Influenza in long‐term care facilities

Long‐term care facility environments and the vulnerability of their residents provide a setting conducive to the rapid spread of influenza virus and other respiratory pathogens. Infections may be introduced by staff, visitors or new or transferred residents, and outbreaks of influenza in such settings can have devastating consequences for individuals, as well as placing extra strain on health services. As the population ages over the coming decades, increased provision of such facilities seems likely. The need for robust infection prevention and control practices will therefore remain of paramount importance if the impact of outbreaks is to be minimised. In this review, we discuss the nature of the problem of influenza in long‐term care facilities, and approaches to preventive and control measures, including vaccination of residents and staff, and the use of antiviral drugs for treatment and prophylaxis, based on currently available evidence.


| INTRODUCTION
The term "long-term care facility" (LTCF) encompasses a diverse range of healthcare settings including nursing homes, rehabilitation centres, long-term care hospitals, psychiatric care facilities and facilities for people with intellectual disabilities. 1 Although people of all ages may reside in these facilities, the majority of residents are elderly. With the population in Europe aged 85 years and above projected to rise from 14 million currently to 19 million by 2020 and to 40 million by 2050, and the expectation that more than 30% of European citizens will be aged over 60 years by 2050, the proportion of the population in countries at all levels of development which requires long-term care is only set to increase dramatically over the coming decades. 2 Outbreaks of seasonal influenza in LTCFs are well recognised, as are the challenges of preventing and controlling influenza outbreaks in these settings. The development of universally applicable guidance on the prevention and control of influenza and other respiratory viruses in LTCFs is difficult due to the huge variation in the size of facilities, patient characteristics, the intensity of care provided and resources available. Although some countries have produced guidance on IPC for use specifically in LTCFs, [3][4][5][6][7][8][9][10][11] most have not.
To help fill this gap, the WHO has recently published a best practice guidance document to support managers of LTCFs in the 53 WHO European Region Member States and which can be tailored according to national and local circumstances 12 (http://www.euro. who.int/__data/assets/pdf_file/0015/330225/LTCF-best-practiceguidance.pdf?ua=1).
In this review, we examine the impact of seasonal influenza in LTCFs, and approaches to the prevention and control of outbreaks, as outlined by the advice and evidence we provided in the WHO best practice document.

| THE IMPACT OF INFLUENZA
Persons residing in LTCFs present a population very susceptible to the acquisition and spread of infectious diseases and for whom the consequences of infection may be serious. Nursing home residents are at greatest risk due to their overall frailty, close quarter living arrangements, shared caregivers, and opportunities for introduction of healthcare-associated infections and the spread of pathogens to other facilities through resident transfers and the movement of staff and visitors in and out of the home. 13,14 Outbreaks of influenza caused by both influenza A and B viruses are well documented in LTCFs, and may be explosive, 15 with high mortality, highlighting the need for early recognition and prompt initiation of control measures. Accurate measurement of the burden of influenza is heavily influenced by circulating types and subtypes of virus and may vary between communities and between institutions so studies that attempt to estimate this burden require temporal, geographical and institutional breadth. 16 Older studies, relying on culture-based detection techniques, may have underestimated total burden. A review of 206 published infectious outbreaks in elderly care facilities across 19 countries over 40 years identified 37 different pathogens, but influenza viruses caused the largest number of outbreaks (23%). 17 In the 49 outbreaks caused by influenza, the median attack rate in residents was 33% (range 4-94%), and 23% (range 3-58%) among staff, with a median case-fatality rate for residents of 6.5% (range 0-55%). Over three consecutive 9-year time periods between 1980 and 2008, there was no observed decrease in attack rates or case-fatality rates; nevertheless, these data should be interpreted cautiously as antiviral use and the stringency of application of infection prevention and control (IPC) practices has changed over time.  19 Modelling studies suggest that the burden on the health services is particularly onerous for those aged 75 and above, with an estimated 36% of all influenza-attributable respiratory hospitalisations and 74% of all influenza-associated deaths occurring in this age group in the UK over 13 seasons, 20 and accounting for 52% of total hospital bed occupancy and 69% of excess bed days occupancy in England over a similar number of seasons. 21

Outbreaks of influenza (and other respiratory virus pathogens) in
LTCFs in the Northern Hemisphere occur most commonly during the winter but may occur at any time of year, particularly in the autumn months, usually due to circulation of influenza A(H3N2) and before seasonal vaccination campaigns have been fully implemented or when matching is poor; also in the spring when influenza B often peaks 22 and when antibody titres may have declined in the vaccinated. 23,24 Influenza virus replicates in the epithelium of the upper and lower respiratory tract, with infected hosts releasing virus into the environment during breathing, talking, coughing and sneezing, producing a spray of virus-containing particles ranging in size from 0.01 to 500 μm. 25 Transmission of influenza may occur by three routes: droplet (larger-sized particles too large to be inhaled into the lungs and which settle quickly to the ground or other surface within 2 m of the source); aerosol or droplet nuclei (small particles <5 μm which can remain suspended in the air much longer and are potentially inhalable into the lower respiratory tract); and contact (transfer of infectious particles to the mucous membranes directly or indirectly through contaminated objects). The relative importance of each of these routes in influenza transmission is unclear, and the contribution of aerosolised infectious droplet nuclei has been particularly contentious. [26][27][28][29][30][31] However, most influenza transmission is short-range, and when it has occurred over longer distances, contact transmission has generally not been ruled out. 32 Transmission studies often do not control for confounders such as vaccination status, handwashing practice, supershedders, amount of coughing, ward layout, surface contamination and ventilation, 33 and further studies which control for these are required in this area.
The incubation period of influenza is typically short, usually reported as ranging from 1 to 4 days, 34 with a serial interval (time

Key Points 1
• LTCFs are susceptible to seasonal influenza outbreaks, which may be explosive and with high attack rates in residents.
• Written IPC policies, vaccination policies for residents and staff, provision of ongoing staff IPC training and the facilities required to promote compliance with IPC practices should be in place throughout the year.
• Although influenza vaccine efficacy is lower in the elderly and in the presence of comorbidities compared to healthy younger adults, vaccination of LTCF residents remains a major public health tool and is recommended. between symptom onset in a secondary case and that of its primary case) of 2.2 to 3.5 days for influenza A and 3.4 to 4.9 days for influenza B. 35 The relatively short incubation period and serial interval enables the virus to spread rapidly through communities, so mitigation measures such as isolation and transmission-based precautions should be instigated as soon as a case of suspected influenza is identified to minimise the risk of transmission to contacts. Viral shedding has generally been considered to be a proxy for influenza infectiousness, 36-38 peaking 1 to 3 days after symptom onset with most healthy volunteers clearing virus by day 6 to day 7. 34 However, a recent study of household influenza transmission found at most only a weak association between viral load in nose and throat swabs and infectivity, possibly due to the weak correlation between virus concentration in exhaled breath and nose and throat samples, or due to the intensity of household transmission so that even those with low viral loads are still capable of infecting those around them. 39 Pre-symptomatic shedding may occur in up to one-third of cases, [40][41][42][43] and prolonged viral shedding has been reported in children, 42,44,45 in patients hospitalised with severe influenza 46 and in immunocompromised patients, 47 in whom prolonged shedding may last weeks or even months. 48,49 The transmission dynamics of influenza infections in residents of LTCFs have not been studied; age >65 years and the presence of major comorbidities were associated with prolonged shedding of virus and higher viral load in a prospective observational study of hospitalised influenza patients 46 ; these findings may raise the possibility of prolonged shedding in LTCF residents.
Transmission of influenza from healthcare workers (HCWs) to hospital patients, including those in geriatric facilities, has been well documented using epidemiological linkage, nucleotide sequence analysis and contact tracking data [50][51][52][53]  Furthermore, a study of HCWs in an acute hospital during a mild epidemic season, found that 23% had serological evidence of new influenza infection during the season, implying a potential transmission risk to patients as between 28% and 59% of infected workers had subclinical infections and continued to work. 57 Although the role of asymptomatic people and those with only mild symptoms in spreading influenza is uncertain, HCWs often continue to work despite having symptoms and may act as a source of infection to those in their care. [58][59][60] Nursing home aides in particular have been shown in one Swedish study to be the occupational group at significantly greatest risk of continuing to work despite the feeling that, in the light of their perceived state of health, they should have taken sick leave. 61 However, in reality the employment status of many LTCF staff is often precarious and taking unpaid sick leave may result in adverse economic consequences.

| Vaccination of LTCF residents
A WHO strategy and action plan for healthy ageing in Europe 2012-2020 recognised the benefit of proper vaccination strategies against infectious diseases, including influenza, both in older people and for health and social care workers in contact with them, and proposed priority interventions including national immunisation schedules and the implementation of infectious disease control programmes in institutions. 63 Furthermore, a WHO position paper published in 2012 recommended that elderly persons ≥65 years and people with specific chronic diseases should be considered for influenza vaccination. 64 Vaccination coverage of the elderly varies considerably between European countries with recent uptake rates reported between 1% and 77.4% and with only two countries (the Netherlands and the UK) achieving, or almost achieving, the WHO target of 75% coverage in the elderly. 65 For residents of LTCFs, recent data available from only three countries indicated vaccination coverage rates of 71% to 89%. 65 Vaccination of residents remains an important public health tool

| Vaccination of LTCF staff
Infection in HCWs affects not only themselves and their immediate family but may further inhibit efforts to control an outbreak if staff shortages result in remaining staff having to care for both affected and unaffected residents. 73 On this basis HCWs are recognised as a priority group for vaccination and are generally recommended to receive it. 64,74 High rates of staff vaccination in LTCFs have been demonstrated in several studies to decrease the risk of all-cause mortality and ILI in frail elderly residents, with lowest rates when both HCWs and patients had high vaccine coverage rates. [75][76][77][78][79] This has been somewhat refuted by a systematic review of four cluster-randomised controlled trials (RCTs) and one cohort study which suggested that offering vaccination to HCW caring for people aged over 60 in LTCFs may have little or no effect on laboratory-confirmed influenza (LCI) (Risk difference (RD) 0 (95% CI −0.03 to 0.03) and respiratory-related hospitalisation in residents (RD 0 (95% CI −0.02 to 0.02), although there may be a small decrease in lower respiratory infections from 6% to 4% in homes where [95% CI 56-67%]). 88 A systematic review specifically addressing the effectiveness of seasonal influenza vaccination in HCWs found just one study reporting laboratory-confirmed influenza in this group with a reported IVE of 88% (95% CI 59% to 96%, P=.0005). 89 Although the currently available evidence may be weak for HCW vaccination to protect the frail and elderly, there is also generally no evidence against it. Therefore, it remains a biologically plausible intervention to provide individual protection to the HCW, act as a barrier against spread of infection and to help reduce the risk associated with influenza infection and prevent staff absenteeism. However, poor vaccine uptake by HCWs has been well documented. In Europe, coverage of HCWs (including those working in LTCFs) varies between countries and is generally much lower than for other vaccination targeted groups, ranging from 9.5% to 75% with a median vaccination coverage rate of 28.6%. 65 In the United States, vaccination rates of 50-70% have been reported for LTCF workers, 78,90,91 with coverage consistently lower than among staff working in hospital settings. 91 Reasons given for declining vaccination include fear of side effects, lack of concern or perception of risk, doubts about vaccine efficacy, lack of availability or inconvenient delivery of vaccine, avoidance of medications and dislike of injections. 92 Although mandatory vaccination is effective if it can be implemented, 93

| Diagnosis in residents
Early recognition of influenza in residents of LTCFs may be problematic due to non-specific symptoms and the possibility of atypical presentation and lack of fever in the elderly with influenza. 97,98 Influenza may present as sudden, unexplained deterioration in physical or mental ability or exacerbation of an underlying condition with no other known cause. 15 The use of surveillance case definitions for ILI in these populations may therefore miss cases, especially if they present without fever. Furthermore, other underlying conditions may impair residents' abilities to verbalise their symptoms. This may impede the early implementation of control and treatment strategies. 99 The precise definition of ILI may vary from country to country; the WHO global surveillance case definition of ILI is an acute respiratory infection with measured fever ≥38°C and cough and onset within the last 10 days, 100 whereas that of the Centers for Disease Control and Prevention (CDC) and European Centre for Disease Prevention and Control (ECDC) definition is sudden onset of symptoms and at least one of four systematic symptoms (fever or feverishness, malaise, headache, myalgia) and at least one of three respiratory symptoms (cough, sore throat, shortness of breath). 3,101 To confirm an outbreak, reverse transcriptase polymerase chain reaction or viral culture are the preferred methods of laboratory testing. Rapid point-of-care diagnostic tests can produce a result within 30 minutes but have lower sensitivity (median 70-75%) 102 and there may be variability between different age groups and influenza subtypes, 103 although they may still be useful in outbreak situations, for example for rapid identification of influenza infection where timely access to more sensitive laboratory testing is unavailable or delayed.
However, clinical judgement is required to interpret negative rapid test results for individual patients during an outbreak and negative rapid test results may not justify delaying the instigation of outbreak control measures if there is clinical and epidemiological suspicion.

| OUTBREAK CONTROL MEASURES
Outbreak definitions vary between countries and are frequently based on the number of cases in a unit during a specified period of time. Although influenza may cause sporadic infection in LTCFs, given the vulnerability of the population and the propensity to spread rapidly, it is wise to have a low threshold for declaring an outbreak and commencing control measures, ideally before virological confirmation.
One case may be indicative of incubating infection in exposed persons, so these should be actively sought through daily surveillance of temperature and symptoms in all residents and staff. LTCFs. Compliance with these measures may be an issue and there is currently a paucity of directly observed studies of handwashing and mask-wearing. 33 There is some evidence that the wearing of a surgical face mask by an infected person decreases their infectiousness to others 108,109 and may be considered for infected LTCF residents, particularly if they have to be moved outside their own room or cohort area; although in reality this measure may not be tolerated by some individuals. Residents sharing a room with an influenza-infected roommate have three times the risk of acquiring infection than those in single rooms. 110 Although there is little convincing evidence that social distancing and isolation are effective in reducing transmission, 105

| Antiviral treatment
Early recognition of an influenza outbreak in a LTCF can facilitate timely antiviral treatment and prophylaxis to end the outbreak and thus avoid influenza-related complications in exposed residents. The neuraminidase inhibitors (NAIs) oseltamivir and zanamivir are currently authorised for the treatment and prophylaxis of influenza in Europe and the United States. However, their effectiveness has been subject to much debate 113 and many clinicians have felt confused about when to use them appropriately.
A modest but significant reduction in time to first alleviation of symptoms has been consistently shown in meta-analyses of RCTs of previously healthy people, representing a 10 to 15% reduction in overall duration of symptoms in those treated with an NAI compared with those receiving placebo, [114][115][116] with similar reductions noted from analysis of observational studies. 117 This effect appears to be somewhat attenuated in the elderly. 115,118 In general there is a lack of credible evidence from RCTs that NAIs reduce the risk of hospitalisation and pneumonia, 114,115,118 although a significant reduction was seen in hospitalisation in the influenza-confirmed intention-to-treat popula-

| Antiviral prophylaxis
Prophylaxis with antivirals is intended to prevent transmission of influenza virus to people who are not exhibiting ILI but who have or may have been exposed. There is a paucity of evidence from recent studies to inform a single approach for antiviral prophylaxis use in LTCFs, so decisions should be based on clinical judgement and outbreak severity. 121 Prophylaxis with oseltamivir or zanamivir was shown to be more effective than placebo at preventing symptomatic influenza in individuals in the community (oseltamivir RR 0. 45 122 However, direct evidence of effectiveness in reducing symptomatic influenza in the frail elderly living in institutions is sparse; a non-significant protective trend with post-exposure zanamivir prophylaxis has been shown in one study (RR 0.08 [95% CI 0.01 to 0.63]) 123 but data for the effectiveness of post-exposure oseltamivir in this setting are lacking. 124 Other studies have seen a non-significant effect of post-exposure prophylaxis and seasonal prophylaxis with zanamivir. 124,125 Prophylaxis for all residents in LTCFs experiencing an outbreak, regardless of vaccination status is recommended by the US Centers for Disease Control and Prevention (CDC) 3 ; the European Centre for Disease Prevention and Control (ECDC) expert opinion on the use of antivirals for prophylaxis recommends consideration of antiviral prophylaxis for residents of LTCFs, especially for those who are unvaccinated or immunocompromised who do not respond to vaccination. 126 This may be particularly important during years when IVE is expected to be low due to vaccine strain mismatch. But the relatively low effectiveness of influenza vaccine in the elderly population even in well-matched years should also be taken into consideration.
There is a lack of studies evaluating the effectiveness of giving prophylaxis to HCWs in LTCFs. The CDC recommends consideration of prophylaxis for unvaccinated HCWs caring for people at high risk of complications, and for all employees regardless of vaccination status if an outbreak is due to a strain which is poorly matched to the current vaccine strains. 3 To protect vulnerable people, ECDC also recommends consideration of prophylaxis for HCWs, particularly when low IVE is expected due to strain mismatch. 120 As IVE is lower in those who are elderly and frail than in younger healthy people, it would seem prudent to have a low threshold for offering prophylaxis to those caring for them, and particularly so if chains of transmission from a resident to staff are described; or from a resident to staff to resident.

Key Points 2
• Early recognition of a potential outbreak is important to facilitate timely antiviral treatment, prophylaxis and instigation of IPC measures (prior to virological confirmation if appropriate).
• Rapid point-of-care tests may be useful, but negative tests do not exclude a diagnosis of influenza.
• Antiviral treatment of symptomatic residents is recommended to be started immediately given their high risk of complications.
• For asymptomatic residents, the decision to give antiviral prophylaxis should be made on an individual basis using clinical judgement and risk of exposure, but as influenza vaccine is considered less effective in the elderly, the threshold for offering antiviral prophylaxis to all residents should be low.