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

STATEMENT ON INFLUENZA VACCINATION FOR THE 2002-2003 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 2002-2003 season. The present statement contains new information on influenza epidemiology, diagnosis and control. Further information on vaccine-associated adverse events during the 2001-2002 season, as well as the results of studies focusing on the oculorespiratory syndrome (ORS), and recommendations regarding the immunization of individuals who have previously experienced ORS, will be published in an upcoming issue of CCDR.

In Canada, two available measures can reduce the impact of influenza: immunoprophylaxis with inactivated (killed-virus) vaccine and chemoprophylaxis or therapy with influenza-specific antiviral drugs (amantadine and neuraminidase inhibitors). At the time of writing of this statement, neuraminidase inhibitors have been licensed for therapy, but not for chemoprophylaxis against influenza in Canada. 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.

During the 2001-2002 influenza season, national surveillance indicators, (laboratory surveillance and provincial and territorial activity level reporting), showed that influenza activity reached a peak during the last 2 weeks of March, 2002 (weeks 12 and 13). During the 1999-2000 and the 2000-2001 influenza seasons, peak activity occurred earlier, at the end of December (week 52) and at the end of February (week 7) respectively. During the 2001-2002 season, increased laboratory-confirmed influenza activity began in Quebec at the end of December (week 52), reaching a peak in that province at the beginning of February (week 5). Ontario reported a peak in influenza activity in week 10, and other areas of Canada (Atlantic provinces, the Prairie provinces and British Columbia) reported peak laboratory-confirmed influenza activity at the end of March (weeks 12 and 13). Sentinel physicians reported 19 to 58 visits for influenza-like illness (ILI) per 1,000 patient visits per week, which is at or below the weekly average for the preceding five influenza seasons. Only three provinces, Nova Scotia, Prince Edward Island and Saskatchewan, reported widespread influenza activity for >= 1 week.

Influenza A predominated in the 2001-2002 season in all provinces and territories. Ontario reported a significantly greater proportion of their isolates as influenza B as compared to other provinces and territories (30.7% vs. 0% to 6.5%). Between 26 August 2001 and 27 April 2002, the Centre for Infectious Disease Prevention and Control (CIDPC) received reports on 48,123 laboratory tests for influenza; 6,432 (13.4%) o of tests were confirmed positive for influenza; of those, 5,584 (88.4%) were identified as influenza A and 743 (11.6%) as influenza B. Of the influenza B identifications, the majority (88%) were from Ontario.

From 4 October, 2001 through 24 April, 2002, the National Microbiology Laboratory (NML) antigenically characterized 452 influenza viruses received from provincial and hospital laboratories: 310 (68.6%) influenza A (H3N2) viruses, 18 (4.0%) influenza A (H1) viruses, and 124 (27.4%) influenza B viruses. The influenza A (H3N2) viruses were similar to the 2001-2002 northern hemisphere vaccine strain A/Panama/2007/99 (H3N2). Antigenic and genetic analyses of the influenza A (H3N2) isolates did not reveal the emergence of a representative new antigenic variant.

Of the 18 influenza A (H1) isolates identified antigenically, one was influenza A (H1N1) and 17 (94.4%) were characterized by genetic analysis to be a new strain of influenza A (H1N2). The H1N2 viruses were identified from clinical specimens collected in Alberta (five), Saskatchewan (two) and Manitoba (two), from December 2001 through March 2002. Influenza A (H1N2) viruses have been previously identified in other areas of the world. Between December 1988 and March 1989, a number of these influenza A (H1N2) viruses were identified in China, but the virus did not spread further. The recent H1N2 strain appears to have resulted from the reassortment of the genes of the currently circulating influenza A (H1N1) and A (H3N2) subtypes. The hemagglutinins of the new H1N2 viruses are antigenically and genetically similar to that of the A/New Caledonia/20/99 (H1N1) vaccine strain and the neuraminidases are similar to that of the A/Panama/2007/99 (H3N2) vaccine strain.

Influenza B viruses currently circulating in humans worldwide can be divided into two antigenically and genetically distinct lineages, represented by the reference strains B/Yamagata/16/88 and B/Victoria/2/87. The B component of the 2001-2002 influenza vaccine, B/Sichuan/379/99, belongs to the B/Yamagata lineage. Viruses of the B/Yamagata lineage have circulated widely and accounted for the majority of isolates in most countries since 1990. In contrast, viruses belonging to the B/Victoria lineage had not been identified outside of Asia since 1991. Since March 2001, B/Victoria lineage viruses were identified for the first time in a decade in Canada, the United States (U.S.) and other countries including Italy, Netherlands, Norway, Philippines, India, and Oman. The first isolation of a B/Victoria lineage virus in Canada in recent years was from a Quebec resident who had travelled to Asia during March 2001. Of the 124 influenza B isolates characterized antigenically by NML this season to date, 120 (96.7%) belonged to the B/Victoria lineage and four belonged to the B/Yamagata lineage. The four B/Yamagata lineage viruses were similar to the 2001-2002 vaccine strain and the B/Victoria lineage viruses were antigenically distinct from the vaccine strain.

Influenza activity in the northern hemisphere was initially reported during the 2^nd week of October 2001, with increasing activity from November 2001 through March 2002. Worldwide, during the same period, A (H3N2), A (H1N1), A (H1N2) and B viruses co-circulated. Influenza A viruses predominated in some countries while influenza B viruses predominated in others. Countries in the Americas, Asia, Europe  and Oceania reported outbreaks of both influenza A (H3N2) and influenza B. Japan reported outbreaks of influenza A (H1N1) in late December and A (H1N1) viruses were isolated sporadically in Asia, Europe, North America, and Oceania.

Worldwide, the majority of recent influenza A (H3N2) isolates were antigenically similar to A/Moscow/10/99-like viruses. Most influenza (H1N1) isolates were antigenically similar to A/New Calendonia/20/99-like viruses. Several countries, including Egypt, France, India, Israel, the United Kingdom, Canada and the U.S. reported sporadic cases and outbreaks of influenza A (H1N2) viruses. These A (H1N2) viruses are reassortants with hemagglutinins that are antigenically and genetically similar to that of the A/New Caledonia/20/99 (H1N1) and their neuraminidases are similar to that of the A/Moscow/10/99-like viruses. Vaccines containing A/Moscow/10/99-like (including A/Panama/2007/99) and A/New Caledonia/20/99-like antigens are expected to provide adequate protection against current circulating A (H3N2), A (H1N1) and A (H1N2) influenza viruses. Influenza B viruses circulated widely causing outbreaks and sporadic cases in both the northern and southern hemisphere. Many isolates were antigenically similar to B/Sichuan/379/99. However, an increasing number of countries in Europe, North America and Asia reported B/Hong Kong/330/01-like viruses belonging to the B/Victoria/2/87 lineage. Current vaccines containing antigens of B/Sichuan/379/99-like viruses induced antibodies that reacted poorly with viruses related to B/Hong Kong/330/2001, and are expected to provide limited cross-protection against these B/Victoria/2/87 lineage viruses. Given the re-emergence of the B/Victoria/2/87 lineage viruses worldwide, the lack of exposure of young children to these viruses in the past decade, and the expected poor coverage by the current B/Sichuan/ 379/99 vaccine strains, the World Health Organization has recommended the inclusion of a B/Victoria/2/87-like strain in the 2002-2003 northern hemisphere vaccines.

The antigenic characteristics of current and emerging influenza virus strains provide the basis for selecting the strains included in each year’s vaccine. NACI recommends that the trivalent vaccine for the 2002-2003 season in Canada contain an A/Panama/ 2007/99 (H3N2)-like, an A/New Caledonia/20/99 (H1N1)-like, and either B/Hong Kong/330/2001-like or B/Shangdong/7/97- like antigens. Vaccine producers may use antigenically equivalent strains because of their growth properties. Influenza A/Panama 2007/99 (H3N2) is antigenically equivalent to the A/Moscow/ 10/99 (H3N2) virus. Circulating influenza A (H1N2) viruses are the result of reassortment of influenza A (H1N1) and A (H3N2) viruses. For this reason, antibodies against influenza A (H1N1) and A (H3N2) vaccine strains will provide protection against circulating influenza A (H1N2) viruses.

Immunization against influenza must be given annually. Continual antigenic drift of the influenza virus means that a new vaccine, updated yearly with the most current circulating strains, is needed to protect against new infections. 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. Immunity declines over the year following vaccination. The production and persistence of antibody after vaccination depends on numerous factors, including age, prior and subsequent exposure to antigens, presence of immunodeficiency states and polymorphisms in human leucocyte antigen (HLA) class II molecules. Humoral antibody levels, which correlate with vaccine protection, are generally achieved by 2 weeks after immunization. It is postulated that immunity after the inactivated vaccine 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 healthcare providers as opportune moments for immunization, and programmatic issues. Further advice regarding the timing of influenza vaccination programs may be obtained through consultation with local medical officers of health. Healthcare 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.

Update on influenza epidemiolgy, diagnosis and control

1. Influenza is a common infection in healthy children < 5 years of age. In one long-term (1974-1999) prospective U.S. study, an average of 9.5% of children in this age group had a healthcare visit associated with symptomatic culture-positive influenza every year⁽²⁾. Influenza infection in children < 2 years of age is associated with high rates of acute otitis media, lower respiratory tract disease and hospitalization⁽²⁾. Compared to older children and adults, young children shed larger quantities of virus over a longer duration, thereby disseminating the virus within households and the community^(2-6). Studies from Japan suggest that herd immunity in children can decrease influenza incidence within a community⁽⁶⁾. Influenza immunization of healthy children >= 6 months of age (as well as healthy adults) is discussed under "Immunization of healthy persons".

2. Early diagnosis is particularly useful in the event of an outbreak of respiratory illness in an institutional setting. Rapidly identifying influenza as the cause of an outbreak allows the timely establishment of control and potential treatment measures, with the goal of reducing morbidity and mortality⁽⁷⁾. Influenza tests may be performed using nasopharyngeal swabs, throat swabs or nasal wash/aspirate. Acute and convalescent serologic tests are available, but they do not provide timely results in the clinical setting. A number of rapid influenza tests have been developed, and are described in detail at the Centres for Disease Control and Prevention’s influenza website at: <www.cdc.gov/ncidod/diseases/flu/flu_dx_table.htm>. Most rapid tests are > 70% sensitive and > 90% specific, with predictive values varying according to local prevalence of influenza infection. While rapid influenza tests provide an important diagnostic service, they do not replace viral culture. The potential for false negative as well as false positive rapid tests must be recognized. In addition, viral culture allows determination of influenza strain and subtype sensitivity testing in select settings, as well as other viral causes of influenza-like illness (ILI)⁽⁸⁾. In selected settings, combining rapid tests with cultures may lead to improved influenza diagnosis, control and surveillance⁽⁹⁾.

Recommendations for the prevention and control of influenza during the 2002-2003 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"). 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. For this reason, healthy adults and their children who wish to protect themselves from influenza should be encouraged to receive the vaccine.

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 very important risk factors for influenza-related morbidity and mortality⁽¹⁰⁾.

• 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.

• 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 healthcare cost savings.

• 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. 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. 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 human immunodeficiency virus (HIV)-infected patients. Influenza may result in significant morbidity and mortality among HIV-infected individuals. Some studies have demonstrated temporarily enhanced HIV replication in HIV- infected persons who develop an immune response to the vaccine and are not receiving suppressive anti-retroviral therapy, while other studies have not shown this effect^(11-14). Influenza vaccination has not been shown to cause a decrease in CD4+ T-lymphocyte cell count or progression of HIV disease in HIV-infected individuals^(15,16). Influenza vaccination is effective in preventing symptomatic laboratory-confirmed influenza infection in HIV-infected individuals with a mean CD4+ T-lymphocyte cell count of 400 cells/mm^{3 (16)}. During a 1996 outbreak of influenza in a residential facility for HIV-infected persons, vaccination efficacy was 65% for those with CD4+ T-lymphocyte counts > 100 cells/mm³, 52% for those with HIV-1 viral load < 30,000 RNA copies/mL, and 75% for those with both CD4+ T-lymphocyte count > 100 cells/mm³ and HIV viral load < 30,000 RNA copies/mL⁽¹⁷⁾. However influenza vaccine may not induce protective antibody titres in those with low CD4+ T-lymphocyte cell counts, and there is evidence that a second dose of vaccine does not improve their immune response^(11,18,19).

• Children and adolescents (6 months to 18 years of age) with conditions treated for long periods with acetylsalicylic acid. This therapy might increase the risk of Reye’s 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. 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 infectious persons from other regions of the world, and to situations which facilitate the transmission of influenza. 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. 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.

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"). The following groups should be vaccinated^(20-22): HCWs 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^(23-26).

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. Influenza immunization of healthy adults and children may be cost-effective, under selected circumstances^(23-25,27). Potential benefits of influenza immunization in healthy adults and children depend 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. Among children, the effects of co-circulating viruses such as respiratory syncytial virus must be separated from those of influenza. 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 programmatic issues^(28-30).
  
  In the U.S. the American Academy of Family Physicians (AAFP) and the Advisory Committee on Immunization  Practices (ACIP) have recommended lowering the age of universal influenza vaccination of adults to 50 years of age⁽³¹⁾. 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 U.S. adults in this age group who have high-risk chronic medical conditions is low. The low immunization rate is caused by persons being unaware they have a high-risk condition, lack of healthcare access, or failure of HCWs to deliver immunization. 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 U.S. guidelines has not been fully assessed.
  
  At the present time NACI suggests that programmatic decisions in Canada regarding how to access and immunize those listed under "Recommended recipients" are best made by authorities responsible for the planning and implementation of such programs.

• Influenza vaccine in pregnancy and during lactation.
  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". The routine immunization of otherwise healthy women in the second or third trimester of pregnancy is recommended by the American ACIP on the basis of case reports, observational studies and a retrospective case-control study of a selected Tennessee population^(32-37). The generalizability of the results of these studies to Canadian and European populations is unknown. 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. Only split-virus vaccines are available in Canada. Previously unvaccinated children < 9 years of age require two doses of the split-virus influenza vaccine, with an interval of 4 weeks. The second dose of influenza vaccine is not needed if the child has received one or more doses of vaccine during a previous influenza season.

In infants < 6 months of age, influenza vaccine is less immunogenic than in infants and children 6 to 18 months of age. Therefore, immunization with currently-available influenza vaccines is not recommended for infants < 6 months of age.

Table 1. Recommended influenza-vaccine dosage, by age, for the 2002-2003 influenza season

Intramuscular administration is preferred. The deltoid muscle is the recommended site in adults and children > 18 months of age. The anterolateral thigh is the recommended site 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. Prophylactic acetaminophen may decrease the frequency of some side effects in adults⁽³⁸⁾. Healthy adults receiving the split virus vaccine showed no increase in the frequency of fever or other systemic symptoms compared to those receiving placebo. 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⁽³⁹⁾. Influenza antigens have not been identified in circulating immune complexes or in vessel walls, and a causal relationship has not been proven.

A recent case report has postulated that influenza vaccination may have caused a significant increase in carbamazepine blood levels in a child, 14 years of age⁽⁴⁰⁾.

Guillain-Barré syndrome (GBS) associated with influenza vaccination has been observed in a minority of influenza seasons over the last 2 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⁽⁴¹⁾, the relative risk of GBS occurring within 6 weeks after influenza vaccination, adjusted for age and sex, was 1.7 (95% confidence intervals [CI] 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⁽⁴¹⁾. 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’s syndrome.

During the 2000-2001 influenza immunization season, Health Canada received 960 case reports of adverse events meeting the case definition for a newly recognized "oculorespiratory syndrome (ORS)". During that season ORS was defined as the presence of bilateral red eyes or at least one of the following respiratory symptoms: cough, wheeze, chest tightness, difficulty breathing, sore throat or facial edema, occurring within 2 to 24 hours of influenza vaccination and resolving within 48 hours. The case definition was revised for the 2001-2002 season. The reader is referred to the supplementary statement published by CCDR on November 15, 2001 for information regarding the epidemiology of ORS during the 2000-2001 season⁽⁴³⁾. Another CCDR supplementary statement giving updated information on ORS occurring during the 2001-2002 season, as well as recommendations regarding the potential public health implications of ORS, will be published in the near future.

Please refer to the Canadian Immunization Guide⁽⁴⁴⁾ 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.

Adults 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

Influenza vaccine may be given at the same time as other vaccines, provided different sites and administration sets (needle and syringe) are used.

The target groups for influenza and pneumococcal vaccination overlap considerably. Healthcare providers should take the opportunity to vaccinate eligible persons against pneumococcal disease when influenza vaccine is given.

Storage

Influenza vaccine should be stored at 2^° C to 8^° 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 laboratory-confirmed influenza illness in approximately 70% to 90% 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 from influenza infection and related complications. Influenza vaccine programs should aim to vaccinate at least 90% of eligible recipients. Nevertheless, only 70% to 91% of LTCF residents and 20% to 40% of adults and children with medical conditions listed previously receive vaccine annually^(45-48). Studies of HCWs in hospitals and LTCFs have shown vaccination rates of 26% to 61%^(46-49).

This low rate of utilization is due both to failure of the healthcare 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. 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^(50-52). 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 healthcare provider is often a very important factor affecting whether a person is immunized or not. 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^{(47,48,53-55)};

• 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 influenza 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. Healthcare institutions should have policies in place to deal with this issue.

Transmission of influenza between clinically or subclinically infected HCWs and their vulnerable patients results in significant morbidity and mortality⁽⁵⁶⁾. 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^(21,56). In a British study, 59% of HCWs with serologic evidence of recent influenza infection could not recall having influenza, suggesting that many HCWs experience subclinical infection⁽⁵⁶⁾. 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 healthcare delivery due to scarcity of replacement workers.

Vaccination of HCWs in healthcare facilities has been shown to reduce total patient mortality, influenza-like illness, and serologically-confirmed influenza^(20-22). 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^{(22,25,57-60)}.

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.

During influenza outbreaks, increased prevalence of amantadine resistance has been reported in families and within semi-closed settings including nursing homes. Amantadine resistance is more likely to occur in populations where the drug is used for both prophylaxis and treatment, as opposed to prophylaxis alone⁽⁶¹⁾. 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⁽⁶¹⁾.

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" section 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. It is reasonable to allow these individuals to work with high risk patients as soon as they start amantadine prophylaxis. Unless there is a contraindication, they should also be immediately vaccinated for influenza. Amantadine prophylaxis should be continued until 2 weeks after the care provider has been vaccinated. These workers must be alert to the symptoms and signs of influenza, particularly within the first 48 hours after starting amantadine, and should be excluded from the patient care environment if these develop.

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^(61,62).

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. A recent Canadian study performed in a care facility for the elderly determined that serum creatinine levels measured <= 12 months previously could be safely used to estimate creatinine clearance⁽⁶³⁾. 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 10 to 64 years of age, and in children weighing > 20 kg, who have normal renal function, may be as effective as the recommended dose of 200 mg daily⁽⁶⁴⁾.

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. An alternate once daily dosage regimen for persons >= 65 years of age, based on renal function, is shown in Table 3⁽⁶⁵⁾. This new dosage regimen is based on pharmokinetic modelling which suggests that it should be as effective and safe as the standard regimen presented in Table 2. 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^(66-77). During institutional outbreaks of influenza, situations in which neuraminidase inhibitors may be indicated as prophylactic agents under appropriate study (off-licence) conditions, include outbreaks of influenza B as well as illness among residents who are at risk of serious side effects from amantadine.

Table 3.  Proposed once daily dosing schedule for amantadine solution (10 mg/mL) in persons >= 65 years of age*

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. 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⁽⁷⁷⁾. 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

[Canada Communicable Disease Report]