Calvin K. Y. Cheng

Facemasks and Hand Hygiene to Prevent Influenza Transmission in Households: A Cluster Randomized Trial

Context Hand hygiene and use of facemasks are key elements of influenza pandemic preparedness plans, but their effects on preventing transmission of infection have not been demonstrated. Contribution In this cluster randomized trial, hand washing and facemasks seemed to prevent influenza transmission when healthy family members started using these measures within 36 hours of symptom onset in an infected family member. Caution Adherence to the interventions was low. Implication Hand hygiene and facemasks seem to reduce influenza virus transmission when implemented early after symptom onset. The Editors Interpandemic human influenza virus infects millions of people every year. Some infections are mild, but othersespecially in young or elderly personscan result in more severe illness requiring hospitalization. Influenza is associated with hundreds of thousands of deaths worldwide annually (1, 2). The 2009 swine-origin influenza A (H1N1) pandemic highlighted the importance of identifying public health measures to mitigate influenza virus transmission. Many countries would use nonpharmaceutical interventions, including facemasks, improved hand hygiene, cough etiquette, isolation of sick and quarantine of exposed individuals, social distancing measures, and travel restrictions, as their primary means to mitigate an influenza pandemic, particularly at its beginning (310). However, data are scarce on the effectiveness of simple personal protective measures, such as facemasks and hand hygiene, against pandemic or interpandemic influenza and on the modes of influenza virus transmission among people (5, 11). After a pilot study in 2007 (12), we conducted a prospective cluster randomized trial to test whether improved hand hygiene or surgical facemasks reduce the transmission of interpandemic influenza in households. We used a cluster design with randomization to interventions at the household level to avoid difficulties in blinding and potential contamination of interventions. Methods Design From 45 outpatient clinics in the private and public sectors across Hong Kong, we enrolled persons who reported at least 2 symptoms of acute respiratory illness (temperature37.8C, cough, headache, sore throat, or myalgia); had symptom onset within 48 hours; and lived in a household with at least 2 other people, none of whom had reported acute respiratory illness in the preceding 14 days. After participants gave informed consent, they provided nasal and throat swab specimens, which were combined and tested with the QuickVue Influenza A+B rapid diagnostic test (Quidel, San Diego, California). Participants with a positive rapid test result and their household contacts were randomly assigned to 1 of 3 study groups: control (lifestyle measures), control plus enhanced hand hygiene only, and control plus facemasks and enhanced hand hygiene. Table 1 provides detailed descriptions of the interventions. Data on clinical signs and symptoms were collected for all participants. An additional nasal and throat swab specimen was collected for laboratory confirmation of influenza virus infection by reverse-transcription polymerase chain reaction (RT-PCR). Table 1. Study Interventions Randomization lists were prepared by a biostatistician. The households of eligible study index patients were allocated to 3 groups in a 1:1:1 ratio under a block randomization structure with randomly permuted block sizes of 18, 24, and 30 by using a random-number generator (R software, R Development Core Team, Vienna, Austria). Interventions were assigned to households by the study manager on the basis of the randomization sequence. The allocation to specific intervention groups was concealed to recruiting physicians and clinics throughout the study. Participants and people who administered the interventions were not blinded to the interventions, but participants were not informed of the specific nature of the interventions applied to other participating households. After randomization, a home visit was scheduled within 2 days (ideally within 12 hours) to implement the intervention and to collect informed consent, baseline demographic data, and nasal and throat swab specimens from all household members 2 years of age or older. During the home visit, index patients and household contacts were instructed in the proper use of a tympanic thermometer. During the 6 days after the initial home visit, all household contacts were asked to keep daily symptom diaries. Further home visits were scheduled around 3 and 6 days after the baseline household visit to monitor adherence to interventions and to collect further nasal and throat swab specimens from all household members regardless of illness. During the final home visit, study nurses collected and reviewed symptom diaries, and they evaluated adherence to interventions by interview and by counting the number of surgical masks remaining and weighing the amount of soap and alcohol left in bottles and dispensers. Households were reimbursed for their participation with a supermarket coupon worth approximately U.S.

Viral Shedding and Clinical Illness in Naturally Acquired Influenza Virus Infections

25. All participants 18 years or older gave written informed consent. Proxy written consent from parents or legal guardians was obtained for persons 17 years or younger, with additional written assent from those 8 to 17 years of age. The study protocol was approved by the institutional review board of The University of Hong Kong and the Hospital Authority Hong Kong West Cluster. Outcome Measures The primary outcome measure was the secondary attack ratio at the individual level: the proportion of household contacts infected with influenza virus. We evaluated the secondary attack ratio by using a laboratory definition (a household contact with a nasal and throat swab specimen positive for influenza by RT-PCR) as the primary analysis and 2 clinical definitions of influenza based on self-reported data from the symptom diaries as secondary analyses (12). The first definition of clinical influenza was at least 2 of the following signs and symptoms: temperature 37.8C or greater, cough, headache, sore throat, and myalgia (13); the second was temperature 37.8C or greater plus cough or sore throat (14). An additional secondary outcome measure was the secondary attack ratio at the household (cluster) level: the proportion of households with 1 or more secondary case. Laboratory Methods Specimens collected from index patients at recruitment were stored in a refrigerator at 2 to 8C. Specimens collected during home visits were stored in an ice chest with at least 2 ice packs immediately after collection. Before the end of the day of a home visit, study nurses obtained samples to the nearest collection point for storage in a refrigerator at 2 to 8C. Samples stored at 2 to 8C in ice chests were delivered to the central testing laboratory at Queen Mary Hospital by courier. Samples were eluted and cryopreserved at 70C immediately after receipt. All specimens were tested by RT-PCR for influenza A and B viruses using standard methods (1517). The Appendix provides additional details of the laboratory procedures that we used. Statistical Analysis On the basis of data collected in our pilot study (12) and other studies with similar design (18, 19), we assumed that 10% to 15% of household contacts in the control group would develop RT-PCRconfirmed influenza, with an average household size of 3.8 and an intracluster correlation coefficient of 0.29. Specifying 80% power and a significance level of 5%, we aimed to follow 300 households in each intervention group to allow us to detect differences in secondary attack ratios of 35% to 45%, depending on the actual secondary attack ratios in the control group (15% or 10%, respectively). Recruiting 100 or 200 households to each group would allow 80% power to detect 55% to 70% and 45% to 55% differences in secondary attack ratios, assuming a secondary attack ratio of 10% to 15% in the control group. To evaluate and compare secondary attack ratios by intervention group, we estimated 95% CIs by using a cluster bootstrap technique with 1000 resamples (20) and chi-square tests and multivariable logistic regression models adjusting for potential within-household correlation (21, 22). We estimated the intracluster correlation coefficient from the mean squared errors in the secondary attack ratio between and within households (21). For the multivariable logistic regression models, we used forced-entry methods to include plausible confounders, including the intervention allocated, the age and sex of the household contacts and their corresponding index patients, vaccination status of the household contacts, and antiviral use in corresponding index patients, whereas missing data on the exact age of 14 household contacts were imputed by comparison with their relationship with the index patient or occupation. Participants were analyzed in the group to which they were randomly assigned, regardless of adherence to the intervention or use of hand washing or facemasks in groups not assigned that intervention. Our protocol specified that households with more than 1 member with RT-PCRconfirmed influenza virus infection at baseline (coindex patients) or index patients in whom influenza virus infection could not be confirmed by RT-PCR would be excluded from analyses. We excluded from analyses participants who dropped out before receiving the intervention and the few participants who dropped out after the intervention but before data on the primary outcome measure were collected (23). In sensitivity analyses, we analyzed all households in which the intervention was applied, using multiple imputation for unobserved outcomes (24) and including an additional explanatory variable for households with more than 1 index patient. Statistical analyses were conducted in R, version 2.7.1 (R Development Core Team). Role of the Funding Source The study was funded by the Centers for Disease Control and Prevention; the Research Fund for the

Protective Efficacy of Seasonal Influenza Vaccination against Seasonal and Pandemic Influenza Virus Infection during 2009 in Hong Kong

Abstract Background. Volunteer challenge studies have provided detailed data on viral shedding from the respiratory tract before and through the course of experimental influenza virus infection. There are no comparable quantitative data to our knowledge on naturally acquired infections. Methods. In a community-based study in Hong Kong in 2008, we followed up initially healthy individuals to quantify trends in viral shedding on the basis of cultures and reverse-transcription polymerase chain reaction (RT-PCR) through the course of illness associated with seasonal influenza A and B virus infection. Results. Trends in symptom scores more closely matched changes in molecular viral loads measured with RT-PCR for influenza A than for influenza B. For influenza A virus infections, the replicating viral loads determined with cultures decreased to undetectable levels earlier after illness onset than did molecular viral loads. Most viral shedding occurred during the first 2–3 days after illness onset, and we estimated that 1%–8% of infectiousness occurs prior to illness onset. Only 14% of infections with detectable shedding at RT-PCR were asymptomatic, and viral shedding was low in these cases. Conclusions. Our results suggest that “silent spreaders” (ie, individuals who are infectious while asymptomatic or presymptomatic) may be less important in the spread of influenza epidemics than previously thought.

Preliminary Findings of a Randomized Trial of Non-Pharmaceutical Interventions to Prevent Influenza Transmission in Households

BACKGROUND The relationship between seasonal influenza vaccine and susceptibility to 2009 pandemic A/H1N1 virus infection is not fully understood. METHODS One child 6-15 years of age from each of 119 households was randomized to receive 1 dose of inactivated trivalent seasonal influenza vaccine (TIV) or saline placebo in November 2008. Serum samples were collected from study subjects and their household contacts before and 1 month after vaccination (December 2008), after winter (April 2009) and summer influenza (September-October 2009) seasons. Seasonal and pandemic influenza were confirmed by serum hemagglutinination inhibition, viral neutralization titers, and reverse-transcription polymerase chain reaction performed on nasal and throat swab samples collected during illness episodes. RESULTS TIV recipients had lower rates of serologically confirmed seasonal A/H1N1 infection (TIV group, 8%; placebo group, 21%; P=.10) and A/H3N2 infection (7% vs 12%; P=A9), but higher rates of pandemic A/H1N1 infection (32% vs 17%; [Formula: see text]). In multivariable analysis, those infected with seasonal influenza A during the study had a lower risk of laboratory-confirmed pandemic A/H1N1 infection (adjusted odds ratio [OR], 0.35; 95% confidence interval [CI], 0.14-0.87), and receipt of seasonal TIV was unassociated with risk of pandemic A/H1N1 infection (adjusted OR, 1.11; 95% CI, 0.54-2.26). CONCLUSIONS TIV protected against strain-matched infection in children. Seasonal influenza infection appeared to confer cross-protection against pandemic influenza. Whether prior seasonal influenza vaccination affects the risk of infection with the pandemic strain requires additional study. CLINICAL TRIALS REGISTRATION ClinicalTrials.gov number NCT00792051 .

Effects of Oseltamivir Treatment on Duration of Clinical Illness and Viral Shedding and Household Transmission of Influenza Virus

Background There are sparse data on whether non-pharmaceutical interventions can reduce the spread of influenza. We implemented a study of the feasibility and efficacy of face masks and hand hygiene to reduce influenza transmission among Hong Kong household members. Methodology/Principal Findings We conducted a cluster randomized controlled trial of households (composed of at least 3 members) where an index subject presented with influenza-like-illness of <48 hours duration. After influenza was confirmed in an index case by the QuickVue Influenza A+B rapid test, the household of the index subject was randomized to 1) control or 2) surgical face masks or 3) hand hygiene. Households were visited within 36 hours, and 3, 6 and 9 days later. Nose and throat swabs were collected from index subjects and all household contacts at each home visit and tested by viral culture. The primary outcome measure was laboratory culture confirmed influenza in a household contact; the secondary outcome was clinically diagnosed influenza (by self-reported symptoms). We randomized 198 households and completed follow up home visits in 128; the index cases in 122 of those households had laboratory-confirmed influenza. There were 21 household contacts with laboratory confirmed influenza corresponding to a secondary attack ratio of 6%. Clinical secondary attack ratios varied from 5% to 18% depending on case definitions. The laboratory-based or clinical secondary attack ratios did not significantly differ across the intervention arms. Adherence to interventions was variable. Conclusions/Significance The secondary attack ratios were lower than anticipated, and lower than reported in other countries, perhaps due to differing patterns of susceptibility, lack of significant antigenic drift in circulating influenza virus strains recently, and/or issues related to the symptomatic recruitment design. Lessons learnt from this pilot have informed changes for the main study in 2008. Trial Registration ClinicalTrials.gov NCT00425893 HKClinicalTrials.com HKCTR-365

Factors affecting QuickVue Influenza A + B rapid test performance in the community setting

BACKGROUND Large clinical trials have demonstrated the therapeutic efficacy of oseltamivir against influenza. We assessed the indirect effectiveness of oseltamivir in reducing secondary household transmission in an incident cohort of influenza index patients and their household members. METHODS We recruited index outpatients whose rapid test results were positive for influenza from February through September 2007 and January through September 2008. Household contacts were followed up for 7-10 days during 3-4 home visits to monitor symptoms. Nose and throat swabs were collected and tested for influenza by reverse-transcription polymerase chain reaction or viral culture. RESULTS We followed up 384 index patients and their household contacts. Index patients who took oseltamivir within 24 h of symptom onset halved the time to symptom alleviation (adjusted acceleration factor, 0.56; 95% confidence interval [CI], 0.42-0.76). Oseltamivir treatment was not associated with statistically significant reduction in the duration of viral shedding. Household contacts of index patients who had taken oseltamivir within 24 h of onset had a nonstatistically significant lower risk of developing laboratory-confirmed infection (adjusted odds ratio, 0.54; 95% CI, 0.11-2.57) and a marginally statistically significant lower risk of clinical illness (adjusted odds ratio, 0.52; 95% CI, 0.25-1.08) compared with contacts of index patients who did not take oseltamivir. CONCLUSIONS Oseltamivir treatment is effective in reducing the duration of symptoms, but evidence of household reduction in transmission of influenza virus was inconclusive.

Protective Efficacy Against Pandemic Influenza of Seasonal Influenza Vaccination in Children in Hong Kong: A Randomized Controlled Trial

Rapid diagnosis of influenza can facilitate timely clinical management. We evaluated the performance of the QuickVue Influenza A + B test (Quidel, San Diego, CA) in a community setting and investigated the factors affecting test sensitivity. We recruited 1008 subjects from 30 outpatient clinics in Hong Kong between February and September 2007. Each subject provided 2 pooled pairs of nose and throat swabs; 1 pair was tested by the QuickVue rapid test on site, and the other pair was sent to a laboratory for reference tests. Among 998 enrolled subjects with valid results, the rapid test had overall sensitivity of 0.68 and specificity of 0.96 compared with viral culture. Sensitivity for both influenza A and B was significantly higher for specimens with viral loads greater than 5 log(10) copies/mL. The QuickVue Influenza A + B test has similar sensitivity in point-of-care community settings to more controlled conditions.

A profile of the online dissemination of national influenza surveillance data

BACKGROUND The efficacy of seasonal influenza vaccination against 2009 pandemic influenza A(H1N1) remains unclear. METHODS One child aged 6-17 years in each of 796 households was randomized to receive 2009-2010 seasonal trivalent inactivated influenza vaccine (TIV) or saline placebo between August 2009 and February 2010. Households were followed up with serology, symptom diaries, and collection of respiratory specimens during illnesses. The primary outcomes were influenza infection confirmed by reverse-transcription polymerase chain reaction (RT-PCR) or a ≥4-fold rise in serum antibody titer measured by hemagglutination inhibition assay. RESULTS Receipt of TIV led to 8-13-fold mean geometric rises in antibody titers against seasonal A and B viruses, but only 1.5-fold mean geometric rises against the pandemic A(H1N1) virus that was not included in the vaccine. Children who received TIV had a reduced risk of seasonal influenza B confirmed by RT-PCR, with a vaccine efficacy estimate of 66% (95% confidence interval [CI], 31%-83%). Children who received TIV also a had reduced risk of pandemic influenza A(H1N1) indicated by serology, with a vaccine efficacy estimate of 47% (95% CI, 15%-67%). CONCLUSIONS Seasonal TIV prevented pandemic influenza A(H1N1) and influenza B infections in children. Pandemic A(H1N1) circulated at the time of vaccination and for a short time afterward with no substantial seasonal influenza activity during that period. The potential mechanism for seasonal TIV to provide protection, possibly short lived, for children against pandemic A(H1N1) infection despite poor cross-reactive serologic response deserves further investigation. Clinical Trials Registration. NCT00792051.

Viral genetic sequence variations in pandemic H1N1/2009 and seasonal H3N2 influenza viruses within an individual, a household and a community

BackgroundInfluenza surveillance systems provide important and timely information to health service providers on trends in the circulation of influenza virus and other upper respiratory tract infections. Online dissemination of surveillance data is useful for risk communication to health care professionals, the media and the general public. We reviewed national influenza surveillance websites from around the world to describe the main features of surveillance data dissemination.MethodsWe searched for national influenza surveillance websites for every country and reviewed the resulting sites where available during the period from November 2008 through February 2009. Literature about influenza surveillance was searched at MEDLINE for relevant hyperlinks to related websites. Non-English websites were translated into English using human translators or Google language tools.ResultsA total of 70 national influenza surveillance websites were identified. The percentage of developing countries with surveillance websites was lower than that of developed countries (22% versus 57% respectively). Most of the websites (74%) were in English or provided an English version. The most common surveillance methods included influenza-like illness consultation rates in primary care settings (89%) and laboratory surveillance (44%). Most websites (70%) provided data within a static report format and 66% of the websites provided data with at least weekly resolution.ConclusionAppropriate dissemination of surveillance data is important to maximize the utility of collected data. There may be room for improvement in the style and content of the dissemination of influenza data to health care professionals and the general public.

Digital Dashboard Design Using Multiple Data Streams for Disease Surveillance With Influenza Surveillance as an Example

BACKGROUND There are few data in the literature on viral sequence variation between host generations/successive transmission events. Relatively little is known about the sequence heterogeneity of the influenza viruses transmitted within families. OBJECTIVES To study the molecular epidemiology of influenza virus and to determine the sequence variation within an individual, a household and a community during the first wave of influenza pandemic in 2009. STUDY DESIGN A prospective study of household transmission of influenza A in Hong Kong was conducted during the pandemic in 2009. The HA and NA sequences of pandemic and seasonal influenza A viral isolates identified in this household transmission study were sequences and analyzed. RESULTS Our results indicated that there were multiple introductions of influenza viruses into Hong Kong. Sequence analysis of these isolates suggested that members of these family clusters acquired the infection by household transmissions. Interestingly, unlike those concluded from previous household transmission studies, we observed sequence variations between sequential samples from the same person and also within the same household. CONCLUSIONS Family clusters of influenza A viral infection are predominantly the result of secondary transmission within a household. Our results also suggested that the intra-host viral sequence variation might be more common that than previously thought.