Description
you will write a paper
outlining the key considerations and questions that would have been reviewed by
the Research Ethics Board (REB) prior to providing approval for this study. The
paper should be a maximum of four (4) pages (not including title page and
references, as applicable). The formatting should be 12-point font, Times New
Roman and double-spaced. In the paper, you should address the following
questions: 1. What are the key ethical and/or safety considerations that would or
should have been carefully reviewed by the REB in relation to this
study prior to approval?
2. Do you feel that this study should have been approved by the
REB? If not, why and what additional information was needed that
may be missing from the study protocol overview provided? If you
feel that this study should have been approved based on the
journal article provided, please justify this with consideration given
to the key ethical and safety concerns.
3. Are there any changes to the study protocol that you would
recommend that would improve the ethics, safety and/or
comprehensiveness of the study? Notes: please write the paper as introduction, discussion, and conclusion. The journal article is attached. It is extremely important you stay within the four-page limit. Try to answer the question without using any other source just the journal article that is attached.
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ORIGINAL RESEARCH
Annals of Internal Medicine
Medical Masks Versus N95 Respirators for Preventing COVID-19
Among Health Care Workers
A Randomized Trial
Mark Loeb, MD; Amy Bartholomew, MScN; Madiha Hashmi, MD; Wadea Tarhuni, MD; Mohamed Hassany, MD;
Ilan Youngster, MD; Ranjani Somayaji, MD; Oscar Larios, MD; Joseph Kim, MD; Bayan Missaghi, MD;
Joseph V. Vayalumkal, MD; Dominik Mertz, MD; Zain Chagla, MD; Maureen Cividino, MD; Karim Ali, MD;
Sarah Mansour, MB BCh BAO; Lana A. Castellucci, MD; Charles Frenette, MD; Leighanne Parkes, MD; Mark Downing, MD;
Matthew Muller, MD, PhD; Verne Glavin, MD; Jennifer Newton, BSc; Ravi Hookoom, BASc; Jerome A. Leis, MD;
James Kinross, MD; Stephanie Smith, MD; Sayem Borhan, PhD; Pardeep Singh, BSc; Eleanor Pullenayegum, PhD; and
John Conly, MD
Background: It is uncertain if medical masks offer similar
protection against COVID-19 compared with N95 respirators.
Objective: To determine whether medical masks are noninferior to N95 respirators to prevent COVID-19 in health care
workers providing routine care.
Design: Multicenter, randomized, noninferiority trial. (ClinicalTrials.
gov: NCT04296643).
Setting: 29 health care facilities in Canada, Israel, Pakistan, and
Egypt from 4 May 2020 to 29 March 2022.
Participants: 1009 health care workers who provided direct
care to patients with suspected or confirmed COVID-19.
Intervention: Use of medical masks versus fit-tested N95
respirators for 10 weeks, plus universal masking, which was
the policy implemented at each site.
Measurements: The primary outcome was confirmed COVID-19
on reverse transcriptase polymerase chain reaction (RT-PCR)
test.
Results: In the intention-to-treat analysis, RT-PCR–confirmed
0.75 to 10.72]), 6 of 17 (35.29%) versus 4 of 17 (23.53%) in
Israel (HR, 1.54 [CI, 0.43 to 5.49]), 3 of 92 (3.26%) versus 2
of 94 (2.13%) in Pakistan (HR, 1.50 [CI, 0.25 to 8.98]), and 35
of 257 (13.62%) versus 38 of 261 (14.56%) in Egypt (HR,
0.95 [CI, 0.60 to 1.50]). There were 47 (10.8%) adverse
events related to the intervention reported in the medical
mask group and 59 (13.6%) in the N95 respirator group.
Limitation: Potential acquisition of SARS-CoV-2 through
household and community exposure, heterogeneity between
countries, uncertainty in the estimates of effect, differences
in self-reported adherence, differences in baseline antibodies, and between-country differences in circulating variants
and vaccination.
Conclusion: Among health care workers who provided routine care to patients with COVID-19, the overall estimates
rule out a doubling in hazard of RT-PCR–confirmed COVID-19
for medical masks when compared with HRs of RT-PCR–
confirmed COVID-19 for N95 respirators. The subgroup results
varied by country, and the overall estimates may not be applicable to individual countries because of treatment effect
heterogeneity.
COVID-19 occurred in 52 of 497 (10.46%) participants in the
medical mask group versus 47 of 507 (9.27%) in the N95
respirator group (hazard ratio [HR], 1.14 [95% CI, 0.77 to
1.69]). An unplanned subgroup analysis by country found
that in the medical mask group versus the N95 respirator
group RT-PCR–confirmed COVID-19 occurred in 8 of 131
(6.11%) versus 3 of 135 (2.22%) in Canada (HR, 2.83 [CI,
Primary Funding Source: Canadian Institutes of Health
Research, World Health Organization, and Juravinski Research
Institute.
H
There is concern that medical masks offer less protection because of their looser fit and that they do not filter as effectively, whereas N95 respirators are fit tested
and provide greater filtration (17). There were insufficient
supplies of N95 respirators globally during the pandemic, and currently there is a lack of access in low- and
middle-income countries because of the high costs (18).
ealth care workers use either medical masks, also
called surgical masks, or N95 respirators for the routine care of patients with COVID-19 as a component of
their personal protective equipment. Medical masks are
recommended by the World Health Organization for routine care (1, 2), whereas N95 respirators are recommended
by the Centers for Disease Control and Prevention for the
routine care of patients with COVID-19 (3–5).
It is uncertain if medical masks offer similar protection against COVID-19 compared with N95 respirators
(6). Observational studies report varied findings and are
limited by self-reported outcomes, potential recall bias,
and ecological analyses (7–14). Systematic reviews of
randomized trials and observational studies of other respiratory viruses suggest similar protection (15, 16).
Annals.org
Annals.org
Ann Intern Med. doi:10.7326/M22-1966
For author, article, and disclosure information, see end of text.
This article was published at Annals.org on 29 November 2022.
See also:
Editorial comment
Summary for Patients
Web-Only
Supplement
Annals of Internal Medicine
© 2022 American College of Physicians
1
ORIGINAL RESEARCH
One randomized controlled trial set in the community
reported a reduction of SARS-CoV-2 with medical masks
(19). It is important to determine the relative protection
of medical masks compared with N95 respirators.
We conducted an international pragmatic randomized
controlled trial where health care workers were randomly
assigned to either medical masks or N95 respirators when
providing routine care to patients with suspected or confirmed COVID-19. We hypothesized that medical masks
would be noninferior to N95 respirators.
METHODS
Trial Design and Oversight
This pragmatic, randomized, open-label, multicenter
trial initially aimed to assess whether medical masks
were noninferior to N95 respirators for protection
against COVID-19 among unvaccinated nurses providing routine care to patients with suspected or confirmed
COVID-19 (see the study protocol and statistical analysis
plan, available at Annals.org). The evolution of the pandemic led to protocol changes (Supplement, available at
Annals.org). Before trial commencement, in addition to
nurses, other health care workers were made eligible to
increase enrollment, and follow-up was reduced from 12
to 10 weeks to minimize loss to follow-up. As circulation
of SARS-CoV-2 increased, health care workers known to
have a previous laboratory-confirmed clinical diagnosis
of COVID-19 at the time of enrollment were excluded. As
vaccine rollout began, participants with receipt of 1 or
more doses of a COVID-19 vaccine with greater than
50% efficacy for the circulating strain (for example, messenger RNA [mRNA] or vector-based COVID-19 vaccine
against the original SARS-CoV-2 strain) were excluded,
and sites in Israel, Pakistan, and Egypt were added to
increase enrollment. Participants that received a single
dose of an mRNA or vector-based COVID-19 vaccine after enrollment (with an estimated >50% efficacy against
the circulating strain) were followed until 2 weeks after
their first dose and then censored. The variable followup time led to a change to a time-to-event analysis, and
a hazard ratio (HR) was used for the noninferiority
margin.
The trial enrolled participants in 29 health care facilities: 17 acute care hospitals in Canada, 4 acute care hospitals in Pakistan, 2 long-term care facilities in Israel (facilities
where trained medical staff are always available to assist
residents and where high-flow oxygen and medication via
inhalation could be administered), and 6 acute care hospitals in Egypt. The study was done from 4 May 2020 to 29
March 2022.
The trial was approved by the Hamilton Integrated
Research Ethics Board and the institutional review boards
at all participating institutions. All participants provided
written informed consent. The trial was restricted to health
care settings where the policy was to use medical masks
while providing routine care to patients with confirmed or
suspected COVID-19. A data monitoring committee provided oversight of safety considerations in the trial.
2 Annals of Internal Medicine
Medical Masks Versus N95 Respirators for COVID-19
Participants
Health care workers who provided direct care to
patients with suspected or confirmed COVID-19 in specialized COVID-19 units and in emergency departments,
medical units, pediatric units, and long-term care facilities were enrolled; intensive care units were not included
in the study. Health care workers were required to spend
60% or more of their time doing clinical work when
enrolled.
Health care workers were excluded if they did not
have a valid fit test within the past 24 months or could
not pass a fit test, had 1 or more high-risk comorbidities
for COVID-19 (hypertension, cardiac disease, pulmonary
disease, chronic kidney disease, diabetes, chronic liver
disease, actively treated cancer, or immunosuppression
due to illness or medications), had a previous laboratoryconfirmed clinical diagnosis of COVID-19 at the time of
enrollment, or had received 1 or more doses of a COVID-19
vaccine with greater than 50% efficacy for the circulating
strain (for example, mRNA or vector-based COVID-19
vaccine against the original SARS-CoV-2 strain).
Randomization and Blinding
Trial participants were randomly assigned (1:1) to either medical masks or N95 respirators. Participants were
randomly assigned centrally by a study statistician who
generated the sequence using a computerized random
number generator. Randomization was stratified by site
in permuted blocks of 4. The randomization scheme was
provided by an interactive web response system and performed centrally. Investigators were blinded to the group
assignment, but it was not possible to conceal the identity
of the medical mask or N95 respirator assignment to the
study staff or participants.
Interventions
Health care workers randomly assigned to the medical mask group were instructed to use the medical mask
when providing routine care to patients with COVID-19
or suspected COVID-19, which aligned with the current
policy in their setting. The ASTM International certified
masks were provided to the health care workers either
by their health care facility or by the study (Supplement
Table 1). As part of the trial protocol, health care workers
could also use the N95 respirator at any time based on a
point-of-care risk assessment.
Health care workers randomly assigned to the N95
respirator group were instructed to use a fit-tested National
Institute for Occupational Safety and Health–approved
N95 respirator when providing routine care to patients
with COVID-19 or suspected COVID-19. Participants
were required to use the type of device they were allocated to, either a medical mask or an N95 respirator, for
10 weeks.
The intervention included universal masking, which
was the policy implemented at each site. This refers to
the use of a mask when in the health care facility for all
activities, whether patient related or not, including in
workrooms, meetings, and treating persons that were
not suspected or known to be positive for COVID-19.
Participants were asked to report the extent to which
Annals.org
ORIGINAL RESEARCH
Medical Masks Versus N95 Respirators for COVID-19
Figure 1. Trial flow diagram.
Health care workers assessed
for eligibility (n = 1191)
Ineligible (n = 182)
Did not meet eligibility criteria: 124
Declined to participate: 58
Randomly assigned (n = 1009)
Censored mRNA vaccine (n = 37)
Withdrawn (n = 14)
Loss to follow-up: 8
Israel: 1
Egypt: 7
Withdrawn by participant: 4
Canada: 1
Egypt: 3
Other: 2
Canada: 1
Egypt: 1
Allocated to medical mask (n = 500)
Canada: 132
Israel: 17
Pakistan: 93
Egypt: 258
Allocated to N95 respirator (n = 509)
Canada: 136
Israel: 17
Pakistan: 94
Egypt: 262
Ineligible (n = 1)
Canada: 1
Withdrew before follow-up (n = 2)
Egypt: 1
Pakistan: 1
Ineligible (n = 1)
Egypt: 1
Withdrew before follow-up (n = 1)
Canada: 1
Included in the ITT analysis* (n = 497)
Canada: 131
Israel: 17
Pakistan: 92
Egypt: 257
Included in the ITT analysis* (n = 507)
Canada: 135
Israel: 17
Pakistan: 94
Egypt: 261
Censored mRNA vaccine (n = 37)
Withdrawn (n = 18)
Loss to follow-up: 7
Canada: 1
Israel: 2
Egypt: 4
Withdrawn by participant: 9
Canada: 6
Egypt: 3
Other: 2
Canada: 1
Egypt: 1
ITT = intention-to-treat; mRNA = messenger RNA.
* Dates of follow-up: Canada (May 2020 to May 2021), Israel (November 2020 to January 2021), Pakistan (June 2021 to December 2021), and Egypt
(December 2021 to March 2022).
they used the mask that they were assigned to on a
weekly basis—that is, “During your last work shift, to what
extent did you wear the mask you were assigned,” where
the possible responses were “Always,” “Sometimes,”
“Never,” or “Do not recall.” In both study groups, health
care workers were required to use the N95 respirator
for aerosol-generating medical procedures, as this was
in keeping with their institutional policies. In keeping
with local policies, eye protection, gowns, and gloves
were worn when caring for patients with suspected or
confirmed COVID-19. Participants were asked to discard the medical mask or N95 respirator if it became
soiled or damaged or if breathing through the device
became difficult. If the institutional policy was for extended
use and masks were not typically removed after a
patient encounter, the extended use procedure was
to be followed.
Outcomes
The primary outcome was time to reverse transcriptase polymerase chain reaction (RT-PCR)–confirmed
COVID-19. This was measured from the date of randomization until the date of procurement of a specimen that
was positive by RT-PCR. Follow-up continued until the
end of 10 weeks, until 2 weeks (1 incubation period) after
receipt of an mRNA vaccine, or until the date of a participant withdrawal from the trial. Laboratory personnel
doing COVID-19 testing were blind to treatment allocation. Testing was done at the health care facility laboratory using health care–administered nasopharyngeal
swabs. Sera from participants was obtained at baseline
Annals.org
and at the end of follow-up and then tested for spike IgG
antibodies and for nucleocapsid IgG antibodies using
EUROIMMUN assays.
Secondary outcomes included serologic evidence
of infection (done in participants who were seronegative at baseline and defined as a change from negative
EUROIMMUN spike IgG and nucleocapsid IgG antibodies
at baseline to positive nucleocapsid IgG antibody),
acute respiratory illness (defined by fever and cough),
work-related absenteeism, lower respiratory tract infection or pneumonia, intensive care admission, mechanical
ventilation, or death. Laboratory-confirmed infection was
defined as COVID-19 confirmed by RT-PCR in symptomatic
participants or seroconversion.
Participants were assessed for signs and symptoms
of COVID-19 through twice-weekly automated text messages. A nasopharyngeal swab was obtained if any one
the following symptoms or signs was present: fever (≥38 C),
cough, or shortness of breath, or if 2 of the following were
present: fatigue, myalgia, headache, dizziness, expectoration, sore throat, diarrhea, nausea, vomiting, abdominal
pain, runny nose, altered taste or smell, conjunctivitis, or
painful swallowing.
Adherence to the assigned medical mask or N95 respirator for routine care and to hand hygiene was measured using weekly self-reporting for all participants and
external monitoring wherever feasible. Audits were done
once at 3 hospitals in Pakistan and were repeated once at
2 of these hospitals within a 2-week period. They were
done at 6 hospitals in Egypt where they were repeated
twice at 2 hospitals and repeated once at 4 hospitals over
Annals of Internal Medicine
3
ORIGINAL RESEARCH
Medical Masks Versus N95 Respirators for COVID-19
Table. Participant Characteristics
Characteristic
Medical Mask (n = 497)
N95 Respirator (n = 507)
Mean age (SD) [range], y
Canada
Israel
Pakistan
Egypt
All sites
35.5 (10.0) [22–61]
29.5 (8.7) [23–58]
27.5 (5.7) [20–54]
36.9 (10.4) [19–59]
34.6 (10.2) [19–61]
36.5 (10.1) [20–69]
31.5 (8.9) [20–51]
26.8 (5.2) [20–45]
37.3 (11.5) [18–78]
34.9 (10.9) [18–78]
Female, n (%)
Canada
Israel
Pakistan
Egypt
All sites
109 (83.2)
13 (76.5)
47 (51.1)
192 (74.7)
361 (72.6)
105 (77.8)
9 (52.9)
47 (50.0)
177 (67.8)
338 (66.7)
96 (73.3)
25 (19.1)
6 (4.6)
4 (3.1)
111 (82.2)
17 (12.6)
4 (3.0)
3 (2.2)
13 (76.5)
0 (0)
0 (0)
4 (23.5)
7 (41.2)
1 (5.9)
0 (0)
9 (52.9)
84 (91.3)
3 (3.3)
0 (0)
5 (5.4)
84 (89.4)
5 (5.3)
0 (0)
5 (5.3)
86 (33.5)
10 (3.9)
119 (46.3)
42 (16.3)
87 (33.3)
9 (3.5)
122 (46.7)
43 (16.5)
279 (56.1)
38 (7.7)
125 (25.2)
55 (11.1)
289 (57.0)
32 (6.3)
126 (24.9)
60 (11.8)
97 (74.1)
34 (26.0)
0 (0)
107 (79.3)
28 (20.7)
0 (0)
0 (0)
0 (0)
17 (100)
0 (0)
0 (0)
17 (100)
71 (77.2)
21 (22.8)
0 (0)
69 (73.4)
25 (26.6)
0 (0)
239 (93.0)
18 (7.0)
0 (0)
243 (93.1)
18 (6.9)
0 (0)
407 (81.9)
73 (14.7)
17 (3.4)
419 (82.6)
71 (14.0)
17 (3.4)
131 (26.4)
17 (3.4)
92 (18.5)
257 (51.7)
135 (26.6)
17 (3.4)
94 (18.5)
261 (51.5)
Distribution by job type, n (%)
Canada
Nurse
Physician
Personal support worker
Allied health
Israel
Nurse
Physician
Personal support worker
Allied health
Pakistan
Nurse
Physician
Personal support worker
Allied health
Egypt
Nurse
Physician
Personal support worker
Allied health
All sites
Nurse
Physician
Personal support worker
Allied health
Distribution by unit type, n (%)
Canada
Acute care
Emergency department
Long-term care
Israel
Acute care
Emergency department
Long-term care
Pakistan
Acute care
Emergency department
Long-term care
Egypt
Acute care
Emergency department
Long-term care
All sites
Acute care
Emergency department
Long-term care
Distribution by region, n (%)
Canada
Israel
Pakistan
Egypt
Continued on following page
4 Annals of Internal Medicine
Annals.org
ORIGINAL RESEARCH
Medical Masks Versus N95 Respirators for COVID-19
Table–Continued
Characteristic
Medical Mask (n = 497)
N95 Respirator (n = 507)
Received vaccine with efficacy ≤50%, n (%)*
Canada
Israel
Pakistan
Egypt
All sites
0 (0)
0 (0)
70 (76.1)
127 (49.4)
197 (39.6)
0 (0)
0 (0)
74 (78.7)
137 (52.5)
211 (41.6)
Seropositivity at baseline, n/N (%)†
Canada
Israel
Pakistan
Egypt
All sites
3/129 (2.3)
2/16 (12.5)
72/92 (78.3)
209/256 (81.6)
286/493 (58.0)
2/128 (1.6)
2/15 (13.3)
82/94 (87.2)
210/261 (80.5)
296/498 (59.4)
* Sinopharm (China National Pharmaceutical Group) or Sinovac (Sinovac Biotech).
† Seropositivity was defined by a positive SARS-CoV-2 spike IgG antibody or nucleocapsid IgG antibody. Data were missing for 4 participants in the
medical mask group and 9 in the N95 respirator group.
a 4-week period. To conduct the audits of adherence to
the intervention (medical mask or N95 respirator), the
coordinating center randomly selected 20% of shifts at a
health care facility, and during these shifts, trial participants
were observed. Wearing an N95 respirator for aerosolgenerating procedures was not considered during the
observed audits. Reported exposures and potential exposures to COVID-19, including community and home exposure, hospital exposures, participation in aerosol-generating
procedures, and hospital outbreaks (as defined by the
health care facility) were measured. Participants were asked
to keep diaries of signs and symptoms of respiratory illness
and exposure to household and community members with
respiratory illness. Cycle threshold values from patients with
COVID-19, obtained while participants were on the same
study units as the patients, were used to estimate viral load
as a surrogate for exposure risk.
Statistical Analysis
The study was powered based on the primary outcome of RT-PCR–confirmed COVID-19. For a noninferiority HR of 2, a sample size of 875 participants provided
90% power at a 0.025 significance level for event rates of
10% and an actual HR of 1. The original design estimated
an event rate of 5% with a noninferiority margin of 5 percentage points (that is, up to a 10% event rate would be
considered noninferior). On changing the outcome from
10-week occurrence of RT-PCR–confirmed COVID-19 to
time to RT-PCR–confirmed COVID-19 so as to allow for
censoring due to vaccination, the original margin on the
absolute effect size corresponds to a relative effect size
(HR) of 2 (see the Supplement for earlier trial design
sample size calculations). A final sample size of 1010
accounted for participants who could not complete
10 weeks of follow-up because of administration of
mRNA vaccine as well as for withdrawals. Hazard
ratios and corresponding 2-sided 95% CIs were estimated using a Cox proportional hazards model stratifying by health care facility. The analysis fulfilled the
Schoenfeld residual test for the assumption of proportional hazards in Cox analysis. The cumulative incidence of RT-PCR–confirmed COVID-19 was estimated
using Kaplan–Meier methods.
Annals.org
Outcomes were analyzed on an intention-to-treat basis, defined by medical mask or N95 respirator assignment
and follow-up until 10 weeks or 2 weeks after the first
mRNA vaccine dose. Participants did not have to complete
10 weeks of follow-up to be included in the intention-totreat analysis. Censoring was assumed independent of
the randomized group assignment. No attempt was
made to impute missing postrandomization values, and
only observed values were used in the analysis. A post
hoc analysis of the primary outcome with participants
restricted to those seronegative at baseline was done
using a Cox proportional hazards model stratifying by
health care facility.
For serology and overall laboratory-confirmed infection, we conducted a logistic regression analysis adjusting for site to obtain odds ratios and 95% CIs. Although
subgroup analyses based on pre-Omicron variant versus
Omicron variant and by universal masking were planned
a priori, these analyses are not reported because of potential confounding of Omicron by country and because of the
mandatory policy of universal masking for all health care
facilities in the trial.
A post hoc subgroup analysis was done to compare
the effect of medical masks versus N95 respirators in participants with no reported exposure to household or community members with respiratory illness to those that reported
at least 1 such exposure. We also conducted an unplanned
subgroup analysis of the primary outcome by country. For
the safety analyses, the number and percentage of participants with an adverse event according to study group
are reported. For participant exposure to patients with
COVID-19 or exposure to patients with suspected COVID19, the number of exposures per week for up to 10 weeks
were counted and categorized (0, 1 to 5, 6 to 10, or ≥11
exposures). The number of exposure categories per 1000
participant-days was then calculated by country and study
group. Statistical analyses were done using R, version
4.2.0 (R Foundation for Statistical Computing).
Role of the Funding Source
The study was funded by the Canadian Institutes of
Health Research, World Health Organization, and Juravinski
Research Institute. The external funders of the study had no
Annals of Internal Medicine
5
ORIGINAL RESEARCH
Medical Masks Versus N95 Respirators for COVID-19
Figure 2. Forest plot of the primary intention-to-treat analysis of RT-PCR–confirmed COVID-19.
Primary Intention-to-Treat Analysis
RT-PCR–Confirmed COVID-19
Events, n/N (%)
N95 Respirator
HR (95% CI)
Medical Mask
Canada
8/131 (6.11)
3/135 (2.22)
2.83 (0.75–10.72)
Israel
6/17 (35.29)
4/17 (23.53)
1.54 (0.43–5.49)
Pakistan
3/92 (3.26)
2/94 (2.13)
1.50 (0.25–8.98)
Egypt
35/257 (13.62)
38/261 (14.56)
0.95 (0.60–1.50)
All sites
52/497 (10.46)
47/507 (9.27)
1.14 (0.77–1.69)
0
3
6
9
There were 86 of 8338 (1%) weekly surveys missing in the medical mask group and 65 of 8468 (0.8%) missing in the N95 respirator group. The subgroup analysis by country was added to show the heterogeneity of treatment effect. HR = hazard ratio; RT-PCR = reverse transcriptase polymerase chain
reaction.
role in study design, data collection, data analysis, or data
interpretation, or in writing this report.
RESULTS
Between 4 May 2020 and 12 January 2022, a total of
1191 health care workers were assessed for eligibility,
and 1009 were enrolled. There were 500 randomly
assigned to medical masks and 509 to the N95 respirator
(Figure 1). There were 268 participants from Canada, 34
from Israel, 187 from Pakistan, and 520 from Egypt. The
baseline characteristics were well balanced overall and
were similar within each country (Table). However, seropositivity at baseline varied by country, with few seropositive participants in Canada (2%) and a majority (81%)
seropositive in Egypt (Table). Overall, there were 185
(37.5%) participants in the medical group versus 185
(37.2%) in the N95 respirator group who were seronegative at baseline—that is, had no SARS-CoV-2 spike IgG or
nucleocapsid IgG antibodies at baseline.
Follow-up began on 4 May 2020 and ended on 29
March 2022. Participants were enrolled from 4 May 2020
to 22 May 2021 in Canada, from 11 November 2020 to
27 January 2021 in Israel, from 24 June 2021 to 18
December 2021 in Pakistan, and from 19 December 2021
to 29 March 2022 in Egypt. The mean duration of followup was similar between the 2 study groups—9.06 weeks in
the medical mask group and 9.03 weeks in the N95 respirator group. Five participants who were randomly assigned
but never followed were excluded from analysis—3 in the
medical mask group (1 was previously positive for COVID19 on RT-PCR and 2 withdrew) and 2 in the N95 respirator
group (1 was previously positive for COVID-19 on RT-PCR
and 1 withdrew) (Figure 1). Of the resulting 1004, followup was complete (that is, full 10 weeks or 14 days after first
vaccination) in 483 (97.1%) in the medical mask group and
489 (96.4%) in the N95 respirator group.
The primary outcome in the intention-to-treat analysis, RT-PCR–confirmed COVID-19, occurred in 52 of 497
(10.46%) in the medial mask group versus 47 of 507
(9.27%) in the N95 respirator group (HR, 1.14 [95% CI,
0.77 to 1.69]). The proportional hazards assumption was
tested for the primary outcome and was plausible. In an
6 Annals of Internal Medicine
unplanned subgroup analysis by country, we found that
in the medical mask group versus N95 respirator group,
RT-PCR–confirmed COVID-19 occurred in 8 of 131
(6.11%) versus 3 of 135 (2.22%) in Canada (HR, 2.83 [CI,
0.75 to 10.72]), 6 of 17 (35.29%) versus 4 of 17 (23.53%)
in Israel (HR, 1.54 [CI, 0.43 to 5.49]), 3 of 92 (3.26%) versus 2 of 94 (2.13%) in Pakistan (HR, 1.50 [CI, 0.25 to
8.98]), and 35 of 257 (13.62%) versus 38 of 261 (14.56%)
in Egypt (HR, 0.95 [CI, 0.60 to 1.50]) (Figure 2). The overall cumulative incidence is shown in Figure 3 and that by
country in Figure 4.
The secondary outcomes, which varied substantially
by country, are shown in Supplement Table 2. The sensitivity analysis for RT-PCR–confirmed COVID-19 in participants who were seronegative at baseline showed withincountry between-group HRs similar to those that include
all participants (Supplement Figure).
Pre-Omicron exposure occurred in Canada, Israel,
and Pakistan, whereas Omicron exposure occurred in
Egypt. This is based on dates of SARS-CoV-2 circulation
given that enrollment in Egypt began on 19 December
2021, whereas enrollment from other countries ended
earlier in the pandemic, with follow-up in Pakistan ending on 28 December 2021. The post hoc intention-totreat subgroup analysis of no reported household or
community exposure to respiratory illness (HR, 1.06 [CI,
0.53 to 2.11]) versus 1 or more reported household or
community exposure to respiratory illness (HR, 1.08
[CI, 0.66 to 1.78]) did not show heterogeneity of treatment effect based on a test of interaction (P = 0.96)
(Supplement Table 3).
There were 2 participants who had serious adverse
events in the medical mask group (both hospitalizations
for COVID-19, where 1 had confirmed pneumonia) and
1 participant in the N95 respirator group (hospitalization
for COVID-19 pneumonia). In addition, there were 3 participants (2 in the medical mask group and 1 in the N95
respirator group) who could not be safely isolated at
home and were hospitalized for isolation. There were no
intensive care admissions and no deaths. There were 47
(10.8%) adverse events related to the intervention reported
in the medical mask group and 59 (13.6%) in the N95 respirator group (Supplement Table 4). There was 1 participant
in the medical mask group and 3 in the N95 respirator
Annals.org
ORIGINAL RESEARCH
Medical Masks Versus N95 Respirators for COVID-19
DISCUSSION
Among health care workers who took care of patients
with suspected or confirmed COVID-19, although the
upper limit of the CIs of the pooled estimate for medical
masks when compared with N95 respirators for preventing
RT-PCR–confirmed COVID-19 was within the noninferiority
margin of 2, this margin was wide, and firm conclusions
about noninferiority may not be applicable given the
between-country heterogeneity.
The heterogeneity in the RT-PCR positivity rate, as
well as the heterogeneity in baseline seropositivity by
country, may be explained by many factors. Enrollment
in Canada occurred early in the pandemic in acute health
care facilities. In contrast, in Israel, the study was done in
long-term care facilities that had substantial outbreaks.
Later in the pandemic, enrollment occurred in Pakistan
and Egypt, countries with a high population density,
where seropositivity in participants due to previous exposure to SARS CoV-2 and receipt of vaccine was more
common. Circulation of Omicron may have been a contributing factor to the high rates of RT-PCR–confirmed
COVID-19 in Egypt.
The observed results are consistent with a range of
protection, from a 23% reduction in the HR with medical
masks to a 69% risk increase. The relative protection of
medical masks compared with N95 respirators varied by
country. However, this finding does not seem to be
explained by differences in baseline seropositivity given
that a post hoc analysis of the effect of medical masks
versus N95 respirators on RT-PCR–confirmed COVID-19
Annals.org
Figure 3. Cumulative incidence of primary analysis of RT-PCR–
confirmed COVID-19.
0.15
Cumulative Hazard
group who withdrew because of discomfort or adverse
events related to the device they were assigned.
Exposure to patients with confirmed or suspected
COVID-19, minutes of exposure to patients with COVID-19,
aerosol-generating procedures, and community exposures
were similar between study groups (Supplement Tables 5
to 9). Mean cycle threshold values of patients positive for
COVID-19 were less than 30 in 84% of the 25 study units
where these data were collected (Supplement Table 10).
Ventilation in the study varied by location (Supplement
Table 11). Outbreaks of COVD-19 were reported in 5 of 29
(17%) study units in Canada, in both long-term care facilities in Israel, and in all 6 acute care hospitals in Egypt
(Supplement Table 12).
Adherence with the assigned medical mask or N95
respirator was self-reported as “always” in 91.2% in the
medical mask group versus 80.7% in the N95 respirator
group and as “always” or “sometimes” in 97.7% in the
medical mask group versus 94.4% in the N95 respirator
group (Supplement Table 13). Of 118 participants
observed in the medical mask group, 116 (98.3%) were
reported by monitors to be adherent to their assigned
mask—14 (100%) in Pakistan and 102 (98%) in Egypt. Of
117 observed in the N95 respirator group, 113 (96.6%)
were reported to be adherent—8 (80%) in Pakistan and
105 (98%) in Egypt (Supplement Table 14). Self-reported
rates of adherence to hand hygiene, eye protection, use
of gowns, and use of gloves were similar between study
groups (Supplement Table 13).
Medical mask
N95 respirator
0.10
0.05
0.00
0
8
16
24
32 40
Time, d
48
56
64
72
At risk, n
Medical mask 497 493 480 460 438 427 416 400 392 383
N95 respirator 507 500 491 469 440 430 419 408 401 390
RT-PCR = reverse transcriptase polymerase chain reaction.
that was restricted to participants seronegative at baseline
led to similar within-country point estimates compared
with analyses that included the seropositive participants.
Point estimates of the HRs for medical masks versus
N95 respirators for both Israel and Pakistan were similar
(HRs of 1.54 and 1.50). For Canada, the point estimate of
2.83 is suggestive of an increased risk with the medical
mask, however, the absolute number of events is small. It
is unclear whether lower COVID-19 rates in that setting,
reducing the possibility of participants acquiring COVID19 in the community, made such an effect more apparent. However, a post hoc subgroup analysis that compared
participants with no reported household or community illness exposures to those that reported at least 1 exposure
showed no heterogeneity in treatment effect and very similar effect sizes for both subgroups.
It is notable that there was a close to null effect of
medical masks compared with N95 respirators in Egypt,
where Omicron was circulating, and from where over
half
