Effectiveness of Adding a Mask Recommendation to Other Public Health Measures to Prevent SARS-CoV-2 Infection in Danish Mask Wearers: A Randomized Controlled Trial

Henning Bundgaard et al. Annals of Internal Medicine November 2020; doi:https://doi.org/10.7326/M20-6817

Clinical Question

• In adults in Denmark reported to spend three hours or more outside of the home during the early stages of the COVID-19 pandemic, did a recommendation to wear a surgical face mask, compared with no recommendation to wear a surgical face mask, reduce SARS-CoV-2 infection at one month?

Background

• SARS-CoV-2 infection is thought to be transmitted mainly through droplet and aerosol spread
• There are a large number of observational studies suggesting that universal mask wearing reduces transmission of SARS-CoV-2 infection (LANCET meta-analysis)
• In countries that have mandated universal mask wearing, such as South Korea, China, Taiwan and the state of Victoria in Australia, community spread of SARS-CoV-2 has been reduced to low levels (Our World In Data)
• It is unclear whether wearing a surgical face mask protects the wearer from COVID-19 infection, in addition to providing source control of SARS-CoV-2 infection
• It has been postulated that wearing an unsealed face mask may reduce the viral load that the wearer is exposed to, and that this could mitigate against the severity of COVID-19 infection (Ghandi et al 2020; Kai et al 2020)
• The authors therefore assessed whether a recommendation to wear a surgical mask when outside the home among others reduced the wearers’ risk for SARS-CoV-2 infection

Design

• Non-blinded randomised controlled trial
• Participants were recruited through media advertisements and contacting private companies and public organisations
• Eligible participants were randomly assigned 1:1 to the mask or control group using a computer algorithm and were stratified by the 5 regions of Denmark
• A sample size calculation determined that 6,000 participants would provide the study with 80% power to detect a 50% absolute risk reduction in SARS-CoV-2 infection (from 2% to 1%), with a significance level of 5% and assuming a 20% participant dropout rate
• A SARS-CoV-2 infection rate of 2% was estimated during the study period
• Study participants tested themselves for SARS-CoV-2 infection using finger prick testing at baseline and at one month
• Study participants were also instructed to perform an oropharyngeal/ nasopharyngeal PCR test if they became symptomatic or at one month
• Data collection was by four follow-up email surveys. These collected information on antibody test results, adherence to recommendations on time spent outside the home, development of symptoms, COVID-19 diagnosis based on PCR testing done in public hospitals, and known COVID-19 exposures
• The primary outcome was SARS-CoV-2 infection, which was a composite outcome defined as a positive result on either an oropharyngeal/nasal swab test for SARS-CoV-2 and/or development of a positive SARS-CoV-2 antibody test result (IgM or IgG) during the study period and/or a hospital-based diagnosis of SARS-CoV-2 infection or COVID-19
• Secondary end points included PCR evidence of infection with other respiratory viruses
• The study was funded through a grant from the Salling Foundations, with tests donated by the BESTSELLER foundation
• The study did not receive ethical approval (the authors state this was not required) and there was no involvement of a data safety and monitoring board

Setting

• Nationwide throughout Denmark between April and June 2020 (during this time facemarks were not universally recommended in Denmark)

Population

• Inclusion: Adults aged 18 years or older without current or prior symptoms or diagnosis of COVID-19 who reported being outside the home among others for at least 3 hours per day and who did not wear masks during their daily work
• Exclusion: Evidence of previous COVID-19 infection with positive SARS-CoV-2 antibody tests at baseline
• 17,258 Danish citizens responded to recruitment and 6,024 completed the baseline survey and fulfilled eligibility criteria
• 1,162 participants did not complete the study, mostly due to not finalising participation
• 4,862 participants completed the study
• The mean age of participants was around 47 years, with more than 60% of participants being female
• 80.1% of the intervention group provided antibody tests at baseline
• Baseline characteristics were similar between intervention and control groups

Intervention

• Instructed to wear a mask
  • Participants were instructed to wear a mask when outside the home during the next month
  • They received 50 three-layer, disposable, surgical face masks with ear loops (TYPE II EN 14683 [Abena]; filtration rate, 98%; made in China)
  • Participants were instructed to change the mask if outside the home for more than 8 hours

Control

• Not instructed to wear a mask
  • Participants were not instructed to wear surgical face masks and were not provided with face masks

Management common to both groups

• Both groups received material and instructions for antibody testing on receipt and at 1 month
• Participants tested for SARS-CoV-2 IgM and IgG antibodies in whole blood using a point-of-care test (Lateral Flow test [Zhuhai Livzon Diagnostics]) according to the manufacturer’s recommendations:
  • After puncturing a fingertip with a lancet, they withdrew blood into a capillary tube and placed 1 drop of blood followed by 2 drops of saline in the test chamber in each of the 2 test plates (IgM and IgG).
  • Participants reported IgM and IgG results separately as “1 line present” (negative), “2 lines present” (positive), or “I am not sure, or I could not perform the test” (treated as a negative result)
• Both groups received materials and written and video instructions for collecting an oropharyngeal/ nasal swab sample for polymerase chain reaction (PCR) testing at 1 month and whenever symptoms compatible with COVID-19 occurred during follow-up
• A help line was available to participants
• Participants were instructed to register symptoms and results of the antibody test in online REDCap system
• They received four follow-up surveys by email to collect information on antibody test results, adherence to recommendations on time spent outside the home among others, development of symptoms, COVID-19 diagnosis based on PCR testing done in public hospitals, and known COVID-19 exposures
• Recommended Danish public health measures included quarantining persons with SARS-CoV-2 infection, social distancing (including in shops and public transportation, which remained open), limiting the number of persons seen, frequent hand hygiene and cleaning, and limiting visitors to hospitals and nursing homes
• Cafés and restaurants were closed during the study until 18 May 2020

Outcome

• Primary outcome: SARS-CoV-2 infection – no significant difference
  • 1.8%  in the mask vs. 2.1% in the control group (Odds Ratio 0.82; 95% CI 0.54-1.23)
• For individual components of primary outcome, comparing face mask vs. control group:
  • positive PCR test for SARS-CoV-2 infection: 0% vs. 0.2%
  • health care diagnosed SARS-CoV-2 infection: 0.2% vs. 0.4%
  • IgM antibodies: 1.3% vs. 1.5%, (Odds Ratio 0.87; 95% CI 0.54-1.41)
  • IgG antibodies: 1.4% vs. 1.3% (Odds Ratio 1.07; 95% CI 0.66-1.75)
  • compared with 10 participants (0.4%) in the control group
• In the preplanned sensitivity analysis excluding participants who did not provide an antibody test at baseline
  • the primary outcome occurred in 1.4% in mask group vs. 1.8% in control group (Odds Ratio 0.77; 95% CI 0.49-1.22)
• Secondary outcome: 9 participants (0.5%) in the mask group were
  • Positive for 1 or more of 11 respiratory viruses other than SARS-CoV-2
    • 0.5% in mask vs. 0.6% in control group (Odds Ratio 0.58; 95% 0.25-1.31)

Authors’ Conclusions

• Our results suggest that the recommendation to wear a surgical mask when outside the home among others did not reduce, at conventional levels of statistical significance, the incidence of SARS-CoV-2 infection in mask wearers in a setting where social distancing and other public health measures were in effect
• The findings were inconclusive and cannot definitively exclude a 46% reduction to a 23% increase in infection of mask wearers in such a setting
• The findings, however, should not be used to conclude that a recommendation for everyone to wear masks in the community would not be effective in reducing SARS-CoV-2 infections, because the trial did not test the role of masks in source control of SARS-CoV-2 infection

Strengths

• This is an important area of investigation and clinical question and the study is both timely and relevant
• A patient-centred endpoint of SARS-CoV-2 infection was used
• The trial was adequately powered to test the hypothesis and the estimated 2% COVID-19 infection rate was accurate
• Compliance with wearing face masks was assessed, which is important in a public health intervention, with 46% of participants wearing the mask as recommended and 47% predominantly as recommended
• A surprisingly high proportion of participants completed the study, particularly in view of the demand for self-monitoring and no face to face contact

Weaknesses

• The main benefit of a surgical face mask is to protect others from droplet and aerosol spread, and not the wearer- the study was not designed to investigate this
  • Whilst not a weakness per se, it is important that the findings are not misinterpreted
• Selection bias is likely to have been an issue, with a non-random sample of trial participants recruited to the study mainly through media adverts
• Participants volunteered for enrolment and it is unclear how this sample represented Danish society as a whole
• Participants were only followed up for one month, which is very short for an infection with an incubation period of 14 days
• Participants may have been infected with SARS-CoV-2 infection during the study but they did not test positive or become symptomatic during the period under surveillance
• The trial was submitted to the scientific ethics committee of the Capital Region of Denmark but did not require ethics approval, which seems unusual for a randomised controlled trial requiring blood tests on 4,800 people
• There was no oversight from a data safety and monitoring board
• Relying on participants to self-test following the development of symptoms in an unblinded study, is problematic, as is the self-reporting of results by trial participants
• No assessment was made of inter-observer variability in the performance or interpretation of the antibody or PCR tests
• A 50% reduction in SARS-CoV-2 infection seems unrealistic for a single non-pharmacological intervention:
  • A sample size of roughly 35,000 would have been required to detect a 20% absolute risk reduction in infection
  • A risk reduction of this magnitude could have major implications, in view of the potential for exponential spread of SARS-CoV-2 infection
• Crossover from the control to the intervention arm was not investigated nor described, other than in the survey of participant behaviour
• In view of the low prevalence of COVID-19 infection (around 2%), there may have been a large number of false positive antibody tests if the true specificity of the finger prick antibody test was anything below 98%
  • Denmark had a mild first wave of COVID-19 and overall population infection rates during this period were likely significantly less than 2% of the population
• No statistical correction was made for the antibody test characteristics
• There were zero (0) confirmed PCR infections in the intervention arm. A PCR test is the gold standard for confirming the presence of SARS-CoV-2 infection
• No intention to treat analysis was performed. It is unclear what “did not finalise participation” meant and this exclusion mean that 1,000 participants did not complete the study
• Cafes and restaurants were closed in Denmark during most of the study period, so the impact of face masks in these at-risk settings was not assessed

The Bottom Line

• This randomised unblinded trial of mask wearing in a society without a mask mandate did not demonstrate a protective  effect of masks against SARS-CoV-2 infection
• The multiple methodological flaws in this study mean that it should not guide public health policy
• No interpretation can be made about the public health impact of face masks on source control of  SARS-CoV-2 infection, which is the main justification for their use

External Links

• [article] DANMASK-19
• [further reading] Face masks: what the data say
• [further reading] NEJM variolation article
• [further reading] REBELEM: the danmask-19 trial masks not effective to prevent covid-19 not so fast
• [further reading] SGEM#309: THAT’S ALL JOE ASKS OF YOU – WEAR A MASK

Metadata

Summary author: Fraser Magee
Summary date: 19/11/2020
Peer-review editor: Segun Olusanya