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

Statement on Influenza Vaccination for the 2004-2005 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 vaccines or drugs discussed in this statement should also be aware of the contents of the relevant product monograph(s). Recommendations for use and other information set out here may differ from that set out in the product monograph(s) of the Canadian licensed manufacturer(s) of the vaccine(s). Manufacturer(s) have sought approval of the vaccine(s) and provided evidence as to its safety and efficacy only when used in accordance with the product monographs. NACI members and liaison members conduct themselves within the context of Health Canada's Policy on Conflict of Interest, including yearly declaration of potential conflict of interests.

Introduction

The antigenic components of the influenza vaccine have been updated for the 2004-2005 season. The present statement contains new recommendations for the immunization of healthy children aged 6-23 months, the immunization of those directly involved in the culling of poultry infected with avian influenza, and on the prophylactic use of neuraminidase inhibitors. The section on human and avian influenza epidemiology has been updated.

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). Immunization is the most effective means to reduce the impact of influenza. Programs should focus on those at high risk of influenza-related complications, those capable of transmitting influenza to individuals at high risk of complications, and those who provide essential community services.

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.

Influenza virus began circulating early in Canada during the 2003-2004 season, the peak of influenza activity occurring during the last week of December 2003 (week 52). This season was more severe than the past three seasons according to a comparison of the national surveillance indicators (laboratory identifications, reporting of provincial and territorial activity levels, and outbreaks). The majority of the viruses antigenically characterized this season were similar to the H3N2 variant, A/Fujian/411/2002.

Laboratory-confirmed influenza activity began in late September and early October in Alberta and Saskatchewan, reaching a peak in these provinces by mid-November 2003 (week 48). Seasonal activity began in early November in Ontario, a peak occurring at week 52. British Columbia reported a fairly broad season of positive influenza detections from the beginning of November to January. The Atlantic provinces and Quebec were the last to begin reporting influenza activity. Quebec reported widespread activity for a longer period (week 52-week 7) than any other province and was also the last to reach the peak of influenza activity, at week 7 (week ending 14 February, 2004).

As of 28 February, 2004, the weekly proportion of patient visits to approximately 200 sentinel providers nationwide for influenza-like illness (ILI) ranged from 15 to a peak of 79 visits per 1000 patient visits (week 52, ending 27 December, 2003). For most of the season, the weekly ILI rate was less than or equal to the weekly average for the preceding seven influenza seasons.

Influenza A predominated across the country this season. Between 24 August, 2003, and 28 February, 2004, the Centre for Infectious Disease Prevention and Control (CIDPC) received reports of 65 844 laboratory tests for influenza, of which 10 927 (16.6%) were positive. The weekly percentages of specimens testing positive for influenza increased from 0.15% at the start of this period to a peak of 31% at week ending 27 December, 2003 (week 52). The peak weekly percentage this season was higher than in the previous four seasons.

Of the 10 927 positive influenza identifications, 10 880 (99.6%) were influenza A viruses, and 47 (0.4%) were influenza B viruses. Most of the influenza B detections occurred in Ontario, Quebec, and Nova Scotia. The National Microbiology Laboratory has antigenically characterized 702 (6.5%) of the 10 880 influenza A viruses to date: 675 (96.2%) are A/Fujian/411/2002 (H3N2)-like viruses, 25 (3.6%) are A/Panama/2007/99 (H3N2)-like viruses, one (0.1%) is an A/New Caledonia/20/9/9-like (H1N1) virus, and one (0.1%) is an influenza A (H1N2) virus. Of the 10 influenza B viruses characterized, two belonged to the Victoria lineage and are similar to the vaccine strain B/Hong Kong/330/2001 (recommended influenza B component of the 2003-2004 influenza vaccine), and eight are similar to B/Sichuan/379/99, which belongs to the B Yamagata lineage and was the recommended influenza B component of the 2001-2002 influenza vaccine. At the beginning of the season (October 2003), 100% of the strains characterized were A/Panama/2007/99-like viruses. In November, the percentage of A/Panama dropped, as A/Fujian/411/2002 strains started predominating. By December, most (96.7%) of the isolates were A/Fujian/411/2002-like. The few influenza B strains appeared in January 2004.

Of the laboratory-confirmed influenza infections reported to Health Canada as of 28 February, 2004, 45.6% were reported in children < 15 years of age (31% in children < 4 years of age). At the end of October 2003, Health Canada requested that the provinces and territories report all influenza-related deaths in children, after having received reports of deaths from influenza A in children in the United Kingdom and the United States at the start of the season⁽¹⁾. From November to December 2003, Health Canada received four reports of deaths associated with laboratory-confirmed influenza A infection in children < 15 years of age (range 7-14 years). There have been no new influenza-related deaths in children reported to Health Canada since December 2003. It is difficult to compare the number of influenza-related deaths in children reported prospectively this year with historical data, which may have underestimated influenza-related deaths⁽¹⁾.

Globally, influenza A (H3N2) viruses predominated in most countries while influenza B viruses circulated at low levels. Many countries in the Northern hemisphere, including the United States, observed the same predominance of A/Fujian/411/2002 (H3N2)-like viruses during the current season. Sporadic activity of influenza B occurred but no outbreaks were reported. Most influenza B viruses were B/Yamagata/16/88-lineage viruses; many were distinguishable from B/Sichuan/379/99 (the previous B/Yamagata-lineage vaccine strain) and were more closely related to B/Shanghai/361/2002⁽²⁾.

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 2004-2005 season in Canada contain A/New Caledonia/20/99 (N1H1)-like, A/Fujian411/2002 (H3N2)-like, and B/Shanghai/361/2002-like virus antigens. Vaccine producers may use antigenically equivalent strains because of their growth properties. A/Wyoming3/2003 and A/Kunamoto/102/ 2002 strains are antigenically equivalent to the A/Fujian/ 411/2002 (H3N2); B/Jilin/20/2003 and B/Jiangsu/10/2003 virus strains are antigenically equivalent to B/Shanghai361/2002. The vaccines to be marketed in Canada for the 2004-2005 flu season contain A/New Caledonia/20/99 (H1N1), A/Wyoming/3/2003 (H3N2) and B/Jiangsu/10/2003 virus antigens.

Immunization against Influenza Must be Given Annually in Order to Provide Optimal Protection

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⁽³⁾. 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 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 administration of the inactivated vaccine lasts < 1 year. However, in the elderly, antibody levels may fall below protective levels within 4 months. Data are not available to support a recommendation for 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 on the basis of local epidemiology, recognition of the need to use patient contact with health care 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. 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 Avian Influenza

Recommendations regarding the use of influenza vaccine in individuals involved in the culling of poultry infected with avian influenza may be found under the next section entitled "Recommended Recipients".

The following update is current as of 26 March, 2004.

Avian Influenza in Asia

Cases in poultry

Since mid-December 2003, eight Asian countries (Republic of Korea, Viet Nam, Japan, Thailand, Cambodia, China, Indonesia, and Laos) have had confirmed avian influenza A (H5N1) outbreaks⁽²⁾. There have also been avian outbreaks due to other strains of avian influenza (including an H5N2 strain of low pathogenicity in poultry in Taiwan and a highly pathogenic H7 strain in Pakistan). The avian influenza outbreak is unprecedented in its scope, geographic spread and economic impact for the countries affected. Most of these countries are experiencing avian influenza outbreaks for the first time, and in many countries the outbreaks are widespread throughout the country.

As of 26 March, 2004, > 100 million birds have either died of illness due to avian influenza or have been culled in an effort to control the outbreaks. The number of birds affected in the current outbreak is greater than the number involved in the previous five largest avian influenza outbreaks combined. The difficulty in controlling the current outbreak has been compounded by the concentration of poultry in backyard farms, the economic significance of poultry production in the affected countries, a lack of control expertise, and a lack of resources.

Human cases of H5N1

As of 26 March, 2004, the World Health Organization (WHO) has confirmed a total of 34 human cases of avian influenza A (H5N1)^(4-6), 23 of whom have died. The human cases have all been confirmed in two Asian countries: Thailand (12 cases, eight of whom have died) and Viet Nam (22 cases of whom 15 have died).

The median age of the 34 confirmed human cases of influenza A (H5N1) is 14 years (range 1-58 years), and the majority of cases (52%) have occurred in the 5- to 19-year age group. The median age of confirmed cases in Thailand is 10 years (range 2-58 years), and half of the cases (50%) are in the 0- to 9-year age group. In contrast, in Viet Nam the median age of confirmed cases is 15.5 years** (range 1-30 years), the majority of cases (57%) occurring in 10- to 29-year-olds and 30% of cases in 0- to 9-year-olds.

It can be anticipated that human cases of avian influenza will continue to be detected in countries where outbreaks in poultry are occurring. The relatively small number of human cases currently detected compared with the large number of infected birds distributed over a wide geographic area suggests that the H5N1 avian influenza virus strain may not easily infect humans. As of 26 March, 2004, there has been no evidence of efficient or sustained human-to-human transmission to account for any of the human cases of avian influenza. All of the human cases have reportedly had exposure to diseased and/or dead poultry or lived in an area where outbreaks have been occurring in birds.

The continuing presence of infection in poultry may create opportunities for the emergence of a new influenza virus subtype with a capacity to spread easily among humans, thus marking the start of an influenza pandemic. Should this rare event occur it would immediately have serious consequences for human health throughout the world.

Avian Influenza in Canada

On 18 February, 2004, the Ministry of Agriculture and Fisheries in British Columbia reported an outbreak of avian influenza in a commercial broiler breeder flock^(7,8). Further testing of samples from this farm by the National Centre for Foreign Animal Diseases, in Winnipeg, confirmed the presence of an avian influenza virus (H7N3) with low pathogenicity in poultry. This is a strain of avian influenza virus that is different from the one (H5N1) causing outbreaks in poultry in Asia. Subsequent testing on the affected farm also identified a highly pathogenic form of the H7N3 avian influenza virus in a younger flock, which was the second flock to be affected in the outbreak.

On 18 February, 2004, the Canadian Food Inspection Agency placed the index farm under quarantine, and all of the poultry (16 000 birds) on the farm were euthanized in accordance with provincial environmental regulations and internationally accepted disease control guidelines. An active surveillance program was established to survey all neighbouring commercial poultry farms within a 5-km radius (high-risk region) of the affected farm. On the basis of these surveillance activities, a second farm was placed under quarantine on 9 March, 2004, after a low level of illness consistent with avian influenza was detected in poultry on the farm. Laboratory results on 12 March, 2004, confirmed the presence of highly pathogenic avian influenza H7N3 on this second farm. The poultry on the farm were euthanized and the premises, including vehicles and tools, were cleaned and disinfected. A 10-km surveillance zone around the premises was created, and a control area within southern British Columbia has been declared to restrict the movement of domestic birds, bird products, and bird by-products within the control area. An epidemiologic investigation is under way to determine whether there is a link between the two farms.

As of 24 March, 2004, avian influenza was detected in poultry on five farms within the high-risk region, and a decision was taken by the Canadian Food Inspection Agency to depopulate all remaining flocks in the high-risk region. This was done to contain further spread by eliminating the pool of infected and susceptible birds. Approximately 275 000 birds from 10 farms and 33 smaller flocks were euthanized. Surveillance activities outside the high-risk region were intensified to include pick-up and sampling of dead birds.

As of 16 March, 2004, all individuals identified as having been in contact with infected birds were placed under active surveillance. Individuals who had not already been vaccinated during this influenza season were offered immunization with the 2003-2004 trivalent influenza vaccine. Several of those exposed on the first farm developed mild respiratory symptoms and were given antiviral medication (oseltamivir). All symptomatic persons recovered quickly. As of 1 April, 2004, two individuals had laboratory-confirmed infection with influenza H7 virus. Asymptomatic individuals with significant exposure to affected poultry were offered oseltamivir for prophylaxis.

Avian Influenza in the United States

As of 24 March, 2004, avian influenza has been confirmed in poultry in five US states (Delaware, Pennsylvania, New Jersey, Maryland, and Texas)⁽⁹⁾. On 6 February, 2004, a low-pathogenic strain of avian influenza (H7N2) was detected in a non-commercial poultry flock in Delaware, followed by identification of a second affected flock in a commercial poultry operation on 9 February, 2004. The poultry on both premises were depopulated.

Routine surveillance of live bird markets in New Jersey on 12 February, 2004, detected evidence of avian influenza virus (H7N2) in four markets. The live bird markets where infection was detected were depopulated, and the markets were cleaned and disinfected. Similarly, routine surveillance detected low-pathogenic avian influenza (H2N2) in one poultry flock in Pennsylvania on 13 February, 2004. Since no clinical signs of illness, increases in mortality or decreases in egg production were observed in the flock, no depopulation was carried out, but the premises were placed under quarantine. As of 17 March, 2004, ongoing surveillance had not detected any further premises with avian influenza.

An outbreak of avian influenza (H5N2) was detected in a single flock in southeast Texas on 17 February, 2004. Further testing performed by the United States Department of Agriculture on 23 February, 2004, determined the strain to be highly pathogenic to poultry. The broiler chickens (6608) were euthanized on 21 February, 2004. Further epidemiologic investigation identified two live bird markets in Houston, Texas, with links to the index premises. As a precaution, all five live bird markets in Houston were depopulated (2300 birds), cleaned and disinfected. As of 24 March, 2004, ongoing surveillance of commercial and non-commercial poultry farms has not detected any further premises with avian influenza.

On 5 March, routine testing detected avian influenza on one farm in Maryland. The poultry on the index farm (118 000 birds) were depopulated on 7 March. As a precaution, the poultry (210 000 birds) from one other farm close to the index farm (both premises are owned by the same individual) were depopulated on 9 March. On 11 March, 2004, the strain was identified as H7N2, and subsequent testing confirmed it to be of low pathogenicity to poultry. As of 24 March, 2004, ongoing surveillance has not detected avian influenza on any other farms.

In all cases, index premises were placed under quarantine, and active surveillance programs were initiated for poultry operations in the vicinity of the index premises. Other actions were also taken to limit the potential for spread of infection (for example, enhanced testing for avian influenza in flocks showing increased mortality or in flocks to be sent for slaughter; movement restrictions of poultry, poultry workers, and agricultural equipment; and cancellation of gatherings involving poultry or poultry workers).

No known human cases of avian influenza have been related to these outbreaks of avian influenza in poultry.

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 of influenza-related complications, those capable of transmitting influenza to individuals at high risk of 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 children should be encouraged to receive the vaccine.

People at High Risk of Influenza-related Complications

• Healthy children aged 6 to 23 months are at increased risk of influenza-associated hospitalization compared with healthy older children and young adults. NACI recommends their inclusion among recommended recipients of influenza vaccine.

Attack rate and burden of morbidity and mortality due to influenza infection and illness in very young children

Estimates of influenza attack rates vary according to the study setting (e.g. community, institution), virus activity during the years studied, and diagnostic methods. However, several early community studies suggest that although the absolute number may vary, influenza attack rates among children < 5 years of age are as high as or higher than those in young adults^(3,10-12).

The spectrum of influenza in children ranges from asymptomatic infection to influenza illness with or without complications. In addition to febrile upper respiratory tract infection, common clinical presentations of influenza in children include lower respiratory tract infection (croup, bronchiolitis, primary viral, or secondary bacterial pneumonia), otitis media, diarrheal illness, and febrile seizures. Less common complications include myocarditis, pericarditis, toxic shock syndrome, transverse myelitis, encephalitis and Reye syndrome.

Rates of hospitalization are higher among children < 2 years of age than older children, during influenza season. These rates of hospitalization are comparable to those seen in other groups identified as being at high risk of influenza-associated complications.

The estimation of morbidity and mortality caused by influenza virus infection relies on the comparison of data between seasons during which the virus circulates, and peri-influenza seasons when it does not. Several studies have attempted to separate the effects of confounding factors such as respiratory syncytial virus, parainfluenza and adenovirus, which frequently circulate during the influenza season and for periods before and after influenza season. However, the activity of other non-influenza viruses may vary unpredictably from season to season.

In a retrospective study of a Tennessee Medicaid population from 1973 to 1993, the authors estimated the influenza-related hospitalization rates for acute cardiac or pulmonary conditions to be 496 to 1038 per 100 000 among children aged 0 to 11 months who did not have risk factors for influenza illness and complications, and 186 per 100 000 among those 1 to 2 years old⁽¹³⁾. Calculated influenza-related hospitalization rates among children with high-risk conditions were 1900 per 100 000 in those 0-11 months old, 800 per 100 000 in 1- to 2-year-olds, 320 per 100 000 in 3- to 4-year-olds, and 92 per 100 000 in 5- to 14-year-olds. In a study of two health maintenance organizations, Izurieta and colleagues estimated the influenza-associated hospitalization rate to be 144 to 187 per 100 000 healthy children aged 0 to 23 months⁽¹⁴⁾. In another Tennessee study, Neuzil et al. reported a culture-positive influenza hospitalization rate of 3 to 4 per 1000 healthy children < 2 years⁽¹⁵⁾. Preliminary results from the ongoing New Vaccine Surveillance Network prospective study in New York and Tennessee suggest that influenza was responsible for 1 to 3 hospitalizations per 1000 healthy children aged 6 to 23 months during the 2000-2003 influenza seasons and 5% to 9% of all emergency room and outpatient visits of healthy children during the 2002-2003 respiratory season (Dr. M.R. Griffin, Vanderbilt University Medical Centre: personal communication, 2003).

In comparison, Barker et al. noted influenza-associated hospitalization rates among adults with high-risk medical conditions to be 56 to 110 per 100 000 persons aged 15 to 44 years, 392 to 635 per 100 000 persons age 45 to 64 years, and 399 to 518 per 100 000 persons >= 65 years⁽¹⁶⁾. In a study of US national hospital discharge data, Simonsen et al. reported influenza-associated hospitalization rates of 125 to 228 per 100 000 healthy persons >= 65 years of age⁽¹⁷⁾.

Mortality associated with influenza infection in young children, however, is low. Estimates of respiratory and cardiac deaths associated with influenza illness per 100 000 person-years are 0.6 among children < 1 year of age, 0.4 among those 1 to 4 years, 0.5 among the 5- to 49-year age group, 7.5 among the 50- to 64-year age group, and 98.3 among those >= 65 years (Dr. W. Thompson, National Immunization Program, US Centers for Disease Control and Prevention: personal communication, 2003).

Efficacy of trivalent inactivated influenza vaccine (TIV) in healthy children aged 6 to 23 months

In infants < 6 months of age, TIV is less immunogenic than in infants and children >= 6 months old. Immunization with TIV is not recommended for infants < 6 months of age.

In a randomized trial among healthy children, Neuzil et al. reported that TIV was 44% to 49%, 74% to 76%, and 70% to 81% effective against serologically confirmed influenza infection in children aged 1 to 5 years, 6 to 10 years, and 11 to 15 years respectively⁽¹⁸⁾. Edwards et al. studied 271 healthy children aged 1 to 5 years given TIV; vaccine was 44% to 48% effective in preventing serologically confirmed influenza⁽¹⁹⁾.

In a 2-year randomized controlled trial among healthy children, TIV efficacy against culture-positive influenza illness was 63%, 66% and 69% in those 6 to 12 months, 13 to 18 months, and 19 to 24 months of age respectively during the first year of the study⁽²⁰⁾. Influenza infection was prevalent during the first study year (attack rates were 5.5% and 15.9% in vaccine and placebo groups respectively). Immunogenicity data were available from 66 children. Seroconversion against strains in the vaccine formulation developed in 88.6% to 96.8%. However in the second year of the study, during which influenza was not prevalent (attack rates 3.6% and 3.3% in vaccine and placebo groups), the vaccine was not efficacious (negative vaccine efficacy of -7%). No overall reduction of acute otitis media (AOM) was reported in this study.

Heikkinen et al. studied 374 day care children aged 1 to 3 years; TIV efficacy was 83% in preventing culture-confirmed influenza and was associated with a 36% reduction in overall AOM morbidity⁽²¹⁾. A study of 186 children aged 6 to 30 months who attended day care suggested that TIV was protective against AOM during influenza season (odds ratio 0.69; 95% confidence interval 0.49-0.98)⁽²²⁾.

NACI recognizes that both the number of studies and the number of participants in the randomized controlled trials of TIV in children aged 6 to 23 months are limited, and that there are unanswered questions including the efficacy of TIV in children within this age group who have not had experience with TIV or infection (unprimed), the impact of immunization on influenza complications (including hospitalization), and the cost-effectiveness of a routine immunization program in this age group. NACI strongly encourages research regarding these issues.

Safety and acceptability of TIV for healthy children aged 6 to 23 months

TIV is safe and well tolerated in healthy children (see section on Adverse Reactions). TIV contains minute quantities of thimerosal, which is used as a preservative. However, studies indicate that thimerosal exposure through recommended childhood vaccines does not cause neurodevelopmental disorders^(23-26).

The advice of the health care provider is one of the most important factors influencing decisions that parents make regarding vaccination of their child. Recommendations for influenza vaccination of children who are in previously defined high-risk groups for influenza complications, such as those with chronic cardio- pu lmonary disease, have been generally accepted by health care providers and parents. The health care provider's recommendation for influenza immunization of healthy children in this age group should be accompanied by efforts to educate parents regarding the risk of influenza in this population.

• 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.

• 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 group above. 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 health care 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 hemoglobino- pathy. Influenza vaccine is effective in reducing the number of hospital admissions in adults with diabetes. The efficacy of the vaccine in 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 of 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 HIV-infected patients. Influenza may result in significant morbidity and mortality in HIV-infected individuals. Influenza vaccination protects against influenza infection and illness in HIV- infected individuals with a mean CD4+ T-lymphocyte cell count of > 100 cells/µL; efficacy varies with degree of immunosuppression. However, influenza vaccine may not induce protective antibody titres in those with very low CD4+ T-lymphocyte cell counts, and there is evidence that a second dose of vaccine does not improve their immune response⁽²⁷⁾.

• Children and adolescents (aged 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. In the tropics, influenza can occur throughout the year. In the southern hemisphere, peak activity occurs from April through September; in the northern hemisphere, it occurs from November through March. Travel may expose individuals to infectious persons from other regions of the world and to situations that facilitate the transmission of influenza (e.g. cruise ships). The effectiveness of influenza immunization for travellers may vary, depending on differences between influenza strains encountered abroad and those included in the current vaccine available in Canada. There is insufficient evidence at this time to advise in favour of 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 of influenza-related complications⁽²⁸⁾.

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) has been immunized. These individuals include the following:

• health care providers who work in facilities and community settings, such as physicians, nurses, and emergency response workers
• health care and other service providers who have contact with residents of continuing care facilities or residences
• those who provide home care for persons in high-risk groups
• those who provide services within closed or relatively closed settings to persons at high risk (e.g. crew on ships)
• household contacts (adults and children) of people at high risk of influenza complications. This includes household contacts of children < 6 months of age, who are at high risk of complications from influenza but for whom there is no currently licensed vaccine, and of children aged 6 to 23 months whether or not they have been immunized. Pregnant women should be immunized in their third trimester if they are expected to deliver during influenza season, as they will become household contacts of their newborn (unless adoption occurs).
• those providing regular child care to children aged 0 to 23 months, whether in or out of the home.
   

• People who provide essential community services. Vaccination for these individuals should be encouraged 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 due to respiratory and other illnesses.

• People in direct contact with poultry infected with avian influenza during culling operations. Concern has been raised regarding the possibility that a pandemic influenza strain may emerge through human-avian gene reassortment within workers directly involved in culling operations, who may become simultaneously infected with a human influenza virus strain and an avian influenza virus strain. This is a theoretical concern, given that this gene reassortment has not been documented to date. A vaccine for avian influenza is not available at the time of writing this statement. The trivalent influenza vaccine (TIV) currently available in Canada protects against human but not avian influenza strains. NACI recommends TIV immunization of those directly involved in the destruction (culling) of avian influenza-infected poultry before the culling operation. It is plausible that TIV immunization may prevent the infection of these individuals with human influenza strains, thereby reducing the potential for human-avian reassortment of genes should they become coinfected with avian influenza during the culling operation. Direct involvement may be defined as sufficient contact with infected poultry to allow transmission of avian virus to the exposed person. The relevant individuals include those performing the cull as well as others (such as supervising veterinarians and inspectors) who may be directly exposed to the avian virus.

  Those persons who would be expected by reason of their employment to come into direct contact with infected poultry during culling operations in the event of potential avian influenza outbreaks should be immunized with TIV on a yearly basis prior to the human influenza season. Those who are immunized with TIV just before exposure to avian influenza will not produce protective antibodies against the human vaccine strains for approximately 10 to 14 days. Antiviral prophylaxis should be used as an adjunct to TIV immunization in order to prevent infection with either avian or human influenza during the culling operation. Advice should be sought from the local medical health officer regarding the use of TIV and influenza antiviral prophylaxis in the control of avian influenza outbreaks.

Further Comments Regarding Recommended Recipients

• Immunization of healthy persons aged 2 to 64 years

Individuals in this age group should be encouraged to receive the vaccine, even if they are not in one of the aforementioned priority groups. In an analysis of randomized controlled trials of inactivated influenza vaccine in healthy adults, Demicheli et al. estimated vaccine efficacy to be 24% in preventing ILI and 68% in preventing laboratory-confirmed influenza infections⁽²⁹⁾. Fewer studies have been performed in children. Depending on whether infection was defined by serology or culture, trials of inactivated trivalent influenza vaccine in children aged 2 to 5 years estimate vaccine efficacy to be 31% to 83%^{(18,28,30-32)}. In a randomized controlled trial, the efficacy of inactivated trivalent influenza vaccine was 91% and 77% in preventing symptomatic culture-positive influenza A H1N1 and H3N2 illness respectively in healthy children aged 1 to 15 years old⁽¹⁸⁾.

The results of cost-effectiveness studies of influenza immunization in adults and children vary according to selected circumstances^(29,33-50). The 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. 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 depend on modelling of these factors within populations as well as on assessing health priorities, resources, and pragmatic programmatic issues.

In the United States, the American Academy of Family Physicians and the Advisory Committee on Immunization Practices recommend that the age of universal influenza vaccination of adults be >= 50 years of age. The primary rationale is that many persons aged 50 to 64 years have high-risk conditions such as diabetes mellitus or heart disease, yet the influenza immunization rate among US adults in this age group who have high-risk chronic medical conditions is low. The low immunization rate is a result of persons being unaware that they have a high-risk condition, lack of health care 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 with previous guidelines based on recognition of the specific high-risk conditions. The cost-benefit of this change in US 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. Current evidence indicates that influenza vaccine is safe for pregnant women at all stages of pregnancy and for breastfeeding mothers. Although it is safe for use in the first trimester, certain HCWs prefer to avoid administration of influenza vaccine during this trimester in order to avoid coincidental association with spontaneous abortion, which occurs most commonly in the first trimester⁽²⁸⁾.

Influenza vaccination is recommended for pregnant and breastfeeding women who are characterized by any of the conditions listed under "Recommended Recipients". This includes pregnant and breastfeeding women who have chronic conditions that put them at high risk of complications from influenza, as well as those who are close contacts of high-risk individuals.

Among healthy pregnant women, morbidity and mortality associated with influenza is increased during pandemics. Studies of the burden of illness among healthy pregnant women in non-pandemic years include case reports, observational studies, and a retrospective case-control study of a predominantly young, urban Tennessee population of African-American, socio-economically disadvantaged women with a high prevalence of chronic disease⁽⁵¹⁾. How well the results of these studies can be generalized to Canadian and other populations is unknown. NACI encourages research to determine the degree of morbidity due to influenza in Canadian women who are pregnant, and the preventable fraction of morbidity potentially achievable through the use of the influenza vaccine in this population. Healthy women who will be in the second or third trimester of pregnancy during influenza season and who wish to avoid morbidity associated with influenza should be encouraged to be vaccinated. Pregnant women should be immunized in their third trimester if they are expected to deliver during influenza season, as they will become household contacts of their newborn.

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. Previously unvaccinated children < 9 years 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.

Immunization with currently available influenza vaccines is not recommended for infants < 6 months of age.

Influenza vaccine should be administered intramuscularly. 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 children <= 18 months of age.

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 in adults but rarely interferes with normal activities. Prophylactic acetaminophen may decrease the frequency of pain at the injection site⁽⁵²⁾. Healthy adults receiving the split-virus vaccine have shown no increase in the frequency of fever or other systemic symptoms compared with those receiving placebo.

Split-virus influenza vaccines are safe and well tolerated in healthy children. Mild local reactions, primarily soreness at the vaccination site, occur in <= 7% of healthy children who are < 3 years of age^(19,53,54). Postvaccination fever may be observed in <= 12% of immunized children aged 1 to 5 years^(18,53).

Several influenza vaccines currently marketed in Canada contain minute quantities of thimerosal, which is used as a preservative. Fluzone® (Aventis Pasteur Inc., USA) contains 40 to 60 µg of thimerosal per 0.5 mL. Fluviral S/F® (Shire Biologics) contains 45 to 55 µg per 0.5 mL. Vaxigrip® (Aventis Pasteur Ltd., France) is produced in a multidose vial that contains 1.7 to 2.3 µg per 0.5 mL. A single dose preparation of Vaxigrip® is also produced in a 0.5 mL pre-filled syringe that does not contain thimerosal. Retrospective cohort studies of large health databases in Denmark and the United States have demonstrated that there is no association between childhood vaccination with thimerosal-containing vaccines and neurodevelopmental outcomes, including autistic-spectrum disorders^(17,24). Results of in vitro studies of neoplastic cells exposed to thimerosal are not reflective of the in vivo situation of immunized children and adults⁽⁵⁵⁾. Nevertheless, in response to public concern, influenza vaccine manufacturers in Canada are currently working towards production and marketing of thimerosal-free influenza vaccines.

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

Guillain-Barré syndrome (GBS) occurred in adults in association with the 1976 swine influenza vaccine, and evidence favours the existence of a causal relation between the vaccine and GBS during that season⁽⁵⁶⁾. In an extensive review of studies since 1976, the United States Institute of Medicine concluded that the evidence is inadequate to accept or reject a causal relation between GBS in adults and influenza vaccines administered after the swine influenza vaccine program in 1976^(56,57).

In Canada the background incidence of GBS was estimated at just over 20 cases per million population in a study done in Ontario and Quebec⁽⁵⁸⁾. 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. Neither is it 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.

Conjunctivitis and/or respiratory symptoms following influenza immunization were reported sporadically before 2000 in Canada, the United States and Europe^(59,60). However, during the 2000-2001 influenza season, Health Canada received an increased number of reports of vaccine-associated symptoms and signs that were subsequently described as oculorespiratory syndrome (ORS)⁽⁵⁹⁾. The case definition (revised in 2001) is as follows: the onset of bilateral red eyes and/or respiratory symptoms (cough, wheeze, chest tightness, difficulty breathing, difficulty swallowing, hoarseness or sore throat) and/or facial swelling occurring within 24 hours of influenza immunization⁽⁶¹⁾. Assessment of the severity of ORS is based on the individual's perceptions of his or her symptoms: mild (easily tolerated; present but not problematic), moderate (interferes with activities of daily living; bothersome, requires activity changes and possibly medication) or severe (prevents activities of daily living; patient unable to work or sleep). The pathophysiologic mechanism underlying ORS remains unknown.

After the 2000-2001 influenza season, fewer ORS cases have been reported to Health Canada⁽⁶¹⁾. Surveillance for all vaccine-associated adverse events (VAAE), including ORS, is ongoing.

Approximately 5% to 34% of patients who have previously experienced ORS may experience a recurrence attributable to the vaccine^(61-67). However, most recurrences are less severe than the previous episode. Persons who experience a recurrence of ORS upon revaccination do not necessarily experience further episodes of ORS associated with further vaccination.

Individuals who have experienced mild or moderate ORS symptoms or severe ORS consisting of non-lower respiratory symptoms (bilateral red eyes, cough, sore throat, hoarseness, facial swelling) may be safely reimmunized with influenza vaccine.

Expert review of the risks and preference for one vaccine product should be sought for those who have previously experienced severe lower respiratory symptoms (wheeze, chest tightness, difficulty breathing) within 24 hours of influenza vaccination, an apparent allergic reaction to the vaccine, or any other symptoms (e.g. throat constriction, difficulty swallowing) that raise concern regarding the safety of reimmunization. This advice may be obtained from local medical officers of health or other experts in infectious disease, allergy/immunology and/or public health. Health care providers who are unsure whether an individual previously experienced ORS versus an IgE-mediated hypersensitivity immune response should seek advice. In view of the considerable morbidity and mortality associated with influenza, a diagnosis of influenza vaccine allergy should not be made without confirmation (which may involve skin testing) from an allergy/immunology expert.

Please refer to the Canadian Immunization Guide⁽⁶⁸⁾ 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 who have known anaphylactic hypersensitivity to eggs manifested as hives, swelling of the mouth and throat, difficulty in breathing, hypotension and shock.

Adults with serious acute febrile illness usually should not be vaccinated until their symptoms have abated. Those with mild non-serious febrile illness (such as mild upper respiratory tract infections) may be given influenza vaccine. Opportunities for immunization should not be lost because of inappropriate deferral of immunization.

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.

Therapy with beta-blocker medication is not a contraindication to influenza vaccination. Individuals who have an allergy to substances that are not components of the influenza vaccine are not at increased risk of allergy to influenza vaccine.

Simultaneous Administration of Other Vaccines

Influenza vaccine may be given at the same time as other vaccines. The same limb may be used if necessary, but different sites on the limb should be chosen. Different administration sets (needle and syringe) must be used.

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.

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, and the degree of similarity between the virus strain included and the characteristics of the strain of circulating virus during influenza season. With a good match, influenza vaccination has been shown to prevent laboratory-confirmed influenza illness in approximately 70% or more of healthy individuals. Under these circumstances, studies have also shown influenza vaccination to be >= 70% effective in preventing hospitalization for pneumonia and influenza among elderly persons living in the community. Studies of 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 be as low as 30%.

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 long-term care facility (LTCF) residents and 20% to 40% of adults and children with medical conditions listed previously receive vaccine annually^(69-73). Recent studies of HCWs in hospitals and LTCFs have shown vaccination rates of 26% to 61%^(70-72,74).

This low rate of utilization is due to failure of the health care system to offer the vaccine and 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 for which they care⁽⁷⁵⁾. Educational efforts aimed at HCWs and the public should address common concerns about vaccine effectiveness and adverse reactions. These include the beliefs of patients at risk, health care workers 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 a very important factor affecting whether a person accepts immunization. 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 these settings, increased vaccination rates are 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.
• vaccinating people at high risk who are being discharged from hospital or visiting the emergency room in the autumn
• promoting influenza vaccination in clinics that see high-risk groups (e.g. cancer clinics, cardiac clinics, and pulmonary clinics)
• using community newspapers, radio, television, and '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 HCWs, 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
• incorporating influenza vaccination within the provision of home health care.

Immunization of HCWs

Person-to-person transmission of influenza virus occurs primarily through small-particle aerosols (< 10 µm in mass median diameter) created by sneezing, coughing, and talking. The virus can also be spread by direct contact with infected persons or contaminated surfaces. Adults may spread influenza to others during a period ranging from 1 day before to 7 days after the onset of symptoms.

Transmission of influenza between infected HCWs and their vulnerable patients results in significant morbidity and mortality⁽⁷⁶⁾. Studies have demonstrated that HCWs who are ill with influenza frequently continue to work, thereby potentially transmitting the virus to both patients and co-workers⁽⁷⁷⁾. 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⁽⁷⁶⁾. 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^(77,78). 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^(78-80).

For the purposes of this document, we may define "direct patient care" as activities that allow opportunities for influenza transmission between HCWs and patient. NACI considers the provision of influenza vaccination for HCWs involved in direct patient care to be an essential component of the standard of care for influenza prevention for the protection of their patients. HCWs involved in direct patient care should consider it their responsibility to provide the highest standard of care, which includes undergoing annual influenza vaccination. In the absence of contraindications, refusal of HCWs who are involved in direct patient care to be immunized against influenza implies failure in their duty of care to their patients.

In order to protect vulnerable patients in an outbreak, it is reasonable to exclude from direct patient care HCWs who develop confirmed or presumed influenza and unvaccinated HCWs who are not taking antiviral prophylaxis. Health care organizations should have policies in place to deal with this issue.

Recommendations for the Prophylactic Use of Amantadine and Oseltamivir

The prophylactic use of antiviral agents against influenza is discussed in this section. Antiviral therapy for influenza is not discussed in this statement.

Antiviral prophylaxis should not replace annual influenza vaccination. Vaccination remains our primary tool for the prevention of influenza infection and illness.

Amantadine hydrochloride is an antiviral agent that interferes with the replication cycle of influenza A virus through the blocking of ion channels of the cell membrane. It is not effective against influenza B. Amantadine may be used for the control of influenza in persons > 1 year of age in the following settings:

• facilities where high-risk residents/patients are exposed
• prophylaxis of household contacts of index cases
• prophylaxis of health care and essential community service personnel
• prophylaxis of those for whom influenza vaccine is contraindicated or not available
• prophylaxis, used as an adjunct to vaccination, in those at high risk of influenza-related complications who are expected to have an impaired immune response to the vaccine
• prophylaxis of unvaccinated individuals who provide home care for high-risk patients during an outbreak.

Rimantadine is a related adamantanamine antiviral agent that is not licensed in Canada. It will not be discussed in this statement.

Randomized trials in healthy adults suggest that amantadine prevents 23% of clinical influenza cases and 63% of serologically confirmed influenza A illness^(81,82). A non-blind randomized trial of amantadine versus placebo during an influenza outbreak in healthy boys aged 13 to 19 living in a boarding school showed 91% efficacy against culture confirmed influenza illness and 86% efficacy against clinical influenza illness⁽⁸³⁾. A non-randomized trial in boys aged 12 to 18 years showed 70% efficacy of amantadine, compared with placebo, in preventing influenza illness⁽⁸⁴⁾.

In non-randomized controlled trials amantadine prophylaxis used for periods varying from 9 days to 16 weeks interrupted influenza A outbreaks and reduced mortality in populations (including disabled children, hospitalized adults, elderly residents of nursing homes, and prison populations) at increased risk of influenza complications^(85-87). Postexposure prophylaxis with amantadine provides protection (protective efficacy 74%) in families when the index case does not receive antiviral therapy^(85,88). Amantadine does not provide protection from influenza A in household contacts when it is also used to treat the index case, likely because of spread of resistant virus within the household^(85,89,90). Amantadine resistance is more likely to occur in populations such as families and within semi-closed settings, including nursing homes where the drug is used for both prophylaxis and treatment as opposed to prophylaxis alone. Simultaneous use of amantadine for prophylaxis and therapy within a family, facility or institution is not advised because of the increased risk of the emergence of viral resistance. Failure to adequately isolate institutional patients receiving 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^(91,92).

Neuraminidase inhibitors prevent the replication of both type A and B influenza viruses by inhibiting influenza virus neuraminidase. Neuraminidase promotes the release of virus from infected cells by preventing virions from self-aggregating and binding to the surface of infected cells. Oseltamivir is a neuraminidase inhibitor that was licensed by Health Canada in December 2003 for postexposure prophylaxis against influenza A and/or B in persons >= 13 years old after close contact with an infected individual (index case). Oseltamivir was not licensed for pre-exposure prophylaxis, although it has been used off-label (outside the licensed indications) for this purpose^(93-95).

Zanamivir is a neuraminidase inhibitor that has not been approved by Health Canada for prophylactic use, although it has been used off-label for this purpose. Zanamivir will not be further discussed in this statement.

A review of randomized placebo-controlled trials in healthy adults reports that neuraminidase inhibitors are 74% effective in preventing naturally occurring cases of clinically defined influenza and 60% effective in preventing laboratory-confirmed influenza^(96-98). Sufficient data are not available to assess the efficacy of neuraminidase inhibitors used prophylactically in healthy children < 13 years old, and they are not licensed for prophylactic use in this age group⁽⁹⁹⁾. Oseltamivir was 92% effective in preventing laboratory-confirmed clinical influenza illness in a randomized, multicentre controlled trial of prophylaxis in elderly individuals in residential care; however, residents with significant renal disease, hepatic dysfunction, cardiac failure, cancer, HIV infection, or history of alcohol/drug abuse were excluded⁽⁹³⁾. The efficacy of oseltamivir in preventing influenza in immunocompromised persons has not been established. Oseltamivir has been successfully used as prophylaxis, along with vaccination and infection control measures, to control outbreaks of influenza in nursing homes and long-term care facilities^(94,95). In a randomized controlled trial oseltamivir was efficacious in protecting healthy household contacts of index influenza cases who were not treated⁽¹⁰⁰⁾. Households with pregnant or breastfeeding women, or individuals with cancer, immunosuppression, HIV infection, chronic liver or renal disease were excluded from this study.

The emergence of oseltamivir-resistant virus during or after prophylactic use of this antiviral has not yet been noted⁽⁹⁸⁾. However, 0.33% to 9% of influenza isolates have been noted to be oseltamivir resistant during follow-up of children and adults in treatment studies^(101,102).

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, as previously indicated, antiviral prophylaxis should not replace annual influenza vaccination.

Amantadine and oseltamivir are not effective in providing prophylaxis for respiratory infections other than influenza. Therefore, it is critically important to base decisions regarding their prophylactic use on appropriate epidemiologic, clinical, and laboratory data regarding the etiology of prevalent infection(s).

NACI recommendations regarding the use of influenza antiviral (amantadine or oseltamivir) prophylaxis:

• For the control of influenza outbreaks among high-risk residents of institutions. Consultation with laboratories and the local medical health officer is important in order to determine whether the circulating strain is type A or B. Amantadine is not effective as prophylaxis against influenza B. Amantadine or oseltamivir 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 until the outbreak is declared over. This date may be defined as a minimum of 8 days after the onset of the last case, based on an average 4-day period of infectiousness for the last case plus an average 4-day incubation period for those potentially exposed.

• For prophylaxis in non-institutionalized people at high risk during an outbreak when vaccine is unavailable, contraindicated, or unlikely to be effective because of a poor match between the vaccine and the circulating viral strain. In this case, prophylactic antiviral medication may be taken each day for the duration of influenza activity in the community. The decision as to what constitutes a "poor match" between vaccine and circulating viral strains should be based on any existing data on vaccine protectiveness during that influenza season, if available, and in consultation with the local medical health officer. Unfortunately, data on vaccine protectiveness are often not available until the season is over. NACI encourages the development of methods for the early assessment of vaccine efficacy in years when the appearance of new circulating strains may result in reduced vaccine efficacy.
  
  Antiviral prophylaxis may also be given to people who are at very high risk during an outbreak and who have been previously vaccinated but are expected to have an impaired immune response to the vaccine. This includes persons with advanced HIV disease and the very frail elderly.

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

• For unvaccinated people who provide care for those at high risk during an outbreak. It is reasonable to allow these individuals to work with high-risk patients as soon as they start antiviral prophylaxis. Unless there is a contraindication, they should also be immediately vaccinated against influenza. Antiviral 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 antiviral prophylaxis, and should be excluded from the patient care environment if these develop.

• Antiviral postexposure prophylaxis may be used for household contacts of index influenza cases. The secondary attack rate among family members of a household in which there is a laboratory-confirmed index case varies from 13% to 25%, according to family composition, virus strain, and exposure outside the household, among other variables^{(100,103,104)}. Prophylaxis of household contacts for 10 days with amantadine (without amantadine treatment of the index case in order to avoid emergence of drug-resistant virus) has reduced confirmed influenza A illness by 74%⁽⁸⁸⁾. A precise time period after onset of illness in the index case during which amantadine should be initiated in order to be effective has not been defined in clinical studies. Seven days of oseltamivir was 89% effective in preventing laboratory-confirmed influenza A or B in household contacts >= 12 years of age when initiated within 48 hours of symptom onset in the index case⁽¹⁰⁰⁾. However, households including pregnant or breastfeeding women, individuals with cancer, immunosuppres- sion, HIV or chronic hepatic or renal disease were excluded from this study.
  
  The diagnosis of influenza in the index case should be based on laboratory confirmation (e.g. using a rapid diagnostic test) or clinical parameters that have high positive predictive value in the setting of prevalent infection in the community. Studies suggest that when influenza is circulating in a community, patients with an influenza-like illness who exhibit both cough and fever within 48 hours of symptom onset are likely to have influenza^(105,106). The presence of sore throat is suggestive of a diagnosis other than influenza (Dr. A. Monto, Professor of Epidemiology, University of Michigan: personal communication, 10 March, 2004).
   
  Despite the availability of antiviral agents for postexposure prophylaxis within households, use of influenza vaccine for pre-exposure prophylaxis at season onset remains the recommended protective strategy of choice. Influenza vaccine provides protection against illness that may result from exposure within the family and community over a more prolonged period of time.

• For prophylaxis of individuals who will be exposed to avian influenza. Consultation with the local medical officer of health is required. Choice of antiviral agent should make use of any available data regarding the susceptibility of the avian virus strain to antiviral agents. At the present time the efficacy of neuraminidase inhibitors in preventing avian influenza has not been established. Experience is limited regarding the prophylactic use of neuraminidase inhibitors for periods of time longer than 6 weeks.

Note that these recommendations encompass off-label (outside of licensed indications) use of oseltamivir.

When prophylaxis is indicated, the decision regarding which antiviral agent to use should take into account the type of influenza strain circulating and the efficacy, potential toxicity, cost, and ability to administer the agent within a particular population.

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 antiviral prophylaxis.

Dosage and potential side effects of amantadine

Amantadine dosage recommendations for prophylaxis of influenza A infection 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. In care facilities for the elderly, serum creatinine levels measured up to 12 months previously can be safely used to estimate creatinine clearance^(107,108). 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⁽⁸⁵⁾.

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 alternative, once daily dosage regimen for persons > 65 years of age, based on renal function, is shown in Table 3⁽¹⁰⁸⁾. 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.

Amantadine was given for 10 days in studies of postexposure prophylaxis of household contacts of index cases with influenza⁽⁸⁸⁾. Amantadine has been given for up to 16 weeks in pre-exposure prophylaxis studies^(85,86).

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 in 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⁽¹⁰⁹⁾. 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 level 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.

Dosage and potential side effects of oseltamivir

Oseltamivir is available in 75 mg capsules as well as a powder that can be reconstituted into an oral suspension at 12 mg/mL. The recommended oral dose of oseltamivir for prevention of influenza in persons >= 13 years of age is 75 mg once daily. For postexposure prophylaxis, oseltamivir should begin within 48 hours of exposure. The duration of household postexposure prophylaxis used in a randomized controlled trial was 7 days⁽¹⁰⁰⁾. Consideration may be given to extending the duration of prophylaxis to up to 14 days if the index influenza case is a child or elderly individual, as these persons may continue to shed virus for up to 14 days after onset of their illness.

No dose adjustment is necessary with a creatinine clearance above 30 mL/min. A recent serum creatinine or creatinine clearance result based on a 24-hour urine collection is not required before starting oseltamivir prophylaxis, unless there is reason to suspect significant renal impairment. For those with a creatinine clearance of 10-30 mL/min, the dosage of oseltamivir should be reduced to 75 mg every other day, or 30 mg of suspension every day orally. No dosing recommendation is available for patients with a creatinine clearance of < 10 mL/min and those undergoing hemodialysis and peritoneal dialysis.

Oseltamivir is converted to oseltamivir carboxylate by esterases located predominantly in the liver. The safety and efficacy of oseltamivir in those with hepatic impairment has not been established.

Oseltamivir should be used during pregnancy and lactation only if the potential benefit justifies the potential risk to the fetus or nursing infant. Insufficient data are currently available regarding possible toxic effects on the fetus. It is not known whether oseltamivir or its active metabolite is excreted in human milk.

Oseltamivir should not be given to children < 1 year of age. Oseltamivir is licensed by Health Canada for prophylactic use only for children aged >= 13 years.

Oseltamivir is contraindicated in persons with known hypersensitivity to any components of the product.

Co-administration of probenecid results in a two-fold increase in exposure to oseltamivir carboxylate, the active metabolite of oseltamivir, as a result of increased active tubular secretion in the kidney.

The most common adverse events reported in oseltamivir prevention studies using doses of 75 mg once daily are headache, fatigue, nausea, cough, diarrhea, vomiting, abdominal pain, insomnia, and vertigo. However, the difference in incidence between oseltamivir and placebo was >= 1% only for headache, nausea, vomiting, and abdominal pain⁽¹⁰¹⁾.

Acknowledgements

NACI gratefully acknowledges the assistance of Samina Aziz, Shelley Deeks, Karen Ellison, Jeannette Macey, Robert Stirling, Theresa Tam, Brian Winchester, Peter Zabchuk and Hui Zheng in the preparation of this manuscript.

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