We present results of a cluster randomised trial on the effectiveness of facemasks and hand hygiene in preventing household transmission of influenza. The trial was conducted in Berlin during the first two seasons after the onset of the influenza A (H1N1)pdm09 pandemic.
In primary intention-to-treat analysis of all data, the interventions did not lead to statistically significant reductions of SAR in household contacts. However, in a secondary analysis among households with full implementation of the intervention within 36 h after symptom onset, the combined participants from M and MH groups had a significantly lower chance of influenza infection compared to controls. With one exception (MH households in 2010/11), we observed a non-significant, but consistent and substantial reduction of the OR for influenza infection in both intervention groups (M, MH) and for both case definitions (laboratory confirmed and clinical).
A per-protocol analysis showed comparable results of lowered influenza transmission in the intervention groups which were statistically significant in the M group when analysing the complete dataset, and - among A (H1N1) pdm09 households - in the combined analysis of the M and MH groups. The main drawback of the study was that we did not reach the number of households that we had aimed and planned for, one of the reasons being the at best moderate influenza season 2010/11. Our sample size calculation was based on a 75% reduction of risk due to the interventions. This may seem questionably high in comparison to other studies, however based on experience from our pilot study we felt that adherence would be better than reported in the Hong Kong  and Bangkok  studies. We therefore expected a larger effect size in our main study.
The reason for the high SAR of 25% in MH households from the 2010/11 season (with 35% the SAR was even higher when only households with Influenza-B positive index patients were considered) remains unclear. However, we hypothesize that the particularly low adherence of MH index patients to both interventions during the 2010/11 season might have influenced this observation.
The fact that we observed a significant effect of the combined M and MH intervention only after restriction of analysis to households with early (< 36 h after symptom onset) implementation of the interventions is in agreement with Cowling et al. who had investigated a hand hygiene intervention as well as hand hygiene plus facemask use . The importance of early implementation of any intervention is plausible given high levels of viral shedding during the initial period of influenza infection  as well as the short incubation period . Recently, Donnelly et al. quantified the probability of a transmission event by an infectious person relative to the onset of symptoms  and showed that peak transmission occurred on days 1, 2 and 3 of the infectious patient's illness. Merely 18% of transmission events took place more than two days after symptom onset of the index patient.
An Australian cluster-randomized household study conducted in a pre-pandemic winter season investigated the effect of the use of facemasks (surgical, or N95) on the risk of respiratory infections with all index cases being children and having an influenza-like illness of any, even unknown, etiology . Intention-to-treat analysis did not yield significant results, however, good adherence to facemask use proved to be significantly protective in a per-protocol analysis.
Two further cluster-randomized household studies failed to see any significant effects of intervention measures (facemasks or hand hygiene) even in secondary analyses. A French study investigated the efficacy of facemasks in the pre-pandemic influenza season 2008/09 . Although a planned second season was not followed through due to the onset of the influenza A (H1N1)pdm09 pandemic, reported SAR after the first season were quite similar in intervention and control groups. Adherence was reported to be good, but only a clinical case definition (ILI) was used for secondary cases, thus probably missing a- and oligosymptomatic secondary cases. Only index patients were supposed to wear the masks, and mean age of index patients in the intervention arm was 25 years. Since young children and infants may play a more important role in the (household) transmission of influenza [23–25], it is possible that these factors may have led to a cumulative underestimation of the real effect of facemasks.
The second study failing to see an effect of NPI in the household setting comes from Bangkok, Thailand and was conducted between April 2008 and August 2009 . Interventions tested were facemasks combined with handwashing, and handwashing alone. Although study size was large corresponding to high statistical power, the fact that 90% of index patients slept in the same bedroom as their parents without wearing facemasks during the night may have overcome any protective effect conferred by the interventions during daytime. In addition, authors describe a considerable amount of contamination between intervention groups, which may have further concealed true effects of the interventions.
In our study adherence to both interventions was good. After full implementation of the interventions approximately 50% of M and MH participants (index and contacts) wore facemasks "mostly" or "always" during the daytime in situations as required by the study protocol, and MH participants disinfected their hands approximately 7-8 times per day; only MH index cases in 2010/11 had lower adherence values for both interventions. Comparison with other studies is difficult for a number of reasons, particularly because interventions differed. Cowling  defined facemask adherence similar to the present study and reported similar facemask adherence in index cases (49%), but worse in household contacts (26%). Adherence to wearing facemasks in the Canini  study can be compared to our study for 2010/11, because the number of facemasks used per day was measured only in this season. The results were comparable in both studies.
Hand hygiene was part of the trial design only in the Simmermann  and Cowling studies . MH index patients in our study disinfected their hands between 4.1 (2010/11) and 7.4 times (2009/10) per day, the index patients in the Simmerman study washed their hands 4.1 times per day. Adherence to hand disinfection by index patients over the course of the study (adherence definition 2) ranged between 9% (2010/11) and 47% (2009/10) in our trial, compared to Cowling et al. with 33% and 36% in the two groups assigned hand hygiene interventions. Among household contacts in the MH group of our study adherence was higher in every parameter measured compared to Simmerman et al. and Cowling et al.. Considering that facemask and perhaps also disinfectant use in household settings may be much less accepted in European compared to Asian countries , the high overall adherence of both interventions in our study is remarkable. However, adherence data in all studies were based on self reporting and differences in reporting behaviour may have influenced results.
Compared to 2010/11 adherence may have been higher during the pandemic season 2009/10, but differences were not statistically significant. Increased use of or willingness to use preventive measures, such as facemasks or hand hygiene, was also documented during the SARS epidemic as well as during the pandemic influenza A (H1N1)pdm09 [27–29]. As we reported previously , adherence was good in adults and children alike, and although difficulties with facemasks were more frequently reported by children compared to adults, the numbers were not high. One notable exception with considerably lower adherence in 2010/11 compared to 2009/10 was observed in index patients of the MH group. Because physical interventions used by infected children may have the largest effect on the reduction of spread  and most index cases were children, it is possible that their reduced adherence has negatively affected transmission rates in MH households resulting in higher SAR in this intervention group in 2010/11.
In general, we believe that our data for adherence and tolerability would support a recommendation to use non-pharmaceutical interventions in a pandemic.
Several limitations may have influenced the results of this study. As in all previous studies on this subject, our study design resulted in delays between symptom onset of the index patients and implementation of the intervention. This delay could be as long as 3 days in some households during the 2010/11 season. Although we tried to address this problem by calling the households for preliminary instructions directly after enrolment at their physicians' office, this does not substitute for a personal visit with a demonstration of the intervention in the household. This may have led to an underestimation of the true effect of the interventions.
A further limitation of our study is that we cannot determine whether a possible protective effect of wearing facemasks is more attributable to their use by index patients or by household contacts (or both), nor can we say if intensified hand hygiene provides any additional protection. Regarding the first question, there are data from a Dutch experimental study suggesting that the use of masks may be more effective for inward than for outward protection which would favour the importance of healthy persons wearing them . This is in line with the results of the French trial  which stated in its protocol that facemasks were only to be worn by index patients and which could not show any significant protective effect in this setting. Regarding the role of hand hygiene, existing data from clinical trials are inconclusive. The study from Thailand found no effect, neither for facemasks nor for hand hygiene . In the analysis of households where the intervention was applied within 36 h the Hong Kong study saw a (non-significant) effect of hand hygiene alone which became stronger and significant in the MH arm . The investigators of a study among university students observed comparable reductions in ILI both in the facemask only as well as the facemasks plus hand hygiene groups suggesting that the addition of a hand sanitizer did not increase the effect of facemasks, or at least not substantially . Nevertheless, a recent Cochrane review on the subject came to the conclusion that hand hygiene is generally effective in reducing the spread of respiratory viruses .
A further limitation is the fact that laboratory testing of household contacts was only conducted for the virus subtype the index patient was infected with. This could have led to an underestimation of secondary cases.
Finally, we cannot rule out the possibility that behaviour of participating households may have been influenced by monetary incentives and frequent household visits. However, they did not differ in all three study arms so we do not expect this to have biased our results. Furthermore, the other clinical trials had a similar design so that it should not endanger comparability of results.
The strengths of this study include laboratory confirmation of primary and secondary cases with qRT-PCR, the serial testing of all household members over the study period irrespective of respiratory symptoms, and the low degree of contamination between the intervention groups.