Advertisement

Research findings from nonpharmaceutical intervention studies for pandemic influenza and current gaps in the research

Published:March 15, 2010DOI:https://doi.org/10.1016/j.ajic.2009.12.007
      In June 2006, the Centers for Disease Control and Prevention released a request for applications to identify, improve, and evaluate the effectiveness of nonpharmaceutical interventions (NPIs)—strategies other than vaccines and antiviral medications—to mitigate the spread of pandemic influenza within communities and across international borders (RFA-CI06-010). These studies have provided major contributions to seasonal and pandemic influenza knowledge. Nonetheless, key concerns were identified related to the acceptability and protective efficacy of NPIs. Large-scale intervention studies conducted over multiple influenza epidemics, as well as smaller studies in controlled laboratory settings, are needed to address the gaps in the research on transmission and mitigation of influenza in the community setting. The current novel influenza A (H1N1) pandemic underscores the importance of influenza research.

      Key Words

      Community mitigation is a collective term for a group of strategies other than vaccines and antiviral medications (ie, nonpharmaceutical interventions) designed to slow or limit the transmission of a pandemic virus.

      US Department of Health and Human Services. Community strategy for pandemic influenza mitigation, 2007. Available from: http://www.pandemicflu.gov/plan/community/commitigation.html#X. Accessed June 16, 2009.

      It includes personal protection strategies and interventions for individuals, institutions (eg, schools), and entire communities.
      • Jefferson T.
      • Foxlee R.
      • Del Mar C.
      • Dooley L.
      • Ferroni E.
      • Hewak B.
      • et al.
      Interventions for the interruption or reduction of the spread of respiratory viruses.
      Community mitigation research may include studies of the feasibility of effectiveness of, and compliance with protective devices, such as face masks. Research also may include the generation of data to inform mathematical models to estimate influenza attacks rates, along with the development and evaluation of interventions to delay the spread of pandemic influenza by travelers crossing international air, land, and sea borders.
      In June 2006, the Centers for Disease Control and Prevention (CDC) released a request for applications to identify, improve, and evaluate the effectiveness of nonpharmaceutical interventions (NPIs) to mitigate the spread of pandemic influenza within communities and across international borders (RFA-CI06-010).
      • Morse S.S.
      • Garwin R.L.
      • Olsiewski P.J.
      Public health. Next flu pandemic: what to do until the vaccine arrives?.
      Eleven studies were funded to identify optimal, discrete, or combined NPIs for implementation during an influenza pandemic. The results of these studies have provided valuable contributions to the knowledge of seasonal and pandemic influenza, identified additional gaps in data, and offered important insights into future research on mitigating the current pandemic of novel A (H1N1) influenza. Here we describe the studies, summarize the results, present a synthesis of the research gaps, and define future research needs.

      Description of studies and findings

      The studies include research using seasonal influenza outbreaks as a model for testing preventive measures for future influenza pandemics, as well as historical research of past pandemics (Table 1). What follows is a summary of the published, accepted, and in-preparation work across all projects.
      Table 1List of projects funded from 2007-2009 under CDC NPI studies for pandemic influenza RFA-CI06-010
      Study titleInstitutionPI(s); co-PI(s)Description
      (A) Stopping Upper Respiratory Infections and Flu in the Family: the Stuffy TrialSchool of Nursing, Columbia UniversityElaine L. Larson, RN, PhD, FAAN, CIC• Tested the effectiveness of alcohol-based hand sanitizer and sanitizer coupled with face masks on reducing the rates of laboratory-confirmed influenza, symptoms of influenza, and viral upper respiratory infection
      (B) Community-based nonpharmaceutical intervention for pandemic influenzaRTI InternationalScott F. Wetterhall, MD, MPH• Assessed, implemented, and evaluated community-level NPI strategies to prevent influenza in rural North Carolina communities
      (C) Evaluation of masks as a source control NPISchool of Health and Environment, University of Massachusetts Lowell in collaboration with Department of Environmental Health, School of Public Health, Harvard UniversityDonald K. Milton, MD, DrPH• Built an exhaled breath sampling device for influenza virus

      • Measured the number and aerosol size distribution of exhaled influenza virus

      • Measured the effect of wearing a surgical mask on generation of large- and fine-particle aerosols containing influenza virus
      (D) Controlled trial of masks and hand hygiene for reducing influenza transmissionSchool of Public Health, University of Hong KongGabriel M. Leung, MD, MPH, CCFP, FFPH, FHKCCM, FHKAM and

      Benjamin J. Cowling, PhD
      • Tested the effectiveness of hand hygiene (hand washing and the use of alcohol-based hand sanitizer), and hand hygiene combined with surgical face masks in preventing influenza transmission within households from subjects at an outpatient clinic
      (E) Reducing Transmission of Influenza by Face Masks (M-FLU)Department of Epidemiology, School of Public Health, University of MichiganArnold S. Monto, MD and Allison E. Aiello, PhD• Evaluated face masks and hand hygiene to estimate the reduction in the rate of influenza infection and ILI among students living in university residence halls
      (F) Pittsburgh Influenza Prevention Project (PIPP)Center for Public Health Practice, Graduate School of Public Health, University of PittsburghDonald S. Burke, MD and Sam Stebbins, MD, MPH• Tested hand hygiene and etiquette, hand sanitizer, and home isolation on the transmission of influenza and other diseases, and absenteeism in K-5 schools
      (G) Pandemic influenza control at the borders of island countries and in householdsPandemic Influenza Research Group, University of Otago, New ZealandMichael G. Baker, MBChB, DPH, FAFPHM, Patricia Priest, MBChB, MPH, DPhil, FAFPHM, Lance Jennings, PhD, Nick Wilson, MBChB, MPH, FAFPHM, and Heath Kelly, MBChB, MPH, FAFPHM• Assessed the effectiveness of maritime quarantine for preventing entry of the 1918 pandemic into Pacific Island countries

      • Estimated the reduction in travel volumes and the quarantine duration needed to exclude pandemic influenza from island nations

      • Analyzed the relationship between influenza hospitalization and levels of household crowding and other potentially modifiable factors among public housing residents

      • Screened travelers on international flights for seasonal influenza
      (H) Bangkok Household Influenza Transmission Study (HITS)Influenza Division, International Emerging Infections Program, Thailand MOPH-US CDC Collaboration, BangkokMark Simmerman, PhD, RN• Evaluated handwashing and handwashing plus face mask use in reducing the spread of influenza in households of pediatric hospital-based clinic patients, testing positive for influenza
      (I) Surveillance of ILI among international air travelersHawaii Department of HealthSarah Y. Park, MD, FAAP• Assessing regional capacity and feasibility to implement voluntary risk-based entry screening of air travelers for ILI
      (J) Reducing Influenza-Like Illness among University Students: REDI-US StudyCenter for Infectious Diseases and Emergency Readiness, School of Public Health, University of California BerkeleyTomas J. Aragon, MD, DrPH• Tested the effectiveness of online education of respiratory and cough etiquette, hand hygiene, hand awareness, and face mask use in reducing the occurrence of ILI among university students
      (K) History Informing Public Health Preparedness Policy in the 21st Century: A Qualitative Study of Nonpharmaceutical Interventions and Community Experiences during the 1918-1919 Influenza PandemicCenter for the History of Medicine, University of MichiganHoward Markel, MD, PhD, Alexandra M. Stern, PhD, and J. Alexander Navarro, PhD• Examined the role of NPI for epidemic mitigation in 43 cities in the continental United States from the 1918-1919 influenza pandemic

      • Creating the first historical atlas on the 1918-1919 influenza pandemic in the United States

      Assessment of NPI acceptability

      Community mitigation of pandemic influenza might be achieved through the use of NPIs, specifically personal protective measures. These measures must gain community acceptance to be effective, however. Studies assessing the acceptability of NPIs have demonstrated that NPI behaviors can be successfully taught to and adopted by a variety of individuals through the use of community health education, interactive classroom teaching, or Internet-based instruction. For example, a study of urban Hispanic households conducted by Columbia University (A) showed that although household members had misunderstandings regarding influenza, their knowledge, attitudes, and practices improved through a community education program.
      • Larson E.
      • Ferng Y.H.
      • Wong J.
      • Alvarez-Cid M.
      • Barrett A.
      • Gonzalez M.J.
      • et al.
      Knowledge and misconceptions regarding upper respiratory infections and influenza among urban Hispanic households: need for targeted messaging.
      (Note: Here the studies are identified by letter, as listed in Table 1.) In all mask and hand hygiene intervention studies, hand hygiene interventions that generally were perceived as typical daily behavior were more readily accepted than mask wearing. For example, hand sanitizing with alcohol-based preparations, handwashing with soap, covering sneezes/coughs, and hand awareness (ie, touching the face) showed relatively high compliance, whereas compliance with face mask use was low in most studies. These findings mirror predictions from an earlier study of acceptability of NPI interventions led by Stebbins.
      • Stebbins S.
      • Downs J.S.
      • Vukotich Jr., C.J.
      Using nonpharmaceutical interventions to prevent influenza transmission in elementary school children: parent and teacher perspectives.
      Studies also support the need for consistent and coordinated NPI response during pandemics. For example, research conducted by RTI International (B) identified that the acceptability of NPIs depends largely on early planning, consistent and targeted communication during implementation, and clear delineation of responsibilities and lines of authority. Acceptability also requires communication from both traditional (eg, emergency response organizations, public health departments, media) and nontraditional (eg, churches, child care centers, businesses) sources.

      Laboratory assessment of face mask efficacy

      The efficacy of face masks for preventing transmission of influenza viruses has yet to be fully determined. In a laboratory study conducted by researchers at University of Massachusetts, Lowell (C), influenza virus nucleic acid was present in fine-particle aerosols from influenza patients in both tidal breathing (14%-33%) and coughing (64%).
      • Fabian P.
      • McDevitt J.J.
      • DeHaan W.H.
      • Fung R.O.
      • Cowling B.J.
      • Chan K.H.
      • et al.
      Influenza virus in human exhaled breath: an observational study.
      Preliminary results demonstrated that surgical ear-loop face masks limit the generation of droplets ≥5.0 μm in diameter containing influenza virus RNA; investigation of fine droplet virus-containing particles is ongoing.

      Examination of the efficacy of NPIs for reducing transmission of influenza in the community setting

      The studies assessed the effectiveness of multilayered NPIs (ie, the use of multiple NPIs in conjunction with one another) based on CDC's hypothesis that this approach could create multiple barriers to stop the transmission of influenza.

      US Department of Health and Human Services. Community strategy for pandemic influenza mitigation, 2007. Available from: http://www.pandemicflu.gov/plan/community/commitigation.html#X. Accessed June 16, 2009.

      Several studies have shown that NPIs can be efficacious for reducing rates of influenza and influenza-like illness (ILI). Results from the University of Hong Kong (D) suggested substantial reductions in household secondary attack ratios when all household members practice frequent handwashing and wear face masks within 36 hours of symptom onset of the index case.
      • Cowling B.J.
      • Chan K.H.
      • Fang V.J.
      • Cheng C.K.
      • Fung R.O.
      • Wai W.
      • et al.
      Facemasks and hand hygiene to prevent influenza transmssion in households: a cluster randomized trial.
      Aiello et al,
      • Aiello A.E.
      • Murray G.F.
      • Perez V.
      • Coulborn R.
      • Davis B.M.
      • Uddin M.
      • et al.
      Mask use, hand hygiene, and seasonal influenza-like illness among young adults: a randomized intervention trial.
      at the University of Michigan (E), reported that hand hygiene with alcohol-based hand sanitizers and mask use among university students was associated with a 50%-65% reduction in the rate of ILI over a 6-week intervention period. Compared with other projects, rates of mask use were relatively high in this study, with averages of 4 hours per day in year 1 and 5 hours per day in year 2, over the 6-week intervention periods. The greater compliance than reported in household studies might have been due to the higher educational level of participants or the fact that they were paid an incentive to participate. In addition, Aiello et al used a unique study design by asking participants to begin mask and hand sanitizer use every day at the beginning of the influenza season, just after the first case of influenza was identified on campus. This design is in contrast with household studies that examined the effect of mask use on secondary transmission when household members may already have been infected before mask implementation. The University of Pittsburgh (F) found that after implementation of a 5-layer NPI approach, including hand hygiene and cough etiquette, elementary school students had significantly fewer laboratory-confirmed influenza A infections and a significant reduction in total absences compared with a control group.

      Assessment of crowding on influenza transmission

      Household crowding can be a factor in community influenza transmission. Investigators from the University of Otago, New Zealand (G) assessed the impact of proximity and crowding indices on influenza by using indices that reflect the geographic distribution (density) and ability of dwellings to provide sufficient shelter and services to their residents.
      • Ranson R.
      Healthy housing: a practical guide.
      Based on the proportion of the New Zealand population residing in public housing (∼6% of the total population), the study found that household crowding as assessed according to the Canadian National Occupancy Standard,
      Canada Mortgage and Housing Corp
      Core housing need in Canada.
      as well as the presence of children in the home, significantly increased the relative risk of hospitalization for pneumonia or influenza. According to preliminary results from a study by the International Emerging Infections Program in Thailand (H), 92% of all children enrolled as index cases of influenza within the household slept in the same room as their parents.

      Estimation of serial intervals of influenza

      The University of Hong Kong (D) evaluated the serial interval, the time between successive cases of infectious diseases in the chain of transmission. The mean serial interval between primary and secondary cases of influenza among pairs of individuals within 14 households was 3.6 days.
      • Cowling B.J.
      • Fang V.J.
      • Riley S.
      • Malik Peiris J.S.
      • Leung G.M.
      Estimation of the serial interval of influenza.
      This finding provides insight into the transmission of influenza among household members.

      Assessment of school dismissal and social contacts

      School dismissal is a significant part of CDC's pandemic planning. But there is concern that students dismissed from schools may congregate elsewhere, undermining efforts aimed at social distancing to mitigate disease transmission. RTI International (B) found that the number of social contacts among adults and children dropped significantly during school holidays. This suggests that students may not increase other social contacts in the event of school dismissal during pandemic influenza.

      Estimation of sensitivity of rapid flu tests

      Rapid influenza testing might be a valuable tool in a pandemic. Three studies [(A), (E), and (F)] assessed the use of the Quidel QuickVue Influenza A+B Rapid Test in their household- or school-based study populations. Uyeki et al
      • Uyeki T.M.
      • Prasad R.
      • Vukotich C.
      • Stebbins S.
      • Rinaldo C.R.
      • Ferng Y.H.
      • et al.
      Low sensitivity of rapid diagnostic test for influenza.
      reported that compared with reverse transcriptase-polymerase chain reaction (RT-PCR), the gold standard test, rapid influenza test sensitivity was very low across these 3 studies, with a median of 27%, despite manufacturer claims of 73% sensitivity. A fourth study conducted in doctors' offices, public outpatient clinics, and hospital emergency rooms in Hong Kong (D), found a sensitivity of 68%, which is more consistent with manufacturer's reports. But that study modified the manufacturer's protocol by combining nasal and throat samples for rapid testing. Thus, the increased sensitivity observed in Hong Kong might have been related to the modification in specimen collection. The Hong Kong study also found greater test sensitivity in outpatients with higher levels of viral shedding, as measured by semiquantitative RT-PCR.
      • Cheng K.Y.C.
      • Cowling B.J.
      • Chan K.H.
      • Fang V.J.
      • Seto W.H.
      • Yung R.
      • et al.
      Factors affecting QuickVue Influenza A+B rapid test performance in the community setting.
      Taken together, these studies raise questions about the usefulness of rapid tests in field situations and as the diagnostic tool for enrolling participants in influenza and NPI studies.

      Assessing transmission of influenza across international borders

      During seasonal epidemics and pandemics, influenza is often spread by travelers crossing international borders. Investigators studied the use of NPIs to mitigate the transmission of influenza across international borders. Historical and modeling evidence support the use of NPIs to control the entry of pandemic influenza into island countries.
      • McLeod M.A.
      • Baker M.
      • Wilson N.
      • Kelly H.
      • Kiedrzynski T.
      • Kool J.L.
      Protective effect of maritime quarantine in South Pacific jurisdictions, 1918-19 influenza pandemic.
      Rapid, large-scale risk-based entry screening of air travelers for ILI using questionnaires and health assessments was conducted successfully at airports in 2 studies, suggesting that this approach may be possible during a real event and might be generalizable to other venues. The Hawaii Department of Health (I) screened 2 flights, and the University of Otago (G) screened 175 of 307 eligible flights (57%). Screened flights included both English-speaking and non-English-speaking passengers. The Otago investigators also attempted to contact, 3 days after arrival, asymptomatic travelers who volunteered their contact details. This approach was successful 75% of the time, but required numerous attempts and considerable resources. The results of these studies will provide further insight into the trade-offs between the time and resources required for health screening in relation to the potential for mitigating disease transmission.
      The Otago investigators estimated the reduction in travel volumes and the quarantine duration needed to exclude pandemic influenza from island nations (G). They estimated that a 99% travel volume reduction would be insufficient to achieve this protective threshold, necessitating other interventions. Quarantine (restriction of asymptomatic, exposed contacts of influenza cases) likely will be a key intervention, but careful planning is required to ensure sufficient capacity for up to 9 days.
      • Nishiura H.
      • Wilson N.
      • Baker M.G.
      Quarantine for pandemic influenza control at the borders of small island nations.
      Based on preliminary analyses, the investigators concluded that voluntary travel restrictions alone would be sufficient to protect isolated populations only with very low numbers of visitors.

      Development of a historical database

      Markel and colleagues at the University of Michigan (K) are compiling The American Influenza Epidemic of 1918-1919: A Digital Encyclopedia, supported by their creation of a massive archive of historical material. This resource provides important data for modeling pandemic disease and NPI interventions. It will have future applications for both community mitigation and prevention of transmission across international borders.

      Summary of study findings and limitations

      The NPI studies had several limitations. Most lacked sufficient statistical power to examine moderate effects in confirmed influenza outcomes due to insufficient sample sizes exacerbated by a mild influenza season during the first funding year, underreporting of disease, and challenges faced by influenza surveillance, including the poor sensitivity of rapid tests. In addition, differences in study designs prevented the combination of data for pooled analyses.
      Taken together, the data provide some evidence that face masks, hand hygiene, cough etiquette, reduced crowding, and school closures are effective in reducing the spread of influenza. Nonetheless, further studies with larger sample sizes, common methodologies to allow pooling of data, and study durations that cover multiple influenza seasons are needed to address some of the aforementioned limitations of the studies. In addition, further laboratory studies are needed to address the relative contribution of transmission modalities (ie, small vs large respiratory droplets and contact transmission).

      Current data gaps

      Currently there are many gaps in the knowledge of seasonal and pandemic influenza and the effectiveness of mitigation practices. The CDC-funded research project investigators and collaborators contributing to this analysis identified gaps in 2 categories: (1) behavioral and social sciences and (2) biological and technological sciences (Table 2). A detailed account of these gaps follows.
      Table 2Summary of gaps in data
      Behavioral and social sciencesBiological and technological sciences
      • Knowledge, attitudes, and practices related to use of NPIs across diverse populations

      • Role of social, demographic, and cultural factors on NPI practice

      • Decision making dynamics with respect to NPI recommendations

      • Effective risk communication strategies for enhancing NPI compliance

      • Extent of barriers to implementation of NPIs

      • How behavioral and social determinants influence NPI efficacy
      • Adequate clinical influenza definitions

      • Prevalence and impact of asymptomatically influenza-infected persons

      • Sensitive and specific influenza rapid tests for community-based studies

      • Relative contributions of influenza virus transmission modalities (ie, large droplet nuclei, small particle droplet nuclei, and contact) to disease spread

      • Clinical implications of influenza viral load

      • Prevalence, risk factors, and impact of influenza superspreaders on disease transmission

      • Impact of environmental crowding and density on influenza transmission

      • The influence of international travel on transmission of influenza

      • Sensitive and specific screening tools for identifying influenza-infected travelers at international borders

      • Efficacy of different types of masks, hand hygiene, and combinations of personal protective measures for reducing transmission of influenza

      Behavioral and social sciences

      Little data exist for evaluating differences in NPI use across diverse populations, especially among socioeconomically disadvantaged and minority populations. More research is needed to assess knowledge, attitudes, and preventive practices related to influenza, especially predictors of the willingness to wear masks, receive immunizations, undergo travel screening, practice social distancing, and self-quarantine across heterogeneous racial and ethnic groups. Investigators at the University of Michigan identified stigma, perceived risk, and fear as factors shaping an individual's willingness to comply with mask wearing, social distancing, travel restrictions, and quarantine recommendations among university students.

      Perez V, Aiello AE, Murray GF, Coulborn R, Monto AS. Fear, stress, and reported pandemic influenza response among university students in the US. Presented at the 13th International Congress on Infectious Diseases, Kuala Lumpur, June 22, 2008. Available from: http://ww2.isid.org/Downloads/13th_ICID_AbsPosters.pdf. Accessed February 15, 2010.

      How these factors lead to differences in influenza transmission is unknown.
      In historical analyses of the 1918 pandemic in the United States, Markel et al
      • Markel H.
      • Stern A.M.
      • Cetron M.S.
      • Theodore E.
      Woodward Award: non-pharmaceutical interventions employed by major American cities during the 1918-19 influenza pandemic.
      found that NPIs tended to be implemented more consistently and with greater compliance in localities where the lines of authority and communication were transparent and clearly delineated, suggesting the importance of health risk communication and a high level of trust in public officials during a pandemic crisis. Nonetheless, in modern times, how and where people obtain their information, along with its subsequent influence on NPI practice and ultimately disease transmission, are unknown. In addition, there have been few studies on the accuracy and consistency of various sources of information about influenza and the effect of different communication styles at the community level, particularly for vulnerable populations (eg, recent immigrants, non-English-speakers). This information gap underscores the importance of further assessing risk communication strategies and their impact in the context of potential uncertainty, as well as the roles of incentives and psychosocial factors that might influence current NPI compliance and influenza transmission. Gathering these types of data on influenza A (H1N1) and future pandemics is warranted.
      Current gaps in research preclude the ability to assert the effectiveness of various mask-wearing protocols, respiratory etiquette, and layered NPIs. The feasibility and acceptability of selective, reactive, or preemptive school and other institutional dismissals across various communities require further evaluation. Furthermore, assessment of the relationships between the quantity and quality of social interactions on influenza transmission rates, the impact of social distancing without dismissals of events and schools, and cost-effective analyses are needed. Large-scale community interventions and research conducted over multiple influenza outbreaks are required to fill these knowledge gaps.

      Biological and technological sciences

      There are many biological and technical gaps in our understanding of influenza diagnostics, transmission, and mitigation measures. The many unanswered questions that we describe below have together contributed to difficulties in quantifying the efficacy of NPIs for preventing particular influenza transmission pathways.

      Clinical definitions, diagnostics, and surveillance

      Studies that assess the accuracy of the clinical definitions of ILI for the purpose of syndrome-based surveillance are needed. Case definitions of influenza vary widely according to the presentation of symptom combinations.
      • Hannoun C.
      Case definition for influenza surveillance.
      • Navarro-Mari J.M.
      • Perez-Ruiz M.
      • Cantudo-Munoz P.
      • Petit-Gancedo C.
      • Jimenez-Valera M.
      • Rosa-Fraile M.
      Influenza-like illness criteria were poorly related to laboratory-confirmed influenza in a sentinel surveillance study.
      Little data exist on how case definitions differ by population demographics and molecular characteristics of the virus. Furthermore, little is known about the association between preexisting immunity (humoral- or cell-mediated) and severity of infection, which may influence the prevalence of subclinical or asymptomatic infections in different populations and subgroups or secondary transmission rates among those who contract influenza following vaccination. Rigorous studies comparing rates of asymptomatic influenza virus infection with symptomatic infection are needed.
      Further studies are needed to examine the factors accounting for the low sensitivity of rapid influenza diagnostic tests compared with other confirmatory methods,
      • Cheng K.Y.C.
      • Cowling B.J.
      • Chan K.H.
      • Fang V.J.
      • Seto W.H.
      • Yung R.
      • et al.
      Factors affecting QuickVue Influenza A+B rapid test performance in the community setting.
      as well as the relationship between viral load and the sensitivity of rapid tests. Surveillance methods providing more accurate influenza rates in individuals not utilizing health care services need identification. The acceptability and use of secure Web-based surveillance systems for monitoring rates of infection and compliance with interventions require assessment.

      Laboratory studies of transmission

      Studies of influenza using laboratory-adapted surrogate strains, similar to the early work done with rhinovirus, may help uncover transmission pathways, that is, the relative contributions of large and small respiratory droplets and surface contact toward the transmission of influenza viruses.
      • Dick E.C.
      • Jennings L.C.
      • Mink K.A.
      • Wartgow C.D.
      • Inhorn S.L.
      Aerosol transmission of rhinovirus colds.
      However, the respiratory droplets shed by persons experimentally infected with laboratory strains and by persons naturally infected with wild-type viruses must be fully characterized to ensure that the laboratory infections accurately model the real world. In addition, laboratory studies should consider whether higher viral loads cause increased viral shedding and transmission and whether the dose of infectious particles or the source of these particles vary between individuals. In other words, are there “superspreaders” for influenza strains?

      Environmental factors and transmission

      Data describing the impact of environmental factors on influenza transmission are limited. The relative influence of contact versus droplet transmission and the roles of surface contamination and humidity in primary or secondary infection are unclear. As Langmuir aptly stated, “what is essential and necessary evidence is the demonstration that the elimination of one or more of the means of spread, keeping the remaining ones constant, radically and consistently reduces the incidence of actual disease.”
      • Langmuir A.D.
      Discussion.
      Environmental studies using engineering interventions that do not require individual compliance are likely to yield valuable information on transmission modes, such as ultraviolet light and air-exchange installations.

      US Department of Health & Human Services. Report of the Surgeon General's Workshop on healthy indoor environment, January 12-13, 2005. Available from: http://www.cdc.gov/niosh/nas/RDRP/appendices/chapter4/a4-40.pdf. Accessed June 16, 2009.

      US Department of Health & Human Services. Interim guidance for cleaning passenger and cargo vessels during an influenza pandemic. Available from: http://www.pandemicflu.gov/travel/cleaning_vessels.html. Accessed June 16, 2009.

      US Department of Health & Human Services. Interim guidance for aircraft cleaning when pandemic influenza is suspected in a passenger or crew member. Available from: http://www.pandemicflu.gov/travel/cleaning_aircraft.html. Accessed June 16, 2009.

      World Health Organization. Guide to hygiene and sanitation in aviation. 3rd ed. Available from: http://www.who.int/water_sanitation_health/hygiene/ships/guide_hygiene_sanitation_aviation_3_edition.pdf. Accessed June 16, 2009.

      Studies that include both personal and environmental virologic sampling are warranted.

      Density and crowding

      Deficits exist in our understanding of the relationship between population densities and influenza rates. For example, research evaluating the impact on influenza rates of living in close quarters (eg, locked wards, prisons, dormitories, military bases, households) is limited. This underscores the importance of developing standardized crowding indices to examine the impact of household or residence size and composition on influenza transmission.

      International travel and border screening

      Research into the risk of disease transmission associated with international travel also contains gaps. For example, border screening and quarantine for delaying the spread of influenza across international borders require further assessment. Asymptomatic and incubating travelers present particular obstacles. Studies of screening measures for travelers, including assessment of the utility of infrared thermography scans, design of sensitive and specific screening questionnaires, and assessment of how to combine screening with quarantine and other approaches, are necessary to provide a useful level of border protection.

      Personal protection measures

      Little data exist on the effectiveness of various types of face masks, hand hygiene, and layered interventions on confirmed influenza outcomes in the community setting. Published experimental data from the hospital setting show that no detectable influenza viral RNA (limit of detection of 250 copies/mL) was detected after 9 influenza cases were asked to cough 5 times into both routine surgical masks and N95 respirators, suggesting that these masks are equally efficacious at preventing transmission of viral RNA among hospital patients.
      • Johnson D.F.
      • Druce J.D.
      • Birch C.
      • Grayson M.L.
      A quantitative assessment of the efficacy of surgical and N95 masks to filter influenza virus in patients with acute influenza infection.
      Whether the use of surgical masks limits the generation of fine particles associated with viral aerosols requires further exploration in the community setting (ie, whether influenza is transmitted through the airborne route, not merely through large droplets and by contact spread). Studies are also needed to assess the effects of mask wearing by uninfected individuals at risk for exposure to influenza or other respiratory viruses and the contribution of embedding masks with microbiocides. In addition, research on specific hygiene habits and compliance levels associated with reductions in illness are merited.

      Discussion

      The studies described here have added much to our understanding of preparedness and mitigation techniques for pandemic influenza. Findings from these studies have provided information on the acceptability and protective aspects of NPIs, as well as on the limitations in implementing these measures on a large scale in varied settings; however, many of the remaining research gaps can be addressed only by laboratory- and community-based studies with common protocols conducted over multiple years, given the consistently variable and unpredictable severity of influenza epidemics and pandemics.
      • Jefferson T.
      • Foxlee R.
      • Del Mar C.
      • Dooley L.
      • Ferroni E.
      • Hewak B.
      • et al.
      Interventions for the interruption or reduction of the spread of respiratory viruses.
      Plans have been developed that describe what needs to occur in the event of pandemic influenza, but these plans fall short in detailing how to carry out the recommendations.
      • Coker R.
      UK preparedness for pandemic influenza.
      The 2009 influenza A (H1N1) pandemic may provide an opportunity to assess the effectiveness of NPIs against the spread of this novel influenza A virus in some communities.
      Outbreak of swine-origin influenza A (H1N1) virus infection—Mexico, March-April 2009.
      • Garten R.J.
      • Davis C.T.
      • Russell C.A.
      • Shu B.
      • Lindstrom S.
      • Balish A.
      • et al.
      Antigenic and genetic characteristics of swine-origin 2009 A(H1N1) influenza viruses circulating in humans.
      • Fraser C.
      • Donnelly C.A.
      • Cauchemez S.
      • Hanage W.P.
      • Van Kerkhove M.D.
      • Hollingsworth T.D.
      • et al.
      Pandemic potential of a strain of influenza A (H1N1): early findings.
      Emergence of a novel swine-origin influenza A (H1N1) virus in humans.
      Additional studies also are needed to identify the relative contributions of large droplet, small particle droplet nuclei, and contact transmission of seasonal influenza, the 2009 influenza A (H1N1), and newly emerging strains. Finally, research should include assessments of psychosocial and cultural factors that shape compliance with NPIs, to explore why certain groups accept NPIs while others do not, and whether barriers to compliance are lifted during a global pandemic.
      In conclusion, the current influenza A (H1N1) pandemic may provide us with an opportunity to address many research gaps and ultimately create a broad, comprehensive strategy for pandemic mitigation; however, the emergence of this pandemic in 2009 demonstrated that there are still more questions than answers. More research is urgently needed, especially in light of the potential for mutations in influenza A (H1N1). If mutations do occur, or if new pandemic strains emerge in the future, NPIs likely will play a crucial role in mitigating the spread of infection when vaccines are unable to provide sufficient protection.
      The authors thank Martin Cetron, MD and Donald S. Burke, MD for their leadership in the overall research effort. This work would not have been possible without the assistance and editorial comments from CDC Project Officers and Staff: Mary M. Agocs, MD, Francisco Alvarado-Ramy, MD, Paul Edelson, MD, Anthony Fiore, MD, Lyn Finelli, DrPH, Dan B. Fishbein, MD, Diane Gross, PhD, Peter M. Houck, MD, William Jackson, MD, Laurie Kamimoto, MD, Jackie Katz, PhD, J. M. Keir, MPH, Harvey Lipman, PhD, Kiren Mitruka, MD, Josh Mott, PhD, Andrew Plummer, MD, Jacquelyn A. Polder, BSN, MPH, David Shay, MD, Mark Simmerman, RN, PhD, Julie Sinclair, DVM, William Thompson, MD, Timothy M. Uyeki, MD, and Steve Waterman, MD. We also thank Leslie Fink for proofreading the manuscript, and Nabiha Megateli-Das and Centers for Disease Control and Prevention administrative staff members Mattie Jackson, Linda Kirk, Trudy Messmer, and Larry Larue for their support of all projects. This research was supported by the Centers for Disease Control and Prevention under a series of cooperative agreements named herein, emanating from RFA-CI06-010, issued on June 16, 2006.

      References

      1. US Department of Health and Human Services. Community strategy for pandemic influenza mitigation, 2007. Available from: http://www.pandemicflu.gov/plan/community/commitigation.html#X. Accessed June 16, 2009.

        • Jefferson T.
        • Foxlee R.
        • Del Mar C.
        • Dooley L.
        • Ferroni E.
        • Hewak B.
        • et al.
        Interventions for the interruption or reduction of the spread of respiratory viruses.
        Cochrane Database Syst Rev. 2007; 4 (CD006207)
        • Morse S.S.
        • Garwin R.L.
        • Olsiewski P.J.
        Public health. Next flu pandemic: what to do until the vaccine arrives?.
        Science. 2006; 314: 929
        • Larson E.
        • Ferng Y.H.
        • Wong J.
        • Alvarez-Cid M.
        • Barrett A.
        • Gonzalez M.J.
        • et al.
        Knowledge and misconceptions regarding upper respiratory infections and influenza among urban Hispanic households: need for targeted messaging.
        J Immigr Minor Health. 2009; 11: 71-82
        • Stebbins S.
        • Downs J.S.
        • Vukotich Jr., C.J.
        Using nonpharmaceutical interventions to prevent influenza transmission in elementary school children: parent and teacher perspectives.
        J Public Health Manag Pract. 2009; 15: 112-117
        • Fabian P.
        • McDevitt J.J.
        • DeHaan W.H.
        • Fung R.O.
        • Cowling B.J.
        • Chan K.H.
        • et al.
        Influenza virus in human exhaled breath: an observational study.
        PLoS ONE. 2008; 3: e2691
        • Cowling B.J.
        • Chan K.H.
        • Fang V.J.
        • Cheng C.K.
        • Fung R.O.
        • Wai W.
        • et al.
        Facemasks and hand hygiene to prevent influenza transmssion in households: a cluster randomized trial.
        Ann Intern Med. 2009; 151: 437-446
        • Aiello A.E.
        • Murray G.F.
        • Perez V.
        • Coulborn R.
        • Davis B.M.
        • Uddin M.
        • et al.
        Mask use, hand hygiene, and seasonal influenza-like illness among young adults: a randomized intervention trial.
        J Infect Dis. 2010; 201: 491-498
        • Ranson R.
        Healthy housing: a practical guide.
        Taylor & Francis, London1991
        • Canada Mortgage and Housing Corp
        Core housing need in Canada.
        Canada Mortgage and Housing Corp, Ottawa1991
        • Cowling B.J.
        • Fang V.J.
        • Riley S.
        • Malik Peiris J.S.
        • Leung G.M.
        Estimation of the serial interval of influenza.
        Epidemiology. 2009; 20: 344-347
        • Uyeki T.M.
        • Prasad R.
        • Vukotich C.
        • Stebbins S.
        • Rinaldo C.R.
        • Ferng Y.H.
        • et al.
        Low sensitivity of rapid diagnostic test for influenza.
        Clin Infect Dis. 2009; 48: e89-e92
        • Cheng K.Y.C.
        • Cowling B.J.
        • Chan K.H.
        • Fang V.J.
        • Seto W.H.
        • Yung R.
        • et al.
        Factors affecting QuickVue Influenza A+B rapid test performance in the community setting.
        Diagn Microbiol Infect Dis. 2009; 65: 35-41
        • McLeod M.A.
        • Baker M.
        • Wilson N.
        • Kelly H.
        • Kiedrzynski T.
        • Kool J.L.
        Protective effect of maritime quarantine in South Pacific jurisdictions, 1918-19 influenza pandemic.
        Emerg Infect Dis. 2008; 14: 468-470
        • Nishiura H.
        • Wilson N.
        • Baker M.G.
        Quarantine for pandemic influenza control at the borders of small island nations.
        BMC Infect Dis. 2009; 9: 27-40
      2. Perez V, Aiello AE, Murray GF, Coulborn R, Monto AS. Fear, stress, and reported pandemic influenza response among university students in the US. Presented at the 13th International Congress on Infectious Diseases, Kuala Lumpur, June 22, 2008. Available from: http://ww2.isid.org/Downloads/13th_ICID_AbsPosters.pdf. Accessed February 15, 2010.

        • Markel H.
        • Stern A.M.
        • Cetron M.S.
        • Theodore E.
        Woodward Award: non-pharmaceutical interventions employed by major American cities during the 1918-19 influenza pandemic.
        Trans Am Clin Climatol Assoc. 2008; 119: 129-138
        • Hannoun C.
        Case definition for influenza surveillance.
        Eur J Epidemiol. 2003; 18: 737-738
        • Navarro-Mari J.M.
        • Perez-Ruiz M.
        • Cantudo-Munoz P.
        • Petit-Gancedo C.
        • Jimenez-Valera M.
        • Rosa-Fraile M.
        Influenza-like illness criteria were poorly related to laboratory-confirmed influenza in a sentinel surveillance study.
        J Clin Epidemiol. 2005; 58: 275-279
        • Dick E.C.
        • Jennings L.C.
        • Mink K.A.
        • Wartgow C.D.
        • Inhorn S.L.
        Aerosol transmission of rhinovirus colds.
        J Infect Dis. 1987; 156: 442-448
        • Langmuir A.D.
        Discussion.
        Bacteriol Rev. 1966; 30: 672-674
      3. US Department of Health & Human Services. Report of the Surgeon General's Workshop on healthy indoor environment, January 12-13, 2005. Available from: http://www.cdc.gov/niosh/nas/RDRP/appendices/chapter4/a4-40.pdf. Accessed June 16, 2009.

      4. US Department of Health & Human Services. Interim guidance for cleaning passenger and cargo vessels during an influenza pandemic. Available from: http://www.pandemicflu.gov/travel/cleaning_vessels.html. Accessed June 16, 2009.

      5. US Department of Health & Human Services. Interim guidance for aircraft cleaning when pandemic influenza is suspected in a passenger or crew member. Available from: http://www.pandemicflu.gov/travel/cleaning_aircraft.html. Accessed June 16, 2009.

      6. World Health Organization. Guide to hygiene and sanitation in aviation. 3rd ed. Available from: http://www.who.int/water_sanitation_health/hygiene/ships/guide_hygiene_sanitation_aviation_3_edition.pdf. Accessed June 16, 2009.

        • Johnson D.F.
        • Druce J.D.
        • Birch C.
        • Grayson M.L.
        A quantitative assessment of the efficacy of surgical and N95 masks to filter influenza virus in patients with acute influenza infection.
        Clin Infect Dis. 2009; 49: 275-277
        • Coker R.
        UK preparedness for pandemic influenza.
        BMJ. 2007; 334: 965-966
      7. Outbreak of swine-origin influenza A (H1N1) virus infection—Mexico, March-April 2009.
        MMWR Morb Mortal Wkly Rep. 2009; 58: 467-470
        • Garten R.J.
        • Davis C.T.
        • Russell C.A.
        • Shu B.
        • Lindstrom S.
        • Balish A.
        • et al.
        Antigenic and genetic characteristics of swine-origin 2009 A(H1N1) influenza viruses circulating in humans.
        Science. 2009 Jul 10; 325: 197-201
        • Fraser C.
        • Donnelly C.A.
        • Cauchemez S.
        • Hanage W.P.
        • Van Kerkhove M.D.
        • Hollingsworth T.D.
        • et al.
        Pandemic potential of a strain of influenza A (H1N1): early findings.
        Science. 2009 Jun 19; 324: 1557-1561
      8. Emergence of a novel swine-origin influenza A (H1N1) virus in humans.
        N Engl J Med. 2009; 360: 2605-2615