key: cord-1046003-za3d9dn2 authors: Poole, Stephen; Brendish, Nathan J.; Clark, Tristan W. title: SARS-CoV-2 has displaced other seasonal respiratory viruses: Results from a prospective cohort study date: 2020-11-15 journal: J Infect DOI: 10.1016/j.jinf.2020.11.010 sha: bae7db9d85bbe975a1a6e5b515e0648d382dac57 doc_id: 1046003 cord_uid: za3d9dn2 OBJECTIVES: The effect of SARS-CoV-2 on existing respiratory viruses in circulation and the overall burden of viral respiratory disease remains uncertain. Traditionally, severe viral respiratory disease disproportionally affects those with underlying chronic lung diseases. This study aimed to assess the impact of SARS-CoV-2 on the prevalence and clinical characteristics of respiratory virus disease in hospitalised adults. METHODS: Data for this cohort study were from hospitalised adults who had multiplex PCR testing for respiratory viruses over several seasons in Hampshire, UK. Respiratory virus detection during the first epidemic peak of SARS-CoV-2 was compared to detection during the same time period across previous years. RESULTS: 856 patients had multiplex PCR for respiratory viruses between March and May over 5 years. Before 2020, a non-SARS-CoV-2 virus was detected in 54% patients (202/371) compared to 4.1% (20/485) in 2020 (p < 0.0001). SARS-CoV-2 was associated with asthma or COPD exacerbations in a smaller proportion of infected patients compared to other viruses (1.0% vs 37%, p < 0.0001). CONCLUSIONS: The emergence of SARS-CoV-2 was associated with substantial reductions in the circulation of seasonal respiratory viruses and large differences in the characteristics of viral-associated disease, including illness in a greater proportion of patients without underlying lung disease. A novel coronavirus, SARS-CoV-2, emerged in Hubei Province, China in December 2019 1 . In the 10 months since it has spread around the world causing a global pandemic leading to catastrophic loss of life and severe economic consequences that are predicted to endure for many years to come 2,3 . Policy makers around the world have enforced strict lockdowns to reduce the spread of the virus with unprecedented restrictions on personal freedoms. These appear to be effective but the effect they have on transmission of other respiratory viruses is largely unknown. Our understanding of risk factors, including chronic lung disease, and clinical features of COVID-19 continue to develop but how it compares to disease caused by other respiratory viruses has not been widely considered. In this study we describe the distribution of respiratory viruses in hospitalised adults in Southampton, UK, during the peak of the coronavirus pandemic from March to May 2020. We compare this to those identified in the same period from preceding years. We compare demographic, clinical and radiographic features in patients testing positive for SARS-CoV-2 with those testing positive for other respiratory viruses. We carried out a large cohort study of patients recruited from hospitals in Hampshire, UK. Data were collected from three large trials carried out between 2015 and 2020: the ResPOC trial 4 (ISRCTN90211642), the FluPOC trial (ISRCTN17197293, article in press) and the COV-19POC trial 5, 6 (ISRCTN14966673). Patients were recruited in the Emergency Department (ED) or Acute Medical Unit (AMU) of Southampton General Hospital or the Royal Hampshire County Hospital, Winchester. The former is a large teaching hospital and tertiary referral centre in the South of the UK, and the latter a large District General Hospital. A small number of patients from the were not included in the circulation of respiratory virus data as they were recruited directly from intensive care rather than from the ED or AMU. A clinically trained investigator summarised each clinical illness into a final diagnosis depending on disease characteristics. Pneumonia was defined as any new pulmonary infiltrate on chest x-ray or CT scan occurring with new respiratory symptoms. If the illness was not defined as pneumonia, then admission symptoms and comorbidities were used to adjudicate the diagnosis. Each trial was prospectively approved by UK regional ethics committees, and patients had to provide written consent to participate or have a consultee provide assent on their behalf. Full trial protocols are publicly available for each trial [7] [8] [9] . were summarised using appropriate descriptive statistics. Continuous data are presented as medians and interquartile ranges, and categorical data as numbers and percentages. Absolute differences between proportions are presented with 95% confidence intervals. Differences and 95% confidence intervals between medians were calculated using the Hodges-Lehmann estimator. Comparative statistical tests were performed between SARS-CoV-2 and non-SARS-CoV-2 viral positive cases. The Mann-Whitney U test was used for analysis of continuous variables, and the ꭓ 2 test or Fisher's exact test was used for categorical variables, as appropriate. Missing data were <4% in all analyses unless reported otherwise. This study is reported according to the STROBE guideline. were positive for a non-COVID-19 respiratory viruses in the same 2-month period (difference of 50%, 95%CI 44% to 56%; p<0.0001). Figure 1 shows the 7-day rolling average positivity rate for SARS-CoV-2 and other respiratory viruses during the first wave. Figure 2 shows the positivity rate for non-SARS-CoV-2 respiratory viruses in the preceding 5 years, by year. The most frequently detected non-COVID-19 virus in March-May during the 5 years prior to 2020 was influenza, which was detected in 26% of patients tested (95/371) followed by rhinovirus in 11% Other commonly detected viruses were human metapneumovirus (64), seasonal coronaviruses (47), SARS-CoV-2 was co-detected with another respiratory virus in 0.5% of cases (1/194), whereas non-COVID-19 respiratory viruses were detected in combination in 7.7% (41/533) (difference of 7.2%, 95%CI 3.3% to 10.4%; p=0.0002). There were some clear differences in the baseline characteristics of those with COVID-19 when compared to those with other respiratory viruses. Patients with SARS-CoV-2 were significantly older Patients with SARS-CoV-2 infection were also much more likely to work in healthcare, with 21% (39/185) of cases occurring in healthcare workers compared to only 6.0% (23/383) of other respiratory viruses (difference of 15%, 95% CI 9.6% to 20%; p<0.0001). It has been theorised that the spread of previous epidemic influenza viruses have been slowed by interaction with existing viral infections 15 , and there is a growing body of epidemiological evidence to support this phenomenon in other respiratory viruses 16 . The mechanisms for this are poorly understood. It was highly unusual for SARS-CoV-2 to be co-detected with other viruses, occurring in only 1% compared to 8% of other seasonal respiratory virus infections. This finding raises the possibility that viral interference may have played a role in the reduced prevalence of other respiratory viruses. SARS-CoV-2 had a disproportionate effect on those without existing respiratory disease when compared to other respiratory viruses. Pre-existing lung disease was present in almost twice as many patients with non-SARS-CoV-2 respiratory virus infection. This is reflected in the pattern of clinical illness, where exacerbations of asthma and COPD associated with SARS-CoV-2 were rare. It is well established that respiratory viruses are a frequent cause of exacerbation in these diseases 17, 18 , and yet these were the main clinical diagnosis in only 1% of SARS-CoV-2 infections. The rate of smoking (5%) in those testing positive for SARS-CoV-2 is consistent with other large reported UK datasets 19 and substantially below the 24% of patients with other respiratory virus detection. It is notable that smoking appears to be a risk factor for developing severe disease but is infrequently present in hospitalised patients with COVID-19 20, 21 . The disproportionately high rates of infection and mortality of COVID-19 on BAME (Black, Asian and Minority Ethnic) groups has been widely acknowledged 22 . Our study shows that this was also the case in our region where Black and Asian patients accounted for a much higher proportion of SARS-CoV-2 infections compared with seasonal respiratory virus infection. Locally these data may be confounded by the rate of infection observed in cruise ship workers who were from a diverse range of ethnic backgrounds. Southampton is a large, maritime city where a number of cruise ships were berthed during the height of the pandemic. More studies are urgently required to investigate the disproportionate effect of COVID-19 on BAME populations. Other groups have described the disproportionate risk to healthcare workers of developing COVID-19 in observational studies 23 . Our findings also suggest this, with 1 in 5 infections being reported in this group, matching other large reports during the height of the pandemic 24 . As a novel finding, we report that this rate of infection requiring hospitalisation was more than five times greater than rates for existing respiratory viruses in previous years. This difference may be explained in part by the impact of annual influenza vaccination of healthcare workers in the UK, which would limit the number of staff developing severe disease. Another contributing factor could be the disproportionately high rates of infection and transmission in care homes in the UK 25 . Almost all patients with any virus detected were given antibiotic therapy, despite the lack of evidence for their utility use in viral infection. Presumably, this was given for suspected secondary bacterial infection and no microbiological data was collected to this end, however it continues to highlight an unmet need for better diagnostic tests which allow differentiation between viral and bacterial infections and the safe withholding of unnecessary antibiotics. Lymphopaenia is a reliable feature of COVID-19 26, 27 and a lower count predicts severe disease 28 . Our work highlights that it remains a common feature of other viral respiratory tract infections and therefore cannot be used to help differentiate between different viral aetiologies. Our data show that CRP and neutrophil count are potentially more useful to differentiate between SARS-CoV-2 and other viral infections although there remains considerable overlap. Large data sets have shown a typical rate of admission to ICU of around 15% 19,29 of hospitalised patients with COVID-19 which is consistent with our findings (19%). The stark difference in mortality rate between SARS-CoV-2 infection and other respiratory viruses are highlighted by our data, with 30-day mortality around 10 times greater. The strengths of our study are that large amounts of data were collected prospectively with a high degree of detail and accuracy. There is minimal missing data, and all of the collection procedures were standardised for each study (i.e. the same electronic data and paper sources were accessed in the same way). As a result, we have a very large cohort who had comprehensive multiplex testing for respiratory viral infection who are directly comparable. The findings of this study are highly generalisable to adults presenting with acute respiratory illness at a time of peak prevalence of disease in a developed healthcare setting. A limitation of the trial is that it was only carried out in two centres. Furthermore, we did not record whether patients were residents of long-term care facilities in these trials. This was an area of widespread transmission that emerged as a potential confounding factor midway through our trial during the UK pandemic 30 . We report a significant drop in the circulation of non-SARS-CoV-2 respiratory viruses during first wave of the 2020 pandemic when compared to the same time period in previous years. SARS-CoV-2 infection was associated with major differences in the clinical characteristics and outcome of respiratory virus associated diseases. These include infrequent association with exacerbations of airways disease, a higher rate of severe pneumonia, and a mortality rate around 10 times higher than that seen with seasonal respiratory virus infection. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. FluPOC was funded by a NIHR Fellowship awarded to TWC (PDF 2016-09-061) and ResPOC and CoV-19POC were funded by the University of Southampton and University Hospital Southampton NHS Foundation Trust respectively. 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We would also like to thank the recruiting fellows, research nurses and clinical trials assistants for the conduct of the studies.