Canada Communicable Disease Report
Vol. 26 (ACS-2)
1 June 2000

An Advisory Committee Statement (ACS)
National Advisory Committee on Immunization (NACI)* +

STATEMENT ON INFLUENZA VACCINATION FOR THE 2000-2001 SEASON

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PREAMBLE

The National Advisory Committee on Immunization (NACI) provides Health Canada with ongoing and timely medical, scientific, and public-health advice relating to immunization. Health Canada acknowledges that the advice and recommendations set out in this statement are based upon the best current available scientific knowledge, and is disseminating this document for information purposes. Persons administering or using the vaccine should also be aware of the contents of the relevant product monograph(s). Recommendations for use and other information set out herein may differ from that set out in the product monograph(s) of the Canadian licensed manufacturer(s) of the vaccine(s). Manufacturer(s) have only sought approval of the vaccine(s) and provided evidence as to its safety and efficacy when used in accordance with the product monographs.

INTRODUCTION

The antigenic components of the influenza vaccine have been updated for the 2000-2001 season. The present statement also contains updated information on pandemic planning, epidemiology, recommended recipients, strategies for influenza control, and prophylaxis.

In Canada, two available measures can reduce the impact of influenza: immunoprophylaxis with inactivated (killed-virus) vaccine and chemoprophylaxis or therapy with an influenza-specific antiviral drug (amantadine). Vaccination of persons at high risk each year before the influenza season is currently the most effective measure for reducing the impact of influenza.

Influenza A viruses are classified into subtypes on the basis of two surface antigens: hemagglutinin (H) and neuraminidase (N). Three subtypes of hemagglutinin (H1, H2, and H3) and two subtypes of neuraminidase (N1 and N2) are recognized among influenza A viruses that have caused widespread human disease. Immunity to these antigens - especially to the hemagglutinin - reduces the likelihood of infection and lessens the severity of disease if infection occurs. Infection with a virus of one subtype confers little or no protection against viruses of other subtypes. Furthermore, over time, antigenic variation (antigenic drift) within a subtype may be so marked that infection or vaccination with one strain may not induce immunity to distantly related strains of the same subtype. Although influenza B viruses have shown more antigenic stability than influenza A viruses, antigenic variation does occur. For these reasons, major epidemics of respiratory disease caused by new variants of influenza continue to occur.

The 1999-2000 influenza season was characterized by a single peak of influenza activity in early January, which appeared to spread rapidly from west to east. Between 4 September 1999 and 22 April 2000, the Laboratory Centre for Disease Control (LCDC) received reports on 51,439 laboratory tests for influenza; 7,027 (14%) were positive, 6,961 (99.1%) were confirmed as influenza type A, and 66 (0.9%) as influenza type B. The provincial distribution of influenza A specimens was as follows: Newfoundland (71), Nova Scotia (188), New Brunswick (98), Prince Edward Island (14), Quebec (1,590), Ontario (2,898), Manitoba (253), Saskatchewan (431), Alberta (1,126), and British Columbia (358). These results reflect influenza activity and also local testing policies and resources. Isolates from the Yukon, Northwest Territories, and Nunavut are included in provincial totals.

As of 30 March 2000, the Bureau of Microbiology, LCDC, has characterized 494 isolates; 437 (88.5%) were A/Sydney/5/97(H3N2)-like, 46 (9.3%) were A/New Caledonia/20/99(H1N1)-like, and 11 (2.2%) were B/Beijing/184/93-like. The provincial distribution of A/Sydney/5/97-like isolates was as follows: Newfoundland (7), Nova Scotia (21), New Brunswick (6), Prince Edward Island (4), Quebec (33), Ontario (260), Manitoba (10), Saskatchewan (37), Alberta (32), and British Columbia (27). Of the 46 A/New Caledonia/20/99-like isolates, 18 were from Nunavut, 20 were from Ontario, five were from Quebec, two were from Alberta, and one was from Saskatchewan. Both Nunavut and Ontario reported outbreaks of A/New Caledonia/20/99-like influenza. Of note, there has been a substantial increase in H1N1 activity in Canada this season as compared with the 1998-1999 season when only one H1N1(A/Bayern/7/95-like) strain was detected.

Since October 1999, there has been influenza activity in both the northern and southern hemispheres. Activity peaked in the northern hemisphere in late December to mid January, with most countries reporting widespread and regional influenza outbreaks. By February, influenza activity had declined in North America and most of Europe, however Russia and pockets in Europe were still reporting widespread influenza outbreaks. Between October and February, most countries reporting in the southern hemisphere indicated sporadic influenza activity throughout the season.

Since October 1999, 54 countries reported laboratory confirmed influenza A to the World Health Organization (WHO), while only 32 countries reported influenza B. Both subtypes of influenza A (H3N2 and H1N1) and influenza B were detected on six continents (Africa, North America, South America, Asia, Europe, and Oceania). Of the influenza A viruses, A/Sydney/5/97(H3N2) appeared to be the predominant circulating strain world wide, including Canada and the United States. Four other H3N2 strains were also in circulation: A/Moscow/10/99, A/Panama/2007/99, A/Perugia/5/99, and A/Lyon/CHU/868/00. These strains were detected in Europe and the eastern hemisphere this season, but were not detected in North America and South America. Less commonly detected were the H1N1 strains. The most commonly detected H1N1 strain was A/New Caledonia/20/99 which was detected in 14 countries on four continents, including Canada and the United States. Two strains of influenza B were detected: B/Beijing/184/93 and B/Yamanashi/166/98. B/Beijing/184/93 was the more common strain detected, isolated in 17 countries on five continents, including Canada and the United States.

The antigenic characteristics of current and emerging influenza virus strains provide the basis for selecting the strains included in each year's vaccine. As suggested by WHO, NACI recommends that the trivalent vaccine for the 2000-2001 season in the northern hemisphere contain an A/Moscow/10/99(H3N2)-like virus, an A/New Caledonia/20/99(H1N1)-like virus, and a B/Beijing/184/93-like virus. It should be noted that A/Panama/2007/99 is an A/Moscow/10/99(H3N2)-like virus, and the most widely used B/Beijing/184/93-like vaccine strain virus is B/Yamanashi/166/98.

Annual immunization is required because there is always a change in the vaccine in response to antigenic drift. As well, immunity declines in the year following vaccination. Each 0.5 mL of vaccine will contain 15 µg of hemagglutinin of each antigen. The vaccine will be available as a split-virus (chemically disrupted) preparation. Both humoral and cell-mediated responses are thought to play a role in immunity to influenza. The production and persistence of antibody after vaccination depends on several factors, including age, prior and subsequent exposure to antigens, and presence of immunodeficiency states. Humoral antibody levels which correlate with vaccine protection are generally achieved by 2 weeks after immunization. Immunity after the inactivated vaccine usually lasts < 1 year⁽¹⁾. However, in the elderly, antibody levels may fall below protective levels in <= 4 months. Data are not available to support the administration of a second dose of influenza vaccine in elderly individuals in order to boost immunity.

The recommended time for influenza immunization is the period from October to mid-November. However, decisions regarding the exact timing of vaccination of ambulatory and institutionalized individuals must be made based on local epidemiology, recognition of the need to use patient contacts with health-care providers as opportune moments for immunization, and program issues. Further advice regarding the timing of influenza vaccination programs may be obtained through consultation with local medical officers of health. Health-care workers (HCWs) should use every opportunity to give vaccine to any individual at risk who has not been immunized during the current season, even after influenza activity has been documented in the community.

RECENT DEVELOPMENTS IN PANDEMIC PLANNING, INFLUENZA EPIDEMIOLOGY, AND THERAPY

• The Canadian Contingency Plan for Pandemic Influenza is being revised as a result of input from several working groups and formal consultation with the provinces and territories. Its purpose is to enhance the capacity of Canada to respond to such an event and to decrease associated mortality, morbidity, and societal disruption. A memorandum of understanding between federal, provincial, and territorial governments is being developed to address issues such as identified roles and responsibilities, as well as choosing options for vaccine and antiviral drug supply and related funding. A meeting to facilitate contingency planning at provincial and territorial, and local levels took place January 2000. At the time of this meeting, approximately half of the provinces and territories had already commenced planning activities.

• In a recently published study from California, the rate of hospitalization during the influenza season for acute respiratory disease among children who did not have conditions that put them at high risk for complications of influenza, was approximately 12 times higher in those < 2 years of age compared to those 5 to 17 years of age⁽²⁾. Another study from Tennessee demonstrated hospitalization rates for illness attributable to influenza, among healthy children < 1 year of age, that were similar to rates for adults at high risk for influenza⁽³⁾. Influenza accounted for a substantial number of outpatient visits and courses of antibiotics in Tennessee children of all ages.

• Two neuraminidase inhibitors, zanamivir and oseltamivir, have been licensed in Canada for therapy of infection due to either influenza A or B virus. At the time of writing of this statement, neither have been approved in Canada for prophylactic use. As NACI's mandate does not encompass influenza therapy, this statement will not specifically discuss the therapeutic use of these agents. Recently published reviews are available for further information⁽⁴⁾.

Recommendations for the prevention and control of influenza during the 2000-2001 influenza season follow.

RECOMMENDED RECIPIENTS

Current influenza vaccines licensed in Canada are immunogenic, safe, and associated with minimal side effects (see "Adverse reactions" and "Contraindications and precautions" below). Influenza vaccine may be administered to any healthy child, adolescent, or adult for whom contraindications are not present.

To reduce the morbidity and mortality associated with influenza and the impact of illness in our communities, immunization programs should focus on those at high risk for influenza-related complications, those capable of transmitting influenza to individuals at high risk for complications, and those who provide essential community services. However, significant morbidity and societal costs are also associated with seasonal interpandemic influenza illness and its complications occurring in healthy children and adults⁽¹⁾. For this reason, healthy adults and their children who wish to protect themselves from influenza should be encouraged to receive the vaccine (see "Immunization of healthy persons" below).

People at high risk for influenza-related complications

• Adults and children with chronic cardiac or pulmonary disorders (including bronchopulmonary dysplasia, cystic fibrosis, and asthma) severe enough to require regular medical follow-up or hospital care. Chronic cardiac and pulmonary disorders are by far the most important risk factors for influenza-related death^(5,6).

• People of any age who are residents of nursing homes and other chronic care facilities. Such residents often have one or more of the medical conditions outlined in the first group. In addition, their institutional environment may promote spread of the disease. Studies have shown that the use of vaccine in this setting will decrease the occurrence of illness, hospital admission, pneumonia, and death^(7,8).

• People >= 65 years of age. The risk of severe illness and death related to influenza is moderately increased in healthy people in this age group, but is not as great as in people with chronic underlying disease. Vaccination is effective in preventing hospital admission and death, and results in direct health-care cost savings⁽⁹⁾.

• Adults and children with chronic conditions, such as diabetes mellitus and other metabolic diseases, cancer, immunodeficiency, immunosuppression (due to underlying disease and/or therapy), renal disease, anemia, and hemoglobinopathy. Influenza vaccine is effective in reducing hospital admissions in adults with diabetes⁽¹⁰⁾. The efficacy of the vaccine among children with chronic metabolic and renal diseases is uncertain, but this uncertainty should not preclude consideration of the vaccine. Immunosuppressed patients are at increased risk for influenza infection, morbidity and mortality^(11,12). Although some immunosuppressed individuals may have a suboptimal immune response, influenza vaccination is safe and can induce protective antibody levels in a substantial proportion of adults and children, including transplant recipients, those with proliferative diseases of the hematopoietic and lymphatic systems, and HIV infected patients^(13-17). Among the latter, enhanced HIV replication may occur in those persons who develop an immune response to the vaccine and are not receiving suppressive anti-retroviral therapy. However the increase appears to be transient and has not been shown to be associated with disease progression^(18,19). Influenza vaccination guidelines for HIV-infected individuals which takes into account CD4+ T-lymphocyte cell counts and anti-retroviral therapy, have been proposed by some investigators⁽¹⁹⁾, pending further studies in this population.

• Children and adolescents (age 6 months to 18 years) with conditions treated for long periods with acetylsalicylic acid. This therapy might increase the risk of Reye syndrome after influenza.

• People at high risk of influenza complications embarking on travel to destinations where influenza is likely to be circulating. Immunization with the most current available vaccine should be considered for all individuals who wish to avoid influenza while travelling to areas where influenza is likely to be circulating. There is insufficient evidence at this time to advise in favour or against routine re-immunization of travellers who were immunized in the fall, and who are subsequently travelling to regions where influenza may be circulating in the late spring and summer months. In the tropics, influenza can occur throughout the year. In the southern hemisphere, peak activity occurs from April through September. In the northern hemisphere, peak activity occurs from November through March. Travel may expose individuals to situations which facilitate the transmission of influenza^(20,21). The effectiveness of the influenza immunization for travellers may vary depending on differences between influenza strains encountered abroad and those included in the current vaccine.

People capable of transmitting influenza to those at high risk for influenza-related complications

People who are potentially capable of transmitting influenza to those at high risk should receive annual vaccination, regardless of whether the high-risk person(s) is immunized.

• HCWs and other personnel who have significant contact with people in the high-risk groups previously described (see "Strategies for Reducing the Impact of Influenza" below). The following groups should be vaccinated^(8,20,22-25): HWCs in long-term care facilities (LTCFs), hospitals, and outpatient settings; employees of LTCFs who have patient contact; and those who provide services within relatively closed settings to persons at high risk (e.g. providers of home-care services, crew on ships that cater to those at high risk).

• Household contacts (including children) of people at high risk who either cannot be vaccinated or may respond inadequately to vaccination. Because low antibody responses to influenza vaccine may occur in some people at high risk (e.g. the elderly, people with immunodeficiency), annual vaccination of their household contacts may reduce the risk of influenza exposure.

People who provide essential community services

Vaccination may be considered for these individuals in order to minimize the disruption of routine activities in epidemics. Employers and their employees should consider yearly influenza immunization for healthy working adults as this has been shown to decrease work absenteeism from respiratory and other illnesses^(26-30).

Further comments regarding recommended recipients

• Immunization of healthy persons. Any individual who wishes to protect him/herself from influenza should be encouraged to receive the vaccine, even if they are not in one of the aforementioned priority groups. Several studies have shown that influenza immunization of healthy adults and children may be cost-effective, under selected circumstances^(26-34). Assessment of the potential benefits of influenza immunization in healthy adults and children depends on numerous factors, including seasonal viral virulence and attack rates, the match between vaccine and circulating viral strains, protective immunity in previously infected individuals, vaccine side-effects, and the costs of vaccination and of influenza-associated morbidity^(32-35). Among children, the effects of co-circulating viruses such as respiratory syncytial virus must be separated from those of influenza⁽³⁶⁾. Policy decisions regarding public funding of influenza vaccine for healthy adults and children depends on modelling of these factors within populations, as well as assessing health priorities, resources, and pragmatic program issues^(35-37).
  
  The American Academy of Family Physicians and the Advisory Committee on Immunization Practices (ACIP) have recommended lowering the age of universal influenza vaccination of adults to 50 years of age^(36,38). The primary rationale is that many persons 50 to 64 years of age have high-risk conditions such as diabetes mellitus, or heart disease, yet the influenza immunization rate among American adults in this age group who have high-risk chronic medical conditions is 24% to 32%^(36,39). The low immunization rate is caused by persons being unaware they have a high-risk condition, lack of health-care access, or failure of HCWs to deliver immunization⁽⁴⁰⁾. Age-based influenza guidelines may be more successful in reaching individuals with medical conditions that put them at higher risk of influenza complications, compared to previous guidelines based on recognition of the specific high risk conditions. The cost-benefit of this change in American guidelines has not been fully assessed.
  
  At the present time, NACI suggests that program decisions in Canada regarding how to access and immunize those listed under "Recommended Recipients" (see above) are best made by agencies responsible for the planning and implementation of such programs.

• Influenza vaccine in pregnancy. Influenza vaccine is considered safe for pregnant women at all stages of pregnancy, and for breastfeeding mothers. Vaccination is recommended for pregnant and breastfeeding women who are characterized by any of the conditions listed under "Recommended Recipients" (see above). The routine immunization of otherwise healthy women in the second or third trimester of pregnancy has been recommended by ACIP on the basis of case reports, observational studies, and one retrospective case-control study of a selected Tennessee population^(36,41-46). Applying the Tennessee study results to Canadian and European populations has been questioned. The degree of morbidity due to influenza in Canadian women who are pregnant has not been established, and the preventable fraction of morbidity that could potentially be achieved through the use of the influenza vaccine in this population is unknown. NACI concludes that there is insufficient evidence at this time to recommend the routine immunization of otherwise healthy Canadian women who are pregnant during influenza season.

ADMINISTRATION OF INFLUENZA VACCINE

Dosage schedule

The recommended dosage schedule and type of influenza vaccine are presented in Table 1. Split-virus vaccines are available in Canada. Children < 9 years require two doses of the split-virus influenza vaccine, with an interval of 4 weeks; however the second dose is not needed if the child received one or more doses of vaccine prepared for a previous season. In infants < 6 months of age, influenza vaccine is less immunogenic than in infants and children aged 6 to 18 months. Therefore, immunization with currently available influenza vaccines is not recommended for infants < 6 months of age.

Table 1 Recommended influenza-vaccine dosage, by age, 2000-2001

Intramuscular administration is preferred. The deltoid muscle is the recommended site in adults and older children, the anterolateral thigh in infants and young children.

Adverse reactions

Influenza vaccination cannot cause influenza because the vaccine does not contain live virus. Soreness at the injection site lasting up to 2 days is common, but rarely interferes with normal activities. Fever, malaise, and myalgia may occur within 6 to 12 hours after vaccination and last 1 to 2 days, especially in young adults who have received the whole-virus vaccine and those receiving vaccine for the first time. Prophylactic acetaminophen may decrease the frequency of some side effects in adults⁽⁴⁷⁾. Healthy adults receiving the split-virus vaccine showed no increase in the frequency of fever or other systemic symptoms compared to those receiving placebo⁽⁴⁸⁾. In children aged 2 to 12 years, fever and local reactions are no more frequent after administration of split-virus vaccine than after placebo injections. In those < 24 months of age, fever occurs more often but is seldom severe.

Allergic responses are rare and are probably a consequence of hypersensitivity to some vaccine component, most likely residual egg protein, which is present in minute quantities.

Rare cases of systemic vasculitis have been reported to occur in individuals within 2 weeks of influenza vaccination^(49,50). Influenza antigens have not been identified in circulating immune complexes or in vessel walls, and a causal relationship has not been proven.

Guillain-Barré syndrome (GBS) associated with influenza vaccination has been observed in a minority of influenza seasons over the last two decades. Apart from the 1976-1977 swine flu season, the risk of GBS associated with influenza vaccination is small. In a retrospective study of the 1992-1993 and 1993-1994 seasons in four American states⁽⁵¹⁾, the relative risk of GBS occurring within 6 weeks after influenza vaccination, adjusted for age and sex, was 1.7 (95% confidence intervals 1.0, 2.8; p = 0.04), suggesting slightly more than one additional case of GBS per million persons vaccinated against influenza. In comparison, the morbidity and mortality associated with influenza are much greater.

In Canada the background incidence of GBS is estimated at just over 20 cases per million population in a study done in Ontario and Quebec⁽⁵²⁾. A variety of infectious agents, such as Campylobacter jejuni, have been associated with GBS. It is not known whether influenza virus infection itself is associated with GBS. It is also not known whether influenza vaccination is causally associated with increased risk of recurrent GBS in persons with a previous history of GBS. Avoiding subsequent influenza vaccination of persons known to have developed GBS within 6 to 8 weeks of a previous influenza vaccination appears prudent at this time.

Influenza vaccine is not known to predispose to Reye syndrome.

Please refer to the Canadian Immunization Guide⁽⁵³⁾ for further details about administration of vaccine and management of adverse events.

Contraindications and precautions

Influenza vaccine should not be given to people who had an anaphylactic reaction to a previous dose or with known anaphylactic hypersensitivity to eggs manifested as hives, swelling of the mouth and throat, difficulty in breathing, hypotension, and shock.

Individuals with acute febrile illness usually should not be vaccinated until their symptoms have abated.

Although influenza vaccination can inhibit the clearance of warfarin and theophylline, clinical studies have not shown any adverse effects attributable to these drugs in people receiving influenza vaccine.

Simultaneous administration of other vaccines The target groups for influenza and pneumococcal vaccination overlap considerably. Health-care providers should take the opportunity to vaccinate eligible persons against pneumococcal disease when influenza vaccine is given. The concurrent administration of the two vaccines at different sites does not increase the risk of side effects. Pneumococcal vaccine, however, is usually given only once, whereas influenza vaccine is given annually. Children at high risk may receive influenza vaccine at the same time but at a different site from that used for routine pediatric vaccines.

Storage

Influenza vaccine should be stored at 2^o C to 8^o C and should not be frozen.

STRATEGIES FOR REDUCING THE IMPACT OF INFLUENZA

The effectiveness of influenza vaccine varies depending upon the age and immunocompetence of the vaccine recipient, the degree of similarity between the virus strain included, and the strain of circulating virus during the influenza season. With a good match, influenza vaccination has been shown to prevent illness in approximately 70% of healthy children and adults. Under these circumstances, studies have also shown influenza vaccination to be approximately 70% effective in preventing hospitalization for pneumonia and influenza among elderly persons living in the community. Studies among elderly persons residing in nursing homes have shown influenza vaccination to be 50% to 60% effective in preventing hospitalization and pneumonia and up to 85% effective in preventing death, even though efficacy in preventing influenza illness may often be in the range of 30% to 40% among the frail elderly.

Vaccination is recognized as the single most effective way of preventing or attenuating influenza for those at high risk of serious illness or death. Influenza vaccine programs should aim to vaccinate at least 90% of eligible recipients. Nevertheless, only 70% of long-term care facility (LTCF) residents and 20% to 40% of adults and children with medical conditions listed previously receive vaccine annually^(54,55). Studies of HCWs in hospitals and LTCFs have shown vaccination rates of 26% to 61%^{(36,22-25,56,57)}.

This low rate of utilization is due both to failure of the health-care system to offer the vaccine, and to refusal by persons who fear adverse reactions or mistakenly believe that the vaccine is either ineffective or unnecessary^(56-58). HCWs and their employers have a duty to actively promote, implement, and comply with influenza immunization recommendations in order to decrease the risk of infection and complications in the vulnerable populations they care for. Educational efforts aimed at physicians and the public should address common concerns about vaccine effectiveness and adverse reactions. These include the beliefs of patients at risk, HCWs, and other service providers that they rarely get influenza, the fear of side effects from the vaccine, and doubt about the efficacy of the vaccine.

The advice of a health-care provider is often a very important factor affecting whether a person is immunized or not⁽⁵⁹⁾. Most people at high risk are already under medical care and should be vaccinated during regular fall visits. Strategies to improve coverage include the following:

• standing-order policies in institutions allowing nurses to administer vaccine, and simultaneous immunization of staff and patients in nursing homes and chronic care facilities (In a recent study of Canadian LTCFs, increased vaccination rates were associated with a single non-physician staff person organizing the program, having program aspects covered by written policies, a policy of obtaining consent on admission that was durable for future years, and automatically administering vaccine to residents whose guardians could not be contacted for consent⁽⁵⁷⁾.)

• vaccinating people at high risk who are being discharged from hospital or visiting the emergency room in the autumn

• promoting influenza vaccination in clinics which see high-risk groups (e.g. cancer clinics, cardiac clinics, and pulmonary clinics)

• using community newspapers, radio, television, flu-information lines, and collaborating with pharmacists and specialist physicians to distribute positively-framed information about the benefits and risks of immunization

• issuing computer-generated reminders to physicians, mailing reminder letters to patients, or using other recall methods to identify outpatients at high risk

• patient-carried reminder cards

• increased accessibility of immunization clinics to staff in institutions and community-based elderly, including implementation of mobile programs

• organized activities, such as vaccination fairs and competitions between institutions

• working with multicultural groups to plan and implement effective programs.

Vaccination of HCWs

In order to protect vulnerable patients in an outbreak situation, it is reasonable to exclude from direct patient care HCWs who develop confirmed or presumed influenza, and unvaccinated HCWs who are not on antiviral prophylaxis.

Transmission of influenza between clinically or subclinically infected HCWs and their vulnerable patients results in significant morbidity and mortality^(22,36). In the absence of contraindications, refusal of HCWs to be immunized implies failure in their duty of care to their patients. Studies have demonstrated that HCWs who are ill with influenza frequently continue to work^(22,24). In a recent British study, 59% of HCWs with serologic evidence of recent influenza infection could not recall having influenza, suggesting that many HCWs experience subclinical infection⁽⁶⁰⁾. These individuals continued to work, potentially transmitting infection to their patients. In addition, absenteeism of HCWs who are sick with influenza results in excess economic costs and in some cases, potential endangerment of health-care delivery due to scarcity of replacement workers.

Vaccination of HCWs in health-care facilities has been shown to reduce total patient mortality, influenza-like illness, and serologically confirmed influenza^(23-25,36). Influenza vaccination programs for HCWs may also result in cost savings and reduced work absenteeism, depending on factors including disincentives to take sick days, strain virulence, and the match between infecting strain and vaccine^{(25,28,60-62)}.

RECOMMENDATIONS FOR THE PROPHYLACTIC USE OF AMANTADINE

Amantadine hydrochloride is an antiviral agent that interferes with the replication cycle of type A (but not type B) influenza viruses. The following are recommendations for its use in prophylaxis. Use of amantadine for therapy of patients with influenza is not discussed in this statement.

At the time of writing of this statement, the only drug currently approved in Canada for the specific prophylaxis of influenza virus infections is amantadine hydrochloride. It is 70% to 90% effective in preventing illness caused by type A influenza viruses but is ineffective against type B strains. Because antiviral agents taken prophylactically may prevent illness but not subclinical infection, some persons who take these drugs may still develop immune responses that will protect them when they are exposed to antigenically-related viruses in later years. However, amantadine prophylaxis should not replace annual influenza vaccination in groups for whom vaccine is recommended.

Three (1.3%) of 224 influenza A field isolates received by the Canadian Science Centre for Human and Animal Health during the 1998-1999 season were found to be amantadine resistant; two of the three resistant virus isolates were from individuals who received amantadine (Dr.Y. Li, Bureau of Microbiology, Canadian Centre for Human and Animal Health, Winnipeg: personal communication, 2000). During the same season, a further 60 isolates were obtained from individuals involved in outbreaks, 75% of whom were given amantadine. Fifteen (25%) of the 60 isolates were amantadine resistant. Increased prevalence of amantadine resistance has been reported in families and within semi-closed settings including nursing homes^(63-65). Amantadine resistance is more likely to occur in populations where the drug is used for both prophylaxis and treatment, as opposed to prophylaxis alone⁽⁶⁶⁾. Failure to adequately isolate institutional patients on amantadine therapy also increases the probability of transmission of any resistant virus that may emerge, which in turn may result in prolongation of an epidemic or a second epidemic wave⁽⁶⁶⁾.

Amantadine prophylaxis may be used as follows:

• For the control of influenza A outbreaks among high-risk residents of institutions. Consultation with the local medical officer of health is important in order to confirm that the circulating strain is type A. Amantadine should be given to all residents who are not already ill with influenza, whether previously vaccinated or not, and to unvaccinated staff (see "Precautions" below). Prophylaxis should also be considered for HCWs, regardless of vaccination status, during outbreaks caused by influenza A strains that are not well matched by the vaccine. Prophylaxis should be given for a minimum of 2 weeks, or until 1 week after the end of the outbreak.

• As the sole agent for prophylaxis in people at high risk during an outbreak when vaccine is unavailable, contraindicated, or unlikely to be effective due to a shift in the antigenic composition of the outbreak strain. In this case, prophylactic amantadine must be taken each day for the duration of influenza A activity in the community.

• As an adjunct to late vaccination of people at high risk. Amantadine should be continued for 2 weeks after appropriate vaccination is completed. For those who require two doses of vaccine (e.g. previously unvaccinated children), amantadine should be continued for 2 weeks after the second dose. Amantadine does not interfere with the antibody response to the vaccine.

• As a supplement to vaccination in people at high risk expected to have an impaired immune response to vaccine. This includes persons with HIV infection, especially those with advanced HIV disease. No data are available on possible interactions with other drugs used in the management of patients with HIV infection. Such patients should be monitored closely if amantadine is administered.

• For unvaccinated people who provide care for people at high risk during an outbreak. Amantadine prophylaxis should be continued until 2 weeks after the care provider has been vaccinated.

Factors including local epidemiology, potential side effects, concern regarding emergence of viral resistance, adherence to medication regimens, and cost may be considered in decisions regarding the duration of amantadine prophylaxis^(66-68).

Dosage recommendations for prophylaxis of influenza A infection with amantadine are presented in Table 2, but the package insert should be read for complete information. Any adjustments for renal function should be made in addition to adjustments for age. Particular caution should be paid to dosages in those > 65 years of age, among whom some degree of renal impairment is common. Dosages may be adjusted according to calculated or laboratory confirmed creatinine clearance. It should be noted that although Table 2 presents the recommended dosage schedule for amantadine prophylaxis, a few studies suggest that a prophylactic dose of 100 mg daily in those aged 10 to 64 years and in children weighing > 20 kg, who have normal renal function, may be as effective as the recommended dose of 200 mg daily^(69-75).

While use of this dosing schedule, when properly adhered to, has been effective in controlling institutional influenza A outbreaks, the intermittent dosages may be confusing^(76,77). A proposed new daily dosage regimen, based on renal function, will be published this year in the Canadian Journal of Infectious Diseases (Dr. A. McGeer, Mount Sinai Hospital, Toronto: personal communication, 2000). HCWs and influenza program planners will need to assess the advantages and disadvantages of the two different schedules when selecting a regimen for their patients.

Although they have not been licensed for prophylactic use in Canada at the time of writing of this statement, neuraminidase inhibitors have been used under study conditions for this purpose in institutional outbreaks^(78-80).

Table 2 Recommended amantadine hydrochloride prophylactic dosage by age and renal status

Precautions

In otherwise healthy young adults given amantadine prophylactically, 5% to 10% report difficulty concentrating, insomnia, light-headedness, and irritability. These side effects are usually mild and cease shortly after the prophylaxis is stopped; however, they can be more frequent in the older population unless a reduced dosage is used.

Serious side effects (e.g. marked behavioural changes, delirium, hallucinations, agitation, seizures) have been associated with high plasma drug concentrations. These have been observed most often among persons who have renal insufficiency, seizure disorders, or certain psychiatric disorders, and among elderly persons who have been taking amantadine as prophylaxis at a dose of 200 mg/day. Lowering the dosage among these persons is effective in reducing the severity of such side effects.

Amantadine is eliminated from plasma wholly by renal tubular secretion and glomerular filtration; it is not metabolized by the liver⁽⁶⁹⁾. Therefore in people with reduced renal function, particularly the elderly, toxic levels can occur if the dosage is not reduced. Recommended prophylactic dosages by age and renal function are shown in Table 2. In patients with dialysis-dependent renal failure, the half-life of amantadine is 200 ± 36 hours⁽⁸¹⁾. It should be noted that the calculated creatinine clearance is reasonably accurate for those with a creatinine clearance > 40 mL/min, and those with a stable serum creatinine and muscle mass. However the calculation becomes less accurate when these conditions are not met. In particular, elderly persons with renal impairment and low muscle mass may have a serum creatinine in the normal range and an estimated creatinine clearance that is higher than the true value. Physicians who prescribe amantadine must be familiar with the limitations of formulas to estimate creatinine clearance, and make clinical decisions regarding dosage adjustments based on these considerations.

Amantadine dosage should be reduced in people with a seizure disorder in order to avoid the risk of increased frequency of seizures, and these individuals should be closely observed.

Drug interactions have been noted during concurrent administration of amantadine with triamterene and hydrochlorothiazide, trimethoprim-sulphamethoxazole, quinine, and quinidine. The patient's age, weight, renal function, comorbid conditions, current medications, as well as the indications for amantadine use should all be considered prior to initiating this medication. Individuals who are given amantadine should be carefully monitored for side effects.

References

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* Members: Dr. V. Marchessault (Chairperson), Dr. J. Spika (Executive Secretary), N. Armstrong (Advisory Secretary), Dr. I. Bowmer, Dr. G. De Serres, Dr. P. DeWals, Dr. J. Embree, Dr. I. Gemmill, Dr. M. Naus, Dr. P. Orr, Dr. B. Ward, A. Zierler.

Liaison Representatives: Dr. J. Carsley (CPHA), Dr. G. Delage (CPS), Dr. M. Douville-Fradet (ACE), Dr. T. Freeman (CFPC), Dr. J. Livengood (CDC), Dr. A.E. McCarthy (ND), Dr. J. Salzman (CATMAT), Dr. L. Samson (CIDS), Dr. J. Waters (CCMOH).

Ex-Officio Representatives: Dr. J. Calver (BBR), Dr. A. King (LCDC), Dr. P. Riben (MSB).

⁺ This statement was prepared by Dr. P. Orr and approved by NACI.

[Canada Communicable Disease Report]