key: cord-0428496-yo3c6ov0 authors: Danino, D.; Ben-Shimol, S.; van der Beek, B. A.; Givon-Lavi, N.; Shemer Avni, Y.; Greenberg, D.; Weinberger, D. M.; Dagan, R. title: Decline in pneumococcal disease in young children during the COVID-19 pandemic associated with suppression of seasonal respiratory viruses, despite persistent pneumococcal carriage: A prospective cohort study date: 2021-08-01 journal: nan DOI: 10.1101/2021.07.29.21261308 sha: 8a07126e41b87a26b51aa8a997ef9bbdaefa65da doc_id: 428496 cord_uid: yo3c6ov0 Background: Invasive pneumococcal disease (IPD) declined during the COVID-19 pandemic. Previous studies hypothesized that this was due to reduced pneumococcal transmission resulting from non-pharmacological interventions. We used multiple ongoing cohort surveillance projects in children <5 years to test this hypothesis. Methods: The first SARS-CoV-2 cases were detected in February-2020, resulting in a full lockdown, followed by several partial restrictions. Data from ongoing surveillance projects captured the incidence dynamics of community-acquired alveolar pneumonia (CAAP), non-alveolar lower respiratory infections necessitating chest X-rays (NA-LRI), nasopharyngeal pneumococcal carriage in non-respiratory visits, nasopharyngeal respiratory virus detection (by PCR), and nationwide invasive pneumococcal disease (IPD). Monthly rates (January-2020 through February-2021 vs. mean monthly rates 2016-2019 [expected rates]) adjusted for age and ethnicity, were compared. Findings: CAAP and bacteremic pneumococcal pneumonia were strongly reduced (incidence rate ratios, [IRRs] 0.07 and 0.19, respectively); NA-LRI and non-pneumonia IPD were also reduced, with a lesser magnitude (IRRs, 0.46 and 0.42, respectively). In contrast, pneumococcal carriage prevalence was only slightly reduced and density of colonization and pneumococcal serotype distributions were similar to previous years. The pneumococcus-associated disease decline was temporally associated with a full suppression of RSV, influenza viruses, and hMPV, often implicated as co-pathogens with pneumococcus. In contrast, adenovirus, rhinovirus, and parainfluenza activities were within or above expected levels. Interpretation: Reductions in pneumococcal and pneumococcus-associated diseases occurring during the COVID-19 pandemic were not predominantly related to reduced pneumococcal transmission and carriage but were strongly associated with the complete disappearance of specific respiratory viruses. Funding: Partially funded by Pfizer, Inc. Streptococcus pneumoniae (pneumococcus) is a leading cause of acute respiratory and invasive infections in all ages, including young children. 1 Rates of disease caused by pneumococcus are influenced both by the frequency of exposure to the bacteria (i.e., prevalence of nasopharyngeal carriage among healthy children) and by host susceptibility. Epidemiological, clinical, and experimental evidence suggests that certain viruses can increase the susceptibility of individuals to pneumococcal disease when they are exposed to the bacteria. [1] [2] [3] Since SARS-CoV-2 is a respiratory virus, concerns were raised that COVID-19 patients could have increased susceptibility to pneumococcal infections, in particular pneumonia and invasive pneumococcal diseases (IPD). However, early reports during the COVID-19 pandemic suggested that, in fact, the incidence of IPD had been reduced, 4 and S. pneumoniae only infrequently co-infected patients with COVID-19 disease, including pneumonia. 5 At the same time, non-pharmacological interventions (NPIs) such as social distancing and travel restrictions surrounding the COVID-19 pandemic were associated with an unexpected global suppression of the activity of several seasonal respiratory viruses, which are often implicated as co-pathogens with pneumococcus. These include respiratory syncytial virus (RSV), influenza viruses, and human metapneumovirus (hMPV). 6, 7 We hypothesized that the reduction in pneumococcal disease in children observed during the COVID-19 pandemic was due mainly to the reduction in the incidence of these seasonal respiratory viruses rather than to reductions in transmission of pneumococcus. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted August 1, 2021. ; https://doi.org/10.1101/2021.07.29.21261308 doi: medRxiv preprint We took advantage of multiple ongoing prospective pediatric cohort surveillance projects in our region to assess the dynamics of various clinical presentations associated with pneumococcus during the COVID-19 pandemic period (January 2020 through February 2021). The patterns of pneumococcal disease during the pandemic were evaluated in comparison to rates during 2016-2019 and to common seasonal respiratory viruses. Uniquely, our data included information on clinical diseases caused by pneumococcus, pneumococcal carriage among healthy children, and the activity of specific respiratory viruses. These data provide an opportunity to understand the factors that influence the incidence of pneumococcal disease in children. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted August 1, 2021. The first case of SARS-CoV-2 was reported in Israel on February 21 st 2020. Three official national lockdown periods, with variable degrees of stringency, were implemented thereafter (supplementary figure 1): 1) April through Mid-May 2020 (including Passover and Ramadan holidays); 2) Mid-September to November 2020 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. or hospitalized from whom a chest radiography was obtained were included. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Clinical Modification (ICD-9-CM) discharge codes. All the above projects, as well as the overall current study were approved by the SUMC Ethics Committee. Demographic characteristics were compared between the pre-COVID-19 years (2016-2019) and the COVID-19 period (2020-2021) using the Pearson χ 2 test or the All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rate ratios were adjusted for ethnicity and age using the Mantel-Haenszel method. The statistical significance threshold was p < 0.05. Data were analyzed using R Pfizer Inc. was not engaged in the preparation of the manuscript in any way and was not given the opportunity to review the manuscript before its submission. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted August 1, 2021. ; https://doi.org/10.1101/2021.07.29.21261308 doi: medRxiv preprint The first case of COVID-19 was identified on February 21 st 2020. All NPIs that followed, along with the dynamics of all new daily nationwide COVID-19 cases, are described in supplementary figure 1. Overall, until February 28, 2021, 777,155 COVID-19 cases were documented. During October 2020 through February 2021, there was a marked reduction in IPD rates vs. expected (IRR 0·47; 95% CI: 0·32 -0·70) (supplementary tables 2, 3; supplementary figure 2). However, while a reduction of 81% was observed for bacteremic pneumonia compared to the pre-COVID period, the observed reduction of non-pneumonia IPD was only 42% (figure 1A-D). Overall LRI rates were reduced during fall and winter 2020-2021 (supplementary supplementary tables 2, 4). In the first quarter of 2020, the dynamics of CAAP were similar to those in previous years. During the second quarter, the rates were strongly reduced, coinciding with the strict first lockdown. During the summer months, CAAP rates caught up with the expected seasonal rates, but in October 2020 through All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted August 1, 2021. ; https://doi.org/10.1101/2021.07.29.21261308 doi: medRxiv preprint February 2021 the rates were extremely low (IRR vs 2016-2019: 0·07; 95% CI 0·05-0·10). Non-alveolar LRIs (NA-LRI): As with CAAP dynamics, in 2016-2019, NA-LRIs incidence peaked during December through February with a nadir in June through August (figure 1G, 1H; supplementary tables 2, 5). However, the variations between seasons were of a lesser magnitude compared to CAAP. As observed for CAAP, during the first quarter of 2020 dynamics were not affected and the second quarter was affected mainly by the first strict lockdown. However, unlike CAAP rates, following the first lockdown, NA-LRIs rates peaked again to reach the expected seasonal rate in July-September, and the reduction during October 2020 to February 2021 was only half compared to that of CAAP (46%, 95% CI 43-50%; vs 93%, 95% CI 90-95%, respectively), comparing the rates seen in summer and early fall, without the typical peak observed from November through February. During 2016-2019, the mean proportion of children under three years old carrying S. pneumoniae was 44·3±1.9%, ranging from 33·8% (August) to 53.8% (December) (figure 2; supplementary table 6). Nasopharyngeal testing was temporarily interrupted during the months of April through May 2020. Although carriage rates were somewhat reduced compared to previous years, during January and February 2021, the rates were very close to those of previous years. Furthermore, using the semiquantitative method, the mean density was within the ranges of the previous years. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted August 1, 2021. ; https://doi.org/10.1101/2021.07.29.21261308 doi: medRxiv preprint Additionally, no notable difference in pneumococcal serotype distribution between the COVID-19 and the pre-COVID period was seen (supplementary table 7) . The detection of respiratory viruses in children during the four years preceding 2020 showed typical dynamics of temperate zone seasonality 17 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted August 1, 2021. ; https://doi.org/10.1101/2021.07.29.21261308 doi: medRxiv preprint Throughout the study duration, excluding the period of the first strict lockdown, the dynamics of pneumococcus-associated disease closely followed those of RSV, influenza viruses, and hMPV. This was most striking with bacteremic pneumonia (supplementary figure 4) and CAAP. For NA-LRI and non-pneumonia IPD, although the association was less apparent, the expected typical peak during late fall and winter, coinciding with the expected activity of RSV, influenza viruses, and hMPV, did not occur (exemplified for NA-LRI in supplementary figure 5). We tested hospitalized visits for trauma, since they are essentially independent of respiratory infections, to examine whether some of the observed reductions in the reporting of LRIs will be related to lower detection rates during the COVID-19 epidemic (supplementary figure 5) . As expected, trauma visits peaked in the warm months, in contrast to the non-trauma visits, peaking during fall and winter. For both, a reduction during the first strict lockdown period was seen, but the trauma visit returned to close-to-normal rates, while the overall visits failed to show the expected fall and winter spike. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted August 1, 2021. ; https://doi.org/10.1101/2021.07.29.21261308 doi: medRxiv preprint This prospective cohort study demonstrates a marked reduction of hospital visit rates in southern Israel both for LRI and for pneumococcal disease in children under five years old during the 2020-2021 winter, coinciding with the peak of the COVID-19 pandemic. This reduction was closely associated with an extreme suppression of the circulation of specific respiratory viruses: RSV, influenza viruses, and hMPV. The most dramatic reductions in disease rates were seen in CAAP and bacteremic pneumonia, but NA-LRI and non-pneumonia IPD were also reduced. In contrast, during the same period, pneumococcal nasopharyngeal carriage prevalence was only slightly reduced, and density of colonization and pneumococcal serotype distribution were similar to those observed in previous years. This was a surprising finding because carriage is a prerequisite for pneumococcal disease. In most published reports, NPIs were suggested to be the cause of the reduction of IPD during the COVID-19 pandemic, assuming that those resulted in the reduction of pneumococcal transmission. 4, 18, 19 Our findings lead to the hypothesis that the reduction in pneumococcus-associated disease during fall-winter 2020-2021 resulted from the complete suppression of specific respiratory viruses rather than reduced transmissibility or serotype selection of S. pneumoniae in the community. These viruses, especially RSV and influenza are epidemiologically associated with both increased pneumococcal bacteremic pneumonia and non-bacteremic CAAP. 12, 20 Furthermore, the most frequently detected viruses during IPD and alveolar pneumonia are RSV, followed by influenza viruses and hMPV. 3, 21 The strong association of these viruses with pneumonia might explain why the reduction during fall-winter All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted August 1, 2021. ; https://doi.org/10.1101/2021.07.29.21261308 doi: medRxiv preprint 2020-2021 was of a higher magnitude in the case of bacteremic pneumonia and CAAP than in non-pneumonia IPD and NA-LRIs. While, by definition, S. pneumoniae is the causative agent for IPD, the extent of pneumococcal involvement in CAAP and NA-LRI is still not fully clarified. This cannot be directly answered, since most frequently, pathogens cannot be isolated in young children and detection of bacteria or viruses in the respiratory tract do not necessarily imply their causative role. However, measuring pneumococcal PCV impact on CAAP and LRI (the "vaccine" probe approach) provides a powerful tool for inference on the likely causative role of S. pneumoniae in these clinical outcomes 22 . Studies from Israel and elsewhere, have demonstrated a ~50% reduction in CAAP in young children following PCV implementation, 11,23 thus strongly suggesting an extensive causative role of S. pneumoniae in CAAP during the pre-PCV era. Our NA-LRI cases were severe enough to warrant a chest radiography, but per definition, those with CAAP were excluded. Studies have shown that in such cases, a rate reduction of ≥ 25% was observed in young children post PCV implementation, including a 34% reduction in our region. 11 Using a similar logic as that for CAAP, it is plausible that vaccine-serotype pneumococci also played an important role in NA-LRI, although of a lesser magnitude compared to CAAP. The similarity in dynamics between CAAP and IPD, in particular pneumococcal bacteremic pneumonia is therefore not surprising. Animal and human models have demonstrated that viral infections predispose not only to post-viral pneumococcal diseases, but frequently the true viral-bacterial coinfections. 1 Using the vaccine probe approach, studies have shown that PCVs could reduce hospitalization for viral infections, including viral pneumonia. 3 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted August 1, 2021. ; https://doi.org/10.1101/2021.07.29.21261308 doi: medRxiv preprint mechanisms by which viruses enhance virulence or invasiveness of S. pneumoniae were described, mainly with RSV and influenza virus. 25,26 It is therefore not surprising that the seasonality of IPD and both bacteremic and non-bacteremic pneumonia are overlapping, especially in regard to CAAP and bacteremic pneumonia. 12 It is also plausible that the suppression of CAAP and IPD (and bacteremic pneumonia in particular) is deeper than that of NA-LRI diseases for which a lower causative role of S. pneumoniae is assumed. The dynamics of NA-LRIs were similar, but not identical to those of CAAP. After the initial rate reduction due to the strict first lockdown, the rates returned to those seasonally expected, similar to those observed in 2016-2019. In spite of this, the expected late-fall and winter increases did not occur, presumably due to the absence of the abrupt increase of RSV, influenza viruses, and hMPV. In spite of this, the rates were not reduced as much as those of CAAP, but rather showed the same magnitude as those in the summer. The NA-LRI pattern in 2020-21 suggests that viruses such as parainfluenza and adenovirus, and potentially also rhinovirus and others could play a greater relative role for this entity than for CAAP, with a further increase in late-fall and winter rates, related to RSV (the main cause of bronchiolitis in young children) and potentially also to influenza and hMPV. The main strength of our study is its prospective conduct, using multiple ongoing cohort surveillance programs in the same population, enabling to compare dynamics during the COVID-19 epidemic to those during previous years, on the one hand, and different outcomes, on the other, with appropriate adjustments for time, age and ethnic group. The main weakness of the current study was the inability to determine with certainty the causative agents in the CAAP and NA-LRI cases, a difficulty All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. inherent to all studies on LRI in infants and young children. An additional weakness was that we did not attempt to diagnose all potential viral pathogens including non- In conclusion, our main message is that unlike common belief, the COVID-19associated reductions in pneumococcal and pneumococcal-associated diseases in children were not predominantly related to reduced or modified pneumococcal transmission and carriage, but most probably was derived from unprecedented suppression of the activity of specific viruses, capable of increasing the virulence of S. pneumoniae in children. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted August 1, 2021. ; https://doi.org/10.1101/2021.07.29.21261308 doi: medRxiv preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted August 1, 2021. All authors take responsibility for the integrity and accuracy of the data reported. Shalom Ben-Shimol has received grant/research support, honorarium for scientific consultancy, speaker bureau and participation in advisory committees from Pfizer Inc.; honorarium for scientific consultancy, speaker bureau and participation in advisory committees from MSD; speaker bureau from GlaxoSmithkline. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted August 1, 2021. The other authors have no conflicts of interest to declare All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted August 1, 2021. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted August 1, 2021. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted August 1, 2021. ; https://doi.org/10.1101/2021.07.29.21261308 doi: medRxiv preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted August 1, 2021. ; https://doi.org/10.1101/2021.07.29.21261308 doi: medRxiv preprint Respiratory viral and pneumococcal coinfection of the respiratory tract: implications of pneumococcal vaccination Evidence from multiplex molecular assays for complex multipathogen interactions in acute respiratory infections Association between respiratory syncytial virus activity and pneumococcal disease in infants: a time series analysis of US hospitalization data PCV13-vaccinated children still carrying PCV13 additional serotypes show similar carriage density to a control group of PCV7-vaccinated children Post-13-valent pneumococcal conjugate vaccine dynamics in young children of serotypes included in candidate extended-spectrum conjugate vaccines Identification of respiratory viruses in adults: nasopharyngeal versus oropharyngeal sampling R: A language and environment for statistical computing. 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