Statement on Influenza Vaccination for the 2007-2008 Season

Canada Communicable Disease Report
Volume 33 • ACS-7
1 July 2007

An Advisory Committee Statement (ACS)

National Advisory Committee on Immunization (NACI)^{†, ††}

PDF Version
38 Pages - 891 KB

Addendum ( Posted: 2007-10-16)

Preamble

The National Advisory Committee on Immunization (NACI) provides the Public Health Agency of Canada with ongoing and timely medical, scientific, and public health advice relating to immunization. The Public Health Agency of 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. People administering the vaccine should also be aware of the contents of the relevant product leaflet(s). Recommendations for use and other information set out herein may differ from that set out in the product monograph(s)/leaflet(s) of the Canadian 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 it is used in accordance with the product monographs. NACI members and liaison members conduct themselves within the context of the Public Health Agency of Canada's Policy on Conflict of Interest, including yearly declaration of potential conflict of interest.

Introduction

The antigenic components of the influenza vaccine have been updated for the 2007-2008 season. This statement contains new information on human and avian influenza epidemiology. Neuraminidase inhibitors are again recommended as the first-line antiviral agents for the prevention of influenza rather than amantadine. This year, recommendations for routine influenza vaccine receipt have been expanded to include all pregnant women.

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. 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 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.

Person-to-person transmission of influenza virus occurs through droplets from the respiratory tract that are spread by direct contact, through coughing or sneezing, or by hands contaminated with respiratory secretions. Adults spread influenza to others during a period from 1 day before symptom onset to up to 7 days afterwards. Children may have more prolonged viral shedding.

National influenza surveillance in the 2006-2007 season

National influenza surveillance is coordinated through the Immunization and Respiratory Infections Division (IRID), Public Health Agency of Canada (PHAC). The program (Flu watch) collects data and information from various sources in order to provide a national picture of influenza activity. The information for the 2006-2007 season given in this statement is based on data reported up to 3 March, 2007¹.

Overall, the results so far suggest that the 2006-2007 influenza season was relatively mild and that, as with the 2005-2006 season, increased influenza activity presented later in the season². Nationally, influenza activity increased across the country from late-January to early March, but remained mild to moderate overall.

Influenza A viruses have predominated overall, with both influenza A(H1N1) and A(H3N2) circulating. Of the 4,423 positive influenza detections reported to, 4,250 (96.1%) were influenza A and 173 (3.9%) were influenza B. Influenza A detections were reported across the country whereas influenza B was isolated primarily in Quebec and British Columbia. Of the laboratory-confirmed influenza infections, almost half (48%) were reported in children < 10 years of age. Although 28% of the influenza B cases were among children < 5 years of age, a large proportion of influenza B cases occurred in the younger adult and elderly age groups (20% each in the 25-44 and > 65 year age groups).

The National Microbiology Laboratory (NML) has antigenically characterized 614 influenza viruses received from sentinel public health and hospital laboratories across Canada: 382 (62.2%) were characterized as A/Wisconsin/67/2005 (H3N2)-like; 202 (32.9%) were A/New Caledonia/20/1999 (H1N1)-like; 7 (1.1%) were B/Malaysia/2506/2004-like; and 23 (3.7%) were B/Shanghai/361/2002-like. All but the B/Shanghai/361/2002-like strain is included in the composition of the 2006-2007 Canadian influenza vaccine. The majority of influenza A viruses identified early in the season were influenza A/New Caledonia/20/1999 (H1N1)-like; however, the number of influenza A/Wisconsin/67/2005 (H3N2)-like viruses have been increasing since mid-January and now represent the majority of influenza strains characterized so far this season. Of the influenza A (H1N1) viruses characterized, 80% were from the west: British Columbia (35%), Alberta (25%) and Saskatchewan (20%). Of the influenza A (H3N2) viruses characterized, 59% were from Ontario and 25% were from British Columbia.

Surveillance of antiviral resistance patterns of circulating influenza strains is now part of the routine surveillance program at the NML. Since the start of the season, the NML has tested 541 influenza A isolates (167 H1N1, 374 H3N2) for amantadine resistance. None of the H1N1 isolates tested were resistant to amantadine; however, 27.8% of the H3N2 isolates were resistant. This is a significant drop in resistance levels compared with last season (91.5%). Of the 497 isolates tested for oseltamivir resistance (170 influenza A (H1N1), 301 influenza A (H3N2) and 26 influenza B) none was found to be resistant.

At this time, there is no change to the November 2006 PHAC recommendation that health care providers in Canada not prescribe amantadine to treat and prevent influenza during the current flu season³.

Weekly influenza-like illness (ILI) consultation rates have remained within or below baseline levels since the beginning of the season. The highest rate observed was in week 09 (late February-early March) with 51 consultations for ILI per 1,000 patient visits, which is similar to the peak observed during the previous season (49 per 1,000 in week 09 last season). The highest ILI consultation rates were reported in children: 46/1,000 patients seen in the 0-4 age group and 30/1,000 in those aged 5 to 19 years.

The number of outbreaks reported this season in long-term care facilities (LTCFs) is higher than this time last season (112 this season compared with 63 last season) but still lower than in previous years. Of the 406 outbreaks of influenza or ILI that have been reported, 112 (27.6%) were in LTCFs, 9 (2.2%) in hospitals, 257 (63.3%) in schools and 28 (6.9%) in other facilities.

Widespread influenza activity has been reported 23 times by 12 regions in 5 provinces since the start of the season. The majority of widespread activity was reported between early February and early March 2007 and was mostly reported in Toronto, Ontario (35%), and in several regions in British Columbia (35%). A total of 185 influenza-associated pediatric hospitalizations have been reported through the Immunization Monitoring Program ACTive (IMPACT) network, compared with 108 cases at the same time last season. Influenza A was identified in the majority of the hospitalized cases (93.5%), and influenza B was identified in the remaining 6.5%. Of the hospitalizations occurring in the 2006-2007 season, 30.8% were of children < 2 years of age, and 23.2% were among 2- to 4-year-olds. One influenza-associated pediatric death has been reported in Canada. The death, due to influenza A infection, was in a child between 5 and 9 years of age, who was previously healthy and had not received influenza vaccine.

International influenza surveillance

Between September 2006 and January 2007, influenza activity was generally low compared with the same periods in recent years⁴. Influenza activity began in November in the northern hemisphere, which was late compared with previous years, and increased from January through mid-February but remained moderate in general. In the southern hemisphere, mild influenza activity continued in September and declined in October⁵. Influenza A (H1N1) viruses circulated in the United States and in a few European countries, whereas influenza A (H3N2) viruses predominated in many European countries and in some Asian countries/areas. Influenza B circulated at low levels⁴. On the basis of characterization data from Europe this season, 70.9% were classified as A/Wisconsin/67/2005 (H3N2)-like, 17.6% were A/California/7/2004 (H3N2)-like, 5.9% were A/New Caledonia/20/1999 (H1N1)-like, 5.5% were B/Malaysia/2506/2004-like and < 1% were B/Jiangsu/10/2003-like⁶.

In the United States, influenza A (H1N1) is the predominant influenza A virus circulating this season. Of the 225 influenza A viruses, 189 (84.0%) were A/New Caledonia/20/1999(H1N1)-like viruses, 11 (4.9%) were H1N1-like viruses showing reduced titres with antisera produced against A/New Caledonia/20/1999 (H1N1), 12 (5.3%) were A/Wisconsin/67/2005 (H3N2)-like viruses, and 13 (5.8%) were H3N2-like viruses showing reduced titres with antisera produced against A/Wisconsin/67/2005 (H3N2). Of the 78 influenza B viruses, 52 (66.7%) belonged to the B/Victoria/2/1987 lineage (29 B/Ohio/01/2005-like viruses and 23 showing somewhat reduced titres with antisera produced against B/Ohio/01/2005), and 26 (33.3%) belonged to the B/Yamagata/16/1988 lineage⁷.

Avian influenza

The now extensive outbreaks of avian influenza (H5N1) began in poultry flocks in South East Asia in 2003 and have since spread to over 50 countries throughout Asia, Africa and Europe. Between 1 December, 2003, and 20 March, 2007, there have been a total of 281 human influenza A (H5N1) cases and 169 deaths (overall case fatality rate 60%) in 12 countries (Thailand, Vietnam, Cambodia, Azerbaijan, China, Egypt, Indonesia, Iraq, Turkey, Djibouti, Nigeria, and Lao People's Democratic Republic). Human cases have followed the geographic extension of the avian outbreaks and have occurred year round; however, the highest incidence has been during the periods roughly corresponding to the winter and spring in the northern hemisphere8.

An epidemiologic analysis of 256 laboratory-confirmed human H5N1 cases officially reported to the World Health Organization (WHO) with an onset date between November 2003 and November 2006 indicates that the median age of confirmed cases was 18 years (range: 3 months to 75 years). Approximately half of all cases (52%) were < 20 years of age, and 89% were < 40 years of age. Half of all cases were male (50%). The highest case fatality rate (76%) was found among those aged 10-19 years; the lowest (40%) was found among those aged > 50 years8.

Although human-to-human transmission among close contacts cannot be excluded in some instances, no evidence of efficient or sustained human-to-human transmission exists to date. Genetic and antigenic analyses reported by the WHO have shown that the influenza A (H5N1) virus (Asian strain) has undergone some changes since 1997 when the first human infections were reported9,10. Moderately reduced susceptibility to oseltamivir in laboratory testing was found in two viruses with a genetic mutation; these viruses were obtained from patients on oseltamivir treatment11. There is no indication that oseltamivir resistance is widespread. More investigation, both virologic and epidemiologic, is needed to better understand the effects of these mutations on the transmissibility of the virus from birds to human as well as from human to human. However, at this time these changes do not appear to have altered the epidemiology of the disease in humans, and the mutations have not become fixed in the circulating viruses. The virus continues to be a zoonotic virus, not a human-adapted one, and human infections remain rare.

Recommendations for the 2007-2008 influenza vaccine

General considerations

The national goal of influenza immunization programs is to prevent serious illness caused by influenza and its complications, including death. NACI therefore recommends that priority be given to immunization of those persons 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, NACI encourages annual vaccine for all Canadians.

The antigenic characteristics of current and emerging influenza virus strains provide the basis for selecting the strains included in each year's vaccine. The WHO recommends that the trivalent vaccine for the 2007-2008 season in the northern hemisphere contain an A/Solomon Islands/3/2006 (H1N1)-like virus; an A/Wisconsin/67/2005 (H3N2)-like virus; and a B/Malaysia/2506/2004-like virus. Vaccine producers may use antigenically equivalent strains because of their growth properties. The two main manufacturers of publicly funded vaccines in Canada have confirmed that the vaccines to be marketed for the 2007-2008 influenza season contain these three WHO-recommended antigenic strains.

Annual immunization against influenza must be given 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. 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 according to 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. Although vaccination prior to the onset of the influenza season is preferred, vaccine can still be administered up until the end of the season. Health care workers (HCWs) should use every opportunity to give vaccine to any individual at risk who has not been immunized during the current season, even after influenza activity has been documented in the community.

Recommended recipients
(see Table 1)

Current influenza vaccines approved for use in Canada are immunogenic, safe and associated with minimal side effects (see Adverse Reactions and Contraindications and Precautions). Influenza vaccine may be administered to anyone ≥ 6 months of age without contraindications.

To reduce the morbidity and mortality associated with influenza and the impact of illness in 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. These groups remain the priority for influenza vaccination programs. However, significant morbidity and societal costs are also associated with seasonal influenza illness and its complications occurring in people who are not considered at high risk of complications (i.e. healthy people aged 2 to 64 years).

Table 1 Recommended recipients of influenza vaccine

People at high risk of influenza-related complications

• Adults and children with selected chronic health conditions. A number of chronic health conditions, if significant enough to require regular medical follow-up or hospital care, are associated with increased risk of influenza-related complications and/or lead to exacerbation of the chronic disease. These conditions include cardiac or pulmonary disorders (including bronchopulmonary dysplasia, cystic fibrosis and asthma); diabetes mellitus and other metabolic diseases; cancer; immunodeficiency and immunosuppression (due to underlying disease and/or therapy); renal disease; anemia or hemoglobinopathy; and conditions that compromise the management of respiratory secretions and are associated with an increased risk of aspiration. This category includes children and adolescents (age 6 months to 18 years) with conditions treated for long periods with acetylsalicylic acid because of the potential increased risk of Reye syndrome associated with influenza.

• People of any age who are residents of nursing homes and other chronic care facilities. Such residents often have one or more chronic medical conditions and live in institutional environments that may facilitate spread of the disease.

• People ≥ 65 years of age. Admissions attributable to influenza in this age group are estimated at 125 to 228 per 100,000 healthy persons¹², and death rates increase with increasing age¹³.

• Healthy children aged 6-23 months. Children in this age group are at increased risk of influenza-associated hospitalization compared with healthy older children and young adults. Hospitalization is most frequent in those under 2 years of age with rates estimated in a variety of North American studies to be from 90 to 1,000 admissions per 100,000 healthy children^14-16. These rates are similar to or greater than those of persons over 65 years of age. Influenza immunization of children aged 2-5 years is efficacious^17-19. Few trials have been conducted in children 6 to 23 months of age. NACI recognizes that both the number of studies and participants in the randomized controlled trials of influenza vaccine in children in this age group are limited, that there are unanswered questions, including the unknown efficacy of vaccine in unprimed children who have not had experience with the vaccine or infection, and that there are varying findings regarding the cost-effectiveness of routine immunization programs in this age group^20,21. NACI strongly encourages further research regarding these issues. However, on the basis of existing data regarding the high incidence of influenza-associated hospitalization in healthy children < 24 months, NACI recommends the inclusion of this age group among high-priority recipients of influenza vaccine.

• Pregnant women. Pregnant women with any of the selected chronic conditions previously described are at high risk of the complications associated with influenza, and NACI has previously considered them as a priority for immunization²². The immunization rates of pregnant women with co-morbidities, however, are uniformly low in all studies, ranging from 0% to 20%^23-28. The implementation of influenza immunization programs that target all pregnant women, rather than sub-populations of them, may be more efficient to deliver and result in more comprehensive coverage of the pregnant women at highest risk. Healthy pregnant women have higher influenza-associated respiratory hospitalizations and medical visits than their non-pregnant peers, although the incidence of these complications is lower than among pregnant women with co-morbidities. For these reasons, NACI recommends the inclusion of all pregnant women among the recommended recipients for influenza vaccine.

  Excess morbidity and mortality associated with pneumonia and influenza were observed in pregnant women during the 1918 and 1957 influenza pandemics^29,30. Pneumonia is the most frequent cause of non-obstetric infection in pregnancy, occurring in 0.11% to 2.3 % of women in hospital-based studies²⁹. The extent to which healthy pregnant women, as opposed to those with co-morbidities, are at risk of complicated influenza infection varies in different studies^{24-26,28,31-33}. In many studies the two populations are considered together. Further, the estimation of the size of the adverse effect associated with influenza, as opposed to another infectious etiology, is not always clear since ILI illness rather than laboratory-confirmed infection may be used as an outcome.

  Immunization of all pregnant women has been recommended since 2004 in the United States34. A population-based assessment of maternal and perinatal morbidity in a Tennessee Medicaid population showed a respiratory hospitalization rate of 200 per 100,000 pregnant and perinatal women without risk factors for influenza-associated complications and 100 to 6,000 per 100,000 in women with asthma, diabetes or other high-risk conditions, but no adverse effects on perinatal outcomes32. A review of a large, US managed-care organization identified ILI in 8.3% of pregnant and postpartum women; 5.4% of these were severe enough to require an emergency department visit or hospitalization26. In both studies risk increased in later pregnancy.

  In another large, managed-care setting in which > 49,000 live births were followed, 4.7% of women had at least one outpatient visit for ILI. There were nine admissions for pneumonia during five influenza seasons (18.2 cases/100,000 population)²⁵. A recent population-based record linkage study in Nova Scotia for the period 1990-2002 showed that in women with co-morbidities 44.9 respiratory-related hospitalizations during influenza season occurred per 10,000 women-months²⁸. Compared with themselves in a non-pregnancy year, this represents a relative risk for hospitalization of 8.5 (95% confidence interval [CI] 5.1-13.9). Healthy third trimester women had 20 admissions in 13 years for which a respiratory- related condition was the most responsible diagnosis, representing an admission rate of 1.94/10,000 women-months (adjusted relative risk = 2.4, CI 1.2-4.9) when compared with themselves in a non-influenza season. Healthy third trimester women had an overall respiratory-related admission rate of 7.36/10,000 women-months during influenza season, compared with 3.06/10,000 in a non-influenza season. In an analysis of hospitalizations attributable to influenza in Canada from 1994 to 2000 in women with and without co-morbidities³³, 60% of respiratory-related admissions in healthy pregnant women during the 4 weeks of peak influenza activity could be attributed to influenza. Overall, 1 in 1,000 healthy pregnant women were hospitalized for influenza-attributed illness yearly. While a relatively infrequent occurrence, this represents an 18 fold increased risk of influenza-attributed hospitalization compared with healthy non-pregnant women.

  There are no randomized controlled trials to assess the efficacy of influenza vaccine in pregnancy. A retrospective review of vaccinated and non-vaccinated pregnant women in a large managed-care organization showed no difference in the occurrence of ILI or hospitalizations with principal diagnoses of influenza or pneumonia, but it was underpowered to do so since only 7% of women had been immunized²⁵. Maternal immunization was not associated with reduced infant visits for ILI in an analysis of the Vaccine Safety Datalink database²⁷.

  Influenza vaccine is considered safe for pregnant women at all stages of pregnancy^{35, 36, 37, 38} and for breastfeeding women. Immunization of pregnant women has the advantage of potentially protecting the fetus through transplacental antibody passage^{39, 40} or through breast milk.

People capable of transmitting influenza to those at high risk of 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) has been immunized. Immunization of care providers decreases death, morbidity and health service use among residents, staff illness and absenteeism^(41-46). Immunization of care providers and residents is associated with decreased risk of ILI outbreaks⁴⁷. Individuals who are capable of transmitting influenza to those at high risk of complications include the following:

• Health care and other care providers in facilities and community settings who, through their activities, are potentially capable of transmitting influenza to those at high risk of influenza complications. This group includes regular visitors, emergency response workers, those who have contact with residents of continuing care facilities or residences, and those who provide home care for persons in high-risk groups.
• Household contacts (adults and children) of people at high risk of influenza complications, whether or not they have been immunized. This group includes household contacts of: infants < 6 months of age (who are at high risk of complications from influenza but for whom there is no available effective vaccine), children aged 6-23 months and pregnant women.
• Those providing regular child care to children < 24 months of age whether in or out of the home.
• Those who provide services within closed or relatively closed settings to persons at high risk (e.g. crew on ships).

Others

• People who provide essential community services. Vaccination for these individuals should be encouraged in order to minimize the disruption of routine activities during annual 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 avian-influenza-infected poultry during culling operations. These individuals may be at increased risk of avian influenza infection because of exposure during the culling operation^48,49. Influenza immunization on a yearly basis for these workers is increasingly being recommended in some countries⁵⁰, with the theoretical rationale that it may prevent the infection of these individuals with human influenza strains and thus reduce the potential for human-avian reassortment of genes should such workers become coinfected with avian influenza⁵¹. 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 who may be directly exposed to the avian virus, such as supervising veterinarians and inspectors. Those who are immunized with influenza vaccine 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 during that interval in order to prevent infection with either avian or human influenza during the culling operation. For further information on human health issues related to domestic avian influenza outbreaks see the PHAC guidance at http://www.phac-aspc.gc.ca/publicat/daio-enia/index-eng.php (see also the section entitled Prophylactic use of Antivirals).

Further comments regarding influenza immunization

• Immunization of healthy persons aged 2-64 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. Systematic reviews of randomized controlled trials in healthy children and adults show that inactivated influenza vaccine is up to 70% effective in preventing laboratory-confirmed influenza infection^17-19,52.

  In the United States, the American Academy of Family Physicians and the Advisory Committee on Immunization Practices (ACIP) recommend that the age of universal influenza vaccination of adults be ≥ 50 years. 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 with high-risk chronic medical conditions in this age group is low. The low immunization rate is a result of individuals 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 as compared with previous guidelines based on recognition of the specific high-risk conditions, and they have been found to be cost-effective in one analysis⁵³.

  Children 24 to 59 months of age have been recommended for annual immunization by the ACIP since 200634, on the basis of their increased risk of influenza-related clinic and emergency department visits54. In the 2004-2005 influenza season in Canada, 374 influenza-related admissions occurred in 12 pediatric hospitals2; 27% of these were of children 2-5 years of age. The mean duration of hospital stay in these children was 4.2 days, and 27% were admitted to an intensive care unit55. Age-specific average annual rates of pediatric respiratory admissions attributable to influenza in Canada are approximately 150/100,000 at 2 years of age and decrease thereafter, reaching rates similar to those among older children and adults by age 514.

  Observational studies and mathematical modelling of influenza transmission in communities suggest that vaccinating schoolchildren would reduce morbidity and mortality associated with influenza deaths in the rest of the population^56-61. In an open-labelled, non-randomized study of two US communities, vaccination of 20% to 25% of children 1.5-18 years of age with a live attenuated influenza vaccine was associated with indirect protection against medically attended respiratory illness in adults > 35 years of age⁶². School-based influenza immunization with a live attenuated vaccine decreased influenza-like symptoms and outcomes in households where children had been vaccinated⁶³. The universal influenza immunization in the province of Ontario since 2000 has been associated with increased vaccine uptake in high-risk populations⁶⁴ and with a decrease in emergency room utilization (Jeff Kwong, Ontario Institute of Clinical and Evaluative Science, University of Toronto: personal communication, 2006).

  The ACIP is considering a proposal to expand annual influenza immunization to include all school-age children up to 18 years of age in the United States and potentially implement this program in 2008-2009 (http://www.cdc.gov/vaccines/recs/acip/downloads/mtg-slides-feb07/05-influenza-1-allos_fiore.pdf).

• Travellers. People with selected chronic medical conditions or other factors that would make them recommended recipients of influenza vaccine should be immunized as previously discussed (Table 1). Healthy persons should be encouraged to receive vaccine. Vaccines prepared specifically against strains that are predicted to circulate in the southern hemisphere are not currently available in Canada. For further information on advising travellers about influenza prevention, the Committee to Advise on Tropical Medicine and Travel statement should be consulted⁶⁵.

  NACI suggests that programmatic decisions in Canada regarding how to access and immunize populations listed under Recommended Recipients are best made by authorities responsible for the planning and implementation of such programs.

Immunogenicity and efficacy

Intramuscular administration of inactivated influenza vaccine results in the production of circulating IgG antibodies to the viral hemagglutinin and neuraminidase, as well as a cytotoxic T lymphocyte response. Both humoral and cell-mediated responses are thought to play a role in immunity to influenza. The production and persistence of antibodies after vaccination depend on several factors, including the age of the recipient, prior and subsequent exposure to antigens and the presence of immunodeficiency states. Humoral antibody levels, which correlate with vaccine protection, are generally achieved 2 weeks after immunization. Because influenza viruses change over time, immunity conferred in one season will not reliably prevent infection by an antigenically drifted strain (heterotypic immunity). For this reason the antigenic constituents of each year's vaccine change, and annual immunization is required.

Repeated annual administration of influenza vaccine has not been demonstrated to impair the immune response of the recipient to influenza virus. Multiple studies show that influenza vaccine is efficacious, with higher efficacy demonstrated against laboratory-confirmed influenza than clinically defined outcomes without laboratory confirmation⁶⁶. With a good match, influenza vaccination has been shown to prevent influenza illness in approximately 70% to 90% of healthy children and adults^{17-19, 52}, whereas a vaccine efficacy of up to 70% has been demonstrated when there are significant antigenic differences between circulating and vaccine viral strains but can be considerably lower^{67, 68}. Systematic reviews have also demonstrated that influenza vaccine decreases the incidence of pneumonia, hospital admission and death in the elderly⁶⁹ and reduces exacerbations in persons with chronic obstructive pulmonary disease⁷⁰. In observational studies immunization reduces physician visits, hospitalization and death in high-risk persons < 65 years of age⁷¹, reduces hospitalizations for cardiac disease and stroke in the elderly⁷², and reduces hospitalization and deaths in persons with diabetes mellitus⁷³.

The first time children < 9 years of age receive influenza immunization a two-dose schedule is required (Table 2). In a review of an administrative dataset of over 5,000 healthy children 6-21 months, two doses of influenza vaccine were 69% and 87% effective in preventing office visits in the 2003-2004 season for ILI, and pneumonia and influenza, respectively. One dose of trivalent inactivated vaccine (TIV) conferred no protection against these outcomes⁷⁴. In a multivariate analysis of medically attended ILI in the 2003-2004 season, children aged 6 months to 8 years given two TIV doses (either spring-fall or fall-fall) had an estimated vaccine effectiveness of 51% against pneumonia and influenza, and 23% against ILI, compared with 23% and 7% against these outcomes, respectively, in children who had had only one dose of vaccine in the fall⁷⁵. In a non-randomized trial comparing the immunogenicity of one TIV dose in year 1 followed by a single dose in the second year of immunization with a two-dose schedule in the first year of immunization, only 27% of healthy children 6-24 months old who had received a single dose in the previous season had a protective antibody response to influenza B virus antigen, as compared with 86% in the two-dose group⁷⁶. The TIV B antigen had changed between the two seasons observed. It is of note that immunogenicity was not significantly different for H3N2 antigen (changed in year 2) or the H1N1 antigen (unchanged). On the basis of these findings, the recommendations for the number of doses of influenza vaccine for children < 9 years of age have been changed. Two doses should be given in the second year of influenza immunization if the child received only one dose of vaccine during the first year of immunization.

A two-dose schedule in year 2 may not be necessary for children who received only one dose in year 1 if the vaccine antigens do not change. For example, a randomized controlled trial of one or no spring doses in healthy children 6-23 months old followed by a two-dose fall schedule with an unchanged vaccine elicited similar antibody responses⁷⁷.

Vaccine efficacy may be lower in certain populations (e.g. the immunocompromised, the elderly) than in healthy adults. However, the possibility of lower efficacy should not prevent immunization in those at high risk of influenza-associated morbidity, since protection is still likely to occur. Influenza vaccination can induce protective antibody levels in a substantial proportion of immunosuppressed adults and children, including transplant recipients, those with proliferative diseases of the hematopoietic and lymphatic systems, and HIV-infected patients. Two studies show that administration of a second dose of influenza vaccine in elderly individuals or other individuals who may have an altered immune response does not boost immunity^{78, 79}.

Administration of Influenza Vaccine Dosage schedule

The recommended dosage schedule and type of influenza vaccine are presented in Table 2. Influenza vaccines available in Canada are available as split-virus or inactivated subunit preparations. Two products (Vaxigrip^®, Fluviral S/F^®) are split-virus vaccines that are treated with an organic solvent to remove surface glycoproteins, producing a split virus resulting in reduced vaccine reactogenicity. Influvac^TM is a surface antigen, trivalent, inactivated subunit vaccine, which is currently approved for use among persons ≥18 years of age. Each 0.5 mL dose of vaccine contains 15 μg of hemagglutinin of each antigen. Children under 9 years of age require two doses of influenza vaccine given 4 weeks apart if they have received one or no doses in the previous influenza season.

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

*Children under 9 years old require two doses of influenza vaccine given 4 weeks apart if they have received one or no doses in the previous influenza season and have never received two doses within a single season.

Influenza vaccine should be administered intramuscularly. The deltoid muscle is the recommended site in adults and children ≥ 12 months of age. The anterolateral thigh is the recommended site in infants < 12 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 site⁸⁰. Healthy adults receiving the TIV show 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% or less of healthy children who are < 3 years of age. Post-vaccination fever may be observed in 12% or less of immunized children aged 1-5 years.

Several influenza vaccines that are currently marketed in Canada contain minute quantities of thimerosal, which is used as a preservative⁸¹. One thimerosal-free vaccine (Influvac™, Solvay Pharma), approved for persons ≥ 18 years of age, is available in Canada⁸². Retrospective cohort studies of large health databases have demonstrated that there is no association between childhood vaccination with thimerosal-containing vaccines and neurodevelopmental outcomes, including autistic-spectrum disorders. 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, such as 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 season⁸³. In an extensive review of studies since 1976, the United States Institute of Medicine concluded that the evidence was inadequate to accept or reject a causal relation between GBS in adults and influenza vaccines administered after the swine influenza vaccine program in 1976⁸⁴.

In a Canadian study, the background incidence of GBS due to any cause was estimated at 2.02 per 100,000 person-years in Ontario and 2.30 per 100,000 person-years in Quebec85. A variety of infectious agents, including Campylobacter jejuni, cytomegalovirus, Epstein-Barr virus and Mycoplasma pneumoniae, have been associated with GBS86. A consistent finding in case series is the occurrence of an infection in the 6 weeks before GBS diagnosis in about two-thirds of patients86. It is not known whether influenza virus infection itself is associated with GBS. A retrospective review of the 1992-1993 and 1993-1994 US influenza vaccine campaigns found a 1.7-fold adjusted relative risk (95% CI 1.0-2.8; p = 0.04) for GBS associated with vaccination87. This is consistent with a more recent Canadian study involving a self-matched case series from the Ontario health care database for the years 1992 to 2004. It found the estimated relative risk of hospitalization for GBS in the 8 weeks following influenza vaccination, compared with controls, to be 1.45 (95% CI 1.05-0.99, p = 0.02)88. These studies suggest that the absolute risk of GBS in the period following vaccination is about 1 excess case per 1 million vaccinees above the background GBS rate. The potential benefits of influenza vaccine (see efficacy and immunogenicity) must be weighed against this low risk. The Ontario study also looked at the incidence of GBS in the entire Ontario population since 2000, when a universal influenza immunization program was introduced in that province; no statistically significant increase in hospital admissions because of GBS was found.

It is 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 8 weeks of a previous influenza vaccination appears prudent at this time. It is not known whether influenza vaccination increases the risk of recurrence of GBS in persons who have previously had this condition due to any cause. Influenza vaccine is not known to predispose vaccine recipients to Reye syndrome.

During the 2000-2001 influenza season, PHAC received an increased number of reports of vaccine-associated symptoms and signs that were subsequently described as oculorespiratory syndrome (ORS)⁸⁹. The case definition 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. The pathophysiologic mechanism underlying ORS remains unknown, but it is considered distinct from IgE-mediated allergy.

Approximately 5% to 34% of patients who have previously experienced ORS may have a recurrence attributable to the vaccine, but these episodes are usually milder than the original one, and vaccinees indicate willingness to be immunized in subsequent years⁹⁰. Persons who have a recurrence of ORS upon revaccination do not necessarily experience further episodes with future vaccinations. Data on clinically significant adverse events do not support the preference of one vaccine product over another when revaccinating those who have previously experienced ORS^52,53.

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

Contraindications and Precautions

Influenza vaccine should not be given to people who have had an anaphylactic reaction to a previous dose.

Persons with known IgE-mediated hypersensitivity to eggs (manifested as hives, swelling of the mouth and throat, difficulty in breathing, hypotension or shock) should not be routinely vaccinated with influenza vaccine. Egg-allergic individuals who are at risk of the complications of influenza should be evaluated by an allergy specialist, as vaccination might be possible after careful evaluation, skin testing and graded challenge or desensitization. If such an evaluation is not possible, the risk of an allergic reaction to the vaccine must be weighed against the risk of influenza disease.

Expert review of the risks and benefits of vaccination 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.

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

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 vaccine 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 polysaccharide vaccines 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° C to +8° C and should not be frozen.

Strategies for Reducing the Impact of Influenza

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 20% to 40% of adults and children with medical conditions listed previously receive vaccine annually. The 2005 Canadian Community Health Survey (CCHS) reports coverage rates of influenza vaccine in the previous year of only 30.3% (95% CI 29.7-30.9, n = 22,693) for adults 18-64 years of age with a chronic medical condition¹⁰⁴. Results from the 2006 Adult National Immunization Coverage Survey on coverage for adults 18-64 years with a chronic medical condition are similarly low, at 38.2% (95% CI 33.3-43.1, n = 395). Results from the latter survey for non-institutionalized adults show that seniors (65+ years) have slightly higher coverage, 69.9% (95% CI 64.1-75.7, n = 287) receiving an influenza vaccine in the previous year. The results for this group have not changed since 2001 (69.1%). The coverage rates for residents of LTCFs range from 70% to 91%^{92, 105, 106}. Studies of HCWs in hospitals and LTCFs reveal influenza vaccination coverage rates of 26%-61%⁹². Coverage rates are higher among those in close contact with patients (69.7%, 95% CI 66.8-72.6, n = 727) (Unpublished results from the 2006 Adult National Immunization Coverage Survey, Immunization and Respiratory Infections Division, Public Health Agency of Canada).

Low rates of utilization are 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 care⁵⁴. 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, the belief that HCWs and other service providers 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, but are not limited to, 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 and instituting a policy of obtaining consent on admission that is durable for future years.
• Vaccinating people at high risk who are being discharged from hospital or visiting the emergency department in the autumn.
• Promoting influenza vaccination in clinics in which high-risk groups are seen (e.g. cancer clinics, cardiac clinics and pulmonary clinics)
• Using community newspapers, radio, television and other media and influenza 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.
• Issuing patient-carried reminder cards.
• Increasing accessibility of immunization clinics to staff in institutions and community-based elderly (e.g. implementing mobile programs).
• Organizing 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 Health Care Workers

Transmission of influenza between infected HCWs and their vulnerable patients results in significant morbidity and mortality. 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. 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. 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 the scarcity of replacement workers.

For the purposes of this document we define a HCW as a person who provides direct patient care, as well as one who provides health services in an indirect fashion, such as through administrative activities in a setting where patient care is conducted. The latter group may come into close contact with patients through the sharing of common areas within facilities, such as cafeterias and waiting areas. The term "direct patient contact" is defined as activities that allow opportunities for influenza transmission between HCWs and a patient.

NACI considers the provision of influenza vaccination for HCWs who have direct patient contact to be an essential component of the standard of care for the protection of their patients. HCWs who have direct patient contact 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 have direct patient contact to be immunized against influenza implies failure in their duty of care to patients.

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

Prophylactic Use of Antivirals

The prophylactic use of antiviral agents against influenza is discussed in this section. Antiviral treatment of influenza is not covered in this statement; recent Canadian treatment guidelines have been published93.

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

There are two available classes of antiviral drugs that have been used for influenza prevention: M2 ion channel inhibitors and neuraminidase inhibitors. M2 ion channel inhibitors, such as amantadine, interfere with the replication cycle of influenza A. They have no effect on influenza B.

Resistance to amantadine has been shown to develop rapidly when this drug is used for treatment purposes. In recent years resistance to amantadine has been high, especially for H3N2, which has led to a recommendation that it not be used for influenza treatment or prevention. Data available from the 2006-2007 season show that amantadine resistance decreased to about 30% for H3N2 isolates, and there was no resistance detected for the H1N1 isolates (Flu Watch report¹).

NACI does not recommend amantadine for prophylaxis for the 2007-2008 season. This recommendation may be revised as new information becomes available. The rest of this report focuses on the neuraminidase inhibitors. The 2005-2006 NACI statement contains additional information on amantadine. 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 Tamiflur^® is a neuraminidase inhibitor that has been approved for use for post-exposure prophylaxis against influenza A and/or B in persons ≥ 1 year of age. Two trials on post-exposure prophylaxis showed a relative efficacy of 58%⁹⁴ and 89%⁹⁵ of oseltamivir compared with controls in preventing symptomatic, laboratory-confirmed influenza (an absolute risk reduction of 15% and 11%, respectively) The efficacy of oseltamivir in preventing influenza has not been established in immunocompromised persons and those with significant renal diseases, hepatic dysfunction, cardiac failure or cancer, as these groups were excluded from clinical trials. No randomized trials have been conducted to assess the efficacy of oseltamivir in controlling outbreaks in LTCFs. However, the results of observational studies of outbreaks in LTCFs have been promising when oseltamivir was used for both treatment and prophylaxis, along with vaccination and infection control measures. The use of oseltamivir is currently contraindicated in children < 1 year of age as their blood-brain barrier is not fully developed and, on the basis of animal studies, there is a concern that this could lead to toxicity. The emergence of oseltamivir-resistant virus during or after prophylactic use of this antiviral has not yet been reported. However, 0.33% to 18% of influenza isolates have been noted to be oseltamivir resistant during follow-up of children and adults in treatment studies.

Zanamivir Relenzar^® is a neuraminidase inhibitor that is administered by inhalation. It was recently approved for use for post-exposure prophylaxis against influenza A and B in persons ≥ 7 years of age. Two trials on post-exposure prophylaxis showed a relative efficacy of 79%⁹⁶ and 81%⁹⁷ of zanamivir (absolute risk reduction of 10% and 15%) compared with placebo in preventing symptomatic, laboratory-confirmed influenza. The efficacy of zanamivir in preventing influenza has not been established in immunocompromised persons and those with significant renal diseases, hepatic dysfunction, cardiac failure or cancer, as these groups were excluded from clinical trials. Zanamivir is not recommended in individuals with underlying airways disease (such as asthma or chronic obstructive pulmonary disease) because of the risk of serious bronchospasm. Two randomized trials have been conducted to assess the efficacy of zanamivir in controlling outbreaks in LTCFs. Although in both trials fewer people had influenza in the zanamivir group than in the placebo group, in one trial the results were statistically significant (p = 0.038)⁹⁸ and in the other they were not⁹⁹. The product monograph in Canada notes that "Relenza has not been proven effective for prophylaxis of influenza in the nursing home setting."

The emergence of zanamivir-resistant virus during or after prophylactic use of this antiviral has not yet been reported. For its use in treatment, there has been one case study reporting zanamivir resistance to influenza A. A recent study has demonstrated resistance during treatment to influenza B in Japan, where neuraminidase inhibitors are widely used¹⁰⁰.

In summary, post-exposure prophylaxis with neuraminidase inhibitors is effective in preventing influenza infections when used soon after identification of an index case. It is a supplemental strategy and should not replace the primary control strategy of annual influenza vaccination.

Neuraminidase inhibitors 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 recommends that neuraminidase inhibitors may be used prophylactically in the following situations:

• For the control of influenza A or B outbreaks among high-risk residents of institutions. Oseltamivir should be given to all residents who are not already ill with influenza, whether previously vaccinated or not, and to unvaccinated staff (see Contraindications and Precautions). Post-exposure prophylaxis should also be considered for HCWs, regardless of vaccination status, during outbreaks caused by influenza 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 5-day period of infectiousness for the last case plus an average 3-day incubation period for those potentially exposed.

• For seasonal prophylaxis in non-institutionalized people at high risk 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. Seasonal prophylaxis, or taking a daily prophylactic medication for 4-6 weeks while influenza is circulating in the community, is currently an "off-label" use in Canada, but clinical trial evidence supports its use. 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 in which the appearance of new circulating strains may result in reduced vaccine efficacy. Patients should be informed that this is "off-label" use in Canada, but clinical trial evidence supports its use for periods up to 6 weeks.

• Antiviral prophylaxis may also be given during an outbreak to people at very high risk who have been previously vaccinated but who 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 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 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 post-exposure prophylaxis may be used for non-vaccinated 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. The diagnosis of influenza in the index case should be based on laboratory confirmation (e.g. by means of 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 ILI who have both cough and fever within 48 hours of symptom onset are likely to have influenza^101,102. The presence of sore throat is suggestive of a diagnosis other than influenza. Antiviral prophylaxis must begin as soon as possible and within 48 hours after onset of symptoms in the index case.

  Despite the availability of antiviral agents for post-exposure 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. Although it is preferred that administration occur in the fall, influenza vaccine may be given through the winter months if the vaccination opportunity was previously missed.

• For prophylaxis among individuals who have been or 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 these drugs 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.

  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 (e.g. some people may not be able to use the inhalation device used to administer zanamivir).

  Factors to be considered in decisions about the duration of antiviral prophylaxis include local epidemiology, potential side effects, concern regarding emergence of viral resistance, adherence to medication regimens, and cost.

Oseltamivir administration

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. The recommended oral dose for prevention of influenza in pediatric patients is based on body weight. For children 15 kg and less, 30 mg once a day; for children over 15 kg and up to 23 kg, 45 mg once a day; for children over 23 kg and up to 40 kg, 60 mg once a day; and for children over 40 kg, 75 mg once a day. For post-exposure prophylaxis, oseltamivir should begin within 48 hours of exposure. The duration of household post-exposure prophylaxis used in a randomized controlled trial was 7 days. Consideration may be given to extending the duration of prophylaxis to up to 14 days if the index influenza case is a child or an 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. Availability of a recent result of a serum creatinine or creatinine clearance test 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 dose 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 < 10 mL/min or 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.

Co-administration of probenecid results in a 2-fold increase in exposure to oseltamivir carboxylate, the active metabolite of oseltamivir, because of increased active anionic tubular secretion in the kidney, so the dosage may need to be adjusted accordingly. A laboratory study has indicated that the anti-platelet drug clopidogrel (Plavix) prevents the conversion of oseltamivir to its active metabolite, oseltamivir carboxylate, so oseltamivir will lose its therapeutic effect if given with clopidrogrel¹⁰³.

Oseltamivir should generally not be used during pregnancy as 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 is not approved for use in children < 1 year of age.

Oseltamivir is contraindicated in persons with known hypersensitivity to any components of the product. It contains sorbitol, so it is unsuitable for people with hereditary fructose insufficiency. In March 2007 Health Canada reported new safety information resulting from adverse reaction reports of abnormal or suicidal behaviour in Japanese children and teenagers. Japan has now restricted use of oseltamivir in patients 10 to 19 years old. As of 28 February, 2007, there have been no Canadian reports of deaths or psychiatric adverse events such as abnormal or suicidal behaviour in children or teenagers. Investigations of these adverse events are ongoing.

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 their incidence between oseltamivir and placebo was ≥ 1% only for headache, nausea, vomiting and abdominal pain.

Zanamivir administration
Zanamivir is inhaled. It is available in a dry powder for use with an inhalation device. Zanamivir is not approved for use in children < 7 years of age. The recommended oral dose of zanamivir for prevention of influenza in persons ≥ 7 years of age is 2 inhalations (5 mg per inhalation, so a total dose of 10 mg) once daily for 10 days. There are no data on the effectiveness of prophylaxis with zanamivir when initiated more than 1.5 days after the onset of symptoms in the index case.

At the therapeutic dose, bioavailability is low (10%-20%), and as a result systemic exposure of patients to zanamivir is limited. This suggests zanamivir is safe in patients with renal failure; safety and efficacy have not been documented in the presence of severe renal insufficiency.

Zanamivir is widely deposited at high concentrations throughout the respiratory tract, thereby delivering drug to the site of influenza infection. Zanamivir is excreted by the kidney unchanged within 24 hours. There is no evidence of metabolism of orally inhaled drug. No studies have been done on people with hepatic insufficiency, but even high doses of intravenous zanamivir did not show evidence of hepatic metabolism.

Zanamivir should be used with caution during pregnancy or lactation only if the potential benefit justifies the potential risk to the fetus or nursing infant. As the drug is inhaled, little is systemically absorbed; however, there are no adequate and well-controlled studies of zanamivir in pregnant or lactating women. Insufficient data are currently available regarding possible toxic effects on the fetus. It is not known whether zanamivir is excreted in human milk. Zanamivir is generally not recommended in patients with severe underlying chronic pulmonary disease or severe asthma because of the risk of serious bronchospasm and decline in respiratory function. If a decision is made to prescribe zanamivir for such a patient, this should be done only under conditions of careful monitoring of respiratory function. Patients who take inhaled brochodilators should be advised to use their bronchodilators before taking zanamivir. Zanamivir is contraindicated in persons with known hypersensitivity to zanamivir or the inhalation powder's components including lactose, which contains milk protein. Rarely, allergic-like reactions, including facial and oropharyngeal edema, bronchospasm, larygospasm, urticaria, serious skin rashes and anaphylaxis have been reported. Zanamivir should be discontinued and immediate medical attention sought if these reactions occur.

The most common adverse events reported in post-exposure prophylaxis studies with zanamivir using doses of 10 mg once daily are headache, fatigue, nausea, cough, muscle pain, fever, chills and sore throat. Howev er there were no differences between zanamivir and placebo in the incidence of these adverse events.

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†Members: Dr. J. Langley (Chairperson), Dr. S. Deeks (Executive Secretary), Dr. K. Laupland, Dr. S. Dobson, Dr. B. Duval, Ms. A. Hanrahan, Dr. A. McGeer, Dr. S. McNeil, Dr. M-N Primeau, Dr. B. Tan, Dr. B. Warshawsky.

Liaison Representatives: Ms. S. Callery (CHICA), Dr. P. Hudson (CPHA), Dr. B. Bell (CDC), Dr. D. Money (SOGC), Ms. E. Holmes (CNCI), Dr. B. Larke (CCMOH), Dr. M. Salvadori (CPS), Dr. S. Rechner (CFPC), Dr. J. Salzman (CATMAT), Dr. D. Scheifele (CAIRE), Dr. P. Orr (AMMI Canada)

Ex-Officio Representatives: Dr. H. Rode (BGTD), Dr. M. Lem (FNIHB), Lt. Col. J.W. Anderson (DND), Dr. B. Law (IRID)

† † This statement was prepared by Dr. Joanne Langley, Dr. Patricia Huston, Ms. Samina Aziz and Ms. Anna-Maria Frescura and approved by NACI and the Public Health Agency of Canada.