key: cord-0910869-bdc7p8rc
authors: Mo, Y.; Eyre, D. W.; Lumley, S.; Walker, T.; Shaw, R.; O'Donnell, D.; Butcher, L.; Jeffery, K.; Donnelly, C. A.; Oxford COVID infection review team,; Cooper, B. S.
title: Transmission dynamics of SARS-CoV-2 in the hospital setting
date: 2021-05-01
journal: nan
DOI: 10.1101/2021.04.28.21256245
sha: 7767cdf2c174d22fa3ef182fb128961afe0948f9
doc_id: 910869
cord_uid: bdc7p8rc

Background: SARS-CoV-2 can spread efficiently in hospitals, but the transmission pathways amongst patients and healthcare workers are unclear. Methods: We analysed data from four teaching hospitals in Oxfordshire, UK, from January to October 2020. Associations between infectious SARS-CoV-2 individuals and infection risk were quantified using logistic, generalised additive and linear mixed models. Cases were classified as community- or hospital-acquired using likely incubation periods. Results: Nine-hundred and twenty of 66184 patients who were hospitalised during the study period had a positive SARS-CoV-2 PCR test within the same period (1%). Out of these, 571 patients had their first positive PCR tests while hospitalised (62%), and 97 of these occurred at least seven days after admission (11%). Amongst the 5596 healthcare workers, 615 (11%) tested positive during the study period using PCR or serological tests. For susceptible patients, one day in the same ward with another patient with hospital-acquired SARS-CoV-2 was associated with an additional eight infections per 1000 susceptible patients (95%CrI 6-10). Exposure to an infectious patient with community-acquired COVID-19 or to an infectious healthcare worker was associated with substantially lower infection risks (2/1000 susceptible patients/day, 95%CrI 1-2). As for healthcare worker infections, exposure to an infectious patient with hospital-acquired SARS-CoV-2 or to an infectious healthcare worker were both associated with an additional one infection per 1000 susceptible healthcare workers per day (95%CrI 1-2). Exposure to an infectious patient with community-acquired SARS-CoV-2 was associated with half this risk (0.5/1000 susceptible healthcare workers/day, 95%CrI 0.3-0.7). Interpretation: Exposure to patients with hospital-acquired SARS-CoV-2 poses a substantial infection risk. Infection control measures to limit nosocomial transmission must be optimised to protect both staff and patients from SARS-CoV-2 infection. Funding: National Institute for Health Research Health Protection Research Unit (NIHR HPRU) in Healthcare Associated Infections and Antimicrobial Resistance at Oxford University in partnership with Public Health England (PHE) (NIHR200915). Medical Research Council, Nosocomial transmission of SARS-CoV-2 (MR/V028456/1).

infected has been lacking and the relative importance of different transmission pathways (e.g. 126

. CC-BY-NC-ND 4.0 International license It is made available under a 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 May 1, 2021. ; https://doi.org/10.1101/2021.04.28.21256245 doi: medRxiv preprint patient to HCW, HCW to patient, HCW to HCW and patient to patient) and has not, to our 127 knowledge, previously been quantified. [ CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

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We assumed that each individual could only be infected once, and hence patients and HCW were 171 no longer at risk for acquiring SARS-CoV-2 after their first positive PCR test. The day each 172 patient with a potential nosocomial infection became infected is unknown, but based on 173 knowledge of the incubation period distribution we expect it to be one to 20 days prior to the 174 date of symptom onset, with 83% falling between 3-7 days. [19] For a given incubation period, 175 d, we assume that each patient with a nosocomial infection became infected d days before the 176 date of symptom onset. 177 178 Among 245 inpatients testing positive after developing SARS-CoV-2 symptoms during 179 hospitalisation, the mean interval between symptom onset and their swab for PCR-testing was 180 one day (interquartile range 1-3). Consequently, we assumed that swabs for SARS-CoV-2 PCR 181 tests after hospital admission were taken in response to COVID-19-like symptom onset one day 182 earlier or, in asymptomatic cases, the swabs were assumed to have been taken one day after the 183 incubation period. The date of each patient's first positive PCR test refers to the date the swab 184 was obtained, rather than tested if this differed (figure 1). 185 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) lf . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

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Nosocomial SARS-CoV-2 infections have previously been defined as 'probable' when 204 symptoms onset is on day 8-14 after admission and 'definite' when symptoms onset is on day 205 >14 after admission.

[20] These increasing thresholds correspond to higher certainties that a case 206 is hospital-acquired (supplementary figure S5 ).

[20] In this study, however, we used incubation 207 periods that are the most likely to identify the exposure risk factors, i.e., the locations and 208 infectious individuals the susceptible individuals were exposed to, which could have resulted in 209 an observed infection event. Our baseline assumption was that the incubation period was five 210 days (which is reported to be the median value [20]) , and we therefore define hospital-acquired 211 infections to be any PCR-confirmed SARS-CoV-2 infection where the patient was a hospital 212 inpatient six days prior to the first positive PCR test. We also report results for sensitivity 213 analyses assuming incubation periods of three and seven days. Community-acquired infections 214 are defined to be any PCR-confirmed infections in patients who were not hospitalised in the 20 215 days prior to their first positive PCR tests. 216 217

We assumed that patients were infectious for a period of ten days starting a day after the day of 219 presumed infection, consistent with estimates that 99.7% of onward infection takes place within 220 the first ten days after the presumed infection event. [21, 26] HCW were assumed to be 221 infectious from a day after the day of assumed infection to the day of symptom onset or one day 222 prior to having a positive PCR test (i.e., staff were assumed to be absent from work after 223 reporting symptoms consistent with SARS-CoV-2 infection or having a positive PCR test). 224 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

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In the main analyses presented in the Results section, we considered infectiousness to be binary. 226

To account for time-varying infectiousness in relation to the time of presumed infection event, 227

we repeated the analysis after scaling the numbers of infectious patients and HCW in a ward on a 228 particular day by their relative infectiousness, using the generation time distribution derived by 229

Ferretti et al [21] such that the sum of daily terms for a single infected patient or HCW who was 230 present in the ward throughout their entire infectious period would equal one. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

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We first performed exploratory analyses using univariable and multivariable logistic regression 248 models to determine associations between risk factors and SARS-CoV-2 infection for given 249 incubation periods (supplementary section 6 code block 1). To assess how well these individual 250 demographic factors and infection pressures from infectious patients and healthcare workers on 251 the same wards accounted for the nosocomial SARS-CoV-2 infections over calendar time, we 252 used generalised additive models which allowed for the risk of infection to depend in a non-253 linear manner on the predictors (supplementary section 6 code block 2) The generalised additive 254 models were implemented using the R package mgcv. The patient characteristics are shown in Table 1 . The patients who likely acquired SARS-CoV-2 286 while in hospital (assuming incubation periods of 5, 3 or 7 days) were older, had longer lengths 287 of stays and more readmissions compared to patients with no positive SARS-CoV-2 PCR tests. 288 289 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) . CC-BY-NC-ND 4.0 International license It is made available under a 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 May 1, 2021. Testing capacity increased substantially after the beginning of March 2020 (figure 2A). The 301 weekly incidence of newly detected SARS-CoV-2 infections in the four hospitals, including both 302 community-acquired and nosocomial cases, peaked between March and May 2020. 303 304 Two-hundred and seventy-one patients had at least one day of hospitalisation in the 20 days prior 305 to being tested positive for SARS-CoV-2. Out of these patients, 130 (48%) were inpatients on 306 their day of infection, based on an assumed incubation period of five days. One-hundred and two 307 out of the 130 patients had at least one negative PCR test during day 1-5 of their hospitalisation 308 . CC-BY-NC-ND 4.0 International license It is made available under a 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 May 1, 2021. ; https://doi.org/10.1101/2021.04.28.21256245 doi: medRxiv preprint (79%). The median length of stay for the admissions during which the patients were infected 309 with SARS-CoV-2 was 21 days (interquartile range 13 to 35 days). The median day of 310 hospitalisation when these patients were assumed to have been infected was day 8 (interquartile 311 range 3 to 18 days). inpatients on the eighth (red), sixth (orange), and forth day (yellow) prior to their first positive 320 tests, and who were not hospitalised in the 20 days prior to their first positive tests (blue). These 321 classifications are not mutually exclusive, e.g., a patient who was admitted for ten days 322 continuously prior to the first positive PCR test would contribute to all first three groups. 323 rs . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

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The copyright holder for this preprint this version posted May 1, 2021. We performed similar analyses to quantify the risk of transmission to HCW. The multivariable 407 logistic regression results showed that nurses were at the highest risk of being infected with 408 rd k . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) 

. CC-BY-NC-ND 4.0 International license It is made available under a 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 May 1, 2021. The background transmission risks to HCW including that from community sources and 434 undetected cases amongst both HCW and patients were similar to those observed in the patients. 435

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The copyright holder for this preprint this version posted May 1, 2021. developed symptoms were not available. Hence, we needed to assume that the PCR test swabs 471 . CC-BY-NC-ND 4.0 International license It is made available under a 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 May 1, 2021. ; https://doi.org/10.1101/2021.04.28.21256245 doi: medRxiv preprint were taken on the symptom onset dates. While this assumption is reasonable based on the 472 analysis of a subset of data early in the pandemic, it is not true from phase three onwards when 473 weekly screening of patients regardless of symptoms was implemented. We addressed this by 474 performing sensitivity analysis comparing model outputs when using data collected during phase 475 one and two versus phase three (supplementary material section 5). Secondly, we assumed that 476 HCW were absent from work after the dates on which their first positive PCR test swabs were 477 taken or COVID-19 symptoms were first self-reported. However, where HCW experienced 478 minimal or no symptoms they may have continued to work. These issues could be further 479 explored using HCW absentee data in subsequent analysis. is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

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In conclusion, our data provide strong evidence that newly infected patients pose a high risk of 514 onward transmission to patients and healthcare workers in hospital. Further investigation is 515 needed into how best to enhance infection control and prevention efforts around these patients. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

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To quantify the daily transmission risk posed by infectious patients and healthcare workers, we 753 used a generalised linear mixed model with an identity link, thus allowing for the daily 754 probability of infection to scale linearly with infection pressure from healthcare workers and 755 patients and for their effects to be additive. Two models, one with interaction terms between the 756 phases and forces of infection from patients and healthcare workers, and one without the 757 interaction terms, were compared. Between these transmission models, the model with the best 758 fit to data by WAIC was the one without interaction terms, which has an intercept (α), 759

representing the infection risk not explained by covariates, and slopes (beta) which represent the 760 infection risk associated with infectious patients (community-and hospital-acquired) and 761 healthcare workers. 762 763 764 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

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The copyright holder for this preprint this version posted May 1, 2021. ; https://doi.org/10.1101/2021.04.28.21256245 doi: medRxiv preprint 797 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted May 1, 2021. ; https://doi.org/10.1101/2021.04.28.21256245 doi: medRxiv preprint 5. Sensitivity analysis 798 799   Table S4 : The main analysis considers infectiousness to be binary, i.e., absolute numbers of 800 infectious patients and healthcare workers in a ward on a particular day were used. Sensitivity 801 analysis considered infectiousness to be scaled according to the time since the day of infection 802 which, in turn, is based on an assumed incubation period of five days. This scaling of the number 803 of infectious patients and healthcare workers in a ward on a particular day makes use of the 804 relative infectiousness distribution derived by He et al [25] such that the sum of daily terms for a 805 single infected patient who was present in the ward throughout their entire infectious period 806 would equal one. Hence, the scaled parameters are an order of magnitude higher than the binary 807 infectiousness model estimates. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

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