Yarza EG, Melero JA, Sanchez-Luna M, Aguilar
MD, Blasco AJ, et al. Social, economic, and health impact of the
respiratory syncytial virus: a systematic search. \emph{BMC infectious
diseases} . 2014;14:544.

2. Young M, Smitherman L. Socioeconomic Impact of RSV Hospitalization.
\emph{Infectious diseases and therapy} . 2021;10(Suppl 1):35-45.

3. Okada T, Matsubara K, Matsushima T, Komiyama O, Chiba N, Hamano K, et
al. {[}Analysis of clinical features of community-acquired pneumonia
caused by pediatric respiratory syncytial virus and human
metapneumovirus{]}. \emph{Kansenshogaku zasshi The Journal of the
Japanese Association for Infectious Diseases} . 2010;84(1):42-47.

4. Mizuta K, Abiko C, Aoki Y, Ikeda T, Matsuzaki Y, Itagaki T, et al.
Seasonal patterns of respiratory syncytial virus, influenza A virus,
human metapneumovirus, and parainfluenza virus type 3 infections on the
basis of virus isolation data between 2004 and 2011 in Yamagata, Japan.
\emph{Japanese journal of infectious diseases} . 2013;66(2):140-145.

5. Casalegno JS, Ottmann M, Bouscambert-Duchamp M, Valette M, Morfin F,
Lina B. Impact of the 2009 influenza A(H1N1) pandemic wave on the
pattern of hibernal respiratory virus epidemics, France, 2009.
\emph{Euro surveillance : bulletin Europeen sur les maladies
transmissibles = European communicable disease bulletin} . 2010;15(6).

6. Achten NB, Wu P, Bont L, Blanken MO, Gebretsadik T, Chappell JD, et
al. Interference Between Respiratory Syncytial Virus and Human
Rhinovirus Infection in Infancy. \emph{The Journal of infectious
diseases} . 2017;215(7):1102-1106.

7. Nickbakhsh S, Mair C, Matthews L, Reeve R, Johnson PCD, Thorburn F,
et al. Virus-virus interactions impact the population dynamics of
influenza and the common cold.\emph{Proceedings of the National Academy
of Sciences of the United States of America} . 2019;116(52):27142-27150.

8. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and
risk factors for mortality of adult inpatients with COVID-19 in Wuhan,
China: a retrospective cohort study.\emph{Lancet (London, England)} .
2020;395(10229):1054-1062.

9. Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, et al. A Novel
Coronavirus from Patients with Pneumonia in China, 2019. \emph{The New
England journal of medicine} . 2020;382(8):727-733.

10. Selin LK, Varga SM, Wong IC, Welsh RM. Protective heterologous
antiviral immunity and enhanced immunopathogenesis mediated by memory T
cell populations. \emph{The Journal of experimental medicine} .
1998;188(9):1705-1715.

11. Chan KF, Carolan LA, Korenkov D, Druce J, McCaw J, Reading PC, et
al. Investigating Viral Interference Between Influenza A Virus and Human
Respiratory Syncytial Virus in a Ferret Model of Infection. \emph{The
Journal of infectious diseases} . 2018;218(3):406-417.

Figure 1

Trends of RSV or hMPV infected patients under 10 years old who admitted
in our hospital were shown. Before COVID-19 pandemic, the epidemic peaks
of RSV and hMPV infections did not overlap in each year. In 2022 and
2023, the epidemic peaks of both infections completely overlapped.

Figure 2

The age distribution of RSV (upper graph) and hMPV (lower graph)
infected patients in three different periods (2015-2017, 2018-2019, and
2021-2023) were presented. The age distribution of 2021-2023 period is
shifted to right (arrows) compared to that of 2015-2017 and 2018-2019
and the mean age of 2021-2023 is significantly older (p\textless{}0.001:
Mann-Whitney U test) than that of 2015-2017 and 2018-2019 in both RSV
and hMPV infections.

\textbf{Hosted file}

\verb`20230802_Figures_RSV_hMPV_post_COVID-19_pandemic.pptx`  available at \url{https://authorea.com/users/646374/articles/658324-covid-19-pandemic-altered-epidemiology-of-respiratory-syncytial-virus-and-human-metapneumovirus-infections-in-young-children}

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