1. Epidemiology and Global Health
  2. Human Biology and Medicine
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Effective control of SARS-CoV-2 transmission between healthcare workers during a period of diminished community prevalence of COVID-19

  1. Nick K Jones
  2. Lucy Rivett
  3. Dominic Sparkes
  4. Sally Forrest
  5. Sushmita Sridhar
  6. Jamie Young
  7. Joana Pereira-Dias
  8. Claire Cormie
  9. Harmeet Gill
  10. Nicola Reynolds
  11. Michelle Wantoch
  12. Matthew Routledge
  13. Ben Warne
  14. Jack Levy
  15. William David Córdova Jiménez
  16. Fathima Nisha Begum Samad
  17. Chris McNicholas
  18. Mark Ferris
  19. Jane Gray
  20. Michael Gill
  21. The CITIID-NIHR COVID-19 BioResource Collaboration
  22. Martin D Curran
  23. Stewart Fuller
  24. Afzal Chaudhry
  25. Ashley Shaw
  26. John R Bradley
  27. Gregory J Hannon
  28. Ian G Goodfellow
  29. Gordon Dougan
  30. Kenneth GC Smith
  31. Paul J Lehner
  32. Giles Wright
  33. Nicholas J Matheson
  34. Stephen Baker
  35. Michael P Weekes  Is a corresponding author
  1. Department of Infectious Diseases, Cambridge University NHS Hospitals Foundation Trust, United Kingdom
  2. Clinical Microbiology & Public Health Laboratory, Public Health England, United Kingdom
  3. Department of Medicine, University of Cambridge, United Kingdom
  4. Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, University of Cambridge, United Kingdom
  5. Wellcome Sanger Institute, United Kingdom
  6. Academic Department of Medical Genetics, University of Cambridge, United Kingdom
  7. Wellcome-MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, University of Cambridge, United Kingdom
  8. Wellcome - MRC Cambridge Stem Cell Institute, University of Cambridge, United Kingdom
  9. Department of Haematology, School of Clinical Medicine, University of Cambridge, United Kingdom
  10. Institute for Manufacturing, Department of Engineering, University of Cambridge, United Kingdom
  11. Improvement and Transformation Team, Cambridge University Hospitals NHS Foundation Trust, United Kingdom
  12. Occupational Health and Wellbeing, Cambridge University Hospitals NHS Foundation Trust, United Kingdom
  13. Cancer Research United Kingdom Cambridge Institute, University of Cambridge, United Kingdom
  14. National Institutes for Health Research Cambridge Biomedical Research Centre, United Kingdom
  15. Cambridge University Hospitals NHS Foundation Trust, United Kingdom
  16. National Institutes for Health Research Cambridge, Clinical Research Facility, United Kingdom
  17. Division of Virology, Department of Pathology, University of Cambridge, United Kingdom
  18. NHS Blood and Transplant, United Kingdom
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Cite this article as: eLife 2020;9:e59391 doi: 10.7554/eLife.59391

Abstract

Previously, we showed that 3% (31/1032)of asymptomatic healthcare workers (HCWs) from a large teaching hospital in Cambridge, UK, tested positive for SARS-CoV-2 in April 2020. About 15% (26/169) HCWs with symptoms of coronavirus disease 2019 (COVID-19) also tested positive for SARS-CoV-2 (Rivett et al., 2020). Here, we show that the proportion of both asymptomatic and symptomatic HCWs testing positive for SARS-CoV-2 rapidly declined to near-zero between 25th April and 24th May 2020, corresponding to a decline in patient admissions with COVID-19 during the ongoing UK ‘lockdown’. These data demonstrate how infection prevention and control measures including staff testing may help prevent hospitals from becoming independent ‘hubs’ of SARS-CoV-2 transmission, and illustrate how, with appropriate precautions, organizations in other sectors may be able to resume on-site work safely.

Introduction

The role of nosocomial transmission of SARS-CoV-2 has been highlighted by recent evidence suggesting that 20% of SARS-CoV-2 infections among patients in UK hospitals and up to 89% of infections among HCWs may have originated in hospitals (Evans et al., 2020; Iacobucci, 2020). Since the introduction of ‘lockdown’ in the UK, community transmission rates of SARS-CoV-2 have generally declined (Public Health England (PHE), 2020). Conversely, concerns have been raised that hospitals could become independent ‘hubs’ for ongoing SARS-CoV-2 transmission between patients and HCWs, which would effectively prolong the epidemic (Iacobucci, 2020). In this context, the evolution of the epidemic curves of a hospital’s symptomatic and asymptomatic workforce has not been well described.

We recently initiated a comprehensive HCW screening programme for SARS-CoV-2 in a large teaching hospital in Cambridge, UK. Over a 3-week period from 6th to 24th April 2020, 3% (31/1032) HCWs in the asymptomatic screening arm, 15.4% (26/169) HCWs in the symptomatic screening arm, and 7.7% (4/52) contacts in the symptomatic household contact screening arm tested positive for SARS-CoV-2 (Rivett et al., 2020). Our data from the asymptomatic screening arm were consistent with the results of Shields et al. (Shields et al., 2020). Over the next 4 weeks from 25th April to 24th May 2020, we performed a further 3388 additional tests. Here, we present these longitudinal data, in the context of the hospital patient population and wider local community.

Results

Testing for SARS-CoV-2 RNA was performed with real-time RT-PCR using throat and nose swab samples of HCWs from Cambridge University Hospitals NHS Foundation Trust (CUHNFT) and their symptomatic household contacts. Over the new study period (25th April to 24th May 2020), 2611 additional tests were performed in the HCW asymptomatic screening arm, 555 additional tests in the HCW symptomatic screening arm, and 216 additional tests in the HCW household contact screening arm. A further six tests did not have a clearly recorded arm of origin. Over the entire study period, the median age of HCWs and their household contacts was 36.5 and 35.5 years, respectively. About 68.4% were female and 31.6% were male. Of the individuals testing positive over the entire study period, the median age of HCWs and their household contacts was 32 and 47 years, respectively. About 77.9% of all positive tests were from females and 22.1% from males. Table 1 summarizes the total number of HCWs testing positive through either arm of the screening programme, according to the job role. A comparison of the proportions of hospital employees from each job role that tested positive through the HCW symptomatic screening arm revealed no statistically significant difference (Pearson’s chi-square test p=0.419). Reasonable comparison of the proportions testing positive through the HCW asymptomatic screening arm was not possible due to non-random sampling of different areas of the hospital, meaning some job roles had been more frequently targeted for asymptomatic screening than others.

Table 1
Combined data for SARS-CoV-2 RNA positive HCWs by role and screening arm, from the present study and our previous study (Rivett et al., 2020).

Difference in proportions of HCWs testing positive through the symptomatic screening arm was analysed using Pearson’s chi-square test.

RoleHCW asymptomatic screening armHCW symptomatic screening armTotal number of hospital employees
Nurse25193621
Healthcare assistant1481734
Doctor861871
Cleaners23560
Radiographer21217
Radiology support worker0135
Physiotherapist10116
  1. Overall, 360 individuals underwent repeat testing, either as part of the asymptomatic screening programme, or for other reasons as previously described (Rivett et al., 2020). The median turnaround time from sample arrival in the laboratory to final verification was 18 hr 45 min. Positive results were called out on the same day, with negative results emailed within 24 hr.

Between 25th April and 24th May 2020, a total of 34 new positive tests were reported. In the HCW symptomatic and HCW symptomatic household contact screening arms combined (reflecting all individuals with self-reported symptoms at the time of testing), 13/771 (1.7%) tests were positive, which was significantly lower than 30/221 (13%) in the original study period (Fisher’s exact test p<0.0001). In the HCW asymptomatic screening arm, 21/2611 (0.8%) tests were positive, which again was significantly lower than 31/1032 (3%) in the original study period (Fisher’s exact test p<0.0001). As we previously observed (Rivett et al., 2020), individuals captured in the HCW asymptomatic screening arm were generally asymptomatic at the time of screening; however, these individuals could be divided into subgroups. In the first subgroup, 8/21 (38%) HCWs had no symptoms at all. Of these, 5/8 (63%) remained entirely asymptomatic 5–7 weeks after their positive test, whereas 2/8 (25%) developed symptoms 24–48 hr after testing. One HCW could not be contacted to obtain further history. In the second subgroup, 6/21 (29%) had retrospectively experienced some symptoms prior to screening. Of these, 5/6 (83%) had symptoms with a high pre-test probability of COVID-19 (Rivett et al., 2020) commencing >7 days prior to screening, of whom 3/5 had appropriately self-isolated then returned to work, and 1/5 was tested shortly after developing symptoms. 1/6 (17%) had symptoms with a low pre-test probability of COVID-19 (Rivett et al., 2020) commencing <7 days prior to screening and had not self-isolated. In the third subgroup, 7/21 (33%) were detected through repeat sampling of HCW who previously tested positive. Of these, 4/7 (57%) were tested to determine their suitability to return to work with severely immunocompromised/immunosuppressed patients, as dictated by UK national guidance (National Institute for Health and Care Excellence (NICE), 2020). The remaining 3/7 (43%) were from HCWs tested incidentally for the second time in the asymptomatic HCW screening programme. The median interval between serial positive tests was 16.5 days (IQR 9.5–19.5). All cases were attributable to prolonged SARS-CoV-2 RNA detection from a single infection, rather than re-infection. Our approach to patients with repeatedly positive SARS-CoV-2 PCR tests is described in the Methods.

The fraction of positive tests among the HCW asymptomatic, and HCW symptomatic and household contact screening groups combined varied over time (Figure 1A, Table 2). In particular, during the last 2 weeks of the study period (11th to 24th May 2020), we identified only four positive SARS-CoV-2 samples from 2016 tests performed, two from the HCW asymptomatic and two from the HCW symptomatic/symptomatic household contact arms. This fall in positive HCW tests mirrored the decline in both patients testing positive at CUHNFT and those tested throughout the wider region (Figure 1B). Similar trends were observed in a smaller cohort study of HCWs in London (Treibel et al., 2020).

Trends in positive SARS-CoV-2 PCR tests among HCWs, hospital patients and the wider community over time.

(a) Positive SARS-CoV-2 tests for asymptomatic and symptomatic screening arms by week. (b) Total HCW SARS-CoV-2 tests in CUHNFT performed by week. (c) Total positive SARS-CoV-2 patient tests in Cambridge University Hospital NHS Foundation Trust (CUHNFT) by week. (d) Total positive SARS-CoV-2 tests in the East of England (EOE) by week.

Table 2
Positive tests and total number of SARS-CoV-2 tests performed in each screening arm categorised according to week since starting the healthcare worker testing programme (6th April–24th May 2020).
Week commencing
6th April13th April20th April27th April4th May11th May18th MayTotal
HCW asymptomatic screening arm4/12120/3837/52911/5508/4831/7381/84052/3644

(1.4%)
HCW symptomatic screening arm1/1514/6011/957/1193/1040/1642/16838/725

(5.2%)
HCW symptomatic household contacts1/73/180/260/621/500/510/535/267

(1.8%)
Unknown0/00/20/130/00/40/10/10/21
All6/143
(4.1%)
37/463
(7.9%)
18/663
(2.7%)
18/731
(2.4%)
12/641
(1.8%)
1/954
(0.1%)
3/1062
(0.2%)
95/4657
(2%)

In our original study between 6th and 24th April 2020, we described in detail two clusters of HCW infections (Rivett et al., 2020). From 25th April to 24th May 2020, we detected one additional cluster on a general medical ward with a separate area for patients with proven COVID-19 and another area for those without. This was identified through targeted screening of the ward over a 24 hr period from 4th to 5th May 2020, in response to four staff testing positive through the HCW symptomatic arm of the screening programme from 27th to 30th April 2020. Reactive screening of a further 40 staff from the same ward identified a further three positive asymptomatic HCWs. In addition, a further two HCWs tested positive in an asymptomatic screen of 30 individuals from a closely related clinical area (designated for non-COVID patients) on 6th May 2020.

Discussion

Our data demonstrate a dramatic fall in the prevalence of symptomatic and asymptomatic SARS-CoV-2 infection among HCWs in our hospital during the study period. On average, the number of secondary infections among HCWs arising from each infected HCW (effectively, the reproduction number (R) for SARS-CoV-2 transmission between HCWs) must therefore be <1.

As well as an acquisition from other HCWs, infections among HCWs may also be acquired from patients, as well as other individuals outside the hospital. Our study period coincided with a decline in the rate of infection across our local community, and our data are consistent with a reduction in transmission within the hospital, a reduction in community-based acquisition of infection by HCWs, or (most likely) a combination of both. In the absence of detailed epidemiological data, it is not possible to formally differentiate between these possibilities or determine their relative effect sizes. Nonetheless, our identification of HCW infection clusters in specific areas of the hospital highlighted the potential for workplace acquisition of SARS-CoV-2, which may lead to self-sustaining outbreaks if left uninterrupted (Rivett et al., 2020; Meredeth et al., 2020). For each of these clusters, timely identification of HCW infection proved effective in terminating chains of hospital transmission between staff, preventing ongoing nosocomial infection.

With the incidence of infection having fallen significantly in hospitalised patients, HCWs and the wider community, many hospitals across the UK and further afield have been afforded precious time to build the infrastructure necessary to establish comprehensive screening programmes in anticipation of a possible second epidemic peak. For hospitals already operating newly established screening programmes, the challenge now is to up-scale to the point that screening can occur at a frequency that permits pre-symptomatic capture of as close to 100% of all new infections as possible. This approach will enable staff to be removed from the workplace at the time of peak infectivity (He et al., 2020). The minimum screening frequency required needs to be carefully modelled, with recent estimates suggesting the need for weekly testing to prevent 16–33% of onward transmission from HCWs, depending on the time taken for results to be reported, and another study estimating the need for daily screening to prevent 65% of HCW-to-HCW transmission events (Evans et al., 2020; Grassly et al., 2020). In practice, we have observed good results in our hospital with a current frequency of asymptomatic screening every 2–4 weeks. Those being screened are prioritised by anticipated ward-based exposure to COVID-19, with additional targeted screens triggered by excess staff sickness or the identification of symptomatic cases on specific wards (Rivett et al., 2020). In addition to asymptomatic screening, testing of symptomatic HCWs is essential for preventing excessive erosion of the hospital workforce by self-isolation on the basis of symptoms alone, and testing of symptomatic HCW household contacts negates the need for unnecessary self-quarantine periods for co-habiting HCWs. We found uptake to the HCW symptomatic household contact screening arm of our programme to be notably lower than the HCW symptomatic arm despite regular communications to advertise the service within CUHNFT. This lack of uptake may reflect a lack of awareness that symptomatic non-HCWs were eligible for testing, provided they shared a household with a hospital employee. Many non-hospital employees may also have been more inclined to attend national testing centres or be less aware of the spectrum of COVID-19 symptoms.

Importantly, our data demonstrate that CUHNFT was not acting as an independent ‘hub’ for ongoing COVID-19 transmission among HCWs. The absence of nosocomial transmission likely reflects the combined efficacy of HCW testing, stringent prospective, and reactive infection prevention and control measures, and appropriate social distancing among the workforce. These findings should give reassurance to both hospital staff and patients that healthcare facilities remain safe places to give and receive care. Furthermore, since CUHNFT, with approximately 11,000 staff members (many of whom are based in the hospital) is a major regional employer, we predict that comparable organisations in other sectors may also be able to resume on-site work safely by instigating similar precautions.

Materials and methods

Staff screening protocols

Request a detailed protocol

We previously described protocols for staff screening, sample collection, laboratory processing, and results reporting in detail (Rivett et al., 2020). These methods remained unchanged throughout this study period. Two parallel streams of entry into the testing programme included (i) HCW symptomatic, and HCW symptomatic household contact screening arms and (ii) an HCW asymptomatic screening arm. In the former, any patient-facing or non-patient-facing HCW could voluntarily refer themselves or a household contact, should they develop symptoms suggestive of COVID-19. In the latter, HCWs could volunteer to take part in a rolling programme of testing for all patient-facing and non-patient-facing staff working in defined clinical areas thought to be at risk of SARS-CoV-2 transmission. Testing was performed (i) at temporary on-site ‘Pods’; (ii) via self-swabbing kits delivered to HCWs in their area of work. All individuals in each arm of the programme performed a self-swab at the back of the throat then the nasal cavity, followed by RNA extraction and amplification using real-time RT-PCR (Sridhar et al., 2020). Cluster investigation was initiated when three or more HCWs working in the same clinical area tested positive for SARS-CoV-2 in 1 week .

Management of HCW with repeat positive tests

Request a detailed protocol

Current National Institute for Health and Care Excellence (NICE) guidelines require a negative test before returning to work with immunocompromised patients (National Institute for Health and Care Excellence (NICE), 2020). In accordance with the UK national guidance, individuals with repeat positive screens following a minimum period of 7 days self-isolation were advised to continue working if they were not scheduled to come into close contact with heavily immunocompromised patients, provided they remained asymptomatic (UK Government, 2020). This approach to managing repeat positive screens is further supported by recent data from the Korea Centers for Disease Control and Prevention, which showed no clear evidence of onward transmission to the contacts of 285 repeat-positive individuals, 108 of whom had samples taken for attempted viral culture, which was universally unsuccessful (Korea Centers for Disease Control & Prevention (KCDC), 2020). Additional small studies have also demonstrated an inability to culture virus from clinical samples obtained later than 8 days after symptom onset, suggesting prolonged detection of viral RNA is unlikely to indicate an ongoing risk of transmission (Wölfel et al., 2020; Bullard et al., 2020).

Data extraction and analysis

Request a detailed protocol

Swab result data for HCWs and patients were extracted directly from the hospital-laboratory interface software, Epic (Verona, WI) and from SARS-CoV-2 point of care testing. Data for SARS-CoV-2 infections from the local community were extracted from Public Health England’s Data Dashboard (Public Health England (PHE), 2020). Data were collated using Microsoft Excel, and figures produced with GraphPad Prism (GraphPad Software, La Jolla, CA). Fisher’s exact test was used to compare the proportion of HCWs testing positive in this study period to that of our previous study period (Rivett et al., 2020). Pearson’s chi-square test was used for comparison of the proportions of HCWs testing positive in each job role.

References

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    Role of Testing in COIVD-19 Control
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    2. M Pons-Salort
    3. EPK Parker
    (2020)
    London, United Kingdom: Imperial College.
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    Stay at home advice. 2020
    1. UK Government
    (2020)
    Accessed June 12, 2020.
  15. 15

Decision letter

  1. Jos WM van der Meer
    Senior and Reviewing Editor; Radboud University Medical Centre, Netherlands
  2. Deenan Pillay
    Reviewer

In the interests of transparency, eLife publishes the most substantive revision requests and the accompanying author responses.

Thank you for submitting your article "Effective control of healthcare worker SARS-CoV-2 transmission in a period of declining community prevalence of COVID-19" for consideration by eLife. Your article has been reviewed by three peer reviewers, and the evaluation has been overseen by Jos van der Meer as the Senior and Reviewing Editor. The following individual involved in review of your submission has agreed to reveal their identity: Deenan Pillay (Reviewer #1).

The reviewers have discussed the reviews with one another and the Reviewing and Senior Editor drafted this decision to help you prepare a revised submission. Please note that there are serious concerns about the ethical aspects of the studies.

As the editors have judged that your manuscript is of interest, but as described below that additional data are required before it is published, we would like to draw your attention to changes in our revision policy that we have made in response to COVID-19 (https://elifesciences.org/articles/57162). First, because many researchers have temporarily lost access to the labs, we will give authors as much time as they need to submit revised manuscripts. We are also offering, if you choose, to post the manuscript to bioRxiv (if it is not already there) along with this decision letter and a formal designation that the manuscript is "in revision at eLife". Please let us know if you would like to pursue this option. (If your work is more suitable for medRxiv, you will need to post the preprint yourself, as the mechanisms for us to do so are still in development.)

Summary:

This is a nice addition to the earlier work published by the team demonstrating high rates of asymptomatic infection in HCW in one hospital. This Research Advance demonstrates an overall lower rate of infection, in conjunction with documented reductions across the UK. This is supportive of the hospital not acting as an independent hub for ongoing infection. The data are useful, but not unexpected.

Essential revisions:

1) There are a mixture of self-swabs and swabbing by a health worker. Has any comparison been made for known positives? Or an assessment of similar cell numbers?

2) Why combine symptomatic and contacts for analysis purposes?

3) We are concerned about those testing positive continuing to work – particularly since no ethics was obtained (exemption is cited)."Individuals with repeat positive screens that were not scheduled to come into close contact with heavily immunocompromised patients were advised to continue working, provided they remained asymptomatic". South Korea data are mentioned as a justification – but there does not seem to be logic to the recommendation used in this case. If immunocompromised patients are at risk, then all patients are at risk. What about those with specific and known risk factors for COVID-19 disease? The reviewers feel that ethical approval would be needed for a study like this.

Regarding these ethical issues we also asked the advice of an expert in medical ethics. The answer was: "I have tried to interpret the decision tool they refer to in their paper, which explains when something is research that is in need of formal ethics review. The authors could be right that their study is exempt from review, because it is service evaluation or usual practice in public health interventions. I am not an expert in British local requirements, so the authors are requested to explain explicitly why they did not obtain consent, and to explain which category of exemption they refer to.

I also agree with you that immunocompromised patients are not the only vulnerable group in hospitals, what about transmission to other categories of patients? Overall, the authors are very concise in their explanations and in giving context. It would be useful if they would reflect on these issues, and then I am happy to review their answer".

4) Even if ethics is not needed for HCW, then what about screening their household contacts, i.e., asymptomatic participants not associated with the hospital? What advice was given to those positive, and follow up?

5) A far smaller number of household contacts was tested than would be expected – why is that?

6) There is a need for the denominator of total staff and household contacts, rather than the positives/all tested.

7) Are there any further details that could be given on the HCW who were tested? E.g. what proportion of positives in the asymptomatic arm later became symptomatic? Was there any association between positivity and characteristics like use of PPE, role in the hospital (e.g. job description, whether they had direct contact with COVID patients etc.), age/gender?

8) "Effectively, the reproduction number (R) for SARS-CoV-2 amongst the

population of HCW in our hospital has been maintained <1". This statement feels oversimplified. Since there is a constant flow of patients from and to the community from hospitals, the reproduction number among HCW depends on (i) R between HCWs, (ii) R between HCWs and patients, (iii) R between hospitals and the community, (iv) R within the community. It is not clear which of these components of R the statement refers to, and whether the authors can even make such a statement given the data they have. For instance, positivity among HCWs may be driven by lower prevalence in the community or among patients, even while R between HCWs remains above 1.

9) Do clusters refer to sequencing? In which case need methods and data to show these clusters.

10) Subsection “Management of HCW with repeat positive tests”: On the issue of lack of evidence of onward transmission from repeat-positive asymptomatic individuals, this depends crucially on whether these individuals are detected positive after recovering from symptomatic illness, just before developing symptoms or asymptomatic throughout their time of positivity. In particular, there is good evidence that viral load (and risk of transmission) is highest just before a patient develops symptoms (He et al., 2020, among others), so a single positive test in an asymptomatic HCW does not imply that they are safe to continue working.

https://doi.org/10.7554/eLife.59391.sa1

Author response

Essential revisions:

1) There are a mixture of self-swabs and swabbing by a health worker. Has any comparison been made for known positives? Or an assessment of similar cell numbers?

Thank you for helping us to clarify this point. Self-swabbing was utilised in both screening arms, and no swabs were performed by second parties. We have amended the Materials and methods to ensure this is clear. “All individuals in each arm of the programme performed a self-swab at the back of the throat then the nasal cavity, followed by RNA extraction and amplification using real-time RT-PCR.”

2) Why combine symptomatic and contacts for analysis purposes?

Our analysis aimed to compare trends in incidence of SARS-CoV-2 infection in symptomatic versus asymptomatic individuals tested through our screening programme, in relation to trends in the hospital’s patient population and the wider regional community. In order to draw a clear distinction between these groups, we combined the HCW symptomatic and HCW symptomatic household contact screening arms to reflect all individuals with self-reported symptoms at the time of testing. One important reason to make this distinction is that lower levels of test positivity could be reasonably expected in the HCW asymptomatic screening arm, as we previously observed (Rivett et al., 2020). In addition, the number of individuals tested screened (and number of positive results) was considerably smaller in the HCW symptomatic household contact screening arm.

We have added “(reflecting all individuals with self-reported symptoms at the time of testing)” to the Results section, to make the reason for this distinction clearer to the reader.

3) We are concerned about those testing positive continuing to work – particularly since no ethics was obtained (exemption is cited)."Individuals with repeat positive screens that were not scheduled to come into close contact with heavily immunocompromised patients were advised to continue working, provided they remained asymptomatic". South Korea data are mentioned as a justification – but there does not seem to be logic to the recommendation used in this case. If immunocompromised patients are at risk, then all patients are at risk. What about those with specific and known risk factors for COVID-19 disease? The reviewers feel that ethical approval would be needed for a study like this.

Thank you for asking us to reflect on these areas of our hospital policy. This policy, based on UK national guidance, was devised by the Occupational Health, Infectious Diseases and Infection Control teams, and was not part of our study, which was performed as a service evaluation (see also below and reviewer point 4). Our study had no role in defining the policy, which dictated the approach to return to work for HCW.

The policy for heavily immunocompromised patients is based on UK national guidance for staff returning to work with stem cell transplant recipients, as cited in the manuscript (National Institute for Health and Care Excellence (NICE), 2020). This requires both a negative test and that the HCW is well for seven days prior to return to work.

For other patients, the policy includes completion of a minimum self-isolation period of seven days prior to return to work and that the HCW was also well for at least 48h. Again, it is based on UK national guidance, which hinges on time elapsed since symptom onset, rather than duration of detectable viral RNA after an initial positive result (https://www.gov.uk/government/publications/covid-19-stay-at-home-guidance/stay-at-home-guidance-for-households-with-possible-coronavirus-covid-19-infection).

The UK national guidance specifically refers to people with a positive SARS-CoV-2 test result (“This guidance is intended for: people with symptoms of coronavirus (COVID-19) infection, who have received a positive test result…”), stating: “If you have had symptoms of coronavirus (COVID-19), then you may end your self-isolation after 7 days and return to your normal routine if you do not have symptoms other than cough or loss of sense of smell/taste. If you still have a high temperature, keep self-isolating until your temperature returns to normal.”

Based on published evidence available at the time our SARS-CoV-2 testing occurred, we agreed with the UK national guidance that both immunocompetent and immunocompromised patients were unlikely to be at risk of infection from exposure to HCW with detectable SARS-CoV-2 RNA beyond day 8 of symptom onset, as long as these HCW had been well for at least 48h prior to return to work. There had not been reported examples of SARS-CoV-2 infectivity beyond day 8 of symptom onset in ex-vivo or human observational studies, as we referenced (UK Government, 2020; Korea Centers for Disease Control and Prevention (KCDC), 2020; Wölfel, Corman and Guggemos, 2020).

To clarify the above, we have re-worded the Results section (“Of these, 4/7 (57%) were tested to determine their suitability to return to work with heavily immunocompromised patients, as dictated by UK national guidance.”) and the Materials and methods section (“In accordance with UK national guidance, individuals with repeat positive screens following a minimum period of seven days self-isolation were advised to continue working if they were not scheduled to come into close contact with heavily immunocompromised patients, provided they remained asymptomatic.”).

Regarding these ethical issues we also asked the advice of an expert in medical ethics. The answer was: "I have tried to interpret the decision tool they refer to in their paper, which explains when something is research that is in need of formal ethics review. The authors could be right that their study is exempt from review, because it is service evaluation or usual practice in public health interventions. I am not an expert in British local requirements, so the authors are requested to explain explicitly why they did not obtain consent, and to explain which category of exemption they refer to.

Many thanks for helping to clarify our methods. In this paper we present the findings of a service evaluation of our health care worker screening programme. We did not change the service provided in any way in order to undertake this evaluation and the conclusion from the NHS Health Research Authority/Medical Research Council decision tool (http://www.hra-decisiontools.org.uk/research/) was “Your study would NOT be considered Research by the NHS”. As explained in our original, linked publication (Rivett et al., 2020), inclusion into the testing programme was voluntary, either arranged by the individual contacting the Occupational Health service (if symptomatic), or volunteering for testing offered to all individuals working in a given ward during the time of sampling (for the HCW asymptomatic screening arm).

We have modified the text as follows:

Materials and methods “Staff screening protocols

We previously described protocols for staff screening, sample collection, laboratory processing and results reporting in detail (Rivett et al., 2020). […] In the latter, HCWs could volunteer to take part in a rolling programme of testing for all patient-facing and non-patient-facing staff working in defined clinical areas thought to be at risk of SARS-CoV-2 transmission.”

Materials and methods “Ethics and consent:

As a study of healthcare-associated infections, this investigation is exempt from requiring ethical approval under Section 251 of the NHS Act 2006 (see also the NHS Health Research Authority algorithm, available at http://www.hra-decisiontools.org.uk/research/, which concludes that no formal ethical approval is required). Our study was performed as a service evaluation of the CUHNFT screening programme. The service provided was not changed in any way in order to undertake this evaluation.”

I also agree with you that immunocompromised patients are not the only vulnerable group in hospitals, what about transmission to other categories of patients? Overall, the authors are very concise in their explanations and in giving context. It would be useful if they would reflect on these issues, and then I am happy to review their answer".

Please see our response above. Our approach to permitting return to work after a positive test result was based on our hospital policy, which was devised by the Occupational Health, Infectious Diseases and Infection Control teams, informed by UK national guidance (https://www.gov.uk/government/publications/covid-19-stay-at-home-guidance/stay-at-home-guidance-for-households-with-possible-coronavirus-covid-19-infection). HCWs involved in the direct care of haematopoietic stem cell transplant recipients are the only group for which there is specific guidance recommending that a negative SARS-CoV-2 PCR test is required prior to returning to work (National Institute for Health and Care Excellence (NICE), 2020). As we describe, available literature up to the date of our study suggested that despite SARS-CoV-2 RNA remaining detectable for several weeks after symptom onset, individuals were unlikely to be infectious beyond day 8 (UK Government, 2020; Korea Centers for Disease Control and Prevention (KCDC), 2020; Wölfel, Corman and Guggemos, 2020).

4) Even if ethics is not needed for HCW, then what about screening their household contacts, i.e., asymptomatic participants not associated with the hospital? What advice was given to those positive, and follow up?

Many thanks for the comment. The same considerations as detailed in our reply to reviewer comment #3 apply. Household contacts were only tested if they were symptomatic and the HCW was consequently in self-quarantine because this contact had symptoms. Referral to the service was again voluntary, and offered via the hospital’s programme. Our study simply evaluated this service. There were no asymptomatic household contacts screened. This is explained in more detail in our original paper (Rivett et al., 2020). We have added further details explaining this into the ‘Staff screening protocols’ part of the Materials and methods section to aid clarity as a standalone paper:

“Two parallel streams of entry into the testing programme included (i) HCW symptomatic, and HCW symptomatic household contact screening arms and (ii) an HCW asymptomatic screening arm. […] In the latter, HCWs could volunteer to take part in a rolling programme of testing for all patient-facing and non-patient-facing staff working in defined clinical areas thought to be at risk of SARS-CoV-2 transmission.”

Advice to those testing positive was described in our original, linked manuscript (Rivett et al., 2020):

“Results reporting

As soon as they were available, positive results were telephoned to patients by Infectious Diseases physicians, who took further details of symptomatology including timing of onset, and gave clinical advice (Table 2). […] Verbal consent was gained for all results to be reported to the hospital’s infection control and health and safety teams, and to Public Health England, who received all positive and negative results as part of a daily reporting stream.”

5) A far smaller number of household contacts was tested than would be expected – why is that?

Testing of symptomatic household contacts (HHCs) was reliant on referral to the service by a co-habiting hospital employee. Uptake to this arm of the screening programme was lower than for self-referral by symptomatic HCWs, which may have either reflected a lack of awareness that symptomatic HHCs were eligible for testing (despite frequent advertising within the hospital), that non-hospital employees may have been more inclined to attend national testing centres, or that these individuals may have been less aware of all of the potential symptoms of COVID-19.

We have added lines to the Discussion section to highlight this point: “In addition to asymptomatic screening, testing of symptomatic HCWs is essential for preventing excessive erosion of the hospital workforce by self-isolation on the basis of symptoms alone, and testing of symptomatic HCW household contacts negates the need for unnecessary self-quarantine periods for co-habiting HCWs. […] Many non-hospital employees may also have been more inclined to attend national testing centres, or may have been less aware of all of the potential symptoms of COVID-19.”

6) There is a need for the denominator of total staff and household contacts, rather than the positives/all tested.

Many thanks for this point. CUH employs 11,000 members of staff, which we describe in the Discussion. The denominator for total staff household contacts is not recorded, as staff are not asked about how many others live in their household.

7) Are there any further details that could be given on the HCW who were tested? E.g. what proportion of positives in the asymptomatic arm later became symptomatic? Was there any association between positivity and characteristics like use of PPE, role in the hospital (e.g. job description, whether they had direct contact with COVID patients etc.), age/gender?

Many thanks for this suggestion. We have now included age and gender of those who tested positive in the Results section. We have also added a more detailed breakdown of the 21 positive tests from individuals in the HCW asymptomatic screening arm, which highlights that two were pre-symptomatic at the time of testing:

“In the HCW asymptomatic screening arm, 21/2,611 (0.8%) tests were positive, which again was significantly lower than 31/1,032 (3%) in the original study period (Fisher’s exact test p<0.0001). […] Our approach to patients with repeatedly positive SARS-CoV-2 PCR tests is described in the Materials and methods.”

We previously performed a detailed analysis of HCW working on ‘red’ vs. ‘green’ wards in our linked study (Rivett et al., 2020), and did not think it particularly informative to repeat this on the smaller sample of positive tests in the current analysis. Similarly, details of PPE used in all areas was previously discussed in detail. Of note, a minimum of masks, disposable aprons and gloves were worn in all patient-facing areas. However, the suggestion to add details of job description was interesting. We have added a table of the roles of all HCW testing positive in this and our previous linked study (Rivett et al., 2020), categorised according to screening arm (new Table 1):

“Table 1 summarises the total number of HCWs testing positive through either arm of the screening programme, according to job role. […] Reasonable comparison of the proportions testing positive through the HCW asymptomatic screening arm was not possible due to non-random sampling of different areas of the hospital, meaning some job roles had been more frequently targeted for asymptomatic screening than others.”

8) "Effectively, the reproduction number (R) for SARS-CoV-2 amongst the

population of HCW in our hospital has been maintained <1". This statement feels oversimplified. Since there is a constant flow of patients from and to the community from hospitals, the reproduction number among HCW depends on (i) R between HCWs, (ii) R between HCWs and patients, (iii) R between hospitals and the community, (iv) R within the community. It is not clear which of these components of R the statement refers to, and whether the authors can even make such a statement given the data they have. For instance, positivity among HCWs may be driven by lower prevalence in the community or among patients, even while R between HCWs remains above 1.

We agree that the original statement was simplified, and we agree in general terms with much of the reviewer’s helpful analysis.

In practice, it is common to refer to a reproduction number (R) for a population which is not completely isolated, such as a region within a country. For example, R in London is currently estimated to be 0.9. In this sort of usage, R is typically taken to refer to transmission between members of the identified population, and that is the way in which we use it here, i.e. in respect of transmission between members of our population of HCW.

Since the prevalence of infection in HCW is declining, we know that, on average, the number of secondary infections amongst HCW arising from each infected HCW must be <1. Put another way, the “R between HCW” (as defined by the reviewer) must be <1. If that wasn’t the case, the prevalence of infection in HCW would be increasing, rather than declining.

Again as stated by the reviewer, new infections amongst HCW may include instances of transmission from patients or other individuals outside the hospital, as well as transmission from other HCW. These introductions mean that the “R between HCW” is, in practice, almost certainly even lower that it appears.

We have adjusted the text in the Discussion to emphasise these points:

“Our data demonstrate a dramatic fall in the prevalence of symptomatic and asymptomatic SARS-CoV-2 infection amongst HCW in our hospital during the study period. […] For each of these clusters, timely identification of HCW infection proved effective in terminating chains of hospital transmission between staff, preventing ongoing nosocomial infection.”

9) Do clusters refer to sequencing? In which case need methods and data to show these clusters.

Apologies for omitting this definition. Clusters were defined pragmatically as three or more positive HCWs working in the same clinical area within a two week period, and did not rely on sequencing. We have added this definition into the Materials and methods section:

“Cluster investigation was initiated when three or more HCWs working in the same clinical area tested positive for SARS-CoV-2 within a one week period.”

10) Subsection “Management of HCW with repeat positive tests”: On the issue of lack of evidence of onward transmission from repeat-positive asymptomatic individuals, this depends crucially on whether these individuals are detected positive after recovering from symptomatic illness, just before developing symptoms or asymptomatic throughout their time of positivity. In particular, there is good evidence that viral load (and risk of transmission) is highest just before a patient develops symptoms (He et al., 2020, among others), so a single positive test in an asymptomatic HCW does not imply that they are safe to continue working.

Thank you for querying this. Repeat positive individuals were only advised to continue working if they had already completed a minimum of seven days in self-isolation, were asymptomatic upon completing their period of self-isolation, and were not scheduled to come into contact with heavily immunocompromised patients. We have re-worded the Materials and methods section to add clarity:

“In accordance with UK national guidance, individuals with repeat positive screens following a minimum period of seven days self-isolation were advised to continue working if they were not scheduled to come into close contact with heavily immunocompromised patients, provided they remained asymptomatic.”

Furthermore, all asymptomatic individuals testing positive for the first time were advised to self-isolate for a minimum of seven days from the time of sample collection, or from the onset of symptoms if they subsequently developed symptoms after the test. This approach was described in detail in our original, linked publication (Rivett et al., 2020, Table 2, ‘asymptomatic’ row). This approach was more cautionary than the national guidance, which stipulates a minimum of seven days isolation in total for individuals who test positive (https://www.gov.uk/government/publications/covid-19-stay-at-home-guidance/stay-at-home-guidance-for-households-with-possible-coronavirus-covid-19-infection).

https://doi.org/10.7554/eLife.59391.sa2

Article and author information

Author details

  1. Nick K Jones

    1. Department of Infectious Diseases, Cambridge University NHS Hospitals Foundation Trust, Cambridge, United Kingdom
    2. Clinical Microbiology & Public Health Laboratory, Public Health England, Cambridge, United Kingdom
    3. Department of Medicine, University of Cambridge, Cambridge, United Kingdom
    4. Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, University of Cambridge, Cambridge, United Kingdom
    Contribution
    Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Writing - original draft, Project administration, Writing - review and editing
    Contributed equally with
    Lucy Rivett, Dominic Sparkes and Sally Forrest
    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4475-7761
  2. Lucy Rivett

    1. Department of Infectious Diseases, Cambridge University NHS Hospitals Foundation Trust, Cambridge, United Kingdom
    2. Clinical Microbiology & Public Health Laboratory, Public Health England, Cambridge, United Kingdom
    Contribution
    Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Writing - original draft, Project administration, Writing - review and editing
    Contributed equally with
    Nick K Jones, Dominic Sparkes and Sally Forrest
    Competing interests
    No competing interests declared
  3. Dominic Sparkes

    1. Department of Infectious Diseases, Cambridge University NHS Hospitals Foundation Trust, Cambridge, United Kingdom
    2. Clinical Microbiology & Public Health Laboratory, Public Health England, Cambridge, United Kingdom
    Contribution
    Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Writing - original draft, Project administration, Writing - review and editing
    Contributed equally with
    Nick K Jones, Lucy Rivett and Sally Forrest
    Competing interests
    No competing interests declared
  4. Sally Forrest

    1. Department of Medicine, University of Cambridge, Cambridge, United Kingdom
    2. Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, University of Cambridge, Cambridge, United Kingdom
    Contribution
    Data curation, Investigation, Methodology, Project administration, Writing - review and editing
    Contributed equally with
    Nick K Jones, Lucy Rivett and Dominic Sparkes
    Competing interests
    No competing interests declared
  5. Sushmita Sridhar

    1. Department of Medicine, University of Cambridge, Cambridge, United Kingdom
    2. Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, University of Cambridge, Cambridge, United Kingdom
    3. Wellcome Sanger Institute, Hinxton, United Kingdom
    Contribution
    Data curation, Investigation, Methodology, Writing - review and editing
    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7453-7482
  6. Jamie Young

    Academic Department of Medical Genetics, University of Cambridge, Cambridge, United Kingdom
    Contribution
    Data curation, Investigation, Methodology, Project administration, Writing - review and editing
    Competing interests
    No competing interests declared
  7. Joana Pereira-Dias

    1. Department of Medicine, University of Cambridge, Cambridge, United Kingdom
    2. Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, University of Cambridge, Cambridge, United Kingdom
    Contribution
    Data curation, Investigation, Methodology, Writing - review and editing
    Competing interests
    No competing interests declared
  8. Claire Cormie

    1. Department of Medicine, University of Cambridge, Cambridge, United Kingdom
    2. Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, University of Cambridge, Cambridge, United Kingdom
    Contribution
    Data curation, Investigation, Methodology, Writing - review and editing
    Competing interests
    No competing interests declared
  9. Harmeet Gill

    1. Department of Medicine, University of Cambridge, Cambridge, United Kingdom
    2. Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, University of Cambridge, Cambridge, United Kingdom
    Contribution
    Resources, Data curation, Investigation, Methodology, Writing - review and editing
    Competing interests
    No competing interests declared
  10. Nicola Reynolds

    Wellcome-MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, University of Cambridge, Cambridge, United Kingdom
    Contribution
    Data curation, Investigation, Methodology, Writing - review and editing
    Competing interests
    No competing interests declared
  11. Michelle Wantoch

    1. Wellcome - MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom
    2. Department of Haematology, School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom
    Contribution
    Data curation, Investigation, Methodology, Writing - review and editing
    Competing interests
    No competing interests declared
  12. Matthew Routledge

    1. Department of Infectious Diseases, Cambridge University NHS Hospitals Foundation Trust, Cambridge, United Kingdom
    2. Clinical Microbiology & Public Health Laboratory, Public Health England, Cambridge, United Kingdom
    Contribution
    Resources, Data curation, Methodology, Project administration, Writing - review and editing
    Competing interests
    No competing interests declared
  13. Ben Warne

    1. Department of Infectious Diseases, Cambridge University NHS Hospitals Foundation Trust, Cambridge, United Kingdom
    2. Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, University of Cambridge, Cambridge, United Kingdom
    Contribution
    Data curation, Methodology, Writing - review and editing
    Competing interests
    No competing interests declared
  14. Jack Levy

    Institute for Manufacturing, Department of Engineering, University of Cambridge, Cambridge, United Kingdom
    Contribution
    Data curation, Investigation, Methodology, Project administration, Writing - review and editing
    Competing interests
    No competing interests declared
  15. William David Córdova Jiménez

    Institute for Manufacturing, Department of Engineering, University of Cambridge, Cambridge, United Kingdom
    Contribution
    Data curation, Investigation, Methodology, Project administration, Writing - review and editing
    Competing interests
    No competing interests declared
  16. Fathima Nisha Begum Samad

    Institute for Manufacturing, Department of Engineering, University of Cambridge, Cambridge, United Kingdom
    Contribution
    Data curation, Investigation, Methodology, Project administration, Writing - review and editing
    Competing interests
    No competing interests declared
  17. Chris McNicholas

    Improvement and Transformation Team, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom
    Contribution
    Data curation, Software, Formal analysis, Writing - review and editing
    Competing interests
    No competing interests declared
  18. Mark Ferris

    Occupational Health and Wellbeing, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom
    Contribution
    Resources, Investigation, Methodology, Project administration, Writing - review and editing
    Competing interests
    No competing interests declared
  19. Jane Gray

    Cancer Research United Kingdom Cambridge Institute, University of Cambridge, Cambridge, United Kingdom
    Contribution
    Data curation, Investigation, Methodology, Writing - review and editing
    Competing interests
    No competing interests declared
  20. Michael Gill

    Cancer Research United Kingdom Cambridge Institute, University of Cambridge, Cambridge, United Kingdom
    Contribution
    Data curation, Investigation, Methodology, Writing - review and editing
    Competing interests
    No competing interests declared
  21. The CITIID-NIHR COVID-19 BioResource Collaboration

    1. Stephen Baker
    2. John Bradley
    3. Gordon Dougan
    4. Ian Goodfellow
    5. Ravi Gupta
    6. Paul J Lehner
    7. Paul A Lyons
    8. Nicholas J Matheson
    9. Kenneth GC Smith
    10. M Estee Torok
    11. Mark Toshner
  22. Martin D Curran

    Clinical Microbiology & Public Health Laboratory, Public Health England, Cambridge, United Kingdom
    Contribution
    Resources, Data curation, Investigation, Methodology, Project administration, Writing - review and editing
    Competing interests
    No competing interests declared
  23. Stewart Fuller

    National Institutes for Health Research Cambridge Biomedical Research Centre, Cambridge, United Kingdom
    Contribution
    Resources, Data curation, Investigation, Methodology, Project administration, Writing - review and editing
    Competing interests
    No competing interests declared
  24. Afzal Chaudhry

    Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom
    Contribution
    Resources, Data curation, Investigation, Methodology, Project administration, Writing - review and editing
    Competing interests
    Afzal Chaudhry reports grants from Cambridge Biomedical Research Centre at CUHNFT, during the conduct of the study.
  25. Ashley Shaw

    Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom
    Contribution
    Resources, Data curation, Investigation, Methodology, Writing - review and editing
    Competing interests
    No competing interests declared
  26. John R Bradley

    1. Department of Medicine, University of Cambridge, Cambridge, United Kingdom
    2. National Institutes for Health Research Cambridge, Clinical Research Facility, Cambridge, United Kingdom
    Contribution
    Conceptualization, Resources, Data curation, Investigation, Methodology, Writing - review and editing
    Competing interests
    No competing interests declared
  27. Gregory J Hannon

    Cancer Research United Kingdom Cambridge Institute, University of Cambridge, Cambridge, United Kingdom
    Contribution
    Resources, Data curation, Supervision, Investigation, Methodology, Writing - review and editing
    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4021-3898
  28. Ian G Goodfellow

    Division of Virology, Department of Pathology, University of Cambridge, Cambridge, United Kingdom
    Contribution
    Data curation, Investigation, Methodology, Writing - review and editing
    Competing interests
    Ian Goodfellow reports grants from Wellcome Trust (Senior Research Fellowships), grants from Wellcome Trust (Collaborative Award), grants from Addenbrooke's Charitable Trust, during the conduct of the study.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9483-510X
  29. Gordon Dougan

    1. Department of Medicine, University of Cambridge, Cambridge, United Kingdom
    2. Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, University of Cambridge, Cambridge, United Kingdom
    Contribution
    Conceptualization, Data curation, Supervision, Investigation, Methodology, Project administration, Writing - review and editing
    Competing interests
    Gordon Dougan reports grants from NIHR, during the conduct of the study.
  30. Kenneth GC Smith

    1. Department of Medicine, University of Cambridge, Cambridge, United Kingdom
    2. Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, University of Cambridge, Cambridge, United Kingdom
    Contribution
    Conceptualization, Data curation, Investigation, Methodology, Project administration, Writing - review and editing
    Competing interests
    Kenneth GC Smith reports grants from Wellcome Trust, during the conduct of the study.
  31. Paul J Lehner

    1. Department of Infectious Diseases, Cambridge University NHS Hospitals Foundation Trust, Cambridge, United Kingdom
    2. Department of Medicine, University of Cambridge, Cambridge, United Kingdom
    3. Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, University of Cambridge, Cambridge, United Kingdom
    Contribution
    Conceptualization, Supervision, Investigation, Methodology, Project administration, Writing - review and editing
    Competing interests
    Paul J Lehner reports grants from Wellcome Trust Principal Research Fellowship, grants from Addenbrooke's Charitable Trust, during the conduct of the study.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9383-1054
  32. Giles Wright

    Occupational Health and Wellbeing, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom
    Contribution
    Conceptualization, Data curation, Supervision, Investigation, Methodology, Project administration, Writing - review and editing
    Competing interests
    No competing interests declared
  33. Nicholas J Matheson

    1. Department of Infectious Diseases, Cambridge University NHS Hospitals Foundation Trust, Cambridge, United Kingdom
    2. Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, University of Cambridge, Cambridge, United Kingdom
    3. NHS Blood and Transplant, Cambridge, United Kingdom
    Contribution
    Data curation, Formal analysis, Investigation, Methodology, Project administration, Writing - review and editing
    Contributed equally with
    Stephen Baker and Michael P Weekes
    Competing interests
    Nicholas J Matheson reports grants from Medical Research Council (Clinician Scientist Fellowship), grants from NHS Blood and Transfusion, during the conduct of the study.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3318-1851
  34. Stephen Baker

    1. Department of Medicine, University of Cambridge, Cambridge, United Kingdom
    2. Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, University of Cambridge, Cambridge, United Kingdom
    Contribution
    Conceptualization, Data curation, Formal analysis, Supervision, Funding acquisition, Investigation, Methodology, Writing - original draft, Project administration, Writing - review and editing
    Contributed equally with
    Nicholas J Matheson and Michael P Weekes
    Competing interests
    Stephen Baker reports grants from Wellcome Trust (Senior Research Fellowships), from Addenbrooke's Charitable Trust, during the conduct of the study.
  35. Michael P Weekes

    1. Department of Infectious Diseases, Cambridge University NHS Hospitals Foundation Trust, Cambridge, United Kingdom
    2. Department of Medicine, University of Cambridge, Cambridge, United Kingdom
    3. Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, University of Cambridge, Cambridge, United Kingdom
    Contribution
    Conceptualization, Data curation, Formal analysis, Supervision, Funding acquisition, Investigation, Visualization, Methodology, Writing - original draft, Project administration, Writing - review and editing
    Contributed equally with
    Nicholas J Matheson and Stephen Baker
    For correspondence
    mpw1001@cam.ac.uk
    Competing interests
    Michael P Weekes reports grants from Wellcome Trust (Senior Research Fellowships), from Addenbrooke's Charitable Trust, during the conduct of the study.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3196-5545

Funding

Wellcome (108070/Z/15/Z)

  • Michael P Weekes

Wellcome (215515/Z/19/Z)

  • Stephen Baker

Wellcome (207498?Z/17/Z)

  • Ian G Goodfellow

Wellcome (206298/B/17/Z)

  • Ian G Goodfellow

Wellcome (210688/Z/18/Z)

  • Paul J Lehner

Wellcome (200871/Z/16/Z)

  • Kenneth GC Smith

Medical Research Council (MR/P008801/1)

  • Nicholas J Matheson

Addenbrooke's Charitable Trust, Cambridge University Hospitals

  • Ian G Goodfellow
  • Paul J Lehner
  • Stephen Baker
  • Michael P Weekes

NHS Blood and Transplant (WPA15-02)

  • Nicholas J Matheson

National Institute for Health Research

  • Afzal Chaudhry
  • John R Bradley
  • Gordon Dougan

Cancer Research UK (C38317/A24043)

  • Jamie Young

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Acknowledgements

This work was supported by the Wellcome Trust Senior Research Fellowships 108070/Z/15/Z to MPW, 215515/Z/19/Z to SGB and 207498/Z/17/Z to IGG; Collaborative award 206298/B/17/Z to IGG; Principal Research Fellowship 210688/Z/18/Z to PJL; Investigator Award 200871/Z/16/Z to KGCS; Addenbrooke’s Charitable Trust (to MPW, SGB, and PJL); the Medical Research Council (CSF MR/P008801/1 to NJM); NHS Blood and Transfusion (WPA15-02 to NJM); National Institute for Health Research (Cambridge Biomedical Research Centre at CUHNFT), to JRB, AC and GD, Cancer Research UK (PRECISION Grand Challenge C38317/A24043 award to JY).

The CITIID-NIHR COVID-19 BioResource Collaboration 

Principal Investigators: Stephen Baker, John Bradley, Gordon Dougan, Ian Goodfellow, Ravi Gupta, Paul J Lehner, Paul A Lyons, Nicholas J Matheson, Kenneth GC Smith, M Estee Torok, Mark Toshner, Michael P Weekes

Infectious Diseases Department: Nicholas K Jones, Lucy Rivett, Matthew Routledge, Dominic Sparkes, Ben Warne

SARS-CoV-2 testing team: Claire Cormie, Sally Forrest, Harmeet Gill, Iain Kean, Joana Pereira-Dias, Nicola Reynolds, Sushmita Sridhar, Michelle Wantoch, Jamie Young

COG-UK Cambridge Sequencing Team: Sarah Caddy, Laura Caller, Theresa Feltwell, Grant Hall, William Hamilton, Myra Hosmillo, Charlotte Houldcroft, Aminu Jahun, Fahad Khokhar, Luke Meredith, Anna Yakovleva

NIHR BioResource: Helen Butcher, Daniela Caputo, Debra Clapham-Riley, Helen Dolling, Anita Furlong, Barbara Graves, Emma Le Gresley, Nathalie Kingston, Sofia Papadia, Hannah Stark, Kathleen E Stirrups, Jennifer Webster

Research nurses: Joanna Calder, Julie Harris, Sarah Hewitt, Jane Kennet, Anne Meadows, Rebecca Rastall, Criona O,Brien, Jo Price, Cherry Publico, Jane Rowlands, Valentina Ruffolo, Hugo Tordesillas

CRUK: Michael Gill, Jane Gray, Greg Hannon

NIHR Cambridge Clinical Research Facility: Karen Brookes, Laura Canna, Isabel Cruz, Katie Dempsey, Anne Elmer, Naidine Escoffery, Stewart Fuller, Heather Jones, Carla Ribeiro, Caroline Saunders, Angela Wright 

Cambridge Cancer Trial Centre: Rutendo Nyagumbo, Anne Roberts

Clinical Research Network Eastern: Ashlea Bucke, Simone Hargreaves, Danielle Johnson, Aileen Narcorda, Debbie Read, Christian Sparke, Lucy Worboys

Administrative staff, CUHNFT: Kirsty Lagadu, Lenette Mactavous

CUHNFT NHS Foundation Trust: Tim Gould, Tim Raine, Ashley Shaw

Cambridge Cancer Trials Centre: Claire Mather, Nicola Ramenatte, Anne-Laure Vallier

Legal/Ethics: Mary Kasanicki

CUHNFT Improvement and Transformation Team: Penelope-Jane Eames, Chris McNicholas, Lisa Thake

Clinical Microbiology & Public Health Laboratory (PHE): Neil Bartholomew, Nick Brown, Martin Curran, Surendra Parmar, Hongyi Zhang

Occupational Health: Ailsa Bowring, Mark Ferris, Geraldine Martell, Natalie Quinnell, Giles Wright, Jo Wright

Health and Safety: Helen Murphy

Department of Medicine Sample Logistics: Benjamin J Dunmore, Ekaterina Legchenko, Stefan Gräf, Christopher Huang, Josh Hodgson, Kelvin Hunter, Jennifer Martin, Federica Mescia, Ciara O’Donnell, Linda Pointon, Joy Shih, Rachel Sutcliffe, Tobias Tilly, Zhen Tong, Carmen Treacy, Jennifer Wood

Department of Medicine Sample Processing and Acquisition: Laura Bergamaschi, Ariana Betancourt, Georgie Bowyer, Aloka De Sa, Maddie Epping, Andrew Hinch, Oisin Huhn, Isobel Jarvis, Daniel Lewis, Joe Marsden, Simon McCallum, Francescsa Nice, Ommar Omarjee, Marianne Perera, Nika Romashova, Mateusz Strezlecki, Natalia Savoinykh Yarkoni, Lori Turner

Epic team/other computing support: Barrie Bailey, Afzal Chaudhry, Rachel Doughton, Chris Workman

Statistics/modelling: Caroline Trotter

Department of Engineering: William David Cordova Jiménez, Jack Levy, Fatima NB Samad

Ethics

Human subjects: As a study of healthcare-associated infections, this investigation is exempt from requiring ethical approval under Section 251 of the NHS Act 2006 (see also the NHS Health Research Authority algorithm, available at http://www.hra-decisiontools.org.uk/research/, which concludes that no formal ethical approval is required). Our study was performed as a service evaluation of the Cambridge Universith Hospitals NHS Foundation Trust screening programme. The service provided was not changed in any way in order to undertake this evaluation.

Senior and Reviewing Editor

  1. Jos WM van der Meer, Radboud University Medical Centre, Netherlands

Reviewer

  1. Deenan Pillay

Publication history

  1. Received: May 28, 2020
  2. Accepted: June 19, 2020
  3. Accepted Manuscript published: June 19, 2020 (version 1)
  4. Version of Record published: June 30, 2020 (version 2)

Copyright

© 2020, Jones et al.

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

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  1. Edited by Jos WM van der Meer et al.
    Collection

    eLife has published the following articles on SARS-CoV-2 and COVID-19.

    1. Epidemiology and Global Health
    2. Microbiology and Infectious Disease
    June H Tan et al.
    Research Advance

    Parasitic helminths use two benzoquinones as electron carriers in the electron transport chain. In normoxia they use ubiquinone (UQ), but in the anaerobic conditions inside the host, they require rhodoquinone (RQ) and greatly increase RQ levels. We previously showed the switch from UQ to RQ synthesis is driven by a change in substrates by the polyprenyltransferase COQ-2 (Del Borrello et al., 2019; Roberts Buceta et al., 2019) - how this substrate choice is made is unknown. Here, we show helminths make two coq-2 splice forms, coq-2a and coq-2e, and the coq-2e-specific exon is only found in species that make RQ. We show that in C. elegans COQ-2e is required for efficient RQ synthesis and for survival in cyanide. Crucially, parasites switch from COQ-2a to COQ-2e as they transition into anaerobic environments. We conclude helminths switch from UQ to RQ synthesis principally via changes in the alternative splicing of coq-2.