Randomization and Intervention

Figure 1

Figure 1. . . Flow diagram of recruitment for the prospective cluster-randomized trial, Sydney, New South Wales, Australia, 2006 and 2007 winter influenza seasons.

Participating households were randomized to 1 of 3 arms by a secure computerized randomization process: 1) surgical masks (3M surgical mask, catalogue no. 1820; St. Paul, MN, USA) for 2 adults, to be worn at all times when in the same room as the index child, regardless of the distance from the child; 2) P2 masks (3M flat-fold P2 mask, catalogue no. 9320; Bracknell, Berkshire, UK), for 2 adults, to be worn at all times when in the same room as the index child, regardless of the distance from the child; and 3) a control group (no masks used). The P2 masks used have an almost identical specification as N95 masks used in the United States (19). According to New South Wales Health guidelines, pamphlets about infection control were provided to participants in all arms. Study participants and trial staff were not blinded, as it is not technically possible to blind the mask type to which participants were randomized. However, laboratory staff were blinded to the arm of randomization. Figure 1 shows the flow diagram for the trial as suggested by CONSORT guidelines (20).

Recruitment and Follow-up

Children 0–15 years of age seeking treatment at pediatric health services with fever (temperature >37.8^oC) and either cough or sore throat were identified by an electronic triage system. Parents or primary caregivers were approached in the waiting room, and that household was invited to join the study if all of the following criteria were satisfied: 1) the household contained >2 adults >16 years of age and 1 child 0–15 years of age; 2) the index child had fever (temperature >37.8^oC) and either a cough or sore throat; 3) the child was the first and only person to become ill in the family in the previous 2 weeks; 4) adult caregivers consented to participate in the study; and 5) the index child was not admitted to the hospital.

If eligibility criteria were satisfied, adults from the household were enrolled in the study. Enrolled adults and any siblings of the index child were then evaluated for respiratory symptoms and signs (fever, history of fever or feeling feverish in the past week, myalgia, arthralgia, sore throat, cough, sneezing, runny nose, nasal congestion, headache). If any of these symptoms were present, the family and household were excluded. Sociodemographic and medical information including influenza vaccination history (both the index child and participating adults) was obtained using a researcher-administered questionnaire. Medication use was also recorded. The index case-patient had combined nasal (each nostril) and throat swabs collected for multiplex reverse transcription–PCR (RT-PCR) testing. The household was randomized to 1 of the 3 arms, allocated the appropriate mask type, and educated about infection prevention. Formal fit testing of the P2 masks was not performed, but information pertaining to the correct method for fitting and disposing of the masks was provided. Over the next week, participants were contacted by telephone daily to determine if symptoms had developed and to record adherence to mask use throughout the day.

Each household was supplied with a thermometer to measure the temperature of symptomatic adult participants twice daily. If study staff determined that a participant had developed respiratory disease symptoms at follow-up, a home visit was conducted on the same day and the participant was swabbed and tested for respiratory viruses (see methods described below). Symptomatic participants were then followed up daily for 2 weeks.

Because all respiratory pathogens share similar transmission mechanisms—aerosol, droplet, and fomite spread (although the relative role of these factors may vary among different viruses and in different clinical situations)—we deliberately considered a broad definition of clinical cases consistent with a wide range of common respiratory viruses. Respiratory viruses detected in the study included influenza A and B, respiratory syncytial virus (RSV), adenovirus, parainfluenza viruses (PIV) types 1–3, coronaviruses 229E and OC43, human metapneumovirus (hMPV), enteroviruses, and rhinoviruses.

Adherence to face mask use was specifically monitored during each household follow-up. Measuring adherence and reasons for nonadherence is critical for evaluating the efficacy of mask use for reducing treatment and for providing practical advice on future use of face masks. Exit interviews with participants in the surgical mask and the P2 mask arms were conducted to gain further insights into adherence.

Sample Collection and Laboratory Testing

Rayon-tipped, plastic-shafted swabs were inserted separately into each participant’s nostrils and pharynx, placed into viral transport media, and transported immediately to the laboratory or stored at 4^oC if transport was delayed. Nose and throat swabs of index children and adult participants with symptoms of respiratory illness were tested by using nucleic acid and a series of multiplex RT-PCR tests (21) to detect influenza A and B and RSV, PIV types 1–3, picornaviruses (enteroviruses or rhinoviruses), adenoviruses, coronaviruses 229E and OC43, and hMPV.

Case Definition

To include the broadest possible spectrum of clinical syndromes occurring among enrolled adults (22), during follow-up we defined ILI by the presence of fever (temperature >37.8°C), feeling feverish or a history of fever, >2 symptoms (sore throat, cough, sneezing, runny nose, nasal congestion, headache), or 1 of the symptoms listed plus laboratory confirmation of respiratory viral infection. The choice of a relatively broad clinical case definition was dictated by our interest in interrupting transmission of a broad range of respiratory viruses. Laboratory-confirmed cases during the follow-up were defined by the presence of >1 of the symptoms listed above plus laboratory detection of a respiratory virus.

Study Outcomes and Analysis

The primary study outcomes in enrolled adults were the presence of ILI or a laboratory diagnosis of respiratory virus infection within 1 week of enrollment. Given that we demonstrated some dual infections and that there may be a variable sensitivity of RT-PCR for different respiratory viruses, we included all incident infections in adults (by clinical case definition and laboratory testing) in the analysis. We also measured the time from recruitment to infection. Causal linking of the outcomes of ILI and adherence to use of face masks required consideration of the timing of both.

Analysis of primary outcomes was by intention to treat. We performed a multivariate Cox proportional-hazards survival analysis to study secondary outcomes and determine how time lag from recruitment to infection of a secondary case-patient was affected by explanatory covariates (23). Gaussian random effects were incorporated in the model to account for the natural clustering of persons in households (24). The day of infection was reconstructed from the day of symptom onset under the assumption that the incubation period was 1–2 days. To account for exposures that occurred before recruitment, the time when survival analysis started was defined as the maximum value between the day of recruitment minus the incubation period and the start of illness in the index case. (For example, assume a household recruited on day 0 and an incubation period of 2 days. If illness in the index case began on day –3, then the survival analysis began on day –2; if illness in the index case began on day –1, then the survival analysis began the same day.)

The following variables were included in the models: daily adherence to use of P2 or surgical masks, number of adults in the household, number of siblings in the household, and index case <5 years of age. This analysis was performed using the survival package of the statistical software R (www.r-project.org). Comparisons among groups were made with the Fisher exact test for categorical variables. A 2-sided p value <0.05 was considered significant.

Power Analysis

Assuming a secondary attack rate in exposed adults of 20% and an intraclass correlation coefficient of 30%, we estimated that 94 adults would be needed in each arm of the study to show efficacy of >75% of P2 or surgical masks at 80% power and with a p value of 0.05. Our efficacy estimate was a conservative assumption based on observational data for the combined effects of all mask types during the SARS epidemic in Hong Kong (25).

Study Population

We recruited 290 adults from 145 families; 47 households (94 enrolled adults and 180 children) were randomized to the surgical mask group, 46 (92 enrolled adults and 172 children) to the P2 mask group, and 52 (104 enrolled adults and 192 children) to the no-mask (control) group. Two families in the control group were lost to follow-up during the study. Characteristics of the families who participated are shown in Table 1, with no significant differences noted among the 3 arms.

Samples were collected from 141 children; respiratory viruses were detected in 90 (63.8%) children. In 79 (56.0%) of 141 cases, a single pathogen was detected: influenza A in 19/141 (13.5%); influenza B in 7/141 (4.9%); adenoviruses in 7/141 (4.9%); RSV in 5/141 (3.5%); PIV in 8/141 (5.5%) (PIV-1 in 1/141 [0.70%]; PIV-2 in 2/141 [1.4%]; PIV-3 in 5/141 [3.5%]); hMPV in 8/141 (5.7%); and coronavirus OC43 in 3/141 (2.1%). Other viruses detected included picornaviruses in 22/141 (15.6%): rhinoviruses in 11/22 (50.0%); enteroviruses in 5/22 (22.7%) (enterovirus 68 in 1/5 [20.0%] and others in 4/5 [80.0%]); and uncharacterized nonsequenced picornaviruses in 6/22 (27.0%). An additional 11 children (7.8%) had dual or co-infection: 4 (2.8%) with adenovirus and rhinovirus, 2 (1.4%) with rhinovirus and coronavirus; and 1 each with influenza A and enterovirus, influenza A and PIV-2, influenza A and rhinovirus, RSV and enterovirus, and adenovirus and hMPV.

Adherence

Figure 2

Figure 2. . . Compliance with mask use by day over 5 consecutive days during the study, Sydney, New South Wales, Australia, 2006 and 2007 winter influenza seasons.

Characteristics of the adherent versus nonadherent participants who were recruited are shown in Table 2; no significant differences were noted between the 2 groups except for the presence of >3 adults in the household. On day 1 of mask use, 36 (38%) of the 94 surgical mask users and 42 (46%) of the 92 P2 mask users stated that they were wearing the mask “most or all” of the time. Other participants were wearing face masks rarely or never. The difference between the groups was not significant (p = 0.37). Adherence dropped to 29/94 (31%) and 23/92 (25%), respectively, by day 5 of mask use (Figure 2).

Table 3 shows reported problems with mask use. There were no significant differences in difficulties with mask use between the P2 and surgical mask groups, but >50% reported concerns, the main one being that wearing a face mask was uncomfortable. Other concerns were that the child did not want the parent wearing a mask and the parent forgot to wear the mask. Additional comments made by some included that the mask did not fit well and that it was not practical to wear at meal time or while asleep. Some adults wore the mask during the day but not at night, even though the sick child was sleeping beside them in their bed.

Intention-to-Treat Analysis

ILI was reported in 21/94 (22.3%) in the surgical group, 14/92 (15.2%) in the P2 group, and 16/100 (16.0%) in the control group, respectively. Samples were collected from 43/51 (84%) sick adults, with respiratory viruses isolated in 17/43 (40%) sick adults. Viral pathogens were isolated from 6/94 (6.4%) in the surgical mask group, 8/92 (8.7%) in the P2 group, and 3/100 (3.0%) in the control group. In 10/17 laboratory-positive cases, the same respiratory virus was isolated in the adult and the child (surgical, 3/94; P2 group, 5/92; and control, 2/100). In 2 cases, the adult was the only person with a laboratory-confirmed virus (1 each from the P2 and surgical groups); in the remaining 5 adults, the virus detected in the child differed from that in the adult (surgical, 2; P2 group, 2; and control group, 1). No dual infections were detected in the adults. Intention-to-treat analysis by households and by participants showed no significant difference between the groups (Table 4).

Risk Factors for ILI

Under the assumption that the incubation period is equal to 1 day (the most probable value for the 2 most common viruses isolated, influenza [21] and rhinovirus [26]), adherent use of P2 or surgical masks significantly reduces the risk for ILI infection, with a hazard ratio equal to 0.26 (95% CI [confidence interval] 0.09–0.77; p = 0.015). No other covariate was significant. Under the less likely assumption that the incubation period is equal to 2 days, the quantified effect of complying with P2 or surgical mask use remains strong, although borderline significant; hazard ratio was 0.32 (95% CI 0.11–0.98; p = 0.046). The study was underpowered to determine if there was a difference in efficacy between P2 and surgical masks (Table 5).