Containing influenza outbreaks with antiviral use in long‐term care facilities in Taiwan, 2008‐2014

Backgrounds Influenza can spread rapidly in long‐term care facilities (LTCFs), and residents are usually at higher risk for influenza infections. Objective Our study aimed to evaluate the effectiveness of antiviral interventions on outbreak control. Methods Taiwan Centers for Disease Control used a syndromic surveillance system to monitor outbreaks in LTCFs. Local public health authorities verified those outbreaks and logged reports to the Epidemic Investigation Report Files Management System (EIRFMS). We conducted a retrospective cohort study by reviewing EIRFMS reports of influenza outbreaks in LTCFs during 2008‐2014. An influenza outbreak was defined as 3 or more cases of influenza‐like illness occurring within a 48‐hours period with ≥1 case of real‐time RT‐PCR‐confirmed influenza in the same LTCF. Antiviral interventions included providing antiviral treatment for patients and antiviral prophylaxis for contacts during outbreaks. Results Of 102 influenza outbreaks, median days from onset of the first patient to outbreak notification was 4 (range 0‐22). Median attack rate was 24% (range 2.2%‐100%). Median influenza vaccination coverage among residents was 81% (range 0%‐100%); 43% occurred during the summer months. Even though antiviral treatment was provided in 87% of the outbreaks, antiviral prophylaxis was implemented in only 40%. Starting antiviral treatment within 2 days of outbreak onset was associated with keeping attack rates at <25% (OR 0.29, 95% CI: 0.12‐0.71). Conclusions Early initiation of antiviral treatment may reduce the magnitude of influenza outbreaks. Clinicians should identify patients with influenza and start antiviral use early to prevent large outbreaks in LTCFs.

Backgrounds: Influenza can spread rapidly in long-term care facilities (LTCFs), and residents are usually at higher risk for influenza infections. Results: Of 102 influenza outbreaks, median days from onset of the first patient to outbreak notification was 4 (range 0-22). Median attack rate was 24% (range 2.2%-100%). Median influenza vaccination coverage among residents was 81% (range 0%-100%); 43% occurred during the summer months. Even though antiviral treatment was provided in 87% of the outbreaks, antiviral prophylaxis was implemented in only 40%. Starting antiviral treatment within 2 days of outbreak onset was associated with keeping attack rates at <25% (OR 0.29, 95% CI: 0.12-0.71).

Conclusions:
Early initiation of antiviral treatment may reduce the magnitude of influenza outbreaks. Clinicians should identify patients with influenza and start antiviral use early to prevent large outbreaks in LTCFs.

K E Y W O R D S
antivirals, influenza outbreak, long-term care facilities, prophylaxis Furthermore, influenza can spread rapidly in congregate settings. 2 As a result, influenza outbreaks in LTCFs last longer, causing more severe complications, and leading to increased mortality.
There are 1058 LTCFs around Taiwan as of August 2016. 3 Every year, 10-15 influenza outbreaks in these facilities were reported.
Previously, control of influenza outbreaks in LTCFs usually relied on non-pharmaceutical interventions, including patient isolation, personal hygiene enhancement, and environmental disinfection. After the licensure of neuraminidase inhibitor, many guidelines started to recommend the use of antiviral interventions, including antiviral treatment and antiviral prophylaxis, for outbreak control. [4][5][6] Although findings from a modeling analysis found that antiviral prophylaxis use was effective in controlling outbreaks, other studies, mainly observational, could not quantify the effectiveness of such interventions and make definitive conclusions. 5,7 In Taiwan, implementation of antiviral interventions in outbreaks increased gradually after the 2009 H1N1 influenza pandemic.
Although the use of antiviral treatment for high-risk groups, such as those with underlying diseases, the elderly and residents in LTCFs, has become standard clinical practice in Taiwan, no guidelines for antiviral use as part of outbreak control have been established yet. The initiation of antiviral prophylaxis depended on the on-site judgment of public health practitioners and varied from outbreak to outbreak, making the evaluation of effectiveness infeasible.
Our study aimed to describe the epidemiological characteristics of influenza outbreaks in LTCFs in Taiwan and to evaluate the effectiveness of antiviral interventions on outbreak control.

| Study design and data collection
Taiwan Centers for Disease Control (Taiwan CDC) used a syndromic surveillance system to monitor outbreaks in populous institutions, including LTCFs, around Taiwan. After outbreaks were notified with an influenza-like illness (ILI), local public health practitioners must verify the outbreaks, submit appropriate patient specimens to the reference laboratory of Taiwan CDC for the identification of causative agents, and log the outbreak investigation reports to the Epidemic Investigation Report Files Management System (EIRFMS). ILI was defined as an acute respiratory infection (symptoms including cough) with fever and had at least one of the following symptoms: soreness, headache, or malaise. Influenza infection was then confirmed using real-time reverse transcription-polymerase chain reaction (RT-PCR) test.
We conducted a retrospective cohort study and reviewed EIRFMSlogged reports of influenza outbreaks in LTCFs during 2008-2014. An influenza outbreak was defined as an incident with 3 or more patients having ILI occurring within a 48-hours period and at least one patient having laboratory-confirmed influenza infection in the same LTCF. 8 Date of outbreak start, notification, public health response, source of infection, total number of persons affected, duration of outbreak, and dates that of antiviral treatment and prophylaxis began were extracted from the outbreak reports. Date of outbreak start referred to the symptom onset date of the first ILI patient, and duration of outbreak was measured as the elapsed time from outbreak start to the date of outbreak end, which was the symptom onset of the last patient. Antiviral treatment was defined as the therapeutic use of antiviral agents for symptomatic patient. Antiviral prophylaxis was defined as the prophylactic use for non-ill contacts who lived in the same room or had daily activities in the same area as patients after the outbreak was notified. The antiviral agents used in an influenza outbreak were neuraminidase inhibitors, including oseltamivir (Tamiflu ® ) and zanamivir (Relenza ® ). The dosages of antiviral treatment and prophylaxis for adults and children were based on the US CDC recommendation. 9 The regimen of antiviral treatment was one dose given twice a day for 5 days, and the regimen of antiviral prophylaxis was one dose given once a day for 10 days. Prophylaxis was given only once during each outbreak, even if subsequent cases occurred. A large outbreak was defined as an outbreak with attack rate ≥ 25% because the median attack rate of the influenza outbreaks during the study period was around 25%.

| Statistical analysis
Descriptive analysis was performed to characterize the influenza outbreaks. Chi-square test for categorical variables and Wilcoxon test for nonparametric continuous variables were used to identify factors associated with the magnitudes of outbreaks, such as viral etiology, the elapsed time from outbreak start to notification and response and the use of antiviral interventions.
In a multiple logistic regression model, starting antiviral treatment within 2 days of outbreak start and use of antiviral prophylaxis at least 2 days, the average incubation period of influenza, before date of outbreak end were evaluated, along with previously reported risk factors, including type of influenza virus 10-12 and outbreak notification within 3 days, 13 to clarify whether these interventions were independently associated with large outbreaks. Data were maintained in Microsoft Excel 2016 (Bellevue, WA) and analyzed using Stata 12.0 (Stata Corp, College Station, TX).

| Ethical approval
Because the data in outbreak reports were collected in response to the influenza outbreaks in those facilities, an ethical approval was waived.

| RESULTS
A total of 102 influenza outbreaks were logged during the 7-year period, with outbreaks involving a median of 12 patients (range 3-75).
The median number of residents in the facilities was 65.5 .
Median days from outbreak start to outbreak notification was 4 (range 0-22 days). Median attack rate was 24% (range 2.2%-100%). Of the 86) were H3N2. In 18% of the outbreaks, an affected staff in the facilities was the first patient with ILI. Outbreaks peaked in August, with 40% of the outbreaks occurring during the summer months (June, July, and August) ( Figure 1).

| DISCUSSION
In this study, we analyze the epidemiological data of influenza outbreaks in LTCFs from 2008 to 2014. The effectiveness of antiviral prophylaxis could not be accurately estimated because it was usually started late in an outbreak, but early use of antiviral treatment may help to prevent a large influenza outbreak by decreasing the chance to only one-third.
Influenza outbreaks in LTCFs in Taiwan mostly occurred during the summer months according to our analysis. Despite having a subtropical climate with mild winters, Taiwan does experience seasonal influenza epidemics with cases rising in December, peaking in late January to early February. This epidemic pattern was similar during our study periods, from 2008 to 2014. 14 Outbreaks of influenza in LTCFs are expected to also occur during this period, as reported by the Canadian study, 13 which found more influenza outbreaks in the winter months. Although antiviral prophylaxis has also been recommended in many guidelines for controlling influenza outbreak, 2,4,19 there were concerns about increase in drug resistance and tremendous costs of antiviral agents. In Taiwan, there is no guidance on using antiviral prophylaxis in influenza outbreaks in LTCFs. The decision was usually made on a case-by-case basis by Taiwan CDC, the agency that stockpiled the antiviral agents for influenza, after an outbreak was notified.
Considerations on whether to initiate an antiviral prophylaxis included the timing, duration and attack rate at notification, vaccination coverage in residents, total cost of prophylaxis, risks for severe influenza infection among residents, and possibly induced drug resistance.  According to Taiwan's laboratory surveillance data, the proportion of oseltamivir-resistant influenza viruses was less than 1% of isolates tested in these years. 26,27 Although oseltamivir-resistant influenza virus had been rarely reported in Taiwan since 2009, antiviral prophylaxis was usually delayed because of late notification or the reluctance of massive antiviral use with enormous cost.
While previous modeling study has demonstrated the effectiveness of antiviral prophylaxis in outbreak control, 7  There are limitations in our study. First, this study is observational rather than interventional. It was difficult to control all the confounding parameters besides the use of antiviral interventions, for example, the awareness of influenza outbreak or the degree of implementation of non-pharmaceutical interventions. However, Taiwan CDC has developed the infection control protocol for LTCFs.
The protocol provides guidance on how to maintain the syndromic surveillance system in LTCFs and how to follow the guidelines of non-pharmaceutical control measures, such as the use of appropriate personal protection equipment and maintaining environmental hygiene. Taiwan CDC also conducts regular checkup and on-job professional education for those healthcare workers in LTCFs to improve their awareness and knowledge. Therefore, we expected the differences among different facilities, such as the preparedness for outbreak, awareness, and capability of healthcare workers and clinicians, could be minimized. Furthermore, the notification and registration of an outbreak relied on local health workers to log in EIRFMS. As a result, the completeness may be questionable and the total number of outbreaks may be underestimated. However, the effect may be minimal because preventing outbreaks from occurring in LTCFs is an important mission of local health departments, and Regional Centers of Taiwan CDC supervise outbreak control and ensure all outbreaks logged after each notification. Lastly, most antiviral prophylaxis was started late in an outbreak; therefore, it is difficult to distinguish whether the outbreak subsided by naturally or through the use of prophylaxis. Further interventional study using standard protocol for antiviral prophylaxis may be required to confirm its effectiveness.
In summary, our study revealed antiviral intervention affect the control of influenza outbreaks in LTCFs and early initiation of antiviral treatment could reduce the risk of development into large outbreaks to about one-third. Early notification of influenza outbreaks in LTCFs and increased awareness of antiviral role in containing outbreaks among clinicians could facilitate timely interventions.