The burden and dynamics of hospital-acquired SARS-CoV-2 in England.

Hospital-based transmission had a dominant role in Middle East respiratory syndrome coronavirus (MERS-CoV) and severe acute respiratory syndrome coronavirus (SARS-CoV) epidemics1,2, but large-scale studies of its role in the SARS-CoV-2 pandemic are lacking. Such transmission risks spreading the virus to the most vulnerable individuals and can have wider-scale impacts through hospital-community interactions. Using data from acute hospitals in England, we quantify within-hospital transmission, evaluate likely pathways of spread and factors associated with heightened transmission risk, and explore the wider dynamical consequences. We estimate that between June 2020 and March 2021 between 95,000 and 167,000 inpatients acquired SARS-CoV-2 in hospitals (1% to 2% of all hospital admissions in this period). Analysis of time series data provided evidence that patients who themselves acquired SARS-CoV-2 infection in hospital were the main sources of transmission to other patients. Increased transmission to inpatients was associated with hospitals having fewer single rooms and lower heated volume per bed. Moreover, we show that reducing hospital transmission could substantially enhance the efficiency of punctuated lockdown measures in suppressing community transmission. These findings reveal the previously unrecognized scale of hospital transmission, have direct implications for targeting of hospital control measures and highlight the need to design hospitals better equipped to limit the transmission of future high-consequence pathogens.

Impact of interventions to reduce nosocomial transmission of SARS-CoV-2 in English NHS Trusts: a computational modelling study.

BACKGROUND: Prior to September 2021, 55,000-90,000 hospital inpatients in England were identified as having a potentially nosocomial SARS-CoV-2 infection. This includes cases that were likely missed due to pauci- or asymptomatic infection. Further, high numbers of healthcare workers (HCWs) are thought to have been infected, and there is evidence that some of these cases may also have been nosocomially linked, with both HCW to HCW and patient to HCW transmission being reported. From the start of the SARS-CoV-2 pandemic interventions in hospitals such as testing patients on admission and universal mask wearing were introduced to stop spread within and between patient and HCW populations, the effectiveness of which are largely unknown. MATERIALS/METHODS: Using an individual-based model of within-hospital transmission, we estimated the contribution of individual interventions (together and in combination) to the effectiveness of the overall package of interventions implemented in English hospitals during the COVID-19 pandemic. A panel of experts in infection prevention and control informed intervention choice and helped ensure the model reflected implementation in practice. Model parameters and associated uncertainty were derived using national and local data, literature review and formal elicitation of expert opinion. We simulated scenarios to explore how many nosocomial infections might have been seen in patients and HCWs if interventions had not been implemented. We simulated the time period from March-2020 to July-2022 encompassing different strains and multiple doses of vaccination. RESULTS: Modelling results suggest that in a scenario without inpatient testing, infection prevention and control measures, and reductions in occupancy and visitors, the number of patients developing a nosocomial SARS-CoV-2 infection could have been twice as high over the course of the pandemic, and over 600,000 HCWs could have been infected in the first wave alone. Isolation of symptomatic HCWs and universal masking by HCWs were the most effective interventions for preventing infections in both patient and HCW populations. Model findings suggest that collectively the interventions introduced over the SARS-CoV-2 pandemic in England averted 400,000 (240,000 - 500,000) infections in inpatients and 410,000 (370,000 - 450,000) HCW infections. CONCLUSIONS: Interventions to reduce the spread of nosocomial infections have varying impact, but the package of interventions implemented in England significantly reduced nosocomial transmission to both patients and HCWs over the SARS-CoV-2 pandemic.

Estimation of the impact of hospital-onset SARS-CoV-2 infections on length of stay in English hospitals using causal inference.

BACKGROUND: From March 2020 through August 2021, 97,762 hospital-onset SARS-CoV-2 infections were detected in English hospitals. Resulting excess length of stay (LoS) created a potentially substantial health and economic burden for patients and the NHS, but we are currently unaware of any published studies estimating this excess. METHODS: We implemented appropriate causal inference methods to determine the extent to which observed additional hospital stay is attributable to the infection rather than the characteristics of the patients. Hospital admissions records were linked to SARS-CoV-2 test data to establish the study population (7.5 million) of all non-COVID-19 admissions to English hospitals from 1st March 2020 to 31st August 2021 with a stay of at least two days. The excess LoS due to hospital-onset SARS-CoV-2 infection was estimated as the difference between the mean LoS observed and in the counterfactual where infections do not occur. We used inverse probability weighted Kaplan-Meier curves to estimate the mean survival time if all hospital-onset SARS-CoV-2 infections were to be prevented, the weights being based on the daily probability of acquiring an infection. The analysis was carried out for four time periods, reflecting phases of the pandemic differing with respect to overall case numbers, testing policies, vaccine rollout and prevalence of variants. RESULTS: The observed mean LoS of hospital-onset cases was higher than for non-COVID-19 hospital patients by 16, 20, 13 and 19 days over the four phases, respectively. However, when the causal inference approach was used to appropriately adjust for time to infection and confounding, the estimated mean excess LoS caused by hospital-onset SARS-CoV-2 was: 2.0 [95% confidence interval 1.8-2.2] days (Mar-Jun 2020), 1.4 [1.2-1.6] days (Sep-Dec 2020); 0.9 [0.7-1.1] days (Jan-Apr 2021); 1.5 [1.1-1.9] days (May-Aug 2021). CONCLUSIONS: Hospital-onset SARS-CoV-2 is associated with a small but notable excess LoS, equivalent to 130,000 bed days. The comparatively high LoS observed for hospital-onset COVID-19 patients is mostly explained by the timing of their infections relative to admission. Failing to account for confounding and time to infection leads to overestimates of additional length of stay and therefore overestimates costs of infections, leading to inaccurate evaluations of control strategies.

The contribution of hospital-acquired infections to the COVID-19 epidemic in England in the first half of 2020.

BACKGROUND: SARS-CoV-2 is known to transmit in hospital settings, but the contribution of infections acquired in hospitals to the epidemic at a national scale is unknown. METHODS: We used comprehensive national English datasets to determine the number of COVID-19 patients with identified hospital-acquired infections (with symptom onset > 7 days after admission and before discharge) in acute English hospitals up to August 2020. As patients may leave the hospital prior to detection of infection or have rapid symptom onset, we combined measures of the length of stay and the incubation period distribution to estimate how many hospital-acquired infections may have been missed. We used simulations to estimate the total number (identified and unidentified) of symptomatic hospital-acquired infections, as well as infections due to onward community transmission from missed hospital-acquired infections, to 31st July 2020. RESULTS: In our dataset of hospitalised COVID-19 patients in acute English hospitals with a recorded symptom onset date (n = 65,028), 7% were classified as hospital-acquired. We estimated that only 30% (range across weeks and 200 simulations: 20-41%) of symptomatic hospital-acquired infections would be identified, with up to 15% (mean, 95% range over 200 simulations: 14.1-15.8%) of cases currently classified as community-acquired COVID-19 potentially linked to hospital transmission. We estimated that 26,600 (25,900 to 27,700) individuals acquired a symptomatic SARS-CoV-2 infection in an acute Trust in England before 31st July 2020, resulting in 15,900 (15,200-16,400) or 20.1% (19.2-20.7%) of all identified hospitalised COVID-19 cases. CONCLUSIONS: Transmission of SARS-CoV-2 to hospitalised patients likely caused approximately a fifth of identified cases of hospitalised COVID-19 in the "first wave" in England, but less than 1% of all infections in England. Using time to symptom onset from admission for inpatients as a detection method likely misses a substantial proportion (> 60%) of hospital-acquired infections.

Beyond the SNP Threshold: Identifying Outbreak Clusters Using Inferred Transmissions.

Whole-genome sequencing (WGS) is increasingly used to aid the understanding of pathogen transmission. A first step in analyzing WGS data is usually to define "transmission clusters," sets of cases that are potentially linked by direct transmission. This is often done by including two cases in the same cluster if they are separated by fewer single-nucleotide polymorphisms (SNPs) than a specified threshold. However, there is little agreement as to what an appropriate threshold should be. We propose a probabilistic alternative, suggesting that the key inferential target for transmission clusters is the number of transmissions separating cases. We characterize this by combining the number of SNP differences and the length of time over which those differences have accumulated, using information about case timing, molecular clock, and transmission processes. Our framework has the advantage of allowing for variable mutation rates across the genome and can incorporate other epidemiological data. We use two tuberculosis studies to illustrate the impact of our approach: with British Columbia data by using spatial divisions; with Republic of Moldova data by incorporating antibiotic resistance. Simulation results indicate that our transmission-based method is better in identifying direct transmissions than a SNP threshold, with dissimilarity between clusterings of on average 0.27 bits compared with 0.37 bits for the SNP-threshold method and 0.84 bits for randomly permuted data. These results show that it is likely to outperform the SNP-threshold method where clock rates are variable and sample collection times are spread out. We implement the method in the R package transcluster.

Risk of unintended consequences from lower antibiotic prescribing for respiratory tract infections in primary care.

OBJECTIVES: About 60% of antibiotic prescribing in primary care is for respiratory tract infections (RTIs), some of which is likely unnecessary. There is limited evidence on the association between reduced antibiotic prescribing and adverse events. We aimed to identify associations between practice-level prescribing rates for RTIs in general practice, and patient-level adverse outcomes. METHODS: We included 1471 English General Practitioner (GP) practices, linked to hospital admissions in England, from the Clinical Practice Research Datalink for 2005 to 2019. Outcomes were hospitalisations, RTI-related re-consultations and additional antibiotic prescriptions, adjusted for practice level case-mix prescribing. RESULTS: Prescribing rates for practices falling within the lowest and highest prescribing quintiles were 52 and 139 prescriptions per 1000 RTI-related consultations. Patients from practices in the lowest prescribing quintile did not have significantly higher risk of hospitalisation, adjusted odds ratio 0·99 (95% CI 0·96 to 1·02). Re-consultations within 30 days were significantly higher for the lowest prescribing practices, adjusted odds ratio 1·209 (1·206 to 1·212). Additional antibiotic prescriptions and subsequent prescriptions upon re-consultation were significantly lower for the lowest prescribing practices, adjusted odds ratio 0·317 (0·314 to 0·321) and 0·706 (0·699 to 0·712), respectively. CONCLUSIONS: Our results contribute to evidence on the safety of reduced antibiotic prescribing for RTIs in primary care. Results suggest that for the majority of practices, further reductions in RTI-related antibiotic prescribing should be possible without an increase in hospitalisation for pneumonia.

Evaluating the impact of testing strategies for the detection of nosocomial COVID-19 in English hospitals through data-driven modeling.

Introduction: During the first wave of the COVID-19 pandemic 293,204 inpatients in England tested positive for SARS-CoV-2. It is estimated that 1% of these cases were hospital-associated using European centre for disease prevention and control (ECDC) and Public Health England (PHE) definitions. Guidelines for preventing the spread of SARS-CoV-2 in hospitals have developed over time but the effectiveness and efficiency of testing strategies for preventing nosocomial transmission has not been explored. Methods: Using an individual-based model, parameterised using multiple datasets, we simulated the transmission of SARS-CoV-2 to patients and healthcare workers between March and August 2020 and evaluated the efficacy of different testing strategies. These strategies were: 0) Testing only symptomatic patients on admission; 1) Testing all patients on admission; 2) Testing all patients on admission and again between days 5 and 7, and 3) Testing all patients on admission, and again at days 3, and 5-7. In addition to admissions testing, patients that develop a symptomatic infection while in hospital were tested under all strategies. We evaluated the impact of testing strategy, test characteristics and hospital-related factors on the number of nosocomial patient infections. Results: Modelling suggests that 84.6% (95% CI: 84.3, 84.7) of community-acquired and 40.8% (40.3, 41.3) of hospital-associated SARS-CoV-2 infections are detectable before a patient is discharged from hospital. Testing all patients on admission and retesting after 3 or 5 days increases the proportion of nosocomial cases detected by 9.2%. Adding discharge testing increases detection by a further 1.5% (relative increase). Increasing occupancy rates, number of beds per bay, or the proportion of admissions wrongly suspected of having COVID-19 on admission and therefore incorrectly cohorted with COVID-19 patients, increases the rate of nosocomial transmission. Over 30,000 patients in England could have been discharged while incubating a non-detected SARS-CoV-2 infection during the first wave of the COVID-19 pandemic, of which 3.3% could have been identified by discharge screening. There was no significant difference in the rates of nosocomial transmission between testing strategies or when the turnaround time of the test was increased. Discussion: This study provides insight into the efficacy of testing strategies in a period unbiased by vaccines and variants. The findings are relevant as testing programs for SARS-CoV-2 are scaled back, and possibly if a new vaccine escaping variant emerges.

Quantifying the contribution of pathways of nosocomial acquisition of COVID-19 in English hospitals.

BACKGROUND: Despite evidence of the nosocomial transmission of novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in hospitals worldwide, the contributions of the pathways of transmission are poorly quantified. METHODS: We analysed national records of hospital admissions and discharges, linked to data on SARS-CoV-2 testing, using an individual-based model that considers patient-to-patient, patient-to-healthcare worker (HCW), HCW-to-patient and HCW-to-HCW transmission. RESULTS: Between 1 March 2020 and 31 December 2020, SARS-CoV-2 infections that were classified as nosocomial were identified in 0.5% (0.34-0.74) of patients admitted to an acute National Health Service trust. We found that the most likely route of nosocomial transmission to patients was indirect transmission from other infected patients, e.g. through HCWs acting as vectors or contaminated fomites, followed by direct transmission between patients in the same bay. The risk of transmission to patients from HCWs over this time period is low, but can contribute significantly when the number of infected inpatients is low. Further, the risk of a HCW acquiring SARS-CoV-2 in hospital is approximately equal to that in the community, thereby doubling their overall risk of infection. The most likely route of transmission to HCWs is transmission from other infected HCWs. CONCLUSIONS: Current control strategies have successfully reduced the transmission of SARS-CoV-2 between patients and HCWs. In order to reduce the burden of nosocomial COVID-19 infections on health services, stricter measures should be enforced that would inhibit the spread of the virus between bays or wards in the hospital. There should also be a focus on inhibiting the spread of SARS-CoV-2 between HCWs. The findings have important implications for infection-control procedures in hospitals.

Effectiveness of infection prevention and control interventions, excluding personal protective equipment, to prevent nosocomial transmission of SARS-CoV-2: a systematic review and call for action.

Many infection prevention and control (IPC) interventions have been adopted by hospitals to limit nosocomial transmission of SARS-CoV-2. The aim of this systematic review is to identify evidence on the effectiveness of these interventions. We conducted a literature search of five databases (OVID MEDLINE, Embase, CENTRAL, COVID-19 Portfolio (pre-print), Web of Science). SWIFT ActiveScreener software was used to screen English titles and abstracts published between 1st January 2020 and 6th April 2021. Intervention studies, defined by Cochrane Effective Practice and Organisation of Care, that evaluated IPC interventions with an outcome of SARS-CoV-2 infection in either patients or healthcare workers were included. Personal protective equipment (PPE) was excluded as this intervention had been previously reviewed. Risks of bias were assessed using the Cochrane tool for randomised trials (RoB2) and non-randomized studies of interventions (ROBINS-I). From 23,156 screened articles, we identified seven articles that met the inclusion criteria, all of which evaluated interventions to prevent infections in healthcare workers and the majority of which were focused on effectiveness of prophylaxes. Due to heterogeneity in interventions, we did not conduct a meta-analysis. All agents used for prophylaxes have little to no evidence of effectiveness against SARS-CoV-2 infections. We did not find any studies evaluating the effectiveness of interventions including but not limited to screening, isolation and improved ventilation. There is limited evidence from interventional studies, excluding PPE, evaluating IPC measures for SARS-CoV-2. This review calls for urgent action to implement such studies to inform policies to protect our most vulnerable populations and healthcare workers.

The contribution of hospital-acquired infections to the COVID-19 epidemic in England in the first half of 2020.

Background SARS-CoV-2 is known to transmit in hospital settings, but the contribution of infections acquired in hospitals to the epidemic at a national scale is unknown. Methods We used comprehensive national English datasets to determine the number of COVID-19 patients with identified hospital-acquired infections (with symptom onset >7 days after admission and before discharge) in acute English hospitals up to August 2020. As patients may leave the hospital prior to detection of infection or have rapid symptom onset, we combined measures of the length of stay and the incubation period distribution to estimate how many hospital-acquired infections may have been missed. We used simulations to estimate the total number (identified and unidentified) of symptomatic hospital-acquired infections, as well as infections due to onward community transmission from missed hospital-acquired infections, to 31 st July 2020. Results In our dataset of hospitalised COVID-19 patients in acute English hospitals with a recorded symptom onset date (n = 65,028), 7% were classified as hospital-acquired. We estimated that only 30% (range across weeks and 200 simulations: 20-41%) of symptomatic hospital-acquired infections would be identified, with up to 15% (mean, 95% range over 200 simulations: 14.1%-15.8%) of cases currently classified as community-acquired COVID-19 potentially linked to hospital transmission. We estimated that 26,600 (25,900 to 27,700) individuals acquired a symptomatic SARS-CoV-2 infection in an acute Trust in England before 31st July 2020, resulting in 15,900 (15,200-16,400) or 20.1% (19.2%-20.7%) of all identified hospitalised COVID-19 cases. Conclusions Transmission of SARS-CoV-2 to hospitalised patients likely caused approximately a fifth of identified cases of hospitalised COVID-19 in the "first wave" in England, but less than 1% of all infections in England. Using time to symptom onset from admission for inpatients as a detection method likely misses a substantial proportion (>60%) of hospital-acquired infections.

The impact of testing and infection prevention and control strategies on within-hospital transmission dynamics of COVID-19 in English hospitals.

Nosocomial transmission of SARS-CoV-2 is a key concern, and evaluating the effect of testing and infection prevention and control strategies is essential for guiding policy in this area. Using a within-hospital SEIR transition model of SARS-CoV-2 in a typical English hospital, we estimate that between 9 March 2020 and 17 July 2020 approximately 20% of infections in inpatients, and 73% of infections in healthcare workers (HCWs) were due to nosocomial transmission. Model results suggest that placing suspected COVID-19 patients in single rooms or bays has the potential to reduce hospital-acquired infections in patients by up to 35%. Periodic testing of HCWs has a smaller effect on the number of hospital-acquired COVID-19 cases in patients, but reduces infection in HCWs by as much as 37% and results in only a small proportion of staff absences (approx. 0.3% per day). This is considerably less than the 20-25% of staff that have been reported to be absent from work owing to suspected COVID-19 and self-isolation. Model-based evaluations of interventions, informed by data collected so far, can help to inform policy as the pandemic progresses and help prevent transmission in the vulnerable hospital population. This article is part of the theme issue 'Modelling that shaped the early COVID-19 pandemic response in the UK'.

Healthcare-associated COVID-19 in England: A national data linkage study.

OBJECTIVES: Nosocomial transmission was an important aspect of SARS-CoV-1 and MERS-CoV outbreaks. Healthcare-associated SARS-CoV-2 infection has been reported in single and multi-site hospital-based studies in England, but not nationally. METHODS: Admission records for all hospitals in England were linked to SARS-CoV-2 national test data for the period 01/03/2020 to 31/08/2020. Case definitions were: community-onset community-acquired, first positive test <14 days pre-admission, up to day 2 of admission; hospital-onset indeterminate healthcare-associated, first positive on day 3-7; hospital-onset probable healthcare-associated, first positive on day 8-14; hospital-onset definite healthcare-associated, first positive from day 15 of admission until discharge; community-onset possible healthcare-associated, first positive test ≤14 days post-discharge. RESULTS: One-third (34.4%, 100,859/293,204) of all laboratory-confirmed COVID-19 cases were linked to a hospital record. Hospital-onset probable and definite cases represented 5.3% (15,564/293,204) of all laboratory-confirmed cases and 15.4% (15,564/100,859) of laboratory-confirmed cases among hospital patients. Community-onset community-acquired and community-onset possible healthcare-associated cases represented 86.5% (253,582/293,204) and 5.1% (14,913/293,204) of all laboratory-confirmed cases, respectively. CONCLUSIONS: Up to 1 in 6 SARS-CoV-2 infections among hospitalised patients with COVID-19 in England during the first 6 months of the pandemic could be attributed to nosocomial transmission, but these represent less than 1% of the estimated 3 million COVID-19 cases in this period.

Evolution and emergence of multidrug-resistant Mycobacterium tuberculosis in Chisinau, Moldova.

The evolution and emergence of drug-resistant tuberculosis (TB) has been studied extensively in some contexts, but the ecological drivers of these two processes remain poorly understood. This study sought to describe the joint evolutionary and epidemiological histories of a novel multidrug-resistant Mycobacterium tuberculosis strain recently identified in the capital city of the Republic of Moldova (MDR Ural/4.2), where genomic surveillance of drug-resistant M. tuberculosis has been limited thus far. Using whole genome sequence data and Bayesian phylogenomic methods, we reconstruct the stepwise acquisition of drug resistance mutations in the MDR Ural/4.2 strain, estimate its historical bacterial population size over time, and infer the migration history of this strain between Eastern European countries. We infer that MDR Ural/4.2 likely evolved (via acquisition of rpoB S450L, which confers resistance to rifampin) in the early 1990s, during a period of social turmoil following Moldovan independence from the Soviet Union. This strain subsequently underwent substantial population size expansion in the early 2000s, at a time when national guidelines encouraged inpatient treatment of TB patients. We infer exportation of this strain and its isoniazid-resistant ancestral precursor from Moldova to neighbouring countries starting as early as 1985. Our findings suggest temporal and ecological associations between specific public health practices, including inpatient hospitalization of drug-resistant TB cases from the early 2000s until 2013, and the evolution of drug-resistant M. tuberculosis in Moldova. These findings underscore the need for regional coordination in TB control and expanded genomic surveillance efforts across Eastern Europe.

Transmission analysis of a large tuberculosis outbreak in London: a mathematical modelling study using genomic data.

Outbreaks of tuberculosis (TB) - such as the large isoniazid-resistant outbreak centred on London, UK, which originated in 1995 - provide excellent opportunities to model transmission of this devastating disease. Transmission chains for TB are notoriously difficult to ascertain, but mathematical modelling approaches, combined with whole-genome sequencing data, have strong potential to contribute to transmission analyses. Using such data, we aimed to reconstruct transmission histories for the outbreak using a Bayesian approach, and to use machine-learning techniques with patient-level data to identify the key covariates associated with transmission. By using our transmission reconstruction method that accounts for phylogenetic uncertainty, we are able to identify 21 transmission events with reasonable confidence, 9 of which have zero SNP distance, and a maximum distance of 3. Patient age, alcohol abuse and history of homelessness were found to be the most important predictors of being credible TB transmitters.