Introduction
Because of its highly communicable and debilitating nature, influenza is the most dramatic infectious organism affecting elderly people. About 90% of the more than 1200 deaths each year in BC due to pneumonia and influenza involve persons 65 years of age and older; half of those occur during the four-month period from December to March. In the confined setting of the long-term care facility, attack rates for influenza can be very high, reaching up to 60% to 70% of residents[1,2] with case fatality rates as high as 30%.[3] Infection among health-care workers during outbreaks is also common (20% to 50% attack rates) leading to absenteeism, disruption of services, and greater risk to patients.[4]

Immunization—still the best form of protection
The best method of protecting institutionalized people against influenza is yearly resident and staff vaccination.[5] Elderly, frail residents may experience waning immunity within 3 to 4 months, so immunization should be timed to allow optimal protection throughout the peak season of December to March.[6] In BC, immunization of institutionalized people should typically begin 1 November, while staff, whose protection lasts 6 months or more, can be immunized beginning in October. Immunization of both groups should be complete by mid-November. Those who have not yet been immunized can still receive vaccine and derive benefit even after peak activity has begun.

Control measures can reduce the impact of influenza outbreaks. To enable swift and effective intervention, facility staff must recognize the signs of influenza-like illness in residents and report outbreaks early. Establishing lines of communication and outbreak protocols in advance facilitates this.

Identification of influenza-like illness
The replication cycle of influenza virus is less than 4 hours, and abrupt onset is characteristic of illness.[7] Influenza-like illness (ILI) typically consists of upper respiratory symptoms including cough accompanied by systemic complaints. The systemic complaints are related to immune phenomena rather than viremia. Fever is the most prominent sign of infection, except in the elderly and very young, in whom it may not be present.[7] Acute illness generally lasts 3 to 4 days but cough, malaise, and lethargy may persist for 1 to 2 weeks after the fever has resolved.[7]

For the purpose of surveillance in long-term care facilities during the 1999–2000 season, ILI is defined as: Acute onset of respiratory illness with cough and one or more of sore throat, arthralgia, myalgia, or prostration. Affected persons often experience fever or feverishness with chills, but these symptoms may not be prominent in the elderly.[9]

Identification of ILI outbreaks in long-term care
Since influenza outbreaks can progress quickly, a low threshold for reporting them in institutional settings is required. Facilities should watch for clusters of upper or lower respiratory tract infections occurring over a brief period. When a greater number of residents than expected are affected with respiratory illness, the local health unit should be notified. Suspect outbreaks, when there are two or more cases of ILI within a 7-day period, should be reported to the local health unit within 1 working day or sooner. Do not wait for lab confirmation before reporting.

First steps in managing an ILI outbreak
When an outbreak is reported, the local health unit will assist in assessing the clinical syndrome and attack rate, as well as in determining whether control measures are needed. Control measures should be tailored to the situation but may include isolation or cohorting of ill residents, environmental control and hygiene, and restriction of visitors, new admissions, elective transfers, or group activities. Even if influenza is not the cause, ensuring residents are up-to-date with influenza and pneumococcal vaccination and staff are up-to-date with influenza vaccination is always appropriate during the influenza season.

Confirmation of influenza A activity
Numerous pathogens can cause illness clinically indistinguishable from influenza A. It is therefore important to establish influenza A as the likely cause of an ILI outbreak before amantadine is considered. Newer antivirals, effective against influenza A and B, may prove useful against institutional outbreaks, but are not currently licensed for this purpose.

Amantadine is the only antiviral currently licensed in Canada for prophylaxis in outbreak control and it is ineffective against influenza B. While it is preferable to confirm influenza A on at least two specimens from within the affected facility, an outbreak of influenza A may also be identified after consultation with the local medical health officer based on what is known to be circulating in the local community.

Laboratory confirmation of influenza A is available within 24 to 48 hours from the BC provincial laboratory using rapid antigen testing when it is requested. Viral cultures are also done on the same specimen, but take longer (up to 1 week). Although nasopharyngeal swabs are more reliable, they can be uncomfortable, and nasal specimens are a practical alternative. Specimens should be collected from a handful of residents who are within 48 hours of onset of the illness.

If it’s influenza A—use of amantadine
Amantadine can be used if a facility outbreak is believed to be due to influenza A. Amantadine was first licensed for prophylaxis and treatment of influenza A in Canada in 1979, and the National Advisory Committee on Immunization has recommended its use since 1986. Scant corporate or public health promotion of this drug has left it grossly underutilized both for community and institutional indications.

Recently, however, amantadine prophylaxis has become the standard of practice in the control of influenza A outbreaks in BC. The unexpected emergence of influenza A/Sydney in 1997 led to an unprecedented number of facility outbreak reports and increased interest in complementary control measures. During the 1996–97 influenza season, only one of ten reported outbreaks in BC were managed with amantadine. During the 1997–98 and 1998–99 seasons, nearly half of 62 and almost 90% of 52 reported influenza A outbreaks, respectively, were managed this way. In the future, the new neuraminidase inhibitors will also likely play an expanded role in outbreak control.

How to use amantadine in the outbreak setting
Amantadine is 70% to 90% effective in preventing illness caused by influenza A.[10] When it is given simultaneously to all residents, regardless of vaccination status, and to unvaccinated staff, outbreak activity stops abruptly within a few days, and those who have witnessed its effect typically become converts to its use. When the outbreak does not stop abruptly, other causes or resistance should be considered. Amantadine should be continued for at least 2 weeks or until approximately 1 week after the onset of the last case in the facility.[8] Cost-effectiveness of this approach was demonstrated as long ago as 1986 by Patriarca. Previous vaccination and prophylaxis of residents during outbreaks in long-term care facilities are associated with reduced illness, hospitalization, and death at only marginally increased cost over vaccination alone.[1]

Amantadine will not benefit residents who have been ill for longer than 48 hours or who have already recovered. It can be used in the treatment of residents who are within 48 hours of illness onset, although its effectiveness in preventing complications in this population is based on results in younger adults.[6] Because resistance can emerge during treatment, it should be limited to 3 to 5 days (or up to 2 days after resolution) and patients being treated should be separated from those receiving prophylaxis.[6,8]

Dosage and side effects with amantadine
Side effects associated with amantadine include mild gastrointestinal and central nervous system symptoms such as insomnia, jitteriness, dizziness, and difficulty concentrating.[8,10] These are dose related and resolve with discontinuation.[8] Lowering the adult daily dose of 200 mg based on calculated creatinine clearance (derived from plasma creatinine, age, weight, and sex) is required in those with renal impairment and in elderly persons who may have reduced kidney function in the absence of obvious illness. Reported side effects in residents are uncommon when dosage is carefully titrated; the National Advisory Committee on Immunization has provided an algorithm for this purpose.[6,8] Table 1 [11] provides dosing guidelines for residents over under 65 years of age during a facility influenza A outbreak, but clinical discretion is still required in prescribing.

Determining each resident’s calculated creatinine clearance and amantadine dosage before the influenza season starts will allow prompt and safe administration at the time of an outbreak. Where this has not been done, a single 100 mg dose may be given while a stat serum creatinine is determined at the time of an outbreak. Creatinine clearance should be calculated for all residents, including those with normal serum creatinines. In a recent chart review of 300 residents in care in two Vancouver facilities, almost 70% of serum creatinines were found to be normal. Despite this, more than 90% of these residents had abnormal calculated creatinine clearances.[11]

A review of amantadine use in six long-term care facility outbreaks in Vancouver in 1998 found reported side effects were generally mild and transient; amantadine was administered to 426 residents and reported to be discontinued in only eight.[12] Similar findings were reported by Simon Fraser Health Region during the 1999 influenza season; 1016 residents were started on amantadine for outbreak control and only five discontinued their medication due to side effects. Nevertheless, reasonable monitoring is required as side effects such as marked behavioral changes, delirium, hallucinations, agitation, and seizures can occur, particularly in people with pre-existing psychiatric or seizure disorders or renal insufficiency.[6,8] In these patients further lowering the dosage is effective in reducing the severity of such side effects.

Making it work
Those who have used amantadine are typically amazed at the speed with which outbreaks are extinguished and at the low incidence of side effects when dosage is properly titrated. Such shared experience and awareness will contribute to its broader use. Physicians and facilities should take the time to familiarize themselves with local outbreak protocols. Recent efforts in several BC health regions have demonstrated the beneficial impact of pre-season planning in improving the efficiency of outbreak control measures, including amantadine administration, and in reducing the burden of illness associated with influenza.

FACT SHEET--Amantadine use in facility outbreaks of influenza [12] 

Dr Danuta Skowronski is a physician epidemiologist with Epidemiology Services, BC Centre for Disease Control. Dr Jane Buxton is a federal field epidemiologist with Health Canada. Dr Robert Parker is the associate medical health officer with Simon Fraser Health Region. At the time of writing, Dr Robert Strang was an associate medical health officer with South Fraser Health Region (he is now the medical health officer in Halifax).