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• W4312417203 abstract "Article Figures and data Abstract Editor's evaluation Introduction Methods Results Discussion Appendix 1 Data availability References Decision letter Author response Article and author information Metrics Abstract Background: Viral sequencing of SARS-CoV-2 has been used for outbreak investigation, but there is limited evidence supporting routine use for infection prevention and control (IPC) within hospital settings. Methods: We conducted a prospective non-randomised trial of sequencing at 14 acute UK hospital trusts. Sites each had a 4-week baseline data collection period, followed by intervention periods comprising 8 weeks of ‘rapid’ (<48 hr) and 4 weeks of ‘longer-turnaround’ (5–10 days) sequencing using a sequence reporting tool (SRT). Data were collected on all hospital-onset COVID-19 infections (HOCIs; detected ≥48 hr from admission). The impact of the sequencing intervention on IPC knowledge and actions, and on the incidence of probable/definite hospital-acquired infections (HAIs), was evaluated. Results: A total of 2170 HOCI cases were recorded from October 2020 to April 2021, corresponding to a period of extreme strain on the health service, with sequence reports returned for 650/1320 (49.2%) during intervention phases. We did not detect a statistically significant change in weekly incidence of HAIs in longer-turnaround (incidence rate ratio 1.60, 95% CI 0.85–3.01; p=0.14) or rapid (0.85, 0.48–1.50; p=0.54) intervention phases compared to baseline phase. However, IPC practice was changed in 7.8 and 7.4% of all HOCI cases in rapid and longer-turnaround phases, respectively, and 17.2 and 11.6% of cases where the report was returned. In a ‘per-protocol’ sensitivity analysis, there was an impact on IPC actions in 20.7% of HOCI cases when the SRT report was returned within 5 days. Capacity to respond effectively to insights from sequencing was breached in most sites by the volume of cases and limited resources. Conclusions: While we did not demonstrate a direct impact of sequencing on the incidence of nosocomial transmission, our results suggest that sequencing can inform IPC response to HOCIs, particularly when returned within 5 days. Funding: COG-UK is supported by funding from the Medical Research Council (MRC) part of UK Research & Innovation (UKRI), the National Institute of Health Research (NIHR) (grant code: MC_PC_19027), and Genome Research Limited, operating as the Wellcome Sanger Institute. Clinical trial number: NCT04405934. Editor's evaluation This article contains valuable information on the potential value of real-time genome sequencing to inform infection control practices. The study, unique in its size, addresses the implementation of this approach during the height of the COVID-19 pandemic. Naturally, the extreme situation limited the options for choices in infection control practices. https://doi.org/10.7554/eLife.78427.sa0 Decision letter Reviews on Sciety eLife's review process Introduction Viral sequencing has played an important role in developing our understanding of the emergence and evolution of the SARS-CoV-2 pandemic (Oude Munnink et al., 2021). Sequencing technologies can now be used for local outbreak investigation in near real time, and this was implemented by some research centres for evaluation of nosocomial transmission from the early stages of the pandemic (Meredith et al., 2020). It has been demonstrated that sequencing can provide additional information on outbreak characteristics and transmission routes in comparison to traditional epidemiological investigation alone (Meredith et al., 2020; Lucey et al., 2021; Snell et al., 2022b). However, limited data are available on the feasibility of routine use of sequencing for infection prevention and control (IPC), or on its direct impact on IPC actions and nosocomial transmission rates. Throughout the pandemic, nosocomial transmission of SARS-CoV-2 has been a major concern (Abbas et al., 2021), with hospital-acquired infections (HAIs) accounting for more than 5% of lab-confirmed cases from March to August 2020 in the UK (Bhattacharya et al., 2021) and representing 11% of COVID-19 cases within hospitals in this period (Read et al., 2021). HAIs also frequently occur within a very vulnerable population with high levels of mortality (Bhattacharya et al., 2021; Oliver, 2021b; Ponsford et al., 2021). There is therefore an unmet need to develop interventions that can reduce the occurrence of nosocomial transmission. The aims of this study were to determine the effectiveness of SARS-CoV-2 sequencing in informing acute IPC actions and reducing the incidence of HAIs when used prospectively in routine practice, and to record the impact of sequencing reports on the actions of IPC teams. When this study was planned in the summer of 2020, there was imperfect knowledge regarding the dominant mode of transmission of SARS-CoV-2 (Greenhalgh et al., 2021), and it was not possible to predict the future course of the pandemic. In conducting this study, substantial difficulties were encountered in implementing the intervention and in responding effectively to any insights generated. As such, this report serves as a record of the challenge of conducting research within a pandemic as well as being a conventional study summary report. Methods We conducted a prospective multiphase non-randomised trial to evaluate the implementation and impact of SARS-CoV-2 sequencing for IPC within 14 acute NHS hospital groups in the UK. All sites were linked to a COG-UK sequencing hub, 13 were university hospitals and 1 a district general hospital. We implemented a bespoke sequence reporting tool (SRT) intervention, developed and previously evaluated for this study (Stirrup et al., 2021), and assessed the importance of turnaround time for sequencing and reporting. The study included integral health economic and qualitative process evaluation (Flowers et al., 2021). The study design comprised a planned 4-week baseline data collection period, followed by intervention periods defined by the time from diagnostic sampling to return of sequence data to IPC teams, comprising 8 weeks of ‘rapid’ (<48 hr) turnaround sequencing and 4 weeks of ‘longer’ (5–10 days) turnaround sequencing for each site. Target turnaround time was 48 hr from diagnostic sampling to return of the SRT report during the ‘rapid’ sequencing phase, and 5–10 days for the ‘longer-turnaround’ phase. Eight sites implemented ‘rapid’ followed by ‘longer-turnaround’ phases with five doing the opposite. One site did not implement longer-turnaround sequencing because they considered it a reduction in their standard practice, comprising outbreak sequencing with weekly meetings to discuss phylogenetic analyses; they nonetheless completed the baseline phase of the study without use of the SRT or automated feedback to IPC teams on all hospital-onset COVID-19 infection (HOCI) cases. The order of the intervention phases was pragmatically determined in some sites by the need to first run the ‘longer-turnaround’ phase to develop sample transport and sequencing procedures before attempting the ‘rapid’ sequencing phase, and the ordering was decided in the remaining sites to ensure a mixture of intervention phases over calendar time – there was no randomisation process in deciding the order of study phases. Data were recorded in all phases for all patients meeting the definition of a HOCI, that is, first confirmed test for SARS-CoV-2 >48 hr after admission and without suspicion of COVID-19 at the time of admission. During the intervention phases, and for at least 3 weeks prior to any intervention period to enable linkage to recent cases, participating sites aimed to sequence all SARS-CoV-2 cases including both HOCI and non-HOCI cases. The SRT aimed to integrate sequence and patient data to produce concise and immediately interpretable feedback about cases to IPC teams via a one-page report. Sites were also able to apply other methods (e.g. phylogenetics) to the sequence data generated, where this was part of their usual practice. Guidance regarding IPC actions was not specified as part of this study. Sites were expected to follow current national guidelines, which evolved throughout the course of the pandemic. Sequencing data from healthcare workers (HCWs) could be utilised in the SRT system, and this was implemented by 8/14 sites. Whether this was done depended on availability of HCW samples for each lab as staff testing was generally managed separately to patient testing. HCW testing protocols followed national guidelines. Data collection on patient characteristics and on implementation and impact of the intervention was conducted using a central study-specific database. Ethical approval for the study was granted by NHS HRA (REC 20/EE/0118), and the study was prospectively registered (ClinicalTrials.gov Identifier: NCT04405934). The primary outcomes of the study as defined in the protocol (Blackstone et al., 2022) were (1) incidence of IPC-defined SARS-CoV-2 HAIs per week per 100 currently admitted non-COVID-19 inpatients, and (2) for each HOCI, identification of linkage to individuals within an outbreak of SARS-CoV-2 nosocomial transmission using sequencing data as interpreted through the SRT that was not identified by pre-sequencing IPC evaluation during intervention phases. The second outcome used all observed HOCI cases as the denominator, and so represented the proportion of cases in which sequencing provided information regarding potential transmission routes where none had been previously uncovered. Secondary outcomes were (1) incidence of IPC-defined SARS-CoV-2 hospital outbreaks per week per 1000 non-COVID-19 inpatients; (2) for each HOCI, any change to IPC actions following receipt of SRT report during intervention phases; and (3) any recommended change to IPC actions (regardless of whether changes were implemented). There was considered to be an impact on IPC actions if this was recorded for any of a number of predefined outcomes (e.g. enhanced cleaning, visitor and staffing restrictions, provision of personal protective equipment), or if it was stated that the report had effected any change to IPC practice on that ward or elsewhere within the hospital. The proportion of HOCI cases for which IPC reported the SRT report to be ‘useful’ was added as a further outcome. To support standardisation across sites, ‘IPC-defined SARS-CoV-2 HAIs’ were considered to be all HOCIs with ≥8 days from admission to symptom onset (if known) or sample date (i.e. UK Health Security Agency definition of a probable/definite HAI; Public Health England, 2020). An IPC-defined SARS-CoV-2 hospital outbreak was defined as at least two HOCI cases on the same ward, with at least one having ≥8 days from admission to symptom onset or sample date. Outbreak events were considered to be concluded once there was a period of 28 days prior to observation of another HOCI (Public Health England, 2020). Further details of outcome definitions are given in Appendix 1. Statistical analysis We used three approaches: intention-to-treat analysis to assess the overall impact of sequencing on IPC activity and the incidence of HAIs, per protocol site-based analysis on a subset of high-performance sites, and pooled analysis to describe how turnaround time was related to impact on IPC irrespective of study phase. Inclusion of sites in the per protocol analysis was based on the proportion of sequence reports returned and speed of return in the rapid phase. Thresholds to define this group were determined following review of the data but before analysis of outcomes. Incidence outcomes were analysed using mixed effects negative binomial regression models, which in this context correspond to Poisson regression with an additional overdispersion parameter. Data for the first week of each intervention period, or in the first week of return to intervention following a break, were considered transition periods and not considered as direct evidence regarding the intervention effect. Analysis was conducted with calendar time divided into ‘study weeks’ running Monday–Sunday. Models were adjusted for calendar time, the proportion of current inpatients that were SARS-CoV-2 positive, as well as local community SARS-CoV-2 incidence for each study site, using 5 knot restricted cubic splines (Kahan et al., 2016). The number of inpatients not positive for SARS-CoV-2 was considered an exposure variable (defining ‘person-time’ at risk of nosocomial infection). Differences between study phases were evaluated using adjusted incidence rate ratios. The primary outcome of identification of SARS-CoV-2 nosocomial transmission using sequencing data and secondary outcomes relating to changes to IPC actions and the ‘usefulness’ of SRT reports were analysed using mixed effects logistic regression models, without covariable adjustment or removal of cases from the first week of each intervention phase. Marginal proportions from fitted models were reported for rapid- and longer-turnaround intervention phases, and differences in outcomes between these phases were evaluated. If the SRT report was not returned, this was interpreted as a ‘failure’, that is, no change to IPC action; however, we also present percentages for these outcomes restricted to HOCIs where the SRT report was returned. For both incidence and ‘per HOCI’ outcomes, we accounted for the structure of the data with hierarchical exchangeable normally distributed random effects for each study site, and for each study phase within each study site. Analyses were conducted using Stata V16, with figures generated using the ggplot2 package for R V4.0. Results A total of 2170 HOCIs were recorded for the study between 15 October 2020 and 26 April 2021. These cases had median age of 76.7 (interquartile range [IQR] 64.4–85.6) years, and 80% had at least one clinically significant comorbidity (Table 1). Table 1 Demographic and baseline characteristics of the participants by study phase. Characteristic at screeningStudy phaseTotalBaselineLonger-turnaroundRapidN HOCI cases8503739472170N HOCI cases per site, median (range); N sites36 (1–207); 1419 (0–86); 1330.5 (4-297); 14103.5 (40-451); 14HAI classification, n (%) Indeterminate (3–7 days)362 (42.6)166 (44.5)371 (39.2)899 (41.4) Probable (8–14 days)236 (27.8)121 (32.4)270 (28.5)627 (28.9) Definite (>14 days)252 (29.6)86 (23.1)306 (32.3)644 (29.7)Age (years), median (IQR, range)77.5 (65.4–85.6, 0.4–100.5)77.6 (64.6–86.7, 0.7–100.7)76.4 (62.6–85.5, 0.6–103.5)76.7 (64.4–85.6, 0.4–103.5)Age ≥70 years, n/N (%)589/850 (69.3)240/373 (64.3)598/947 (63.1)1427/2170 (65.8)Sex at birth: female, n/N (%)457/850 (53.8)177/372 (47.6)460/947 (48.6)1094/2169 (50.4)Ethnicity, n (%) White668 (78.6)275 (73.7)732 (77.3)1675 (77.2) Mixed ethnicity9 (1.1)6 (1.6)8 (0.8)23 (1.1) Asian46 (5.4)26 (7.0)34 (3.6)106 (4.9) Black Caribbean or African36 (4.2)18 (4.8)46 (4.9)100 (4.6) Other6 (0.7)1 (0.3)4 (0.4)11 (0.5) Unknown85 (10.0)47 (12.6)123 (13.0)255 (11.8)Symptomatic at time of sampling, n/N (%)167/739 (22.6)58/322 (18.0)106/659 (16.1)331/1720 (19.2)Significant comorbidity present, n/N (%)650/776 (83.8)260/323 (80.5)574/757 (75.8)1484/1856 (80.0)Pregnant, n/N (%)6/451 (1.3)1/177 (0.6)4/445 (0.9)11/1073 (1.0)Hospital admission route, n (%) Emergency department605 (71.2)258 (69.2)549 (58.0)1412 (65.1) Hospital transfer59 (6.9)21 (5.6)51 (5.4)131 (6.0) Care home3 (0.4)0 (0)0 (0)3 (0.1) GP referral38 (4.5)15 (4.0)76 (8.0)129 (5.9) Outpatient clinic ref.27 (3.2)20 (5.4)30 (3.2)77 (3.5) Other42 (4.9)9 (2.4)48 (5.1)99 (4.6) Unknown76 (8.9)50 (13.4)193 (20.4)319 (14.7) GP, general practitioner; HAI, hospital-acquired infection; HOCI, hospital-onset COVID-19 infection. All 14 sites completed baseline and rapid sequencing intervention phases (Appendix 1—figure 1). Thirteen sites completed the longer-turnaround sequencing intervention phase. 49.2% (650/1320) SRT reports for HOCIs were returned in the intervention phases, with only 9.3% (123/1320) returned within the target time frames (Table 2). This figure was greater in the longer-turnaround phase at 21.2% (79/373) than in the rapid phase (4.6%; 44/947). The median turnaround time from diagnostic sampling for reports returned was 5 days in the rapid phase and 13 days in the longer-turnaround phase, substantially longer than the targets of 48 hr and 5–10 days, respectively. A detailed breakdown of reporting turnaround times is reported separately (Colton et al., 2022). Table 2 Per hospital-onset COVID-19 infection (HOCI) implementation and outcome summary by study intervention phase, overall and within the 7/14 sites included in the ’per protocol’ sensitivity analysis. All study sitesSensitivity analysisStudy phaseTotalStudy phaseLonger-turnaroundRapidLonger-turnaroundRapidN HOCI cases3739471320143533ImplementationSequence returned within expected timeline, n (%)*229 (61.4)377 (39.8)606 (45.9)81 (56.6)204 (38.3)Sequence returned within study period, n (%)*277 (74.3)596 (62.9)873 (66.1)98 (68.5)347 (65.1)SRT report returned within target timeline (10 days for longer-turnaround, 2 days for rapid), n (%)79 (21.2)44 (4.6)123 (9.3)35 (24.5)44 (8.3)SRT report returned within study period, n (%)215 (57.6)435 (45.9)650 (49.2)92 (64.3)317 (59.5)Time from sample to report return (days), median (IQR, range) [n]13 (9–15, 0–36) [215]5 (3-11, 2-84) [430]9 (4-14, 0-84) [645]13 (9–17, 6–29) [92]4 (3-6, 2-64) [312]Sequencing resultsSRT-suggestive patient acquired infection post-admission, n/N (%)196/212 (92.5)384/423 (90.8)580/635 (91.3)85/92 (92.4)287/311 (92.3)SRT-suggestive patient is part of ward outbreak, n/N (%)151/212 (71.2)260/423 (61.5)411/635 (64.7)65/92 (70.7)202/311 (65.0)Linkage identified not suspected at initial IPC investigation: All HOCIs in phase n/N (%†, 95% CI)24/348 (6.8, 1.7–11.8)46/915 (6.7, 2.0–11.3)70/1263 (5.5)11/139 (7.9, 3.4–12.4)39/512 (7.6, 5.3–9.9) When SRT returned n/N (%)24/190 (12.6)46/403 (11.4)70/593 (11.8)11/88 (12.5)39/296 (13.2)SRT excluded IPC-identified hospital outbreak, n/N (%)14/213 (6.6)27/428 (6.3)41/641 (6.4)9/92 (9.8)25/310 (8.1)Impact on IPCSRT changed IPC practice: All HOCIs in phase n/N (%†, 95% CI)25/373 (7.4, 1.1–13.6)74/941 (7.8, 2.4–13.2)99/1314 (7.5)1/143 (0.7, 0.0–2.1)52/527 (9.9, 7.3–12.4) When SRT returned n/N (%)25/215 (11.6)74/429 (17.2)99/644 (15.4)1/92 (1.1)52/311 (16.7)SRT changed IPC practice for ward, n/N (%)13/215 (6.0)31/429 (7.2)44/644 (6.8)0/92 (0.0)28/311 (9.0)SRT used in IPC decisions beyond ward, n/N (%)12/215 (5.6)45/428 (10.5)57/643 (8.9)1/92 (1.1)27/310 (8.7)IPC team reported SRT to be useful, n/N (%) Yes107/215 (49.8)303/428 (70.8)410/643 (63.8)25/92 (27.2)245/310 (79.0) No67/215 (31.2)71/428 (16.6)138/643 (21.5)50/92 (54.3)57/310 (18.4) Unsure41/215 (19.1)54/428 (12.6)95/643 (14.8)17/92 (18.5)8/310 (2.6)HCW absence on wardProportion of HCWs on sick leave due to COVID-19, median (IQR, range) [n]0.09 (0.00–0.15, 0.00–0.30) [49]0.13 (0.07–0.29, 0.00–1.00) [162]0.13 (0.04–0.27, 0.00–1.00) [321] ‡0.09 (0.00–0.15, 0.00–0.30) [49]0.13 (0.08–0.29, 0.00–1.00) [143] HCW, healthcare worker; HOCI, hospital-onset COVID-19 infection; IPC, infection prevention and control; IQR, interquartile range; SRT, sequence reporting tool. * As recorded by site, not based on recorded date or availability on central CLIMB server. † Estimated marginal value from mixed effects model, not raw %, evaluated on intention-to-treat basis with lack of SRT report classified as ‘no’. ‡ Includes data for baseline phase: 0.13 (0.00–0.30, 0.00–0.88) [110]. Ordering the sites by proportion of cases with sequencing results returned and median turnaround time during the rapid phase (Figure 1) identified no obvious clustering of highest vs. lowest performing sites. We therefore also carried out a ’per protocol’ sensitivity analysis on the seven highest performing sites; these sites returned ≥40% of SRTs within a median time from diagnostic sample of ≤8 days within their rapid phase. The criteria for this analysis were decided after data collection but prior to data analysis, as per the statistical analysis plan (SAP). However, we acknowledge that the ‘higher performing sites’ did not meet the target turnaround time for reporting in the rapid phase; criteria were therefore set to split the sites into upper and lower 50% based on the level of implementation. Figure 1 Download asset Open asset Plots of the median turnaround time against the percentage of hospital-onset COVID-19 infection (HOCI) cases with sequence reporting tool (SRT) reports returned for the rapid (left panel) and longer-turnaround (right panel) sequencing phases across the 14 study sites. The size of each circle plotted indicates the number of HOCI cases observed within each phase for each site, with letter labels corresponding to study site. The criteria for inclusion in our sensitivity analysis are displayed as the green rectangle in the rapid phase plot, and sites on the longer-turnaround phase plot are colour-coded by their inclusion. In the rapid phase, SRT reports were returned for 0/4 HOCI cases recorded for site H. Site N did not have a longer-turnaround phase, Site A observed 0 HOCI cases, and sites D and E returned SRT reports for 0/1 and 0/2 HOCI cases, respectively, in this phase. We did not detect a statistically significant change in weekly incidence of HAIs in the longer-turnaround (incidence rate ratio 1.60, 95% CI 0.85–3.01; p=0.14) or rapid (0.85, 0.48–1.50; 0.54) intervention phases in comparison to baseline phase across the 14 sites (Table 3), and incidence rate ratios were comparable in our ‘per protocol’ analysis. Similarly, there was only weak evidence for an effect of phase on incidence of outbreaks in both intention-to-treat and ‘per protocol’ analyses, with wide confidence intervals inclusive of no difference in incidence (Table 3). Table 3 Incidence outcomes by study intervention phase, overall and within the 7/14 sites included in the ’per protocol’ sensitivity analysis. Study phaseIRR† (95% CI, p-value)BaselineLonger-turnaroundRapidLonger-turnaround vs. baselineRapid vs. baselineAll sitesn HOCI cases850373947––n IPC-defined HAIs488207576––Weekly incidence of IPC-defined HAIs per 100 inpatients, mean (median, IQR, range)* [primary outcome]1.0 (0.5, 0.0–1.4, 0.0–5.6)0.7 (0.3, 0.0–0.7, 0.0–7.6) ‡0.6 (0.3, 0.0–0.8, 0.0–5.3) ‡1.60 (0.85–3.01; 0.14)0.85 (0.48–1.50; 0.54)n IPC-defined outbreak events12933114––Weekly incidence of IPC-defined outbreak events per 1000 inpatients, mean (median, IQR, range)*2.7 (1.1, 0.0–4.1, 0.0–23.0)0.8 (0.0, 0.0–1.0, 0.0–8.9) ‡0.7 (0.0, 0.0–0.0, 0.0–8.9) ‡1.09 (0.38–3.16; 0.86)0.58 (0.24–1.39; 0.20)n IPC + sequencing-defined outbreak events–40133––Weekly incidence of IPC + sequencing-defined outbreak events per 1000 inpatients, mean (median, IQR, range)*–1.1 (0.0, 0.0–1.5, 0.0–13.4) ‡0.9 (0.0, 0.0–1.4, 0.0–7.6) ‡––Sensitivity analysisn HOCI cases290143533––n IPC-defined HAIs17991337––Weekly incidence of IPC-defined HAIs per 100 inpatients, mean (median, IQR, range)* [primary outcome]0.3 (0.0, 0.0–0.3, 0.0–3.0)0.3 (0.0, 0.0–0.0, 0.0–3.4) ‡0.4 (0.0, 0.0–0.3, 0.0–5.3) ‡2.21 (0.82–5.92; 0.10)1.75 (0.75–4.08; 0.16)n IPC-defined outbreak events581455––Weekly incidence of IPC-defined outbreak events per 1000 inpatients, mean (median, IQR, range)*1.1 (0.0, 0.0–1.3, 0.0–12.9)0.3 (0.0, 0.0–0.0, 0.0–5.7) ‡0.4 (0.0, 0.0–0.0, 0.0–8.9) ‡0.83 (0.14–4.93; 0.80)0.46 (0.11–1.86; 0.21)n IPC + sequencing-defined outbreak events–1467––Weekly incidence of IPC + sequencing-defined outbreak events per 1000 inpatients, mean (median, IQR, range)*–0.3 (0.0, 0.0–0.0, 0.0–5.7) ‡0.5 (0.0, 0.0–0.0, 0.0–7.6) ‡–– IPC-defined HAIs are considered to be ‘probable’ or ‘definite’ HAIs. HAI, hospital-acquired infection; HOCI, hospital-onset COVID-19 infection; IPC, infection prevention and control; IQR, interquartile range; IRR, incidence rate ratio. * Descriptive data over all week-long periods at all study sites. † Adjusted for proportion of current inpatients at site that are COVID-19 cases, community incidence rate, and calendar time (as displayed in Appendix 1—figure 5 and Appendix 1—figure 6 for all sites). ‡ Not including data from the first week of each intervention period or in the week following any break in the intervention period. We compared HOCI-level impacts of the sequence report between phases. Nosocomial linkage to other individual cases, where initial IPC investigation had not correctly identified any such linkage, was identified in 6.7 and 6.8% of all HOCI cases in the rapid and longer-turnaround phases, respectively (OR for ‘rapid vs. longer-turnaround’ 0.98, 95% CI 0.46–2.08; p=0.95) (Table 2) and in 11.4 and 12.6% respectively of cases where the report was returned. For 25 cases in the rapid and 5 cases in the longer-turnaround phase, phylogenetic trees were used for sequences with <90% genome coverage, with 3 from the rapid phase showing previously unidentified linkage. IPC practices were changed in 7.8 and 7.4% of all HOCI cases in the rapid and longer-turnaround phases, respectively (OR for ‘rapid vs. longer-turnaround’ 1.07, 0.34–3.38; p=0.90), and 17.2 and 11.6%, respectively, of cases where the report was returned. No one specific change to IPC action dominated those recorded among the options included within study reporting forms (Appendix 1—table 2, Appendix 1—table 3). When restricted to higher performing sites (i.e. ‘per protocol’), IPC practice was changed in a greater proportion of all HOCI cases in the rapid (9.9%) in comparison to the longer-turnaround (0.7%) sequencing phase (OR for ‘rapid vs. longer-turnaround’ 15.55, 1.30–1.85; p=0.01) and 16.7 and 1.1%, respectively, of cases where SRT reports were returned. The impact of phase on detecting nosocomial linkage was similar. IPC teams more commonly reported finding the sequence reports useful in the rapid sequencing, 303/428 (70.8%) compared to the longer-turnaround phase, 107/215 (49.8%) (although this association was reversed on analysis within the multi-level mode specified, OR 0.82 rapid vs. longer-turnaround, 0.12–5.46; p=0.82), and the difference was more pronounced in the ‘per protocol’ analysis (79.0 vs. 27.2%, respectively; OR 3.44, 0.28–42.61; p=0.41). We explored this association further using the actual time to return of the reports, going beyond the analyses pre-specified in the SAP (Figure 2). In the ‘per protocol’ analysis, an impact on IPC actions was observed in 20.7% (45/217) of HOCI cases in which the SRT report was returned within 5 days, but in very few cases beyond this, with this trend less apparent when data from all sites were considered. Figure 2 also displays a strong decline in reported usefulness of the SRT with increasing turnaround time, both across all sites and in the ‘per protocol’ analysis. Sequence reports were considered useful in 79.1% (182/230) of cases if returned within 5 days for all sites (169/216, 78%, in ‘per protocol’ analysis). However, we note that many of the HOCI cases with SRT returned within 5 days were from a single study site, and some sites did not seem to have clearly differentiated ‘useful’ SRT reports when completing data collection (Appendix 1—figure 2 and Appendix 1—figure 3). Figure 2 Download asset Open asset Plots of the proportion of returned sequence reporting tool (SRT) reports that had an impact on infection prevention and control (IPC) actions (a, b) and that were reported to be useful by IPC teams (c, d). Data are shown for all sites in (a) and (c), and for the seven sites included in the ’per protocol’ sensitivity analysis in (b) and (d). Results are only shown up to turnaround times of ≤28 days, and grouped proportions are shown for ≥9 days because of data sparsity at higher turnaround times. Error bars show binomial 95% CIs. ‘Yes’ and ‘No’ outcomes for individual hospital-onset COVID-19 infection (HOCI) cases are displayed, colour-coded by rapid (red) and longer-turnaround (blue) intervention phases and with random jitter to avoid overplotting. ‘Unsure’ responses were coded as ‘No’ for (c) and (d). SRT reports suggested that 91.3% of HOCI patients had acquired their infection post-admission (580/635, Table 2). In 91.9%, (589/641, Appendix 1—table 2) of cases, the reports were interpreted as supportive of IPC actions already taken. SRT reports also suggested post-admission infection in the majority of indeterminate HAIs (diagnosed 3–7 days from admission) (176/223, 78.9%). Our analysis models reveal important findings beyond the effect of the intervention. The analysis model for the incidence of HAIs identified independent positive associations with the proportion of current SARS-CoV-2-positive inpatients, the local community incidence of new SARS-CoV-2 cases (which peaked from December 2020 to January 2021, Appendix 1—figure 4 and Appendix 1—figure 5), and calendar time (modelled as ‘study week’). Adding the proportion of local community cases that were Alpha (lineage B.1.1.7) variant did not lead to a statistically significant improvement in model fit (p=0.78). The observed weekly HOCI incidence rates varied substantially from 0 to 7.6 per 100 SARS-CoV-2 negative inpatients, with peaks aligning with those for local community incidence (Appendix 1—figure 4). From modelling outbreaks, positive associations were similarly found for both hospital prevalence and community incidence of SARS-CoV-2 (Appendix 1—figure 6). The median number of HOCIs per IPC-defined outbreak event was four, with the largest observed outbreak including 43 HOCIs (Appendix 1—table 1). Extensive qualitative analyses (Mapp et al., under review; Flowers et al., 2022) found high levels of acceptability for the SRT se" @default.
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• W4312417203 date "2022-07-07" @default.
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• W4312417203 title "Author response: Effectiveness of rapid SARS-CoV-2 genome sequencing in supporting infection control for hospital-onset COVID-19 infection: Multicentre, prospective study" @default.
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