key: cord-0803357-i89b94yn
authors: Pham, T. M.; Tahir, H.; van de Wijgert, J. H.; Van der Roest, B.; Ellerbroek, P.; Bonten, M. J.; Bootsma, M. C.; Kretzschmar, M. E.
title: Interventions to control nosocomial transmission of SARS-CoV-2: a modelling study
date: 2021-03-12
journal: nan
DOI: 10.1101/2021.02.26.21252327
sha: 11f80b74088561a60a33a913a7aa4b769810fa94
doc_id: 803357
cord_uid: i89b94yn

Background: Emergence of more transmissible SARS-CoV-2 variants requires more efficient control measures to limit nosocomial transmission and maintain healthcare capacities during pandemic waves. The relative importance of different strategies is unknown. Methods: We developed an agent-based model and compared the impact of personal protective equipment (PPE), screening of healthcare workers (HCWs), contact tracing of symptomatic HCWs, and HCW cohorting on nosocomial SARS-CoV-2 transmission. The model was fit on hospital data, assuming 90% effective PPE use in COVID-19 wards. Intervention effects on the effective reproduction number (R), HCW absenteeism and the proportion of infected individuals among tested individuals (positivity rate) were estimated for a more transmissible variant. Findings: Introduction of a variant with 56% higher transmissibility increased - all other variables kept constant - R from 0.4 to 0.65 (+63%) and nosocomial transmissions by 303%, mainly because of more transmissions caused by pre-symptomatic patients and HCWs. Compared to baseline, PPE use in all hospital wards (assuming 90% effectiveness) reduced R by 85% and absenteeism by 57%. Screening HCWs every three days with perfect test sensitivity reduced R by 67%, yielding a maximum test positivity rate of 5%. Screening HCWs every three or seven days assuming time-varying test sensitivities reduced R by 9% and 3%, respectively. Contact tracing reduced R by at least 32% and achieved higher test positivity rates than screening interventions. HCW cohorting reduced R by 5%. Interpretation: PPE use in all hospital wards and regular screening of HCWs seem most effective in preventing nosocomial transmissions of SARS-CoV-2 variants with higher transmissibility.

Introduction sporadically. 14 Yet, with the emergence of more transmissible variants, current infection control measures may 123 become less effective. We, therefore, explored the relative effectiveness of different infection prevention 124 strategies for HCWs in hospitals using an agent-based model of nosocomial SARS-CoV-2 transmission. First, 125 we fitted the model to real-life data from the University Medical Center Utrecht (UMCU) during the period 126 February-August 2020. Next, we evaluated the impact of various interventions on transmission, HCW 127 absenteeism and test positivity as a marker of intervention efficiency for a more transmissible variant (e.g.,

B.1.1.7).

Agent-based model 133

We developed an agent-based model that describes the dynamics of SARS-CoV-2 transmission in a hospital 134 allowing for importations of infections from the community ( Figure 1A ). We modeled a hospital comprising 135 four ward types: 1) general COVID wards, 2) general non-COVID wards, 3) COVID intensive-care units 136 (ICUs), and 4) non-COVID ICUs. Within the hospital we distinguish patients, nurses, and doctors. Patients are 137 assumed to occupy a hospital bed in a single room. HCWs (nurses and doctors) work in duty shifts. HCWs meet 138 patients in a number of rounds per shift (Appendix Table 1 ), and HCWs meet other HCWs in the common staff 139 room of each ward.

Individuals may be in one of the disease states: susceptible (S), exposed (E), asymptomatically infected (IA), 142 infected with moderate symptoms (IM), infected with severe symptoms (IS), and recovered (IR). We did not 143 explicitly model other respiratory tract infections with similar symptoms. Hence, all symptomatic individuals 144 are necessarily infected with SARS-CoV-2. We did not model death in our simulations. Patients may be 145 admitted to the hospital for non-COVID reasons or with moderate or severe COVID-19 symptoms. In the first 146 case, they may be susceptible, pre-symptomatically, or asymptomatically infected. Symptomatically infected 147 patients are admitted to COVID wards (moderate symptoms) or COVID ICUs (severe symptoms). Patients in 148 non-COVID wards that develop symptoms during their stay are immediately transferred to COVID wards. We 149 assumed that moderately and severely infected patients recover after 14 and 35 days, respectively. 15

Transmission events can occur between patients and HCWs, and among HCWs. We assumed no patient-to-152 patient transmission as patients are assumed to occupy single-bed rooms. Only HCWs in their asymptomatic or 153 pre-symptomatic phase contribute to transmission. The reproduction number (average number of secondary 154 cases caused by an infected individual) is assumed to differ between symptomatically ( " ) and 155 asymptomatically ( # ) infected individuals. We assumed that the incubation period has a Gamma distribution 156 with mean 5·5 days and that the individual's infectiousness over time has a Weibull distribution with a mean of Public Health and the Environment (RIVM) from 17 February until 24 August 2020 (Appendix pp. 2). 18 We 170 additionally used publicly available age-specific hospitalization rates in the Netherlands in 2012 and age-171 specific SARS-CoV-2 infection incidence rates in Utrecht province to scale the daily probability of being 172 infected in the community for non-COVID patients and HCWs arriving in the hospital. 19, 20 173 Based on a published meta-analysis, we assumed that 20% and 31% of SARS-CoV-2 infections in patients and

HCWs, respectively, were asymptomatic (Table 1) . 21

First, we chose the reproduction numbers " and # such that the numbers of occupied beds by 177 patients predicted by our model were in good agreement with real-life UMCU data on the number of COVID-178 19 patients at UMCU during the first epidemic wave (Table 1 and Figure 2A ). These reproduction numbers 179 incorporated the effects of typical (but not COVID-specific) infection prevention measures in the hospital. We 180 will refer to the model parameterized with these reproduction numbers as the wild-type scenario. This scenario 181 also assumed that HCWs use 90% effective PPE in COVID wards and isolate at home immediately upon 182 symptom onset for seven days, after which they return recovered to work. Next, we introduced a more 183 transmissible SARS-CoV-2 variant into the hospital, keeping all other parameters -including PPE use in 184 COVID wards and self-isolation after symptom-onset -the same. Based on recent results for B.1.1.7, we 185 assumed a 56% increase in transmissibility. 22 We will refer to the model parametrized with these higher 186 reproduction numbers as our baseline scenario. Various intervention scenarios were compared to this baseline 187 scenario.

Diagnostic performance of the PCR test

We assumed a PCR test specificity of 100% and distinguished two scenarios for the test sensitivity: 1) a time-191 invariant perfect sensitivity of 100%; and 2) a sensitivity increasing with time since infection with a maximum 192 sensitivity of 93·1% close to symptom onset and declining afterward (time-varying sensitivity). 17 We considered 193 two sensitivity analyses to test the impact of PCR test sensitivity assumptions on our results (Appendix pp.3).

Hospital staff typically self-quarantine from symptom onset, get tested and receive their test results within hours 195 (based on UMCU data). We, therefore, assumed no delay between testing and receiving test results, and that 

In the baseline scenario, HCWs were assumed to use PPE in COVID wards when attending to patients, but not 203 during breaks or in other parts of the hospital. The baseline reduction factor (PPE effectiveness) was assumed 204 to be 90%, which includes both perfect-use PPE efficacy and expected PPE use adherence level. We assumed 205 that 95% of the HCWs work in the same ward as during their previous shift.

All interventions described below were in addition to the baseline scenario.

Intervention: PPE in all wards

In this scenario, all HCWs used 90% effective PPE in all (non-COVID and COVID) wards. However, no PPE 211 was used when HCWs meet each other off-ward. We performed sensitivity analyses assuming PPE effectiveness 212 of 50% and 70%.

Intervention: HCW cohorting (no ward change)

This scenario restricted HCWs to work only in specific wards and did not allow any ward changes.

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The copyright holder for this this version posted March 12, 2021. ; https://doi.org/10.1101 https://doi.org/10. /2021 217 Intervention: Regular HCW screening 218 All HCWs were tested for SARS-CoV-2 either with a) a test with perfect sensitivity every three days, or a test 219 with time-varying sensitivity, b) every three days, or c) every seven days. If tested positive, HCWs were 220 assumed to immediately self-isolate at home for seven days.

Intervention: HCW contact-tracing

If a HCW developed symptomatic SARS-CoV-2 infection, all contacts in the hospital during a time window of 225 either two or seven days before symptom onset were traced and tested. We will refer to these scenarios as 2-day 226 Contact tracing and 7-day contact tracing. For 2-day contact tracing, contacts were always tested assuming a 227 time-varying test sensitivity. For 7-day contact tracing, we distinguished between perfect and time-varying 228 sensitivity sub-scenarios. In the perfect sensitivity sub-scenario, contacts were instantaneously tested on the day 229 of symptom onset of the index (the HCW). In the time-varying test sensitivity sub-scenario, the test was 230 performed on the day of symptom onset if the contact with the index was more than five days ago. Otherwise,

it was performed on day five after the contact. Exposed HCWs awaiting tests were assumed to wear PPE during 232 contact with any patient and with other HCWs. In case of a positive test, patients were moved to a COVID ward 233 while infected HCWs were sent home for self-isolation for seven days and replaced by susceptible HCW. We 234 did not model any absences of HCWs with disease symptoms caused by other respiratory pathogens.

Outcome measures

We computed the effective reproduction number ! (average number of secondary cases caused by an infected 238 individual) to evaluate an intervention's effectiveness. We calculated an overall ! for an average individual 239 (patients and HCWs combined) but also stratified ! by patients, HCWs, and symptom status. The reproduction 240 numbers of patients were calculated for those who eventually developed symptoms ( " $%& ) and those who 241 remained without symptoms ( # $%& ). Since HCWs were assumed to immediately self-isolate upon symptom 242 onset, we calculated during pre-symptomatic ( " '() ) and asymptomatic states ( # '() ). To evaluate the 243 maximum demand on hospital capacity, we considered the total number of nosocomial infections among 244 patients and HCWs over time. In addition, we computed the percentage of absent HCWs due to self-isolation 245 (because of symptom onset or detection via screening or contact-tracing) over time. We assessed the efficiency 246 of screening and contact-tracing interventions by their positivity rates (percentage of detected infected 247 individuals among tested individuals). We did not include individuals that developed symptoms prior to being 248 tested in the positivity rate calculations since those were already detected and isolated in our model. For every 249 scenario, we calculated the mean and 95% percentiles over 100 simulation runs (95% uncertainty interval). We 250 calculated positivity rates over time merging data from all simulation runs and computed 95% Bayesian beta-251 binomial credibility intervals.

A detailed description of the full model and the parameters can be found in the appendix. We performed 254 sensitivity analyses to test the robustness of our results ( is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

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We observed good agreement between the number of patients in COVID wards predicted by our wild-type 262 scenario and the real-life UMCU data during the first wave for " =1·25 and # =0·5. However, the model 263 slightly overestimates hospitalizations for the second half of the first wave ( Figure 2A) . We subsequently 264 assumed the introduction of a SARS-CoV-2 variant with a 56% increase in transmissibility (based on B.1.1.7 265 data), resulting in " =1·95 and R * =0·8. Keeping all other parameters the same, including HCWs using PPE in 266 COVID wards and self-isolating at symptom-onset, the total number of nosocomial transmissions increased by 267 303% ( Figure 2B ) and the overall effective reproduction number increased by 62·5% ( Figure 2C 

Intervention effects on reproduction numbers

In the context of this SARS-CoV-2 variant with higher transmissibility, the baseline scenario of 90% effective 273 PPE use in COVID wards yielded an overall ! of 0·65 ( Figure 3A ). 

varying test sensitivity, the 2-day and 7-day contact-tracing scenarios reduced ! to 0·41 and 0·39 (reductions 280 of 37% and 40%), respectively. The additional reductions of ! by the intervention scenarios over and above 281 the baseline scenario were most prominent for pre-symptomatic HCWs ( Figure 3B ).

Intervention interventions with time-varying test sensitivity: screening every three days would lead to a 20·4% reduction and 288 screening once a week to a 10·1% reduction. Testing with perfect test sensitivity followed by 7-day contact-

tracing was more effective (55·8% reduction of transmissions) than regular screening every three or seven days.

Testing with time-varying sensitivity followed by 2-day or 7-day contact tracing were similarly effective as 291 testing with perfect sensitivity followed by 7-day contact tracing (reductions of 61·4% and 64·1%, respectively).

HCW cohorting would decrease the total number of nosocomial infections by 13%. Note that our model 293 predicted that 62%-78% of all nosocomial infections are diagnosed in the hospital either due to testing after 294 symptom onset or testing as part of an intervention (Appendix Figure 2 ). The remaining 22%-38% of 295 nosocomial infections are undiagnosed infections in patients without symptoms (yet) at the time of discharge.

Intervention effects on HCW absenteeism 298 Our baseline scenario predicted a maximum HCW absenteeism of 5·4%, including absenteeism due to 299 symptoms or home isolation. When comparing intervention scenarios to the baseline scenario, HCW 300 absenteeism is lowest for PPE use in all wards (a maximum of 2·3% is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted March 12, 2021. ; https://doi.org/10.1101 https://doi.org/10. /2021 Efficiency of screening and contact-tracing interventions 307 HCW screening every three days with a perfect test would lead to the lowest test positivity rate of all testing-308 based interventions ( Figure 7A ). Screening of HCWs every week compared to every three days yields higher 309 positivity rates with its mean reaching a maximum value of 5·1%. The positivity rate of screening interventions 310 linearly increases with increasing prevalence (Appendix Figure 8 ).

Positivity rates for contact-tracing interventions are much higher than for screening interventions, reaching as 312 high as 15·1% when a perfect test sensitivity is assumed ( Figure 8A ). The maximum positivity rates for 2-day 313 and 7-day contact tracing with time-varying test sensitivities are only slightly lower at 11·3% and 10·4%, 314 respectively ( Figure 8B -C). Positivity rates of contact-tracing interventions are stable across prevalence values 315 (Appendix Figure 9 ).

Sensitivity analyses show that our findings do not change significantly when the assumed PPE effectiveness is 318 reduced to 70%. When PPE effectiveness is assumed to be as low as 50%, screening every three days with 319 perfect sensitivity becomes more effective than PPE use in all wards. However, PPE use in all wards is still 320 more effective than all other interventions (Appendix pp. 6). is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint 

Our model also suggested that regular screening of HCWs could have a strong impact, but only if the test 347 sensitivity is high throughout the infectious period. Tests with imperfect time-varying sensitivity miss many 

Our study has several limitations. First, we assumed that transmission occurs solely via HCWs in the absence 369 of a direct patient-to-patient contact pathway, as has been used before in an individual-based model of 370 nosocomial influenza transmission. 29 Assuming similar transmission modes for SARS-COV-2, we consider this 371 assumption reasonable for hospital settings in Western countries where direct patient-to-patient contact is rare.

When this assumption is violated, our estimated impact of HCW-based interventions is likely to be is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted March 12, 2021. ; https://doi.org/10.1101 https://doi.org/10. /2021 symptom onset and isolation, or delays between test application and test result were not included. We have not 377 used formal fitting procedures to match our model results to the data given the large number of parameters.

However, qualitatively, our conclusions were robust in sensitivity analyses to variation of the most important 379 model parameters.

In conclusion, our model demonstrates that PPE use in all wards is the most effective measure to substantially 382 reduce nosocomial spread of SARS-CoV-2 variants with higher transmissibility. However, contact-tracing and 383 regular screening using high-sensitivity tests are also effective interventions, which might be preferred in some 384 settings.

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Results shown are based on " =1·95 and # =0·8 (reproduction numbers for the SARS-CoV-2 variant with 56% 500 higher transmissibility with respect to the wild-type SARS-CoV-2 variant). The 7-day moving average of the 501 mean percentage (over 100 simulation runs) of HCWs absent from work due to symptom onset or a detected 502 SARS-CoV-2 infection screening or contact tracing is shown. For screening every 3 days and contact tracing 7 503 days prior to symptom onset of SARS-CoV-2 infected HCWs, we considered two different test sensitivity is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

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