key: cord-306083-juysx6yo
authors: Choe, Young June; Park, Sangshin; Michelow, Ian C.
title: Co-seasonality and co-detection of respiratory viruses and bacteraemia in children: a retrospective analysis
date: 2020-09-10
journal: Clin Microbiol Infect
DOI: 10.1016/j.cmi.2020.09.006
sha: 
doc_id: 306083
cord_uid: juysx6yo

OBJECTIVES: The aim of this study was to assess the co-seasonality and co-detection of respiratory viral infections and bacteraemia in children since the introduction of the 13-valent pneumococcal conjugate vaccine (PCV13). METHODS: Children <18 years were eligible for inclusion if they had a respiratory infection and a positive PCR-based assay for respiratory viruses as well as a positive blood culture from 2010 to 2018 at a single referral centre in the United States regardless of their underlying medical condition or antibiotic treatment history. Monthly incidence rates of respiratory viruses and bacteraemia were analysed with a seasonal-trend decomposition procedure based on loess (STL) and cross-correlation functions using time series regression modelling. RESULTS: We identified 7,415 unique positive respiratory virus tests, including 2,278 RSV (31%), 1,825 influenza viruses (24%), 1,036 parainfluenza viruses (14%), 1,017 hMPV (14%), 677 seasonal coronaviruses (9%), and 582 adenoviruses (8%), and a total of 11,827 episodes of bacteraemia. Significant co-seasonality was found between all-cause bacteraemia and RSV (OR=1.76, 95% CI 1.50-2.06, P<0.001), influenza viruses (OR=1.38, 95% CI 1.13-1.68, P=0.002), and seasonal coronaviruses (OR=1.18, 95% CI 1.09-1.28, P<0.001), respectively. Analysis of linked viral-bacterial infections in individual children indicated that the rate ratio (RR) of bacteraemia associated with hMPV (RR=2.73, 95% CI 1.12-6.85, P=0.019) and influenza (RR=2.61, 95% CI 1.21-6.11, P=0.013) were more than double that of RSV. Staphylococcus aureus and Streptococcus pneumoniae were the most commonly identified pathogens causing bacteraemia. CONCLUSIONS: There is a significant association between hMPV and influenza viruses, and bacteraemia of all causes in hospitalised children at a single paediatric centre in the United States. Large multicentre studies are needed to confirm these findings and to elucidate the mechanisms by which hMPV potentiates the virulence and invasive capacity of diverse bacteria.

Children with respiratory viral infections are susceptible to infection with bacteria that may 2 cause pyogenic complications such as empyema, necrotising pneumonia and bacteraemia [1] . 3 Since the influenza pandemic of 1918, Streptococcus pneumoniae and Staphylococcus aureus 4 have been recognized as the predominant causes of invasive bacterial infections complicating 5 influenza infections [2] . 6

The direct relationship between respiratory viruses and bacteraemia in children remains 7 poorly defined, especially since the introduction of the 7-valent pneumococcal conjugate 8 vaccine (PCV7) in the United States in 2000 [3, 4] . A study conducted in children before the 9 implementation of PCV13, demonstrated significant associations between invasive 10 pneumococcal disease (IPD) and influenza viruses and respiratory syncytial virus (RSV), as well 11 as human metapneumovirus (hMPV), which was a novel observation [5] . 12

The deployment of PCV13 in the United States in 2010 has led to a substantial decline in 13 IPD but it is not currently known which bacteria complicate respiratory viral infections [3] . We 14 hypothesised that respiratory viruses detected in hospitalised children are associated with 15 multiple causes of bacteraemia. To test this hypothesis, we analysed the relationship between 16 16 respiratory viruses and all-cause bacteraemia in children at a single paediatric centre in the 17 United States over 8 years since the introduction of PCV13. 18

Care Clinic or during hospitalisation from June 2010 to May 2018. Blood cultures and 1 respiratory viral PCR assays were obtained at the discretion of attending physicians according to 2 usual local practise for children with fever and respiratory symptoms. No systematic changes 3 were made during the study period. Based on the knowledge that respiratory viruses incubate for 4 up to 1 week and are shed for 14 days or longer [6, 7] , we made an a priori assumption that 5 detection of a virus 2 weeks before or up to 1 week after a positive blood culture could 6 potentially be causally associated with bacteraemia. Children were eligible regardless of their 7 underlying medical condition or antibiotic treatment history. Aggregated laboratory results, 8 season and patients' age were collated using TheraDoc (Premier, Charlotte, North Carolina), an 9 infection control software system. 

We constructed a longitudinal database to track monthly incidence of respiratory viruses and 23 bacteraemia. A filtering procedure, called a seasonal-trend decomposition procedure based on 24 loess (STL) was conducted separately for respiratory viruses and bacteria in order to decompose 25 and smooth time series data with seasonal, trend and remaining components [8] . Cross-correlation functions were applied using time series regression modelling to determine the 1 highest correlation between overall incidence of various respiratory viruses and bacteraemia. We 2 calculated the incidence of cases with viral-bacterial co-detections as well as a rate ratio (RR) of 3 various respiratory viruses relative to that of RSV. RR was calculated using the median unbiased 4 estimator method. Statistical analyses were performed using R (ver. 3.4.3; R Development Core 5

Team, Vienna, Austria). 6

The Institutional Review Board at Rhode Island Hospital provided ethics approval for this 8 study and exemption from informed consent. Table 1 ). There were no significant seasonal 22 associations between adenovirus, hMPV, or parainfluenza viruses and bacteraemia. 23

We used RSV as a reference for computing RR because it had the lowest proportion of 24 bacteraemia episodes. Children with hMPV had the highest proportion of bacterial co-detections 25 with an RR of 2.7 relative to RSV (P = 0.019). Similarly, the RR for bacteraemia associated 26 with influenza viruses was 2.6 compared with RSV (P = 0.013). Adenoviruses, seasonal 1 coronaviruses and parainfluenza viruses had respective RR of 0.92, 1.90 and 2.20 relative to 2 RSV, but the differences were not statistically significant (Table 1) . 3 S. aureus (n = 15) and S. pneumoniae (n = 12) were the mostly commonly identified 4 pathogens causing bacteraemia (Supplementary Table) . 5 6 Discussion 7

We observed that the seasonality of coronaviruses, influenza viruses and RSV strongly 8 correlated with that of bacteraemia among hospitalised children. These findings corroborate 9 those of other investigators [5, 9] and indicate that the co-seasonality of respiratory viruses and 10 bacteria is conducive to concurrent host colonisation. After we linked episodes of viral and 11 bacterial infections in individual children, we found that the proportion of co-detections was 12 generally low, ranging from 0.4% for RSV to 1.1% for hMPV, which is within the range of 13 other recent reports (0.4-1.6%) [10] [11] [12] [13] [14] . However, children with hMPV or influenza viruses had 14 more than double the rate of bacteraemia compared with RSV. 15

This report validates the association between influenza and hMPV, and bacteraemia that was 16 reported by Ampofo et al [5] before the introduction of PCV13. In addition to S. pneumoniae, 17 we identified S. aureus and a variety of other bacteria, which emphasizes the importance of 18 emerging non-vaccine preventable pathogens. In addition to influenza, hMPV is known to cause 19 degenerative changes in the lower respiratory epithelium, potentially permitting colonising 20 bacteria to invade, and to impair signalling at the immunological synapse between dendritic cells 21 and T cells, potentially disrupting host defences, which may explain its virulence [4, 15] . 22

This study is limited by its retrospective design and lack of detailed patient-level clinical 23 data, such as evidence of upper versus lower respiratory tract infection, underlying 24 comorbidities, antibiotic treatment history, and evidence of prior immunisations. Also, the role 25 of multiple viruses detected simultaneously and possible role of presumed contaminants was not 26 assessed due to the aggregated nature of our data. Furthermore, the small number of patients 1 with co-detections derived from a single institution limits the generalisability of these findings. 2

On the other hand, this is the first study to appraise the association between respiratory 3 viruses and bacteraemia in children since the deployment of PCV13. Despite the small sample 4 size, we employed a rigorous statistical approach to account for seasonal and secular trends, and 5 our findings are consistent with those of a previous larger study conducted before the 6 introduction of PCV13 [5] . 7

In conclusion, we found a strong association between both hMPV and influenza, and 8 bacteraemia in children. Large multicentre studies are needed to confirm these findings and to 9 elucidate the mechanisms by which hMPV potentiates the virulence and invasive capacity of 10 diverse bacteria. Empiric antibacterial treatment of severely ill children infected with these 11 viruses appears to be warranted. 12 13 J o u r n a l P r e -p r o o f

YJC and ICM developed the study concept and design. All authors had full access to the data and take responsibility for the integrity of the data and accuracy of the data analysis. YJC was responsible for data collection. YJC and SP performed the statistical analyses. All authors assisted with data interpretation. YJC and ICM performed the literature search. YJC wrote the first draft of the manuscript. All authors have critically read and commented on draft versions of the report, and approved the final version.

The authors declare no competing interests. This work was supported by a grant from National Institute of Allergy and Infectious Diseases at the National Institutes of Health (grant number R25AI140490 to ICM). J o u r n a l P r e -p r o o f

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