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      The TransFLUas influenza transmission study in acute healthcare - recruitment rates and protocol adherence in healthcare workers and inpatients

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          Abstract

          Background

          Detailed knowledge about viral respiratory disease transmission dynamics within healthcare institutions is essential for effective infection control policy and practice. In the quest to study viral transmission pathways, we aimed to investigate recruitment rates and adherence of healthcare workers (HCWs) and hospital inpatients with a study protocol that involves prospective surveillance based on daily mid-turbinate nasal swabs and illness diaries.

          Methods

          Single center prospective surveillance of patients and HCWs in three different hospital departments of a tertiary care center during an entire influenza season in Switzerland. Inpatients and acute care HCWs were asked to provide mid-turbinate nasal swabs and illness diaries on a daily basis. Study protocol adherence and recruitment rates were the primary outcomes of interest.

          Results

          A total 251 participants (59 (23.5%) health care workers and 192 (76.5%) inpatients) were recruited from three different hospital wards. Recruitment rates differed between HCWs (62.1% of eligible HCWs) and inpatients (32.5%; P < 0.001), but not within HCWs ( P = 0.185) or inpatients ( P = 0.301) of the three departments. The total number of study-days was 7874; 2321 (29.5%) for inpatients and 5553 (70.5%) for HCWs. HCWs were followed for a median of 96 days (range, 71–96 days) and inpatients for 8 days (range, 3–77 days). HCWs provided swabs on 73% (range, 0–100%) of study days, and diaries on 77% (range 0–100%). Inpatients provided swabs and diaries for 83% (range, 0–100%) of days in hospital. In HCWs, increasing age, working in internal medicine and longer duration of total study participation were positively associated with the proportion of swabs and diaries collected. Adherence to the study protocol was significantly lower in physicians as compared to nurses for both swabs ( P = 0.042) and diaries ( P = 0.033). In inpatients, no association between demographic factors and adherence was detected.

          Conclusions Prospective surveillance of respiratory viral disease was feasible in a cohort of inpatients and HCWs over an entire influenza season, both in terms of recruitment rates and adherence to a study protocol that included daily specimen collection and illness diaries.

          Trial registration

          clinicaltrials.gov NCT02478905. Date of registration June 23, 2015.

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          Most cited references16

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          Nonpharmaceutical Interventions for Pandemic Influenza, International Measures

          (2006)
          Pandemic preparedness ideally would include pharmaceutical countermeasures (vaccine and antiviral drugs), but for the foreseeable future, such measures will not be available for the global population of >6 billion ( 1 ). Thus, in 2005, after consultations with experts, the World Health Organization (WHO) recommended nonpharmaceutical public health interventions in its updated global influenza preparedness plan ( 2 ). The recommendations are intended as guidance, not as formal WHO advice ( 3 ). Such interventions, designed to reduce exposure of susceptible persons to an infectious agent, were commonly used for infection control in previous centuries. This report (part 1) and a companion article (part 2 [4]) summarize the scientific data, historic experience, and contemporary observations that make up the limited evidence base for these interventions as applied to influenza. Part 1 summarizes the relevant transmission characteristics of influenza and the basis for interventions to prevent spread from 1 country to another; part 2 summarizes the basis for measures within countries at the national and community levels. Both parts are designed to be read in conjunction with WHO recommendations ( 2 , 3 ). Nonpharmaceutical interventions outside of healthcare settings focus on measures to 1) limit international spread of the virus (e.g., travel screening and restrictions); 2) reduce spread within national and local populations (e.g., isolation and treatment of ill persons; monitoring and possible quarantine of exposed persons; and social distancing measures, such as cancellation of mass gatherings and closure of schools); 3) reduce an individual person's risk for infection (e.g., hand hygiene); and 4) communicate risk to the public. We discuss the first category; categories 2 and 3 are addressed in part 2. We do not address infection control measures for patient care or risk communication. Transmission Characteristics of Influenza Viruses Most information on transmission of influenza viruses is based on older experimental studies, inference from observations during outbreaks, and studies with other objectives, especially the assessment of vaccine or drug efficacy. These sources have substantial limitations: investigations often used different methods, involved small numbers of persons, and reflected the behavior of influenza A and B viruses in seasonal rather than pandemic settings (the level of preexisting immunity in populations is substantially higher in seasonal epidemics). For this reason, data from young children, who presumably lack prior exposure and therefore immunity to influenza, may better reflect illness and viral shedding patterns of pandemic disease. The "infectiousness" of patients is virtually always inferred on the basis of viral shedding from the upper respiratory tract rather than from directly observed transmission, but the relationship between nasopharyngeal shedding and transmission is uncertain and could vary. Detailed studies of lower respiratory tract virus loads, particularly relevant to small-particle aerosol transmission during coughing and sneezing, are not available. In many studies, the preexisting influenza antibody status of study participants is not reported, even though this factor is critical in influencing illness and viral shedding patterns. In controlled studies, in which susceptible study participants are typically screened for preexisting influenza antibody by hemagglutination inhibition assays to the challenge virus, the routes of infection and the challenge virus can differ. Other factors that differ among studies are the age and preexisting medical conditions of study participants and the timing of specimen collections for virus testing. Viral Shedding and Transmission by Persons with Symptoms In otherwise healthy adults with influenza infection, viral shedding 24–48 h before illness onset has been detected but generally at much lower titers than during the symptomatic period (Table A1). Titers of infectious virus peak during the first 24–72 h of illness (103–107 50% tissue culture infective dose [TCID50]/mL nasopharyngeal wash) and decline within several days, with titers usually low or undetectable by day 5. Shedding in highly immunocompromised persons may last weeks to months. Compared with adults, children can shed virus earlier before illness begins and for longer periods once illness starts. As in adults, peak shedding in children occurs during the first 1–3 days of illness, but absolute levels may be higher than those in adults. In 1 report, at least 4 illnesses (8% of the total) in children were associated with presymptomatic shedding that began 6, 4, 3, and 3 days, respectively, before illness onset ( 5 ). The median duration of virus detection is typically 7–8 days after illness onset, but shedding for up to 21 days has been recorded. In 1 study, virus was shed by 10% of children on days 8–11, by 5% on days 12–15, and by 0% on days 16–19 ( 6 ). Infants with infection requiring hospitalization may shed virus longer. In both adults and children, shedding does not usually continue once illness has resolved. Serologic testing indicates that ≈30%–50% of seasonal influenza infections may not result in illness. Viral Shedding and Transmission by Infected Persons without Symptoms During the incubation period, persons with presymptomatic influenza infection shed virus at lower titers than persons with symptoms (Table A1); however, the infectiousness of those with presymptomatic infection has not been studied. Apparently the only published report implicating transmission during the incubation period involves a group of adults in New Zealand in 1991. Of 26 adults who bagged fertilizer for 8 h, influenzalike illness (fever, headache, sore throat, myalgia, respiratory symptoms) developed in 16 and mild, "cold-like" illnesses developed in 3 persons within 24 to 48 h after working with the fertilizer. A person considered to be the probable index patient had felt unwell during work, although he did not have respiratory symptoms; an influenzalike illness began to develop 6 h after he finished work. Influenza A virus H1N1 was isolated from 2 symptomatic persons; whether these included the suspected index patient and whether that person transmitted infection during an incubation period or the cluster resulted from community exposure are unknown. The group shared drinking bottles and worked in a dusty environment, both of which could have facilitated transmission ( 7 ). Large-Droplet and Aerosol Respiratory Transmission Animal studies and most influenza outbreaks among humans suggest that virus-laden large droplets (particles >5 mm in diameter) generated when infected persons cough or sneeze are the predominant mechanism of influenza virus transmission ( 8 ). However, evidence for aerosol spread (especially in unventilated conditions) is available ( 9 ). Although a direct comparison has not been made, experimental studies suggest that the infectious dose for humans exposed by aerosol is lower than that seen with experimental nasopharyngeal instillation ( 10 ). The precise proportion of infections transmitted by large droplets versus aerosols is difficult to assess and likely depends on the setting but is relevant when developing recommendations on mask use. Data do not exist to quantify the relative efficacy of surgical masks versus respirators in preventing influenza infections in exposed persons, but surgical masks should protect against large droplets, believed to be the major mode of transmission ( 8 ). Transmission by Contaminated Hands, Other Surfaces, or Fomites Transmission of influenza viruses by contaminated hands, other surfaces, or fomites has not been extensively documented but is believed to occur. In a nursing home outbreak in Hawaii, an investigation concluded that transmission of oral secretions from patient to patient by staff who were not gloved best explained the outbreak ( 11 ). In an environmental survival study, influenza A virus placed on hard, nonporous surfaces (steel and plastic) could be cultured from the surfaces at diminishing titer for 99°F (37.2°C) were isolated at hospitals for observation. Measures taken by hospital staff to avoid infection included the use of masks and other "routine precautions taken at isolation hospitals." Reportedly, no direct evidence of escape of infection from any vessel to the shore occurred. From October 1918 through May 1919, a total of 79 "infected vessels" containing 2,795 patients, 48,072 passengers, and 10,456 crew and 149 "uninfected vessels" containing 7,075 passengers and 7,941 crew arrived at Australian ports ( 17 , 18 ). The first cases of pandemic influenza in Australia were reported in January 1919, suggesting that these measures delayed entry of the disease for ≈3 months. Although the national quarantine director believed that pandemic influenza had entered Australia before quarantine was established, this belief was not documented, and other reports indicate that some ships' officers and soldiers returning to Australia from Europe had concealed illness to avoid protracted quarantine ( 18 ). When the infection did emerge in Australia, case-fatality rates were lower than those in many places affected earlier. According to a report from the New South Wales Department of Public Health, ships with ill passengers arrived regularly at Sydney (the state capital) from October 1918 to January 1919. Of 326 passengers or crew treated at the quarantine hospital, 49 died. Recovered patients and contacts emerging from quarantine were released into the general population and monitored by health officials for a few days to a few weeks. Two cases were in nurses who had contracted influenza while caring for patients at the quarantine hospital. "In no case did any suspicion arise that such persons had spread influenza among those with whom they had come in contact" ( 19 ). The first cases of influenza in New South Wales were in soldiers who arrived overland by train from the port city of Melbourne, Victoria, where recent cases were known to have occurred but were not promptly disclosed by the authorities ( 19 ). In 1918, the island of Madagascar, then a French colony, also implemented a "rigorous quarantine" and did not report cases of influenza until April 1919. In contrast, nearby coastal regions of eastern and southern Africa reported cases beginning in September to December 1918. Contact between Madagascar and South Africa, where the disease was epidemic, was limited to a single coastal steamboat ( 20 , 21 ). In the Pacific, American Samoa implemented quarantine measures and was spared infection, while nearby islands were severely affected ( 22 ). The French colony of New Caledonia was spared infection by requiring ships to remain in quarantine at their ports of departure, a form of "exit screening," discussed below ( 23 ). Other Quarantine Experiences On the African mainland, quarantine was enacted in 1918 in some port cities in, for example, Liberia, Gabon, and Ghana (formerly known as the Gold Coast). Details generally are unavailable, but, on the whole, even though entry may have been delayed by some weeks, the experience was less successful than that of islands that enacted quarantine. Disease arrived from inland routes and, according to 1 report, quarantine of a ship in Accra, Ghana, known in advance to be carrying persons with influenza was not successful; disease spread to dock workers and subsequently entered the country ( 21 , 24 ). In 1918, closing roads at the northern land border of Ghana was not feasible because of the volume of trade and the probability that police barriers would be evaded. An attempt was nevertheless made to close roads at the border town of Tumu, but authorities concluded that "a handful of constables could not stop the epidemic and the effort was soon abandoned" ( 24 ). In Canada and Australia, substantial measures, including police checkpoints and interruption of road and rail traffic, did not prevent or appear to delay the spread of infection between Canadian provinces or Australian states ( 4 , 18 ). A WHO expert consultation on the 1957 influenza pandemic summarized the effect of quarantine measures at international borders as follows. Onset in Israel was delayed by 2 months in comparison to neighboring countries, attributed to absence of international travel with neighboring countries (for political, not quarantine reasons). In South Africa, "some delay" occurred from restrictions on ships arriving at ports, but the evidence was "less convincing." Elsewhere, "no effect was detected. It seems that if such measures are to be effective, they must be very severe…. a high price to pay for a few additional weeks freedom from the disease" ( 25 ). Experience from Contemporary SARS and Influenza Outbreaks In modern times, the most extensive use of nonpharmaceutical public health interventions to contain a transmissible respiratory viral infection occurred during the SARS epidemic of 2003. Some lessons learned from that experience may be applicable to influenza, although important differences exist between the epidemiologic parameters of influenza virus and SARS-CoV. The most notable of these are that influenza has a serial interval of 2 to 4 days and infectivity is maximal early in illness, whereas for SARS the serial interval is 8–10 days and infectivity peaks during week 2 of illness. These factors allow little time for instituting the isolation and quarantine interventions that were essential in controlling SARS. Entry Screening of Air-travel Passengers during 2003 SARS Outbreak In the 2003 SARS experience, data from 4 Asian locations and Canada indicated that body temperature–sensing devices did not detect anyone with SARS among >35 million entering travelers screened. Administration of health declarations (a questionnaire completed by the traveler to report health information, e.g., symptoms and history of exposure) to >45 million entering travelers detected 4 SARS cases. At least 31 million health alert notices were distributed to entering international travelers in several countries, but follow-up information is limited. Mainland China reported the distribution of 450,000 notices and detection of 4 SARS cases possibly linked to the notices. Thailand reported printing 1 million notices and detecting 24 cases directly linked to them ( 26 ). The 5 persons with SARS who entered Canada did not have signs or symptoms at international airports; Canadian authorities concluded that border screening for SARS was insensitive and not cost-effective and that surveillance allowing for early detection of imported cases was preferable ( 27 ). The possible effect of entry screening for pandemic influenza has been estimated for the United Kingdom, with the assumption that exit screening is in place at international airports in countries with pandemic influenza. A mean of 9% of persons infected by influenza who were asymptomatic on departure would be estimated to develop influenza symptoms en route to the United Kingdom; the percentage would be higher during longer flights. Symptoms would develop in an estimated mean of 17% (range 12%–23%) of infected persons traveling from Asian cities. Airplanes that arrive daily at 12 airports in the United Kingdom from the Far East have >12,000 seats; entry screening would fail to detect ≈83% of infected persons ( 28 ). Travelers arriving on connecting flights were not considered. In Taiwan during the 2003 SARS outbreak, 80,813 incoming air-travel passengers from affected areas were quarantined; 21 (0.03%) were diagnosed with suspected or probable SARS. None of these 21 cases had been detected by entry screening ( 26 , 29 ). Another modeling study from the UK Health Protection Agency suggests that reduction of air travel to and from affected areas, if implemented, must be almost total and nearly instantaneous to delay pandemic spread significantly (B. Cooper, pers. comm.). Exit Screening of Travelers during SARS Outbreak After WHO recommended exit screening of international travelers departing from affected areas on March 27, 2003, no additional spread of SARS through air travel was documented from countries with exit screening. This finding may reflect a deterrence effect, a generally low incidence of SARS cases, or both. Combined data from several countries indicate 1 case detected among 1.8 million departing passengers completing health questionnaires and no cases among 7 million persons who underwent thermal scanning on departure ( 26 ). Measures To Limit Influenza Virus Transmission on Conveyances Influenza has been transmitted on airplanes ( 30 ) and ships ( 31 ). In 1 cluster, influenzalike illness developed in 72% of passengers seated in an airplane that was on the ground for 3 h without ventilation and that held a person with symptomatic influenza ( 9 ). On a 75-seat aircraft, 15 passengers traveling with an influenza-infected person became ill. All 15 persons were seated within 5 rows of the index patient, and 9 were seated within 2 rows ( 32 ). In a review of the Australian experience with pandemic influenza aboard ships in 1918 to 1919, a "Daily thermometer parade and removal of any person febrile or reporting sick (was) most thoroughly and efficiently carried out" ( 17 ). Despite these measures, examples were given of 3 ships with 89%, 46%, and 30%, respectively, of those onboard who were ill, which led to the "conclusion that neither inhalation, inoculation, nor isolation of the sick would stop an epidemic. . . . No administrative measure was successful in modifying the time factor of a shipboard epidemic, although there is some reason for believing that the measures employed were, by their combined influence, successful in reducing the potential volume of actual cases" ( 17 ). Influenza outbreaks have been reported on cruise ships during international voyages ( 31 ). A large summertime outbreak involved both international travelers and crew during 3 cruises of 1 ship. Control measures included surveillance, isolation of ill crew, immunization of the crew, and use of antiviral drugs for treatment and prophylaxis of crew and passengers ( 31 , 33 ). During the 2003 SARS outbreak, the disease was transmitted on and spread internationally via aircraft. The most extensive investigation included 3 flights on which an index passenger had SARS; on 1 of these flights, 22 (18.3%) of 120 other passengers and crew became infected. A higher risk was noted for passengers seated near the index patient, but most passengers who became infected were seated farther away, even though their individual risk was lower ( 34 ). In most other investigations, no transmissions were documented, although the investigations were limited ( 26 ). Discussion The effectiveness of nonpharmaceutical public health interventions in affecting the spread of pandemic influenza depends on transmission characteristics of the virus. If a substantial proportion of transmission occurs during the incubation period or during asymptomatic infection, the population impact of health screening and case-patient isolation will be diminished. The age distribution of patients is also important: if children play a central role in initial community transmission, school closure would likely be more effective. Since a new pandemic subtype might have different transmission characteristics than previous subtypes, these characteristics and associated illness patterns must be assessed in the field as soon as human-to-human transmission begins. Monitoring over time is also needed to assess possible changes as the virus becomes more adapted to human hosts. WHO has developed recommendations to provide guidance until transmission characteristics can be determined. The recommendations are based on limited information, including virologic data from seasonal epidemics and volunteer studies rather than pandemics, in which shedding and transmission may be more intense and prolonged because of lack of population immunity. These data indicate that influenza viral shedding in the upper respiratory tract (and presumably also infectiousness) is correlated with fever and the severity of respiratory symptoms in both adults and children. The importance of transmission from infected persons during the incubation period or from persons with asymptomatic infection is uncertain but appears to be substantially less than from symptomatic persons. The principal difficulties in using nonpharmaceutical interventions to reduce influenza transmission among humans include the peak infectivity early in illness and the short incubation period, which both result in a short serial interval between related cases. Recent reports suggest that the 1918 virus may have been less transmissible than previously thought (R 0 1.8–3), although whether public health interventions in 1918 might have affected these estimates is uncertain. If a novel human influenza subtype behaves in a manner similar to the pandemic virus of 1918–1919, available information supports the use of nonpharmaceutical interventions to delay or contain transmission during WHO phases 4 and 5 (limited human-to-human transmission) and use of different interventions to reduce the impact in phase 6 (pandemic phase) ( 2 , 3 ). At the international level, experience in past influenza pandemics indicates that screening and quarantine of entering travelers at international borders did not substantially delay introduction, except in some island countries. Similar policies, even if they could be implemented in time and regardless of expense, would doubtfully be more effective in the modern era of extensive international air travel. WHO instead recommends that travelers receive health alert notices, although entry screening may be considered when the host country suspects that exit screening at the traveler's point of embarkation is suboptimal; in geographically isolated, infection-free areas (e.g., islands); and where a host country's internal surveillance capacity is limited ( 2 ). WHO recommends consideration of exit screening by health declaration and temperature measurement for international travelers departing countries with human infection at phases 4, 5, and 6. Exit screening in affected countries is a better use of global resources: fewer persons would need to be screened, the positive predictive value for ill persons detected would be higher, and transmission on conveyances, such as aircraft, would be reduced. Exit screening is disruptive and costly, however, and will not be fully efficient as influenza viruses can be carried by asymptomatic persons who will escape detection during screening ( 2 , 3 ). As was true for SARS, the principal focus of WHO-recommended nonpharmaceutical interventions is not at international borders but at national and community levels ( 4 ).
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            Viral Shedding and Clinical Illness in Naturally Acquired Influenza Virus Infections

            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.
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              Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2008.

              This report updates the 2007 recommendations by CDC's Advisory Committee on Immunization Practices (ACIP) regarding the use of influenza vaccine and antiviral agents (CDC. Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices [ACIP]. MMWR 2007;56[No. RR-6]). The 2008 recommendations include new and updated information. Principal updates and changes include 1) a new recommendation that annual vaccination be administered to all children aged 5--18 years, beginning in the 2008--09 influenza season, if feasible, but no later than the 2009--10 influenza season; 2) a recommendation that annual vaccination of all children aged 6 months through 4 years (59 months) continue to be a primary focus of vaccination efforts because these children are at higher risk for influenza complications compared with older children; 3) a new recommendation that either trivalent inactivated influenza vaccine or live, attenuated influenza vaccine (LAIV) be used when vaccinating healthy persons aged 2 through 49 years (the previous recommendation was to administer LAIV to person aged 5--49 years); 4) a recommendation that vaccines containing the 2008--09 trivalent vaccine virus strains A/Brisbane/59/2007 (H1N1)-like, A/Brisbane/10/2007 (H3N2)-like, and B/Florida/4/2006-like antigens be used; and, 5) new information on antiviral resistance among influenza viruses in the United States. Persons for whom vaccination is recommended are listed in boxes 1 and 2. These recommendations also include a summary of safety data for U.S. licensed influenza vaccines. This report and other information are available at CDC's influenza website (http://www.cdc.gov/flu), including any updates or supplements to these recommendations that might be required during the 2008--09 influenza season. Vaccination and health-care providers should be alert to announcements of recommendation updates and should check the CDC influenza website periodically for additional information.
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                Author and article information

                Contributors
                +41 (0)44 255 43 10 , stefan.kuster@usz.ch
                Journal
                BMC Infect Dis
                BMC Infect. Dis
                BMC Infectious Diseases
                BioMed Central (London )
                1471-2334
                21 May 2019
                21 May 2019
                2019
                : 19
                : 446
                Affiliations
                [1 ]ISNI 0000 0004 1937 0650, GRID grid.7400.3, Division of Infectious Diseases and Hospital Epidemiology, , University Hospital and University of Zurich, ; Raemistrasse 100 / HAL14 D6, 8091 Zürich, Switzerland
                [2 ]ISNI 0000 0004 1937 0650, GRID grid.7400.3, Institute of Medical Virology, , University of Zurich, ; Zurich, Switzerland
                [3 ]ISNI 0000 0004 1937 0650, GRID grid.7400.3, Department of Internal Medicine, , University Hospital and University of Zurich, ; Zurich, Switzerland
                [4 ]ISNI 0000 0004 1937 0650, GRID grid.7400.3, Pulmonary Division, , University Hospital and University of Zurich, ; Zurich, Switzerland
                [5 ]ISNI 0000 0004 1937 0650, GRID grid.7400.3, Hematology, , University Hospital and University of Zurich, ; Zurich, Switzerland
                [6 ]ISNI 0000 0004 0478 9977, GRID grid.412004.3, University Hospital Zurich, ; Zurich, Switzerland
                [7 ]GRID grid.492573.e, Department of Microbiology, , Sinai Health System, ; Toronto, Canada
                Author information
                http://orcid.org/0000-0002-0525-6529
                Article
                4057
                10.1186/s12879-019-4057-5
                6528321
                31113375
                6999ad71-5431-40db-bdc5-c40d28d741fb
                © The Author(s). 2019

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 22 November 2018
                : 1 May 2019
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001711, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung;
                Award ID: 32003B_156902
                Award Recipient :
                Funded by: Bundesamt für Gesundheit (CH)
                Award ID: 16.927730
                Award Recipient :
                Categories
                Research Article
                Custom metadata
                © The Author(s) 2019

                Infectious disease & Microbiology
                influenza,transmission,asymptomatic infection,surveillance,healthcare-associated infection

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