key: cord-0888764-zyqvmnua
authors: Lumley, Sheila F.; Richens, Nicholas; Lees, Emily; Cregan, Jack; Kalimeris, Elizabeth; Oakley, Sarah; Morgan, Marcus; Segal, Shelley; Dawson, Moya; Walker, A. Sarah; Eyre, David W.; Crook, Derrick W.; Beer, Sally; Novak, Alex; Stoesser, Nicole E.; Matthews, Philippa C.
title: Changes in paediatric respiratory infections at a UK teaching hospital 2016-2021; impact of the SARS-CoV-2 pandemic
date: 2021-10-29
journal: J Infect
DOI: 10.1016/j.jinf.2021.10.022
sha: 2170e39063ac472969ae3ede97c5c79b6b112d2b
doc_id: 888764
cord_uid: zyqvmnua

Objective To describe the impact of the SARS-CoV-2 pandemic on the incidence of paediatric viral respiratory tract infection in Oxfordshire, UK. Methods Data on paediatric Emergency Department (ED) attendances (0-15 years inclusive), respiratory virus testing, vital signs and mortality at Oxford University Hospitals were summarised using descriptive statistics. Results Between 1-March-2016 and 30-July-2021, 155,056 ED attendances occurred and 7,195 respiratory virus PCRs were performed. Detection of all pathogens was suppressed during the first national lockdown. Rhinovirus and adenovirus rates increased when schools reopened September-December 2020, then fell, before rising in March-May 2021. The usual winter RSV peak did not occur in 2020/21, with an inter-seasonal rise (32/1,000 attendances in 0-3yr olds) in July 2021. Influenza remained suppressed throughout. A higher Paediatric Early Warning Score (PEWS) was seen for attendees with adenovirus during the pandemic compared to pre-pandemic (p=0.04, Mann-Witney U test), no other differences in PEWS were seen. Conclusions SARS-CoV-2 caused major changes in the incidence of paediatric respiratory viral infection in Oxfordshire, with implications for clinical service demand, testing strategies, timing of palivizumab RSV prophylaxis, and highlighting the need to understand which public health interventions are most effective for preventing respiratory virus infections.

impact of the SARS-CoV-2 pandemic. Sheila 

Respiratory tract infections (RTI) represent a major global disease burden in children, particularly in children under five years of age. Lower RTI are one of the top ten causes of mortality and morbidity considered by the World Health Organisation (WHO) (1) . Although many RTIs are mild and self-limiting, they remain one of the commonest reasons for primary care consultation, attendance in emergency departments, hospital admission and antibiotic prescribing. In the UK, incidence of upper RTI is around 300,000 cases per 100,000 people per year (2) , with children <5 years experiencing as many as 10

infections/year (3) .

Prior to the SARS-CoV-2 pandemic, common causes of RTI included bacterial pathogens (e.g.

Streptococcus pneumoniae [in settings with low vaccination rates], Haemophilus influenzae) and viruses such as respiratory syncytial virus (RSV), influenza, parainfluenza, adenoviruses, rhinovirus, respiratory enteroviruses and non-SARS-CoV-2 human coronaviruses (hCov), with viral infections accounting for ~40-50% of RTI presentations. Symptomatic paediatric SARS-CoV-2 infection remains uncommon, accounting for <2% of COVID-19 cases in England, with few severe infections and deaths (1-5/100,000 paediatric infections requiring admission, and even fewer requiring intensive care admission). Particular attention has been related to rare presentations in children with paediatric multisystem inflammatory syndrome temporally-associated with SARS-CoV-2 (PIMS-TS) which can be life-threatening, with 44% of PIMS-TS admissions in the UK requiring intensive care (4) (5) (6) .

Notably however, the SARS-CoV-2 pandemic has resulted in major observed changes to the wider epidemiology of RTIs, driven by social distancing, use of face coverings and periods of lockdown including closure of daycare and educational settings. This has led to reduced opportunities for virus transmission, and potential shifts in interactions and competition amongst respiratory pathogens. This includes significant reductions in non-SARS-CoV-2-associated RTIs in adult and paediatric populations (7) (8) (9) (10) (11) (12) (13) . Atypical rebounds and peaks in rhinovirus and RSV infections have been observed following the loosening of social restrictions and reopening of educational settings, likely partly driven by waning population immunity given the lack of exposure to these pathogens during 2020 (14) (15) (16) (17) (18) (19) (20) (21) (22) (23) . This has been particularly prominent in the case of RSV, with presentations reported in a significantly older population of children than would usually be affected (23) .

Here, we describe the impact of the COVID-19 pandemic on the incidence of paediatric viral RTI in Oxfordshire, UK. England). There were small but statistically significant differences in age, ethnicity and IMD score between pre-pandemic and pandemic periods ( Table 2) .

Pre-pandemic, a median of 2,580 attendances were recorded per month, with peaks in attendance each November in the 0-3 year age group. A median of 211 cases (8.2% of attendances) were admitted per month, 8 (0.3%) to critical care. During the pandemic, median attendance was lower at 1,871 per month (p = 0.0002), and the usual seasonal winter peaks were lost, with an atypical summer peak in attendance in June/July 2021 (>1,250 attendances per month, compared to usual June/July attendance rates of ~900/month). A median of 186 cases were admitted per month (10% of attendances), 2 (0.1%) to critical care (p=0.02 and p<0.0001 compared to pre-pandemic, respectively) (Table 2, Figure 1A ). 

One or more respiratory viruses was identified on 1,128/7,195 (16%) respiratory virus tests, on 935/155,056 ED attendances. The distribution of viruses in pre-pandemic and pandemic periods are shown in Figure 2 and Supplementary table 3. Rates of pathogen detection varied over the study period and by assay performed ( Figure 1C ). The first case of paediatric SARS-CoV-2 in this study was seen on 24-Mar-20, and in the period since the start of the pandemic it has accounted for 15% of respiratory viruses diagnosed in patients attending Paediatric ED.

December-March respectively, and to a lesser extent with hCoV in December-March. Rhinovirus and adenovirus exhibited less seasonal variation, with rising case numbers in February in some years.

Numbers of parainfluenza and metapneumovirus were too low to detect seasonal variation. The highest incidence of diagnoses was seen in the 0-3 year olds for all pathogens (Figure 3 ).

The patterns of suppression and resurgence during the pandemic varied by pathogen ( Figure 3 ,

. Detection of all pathogens was suppressed during the first national lockdown and during summer 2020 (7 months). Rhinovirus ( Figure 3B ) and adenovirus ( Figure 3D ) were the first pathogens to re emerge in September 2020 with incidence rising to to 25 In contrast, RSV ( Figure 3A ) cases remained suppressed for the first 15 months of the pandemic, much longer than rhinovirus and adenovirus; the usual seasonal winter peak did not occur in 2020/21. In July 2021 RSV rates rose out of season in the pre-school age group (32/1,000 attendances/month in 0-3yr olds), more than double the rate seen pre-pandemic in December 2019 (14/1,000 attendances/month). Influenza A/B ( Figure 3C ) remained suppressed throughout the pandemic period reported here, with only 1 sample positive in October 2020. This was from a two year old child, with both Influenza A and B detected by PCR, which is highly likely to represent detection of vaccine strain following recent intranasal seasonal influenza vaccination (Fluenz Tetra, which contains live attenuated influenza A and B).

Parainfluenzavirus and hCoV rates were unusually high in May-June 2021 to 12 and 7 cases/1,000 attendances/month in the 0-3 year age group respectively ( Figure 3F,G) . Very few cases of metapneumovirus ( Figure 3E ) were seen during the pandemic, however baseline rates are usually low.

Of 

Major changes in the incidence of paediatric viral RTI occurred in Oxfordshire during the pandemic, similarly to the rest of the UK. Following an initial period of low incidence for all pathogens during the first national lockdown, pathogen-dependent patterns of resurgence were seen from September 2020 onwards, with early resurgence of rhinovirus and adenovirus, and a delayed inter-seasonal resurgence of RSV. Although RSV detection rates in July 2021 were high, and occurred in older infants, cases were not clinically more severe.

Oxfordshire data pre-pandemic are representative of seasonal paediatric viral infections, with seasonal winter fluctuations of RSV and influenza (26) . Seasonal winter patterns were eliminated during the first UK lockdown period and incidence remained low, as had been the case across Europe (with the exception of This inter-seasonal RSV peak required a change of testing strategy with an introduction of out-of-season RSV testing and an extension of monthly preventative palivizumab for infants at risk for severe RSV disease (26, 28) , and contributed to an uncharacteristic summer peak in paediatric ED attendances and pressure on staffing. Influenza remained suppressed throughout, a pattern seen globally(32), presenting challenges for the selection of vaccine strains for the future winter influenza vaccination campaign.

In contrast, less seasonal variability was seen with rhinoviruses pre-pandemic; although their relative prevalence decreases in winter due to influenza interference, they are usually the most prevalent respiratory viral agent during summer months (33, 34) . Rhinovirus incidence increased to rates above those seen pre-pandemic in September-December 2020 (a period where schools and daycare were open and lockdown rules were relaxed), fell in January-February 2021, and rose again March-May 2021.

Similar rhinovirus resurgences were seen in Australia (35), Germany (18) , New Zealand (19), Japan (20) and in adults in England (17) . A rapid rise in adenovirus, similar to that seen for rhinoviruses after school re-opening, was seen in this study. HCoV show a winter seasonal pattern pre-pandemic, with a rise in detection in May-June 2021. Parainfluenza virus patterns were inconsistent pre-pandemic, rising in June 2021. SARS-CoV-2 incidence reflects the national pandemic infection curves. Reassuringly, no increase in severity (measured by PEWS) was seen in the pandemic period, except for adenovirus.

Although it is clear that social distancing measures and school/daycare closures dramatically decreased the incidence of all respiratory viruses at the start of the pandemic, it is difficult to disaggregate the effect of social distancing in general vs. the specific impact of school closures thereafter. It is interesting to note that whilst rhinovirus and adenovirus cases tend to fluctuate with school openings, the rise in RSV cases in July 2021 occurred at the point when schools were closing for the summer holidays. Furthermore, the majority of cases in this study are in pre-school aged children, likely a combination of a true high incidence in this age group (as is usually the case) and a higher likelihood of severe illness in pre-school age children requiring hospital attendance. Therefore paradoxically, the greatest benefit of school closures and lockdown might be reducing community incidence of respiratory viruses and therefore acquisition and hospitalisation in the pre-school age group. An important piece of future work will be to understand which components of the public health interventions were most effective for preventing various respiratory virus infection and hospitalisation in different age groups, in particular understanding the contribution of school closures, given the many negative effects of closing schools on children and on society.

There are several hypotheses exploring the different patterns of resurgence between viral pathogens, including differences in the durability of immunity and the impact of reduced exposures on natural "boosting", respiratory virus "interference" in which one epidemic delays the start or accelerates the end of the other viral epidemic (as was seen in the 2009 influenza pandemic in which the RSV epidemic was also delayed) (36) (37) (38) , and differences in viral structure (for example the presence of an envelope) or transmission altering susceptibility to social distancing and inactivation by handwashing and surface cleaning.

There were limitations to this study. The retrospective nature of this study is subject to biases in data collection; respiratory diagnoses amongst ED attendees represent the more severe end of the disease spectrum and although these reflect community prevalence (this study shows similar trends to Public Health England surveillance data(39)), they likely over-represent diagnoses in the pre-school children more likely to require hospital care for respiratory infection. Furthermore, some children, for example those with croup who are not conventionally sampled, are not represented in the dataset. Changes in healthcare seeking behaviours during the pandemic impact the calculated rates of infection, for example, families may have been deterred from attending hospital in person during the pandemic due to concerns about exposure to SARS-CoV-2. However this is partly mitigated by presenting respiratory diagnoses per 1000 attendances. The increased incidence of rhinovirus, adenovirus, hCoV and parainfluenza in the pandemic relative to pre-pandemic in this study is likely exaggerated by an ascertainment bias, due to increased use of the more comprehensive Biofire respiratory pathogen panel test for deteriorating patients or those requiring aerosol generating procedures during the pandemic and introduction of quadruple Influenza A/B/RSV/SARS-CoV-2 admission screening in July 2021.

Although we have divided the study period into "pandemic" and "pre-pandemic" periods, SARS-CoV-2 circulated in the UK during the early weeks of 2020, defined here as "pre-pandemic". Since not all periods of lockdown are equivalent in terms of stringency, we used the Oxford COVID-19 government response tracker's Stringency Index (24) to indicate the degree of restrictions in place throughout the study.

However this stringency index does not capture population adherence to lockdown and social distancing measures.

Further studies, including the 'Bronchstart' study (40) , will be required to assess the ongoing impact of the COVID-19 pandemic on respiratory virus incidence in both paediatric and adult populations, to inform workforce planning to adapt to changing seasonal patterns of service demand, altered testing strategies and use of anti-viral prophylaxis in high risk groups. We also need to understand which public health 

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