Canada Communicable Disease Report
Statement on Influenza Vaccination for the 2008-2009 Season
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 and certain prophylaxis agents. 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 or antivirals 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). Manufacturer(s) have sought approval of the vaccine(s)/ antiviral(s) and provided evidence as to 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.
The antigenic components of the influenza vaccine have been updated for the 2008-2009 season. This statement contains new information on human and avian influenza epidemiology. Recent issues related to amantadine and oseltamivir resistance are outlined. Updated information on influenza and pregnancy, and the pediatric immunization schedule is provided.
In Canada, two available measures can reduce the impact of influenza: immunoprophylaxis with trivalent inactivated influenza vaccine (TIV) and chemoprophylaxis or therapy with influenza-specific antiviral drugs. Immunization is the cornerstone of influenza prevention. Programs should focus on 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.
Influenza A viruses are classified into subtypes on the basis of two surface proteins: 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; currently the H3N2 and H1N1 influenza A subtypes contribute to influenza illness to varying degrees each year. Immunity to the H and N antigens reduces the likelihood of infection and lessens the severity of disease if infection occurs.
Influenza B viruses have evolved into two antigenically distinct lineages since the mid-1980s, represented by B/Yamagata/16/88-like and B/Victoria/2/87-like viruses. Viruses of the B/Yamagata lineage accounted for the majority of isolates in most countries from 1990 to 2001. In contrast, viruses belonging to the B/Victoria lineage had not been identified outside of Asia between 1991 and 2001. In March 2001, B/Victoria lineage viruses re-emerged for the first time in a decade in North America(1). Since then, viruses within the B/Yamagata or B/Victoria lineages have variously contributed to influenza illness each year.
TIV is reformulated annually to include standardized amounts of the H protein from representative seed strains of the two influenza A subtypes (H3N2 and H1N1) and one of the two influenza B lineages (Yamagata or Victoria). H-based serum antibody produced to one influenza A subtype is anticipated to provide little or no protection against strains belonging to the other subtype. Similarly, H-based serum antibody to one B lineage is expected to provide little protection against B viruses belonging to the other lineage. Over time, antigenic variation (antigenic drift) of strains within an influenza A subtype or B lineage occurs. Despite this antigenic drift, some cross-protection among strains belonging to the same A/subtype or B/lineage is expected. To provide optimal protection, representative strains included as the three vaccine components must be updated each year and vaccine re-administered annually.
National influenza surveillance in the 2007-2008 season
Laboratory and epidemiologic indicators of activity
National influenza surveillance is coordinated through the Centre for Immunization and Respiratory Infectious Diseases, Public Health Agency of Canada (PHAC). The program (FluWatch) collects data and information from five different sources in order to provide a national picture of influenza activity. The detailed methodology of the FluWatch program has been described elsewhere(2). The information in this statement for the 2008-2009 season is based on surveillance data reported up to 18 April, 2008(3). As the influenza season progresses, the information in this section may change. For a full description of the influenza season, please refer to the final influenza seasonal surveillance report published yearly in the Canada Communicable Disease Report at http://www.phac-aspc.gc.ca/publicat/ccdr-rmtc/index-eng.php.
Nationally, influenza activity increased across the country from late-December and persisted late into the season. The season was characterized by a mix of both influenza A subtypes (H1N1 and H3N2) as well B activity. As of 18 April, 2008, influenza A viruses predominated overall during the 2007-2008 season; however, influenza B virus detections also significantly contributed. Of the 9,928 positive influenza detections reported up to 18 April, 2008, 6.034 (60.8%) were influenza A and 3,892 (39.2%) were influenza B. Influenza A and B virus predominated in Quebec, Ontario and Manitoba, and influenza B virus detections predominated in the Atlantic region.
During the above period, the National Microbiology Laboratory (NML) antigenically characterized 1,078 influenza viruses received from sentinel public health and hospital laboratories across Canada: 422 (39.1%) were antigenically similar to A/Solomon Islands/3/2006 (H1N1)-like; 18 (1.7%) were A/Brisbane/59/2007 (H1N1)-like; six (0.6%) were A/Wisconsin/67/2005 (H3N2)-like; 141 (13.1%) were A/Brisbane/10/2007 (H3N2)-like; eight (0.7%) were B/Malaysia/2506/2004 (Victoria lineage)-like; and 483 (44.8%) were B/Florida/4/2006 (Yamagata lineage)-like. The majority of influenza A viruses identified early in the season were influenza A/Solomon Islands/3/2006 (H1N1)-like; however, the number of influenza B/Florida/4/2006-like viruses increased from early January, and since week 14 (late March/early April 2008) the total proportion of B/Florida/4/2006 strains characterized for the season has exceeded the total proportion of A/Solomon Islands/3/2006 (H1N1)-like viruses characterized. In addition, the proportion of A/Brisbane/10/2007 (H3N2)-like viruses characterized steadily increased from week 5 (late January/early February 2008) at 8% to week 15 at 13%. For the data collection period up to 18 April, 2008, influenza A (H1N1) virus characterizations predominated in Newfoundland and Labrador, Quebec and Manitoba, whereas influenza B virus characterizations predominated in Prince Edward Island, New Brunswick, Saskatchewan and Alberta. Similar proportions of influenza A (H1N1) and B viruses were characterized in Nova Scotia, Ontario, British Columbia and the Territories. It should be noted that the 2007-2008 influenza vaccine was a good match for the A/Solomon Islands/3/2006 (H1N1)-like virus, although the A/Brisbane/10/2007 (H3N2)-like and the B/Florida/4/2006 (Yamagata lineage)-like strains were not included in the composition of the vaccine.
Weekly influenza-like illness (ILI) consultation rates have remained within or below baseline levels since the beginning of the season except in week 15 (early to mid-April) when the rate increased to slightly above baseline levels. The highest rate observed was in week 01 (early January) at 32 consultations for ILI per 1,000 patient visits, which is nevertheless lower than the peak observed during the previous season (50 per 1,000 in week 09 last season). The highest ILI consultation rates were reported in children 0 to 4 years of age at 34 ILI consultations per 1,000 patient visits.
Of the 407 outbreaks of influenza or ILI that have been reported, 214 (52.6%) were in long-term care facilities (LTCFs), 15 (3.7%) in hospitals, 134 (32.9%) in schools and 44 (10.8%) in other facilities. The number of outbreaks reported for the 2007-2008 season in LTCFs was higher than for the same period in the previous two seasons (214 this season compared with 168 in 2006-2007 and 142 in 2005-2006) but lower than in the 2004-2005 and 2003-2004 seasons (847 and 449 LTCF outbreaks respectively).
Widespread influenza activity has been reported 42 times by 10 regions in four provinces (British Columbia, Ontario, Alberta and Quebec) since the start of the season, most of which was reported in British Columbia (52%). The majority of widespread activity was reported between mid-February and late March 2008.
A total of 398 influenza-associated pediatric hospitalizations were reported through the Immunization Monitoring Program ACTive (IMPACT) network, compared with 313 cases at the same time last season. Influenza A was identified in the majority of the hospitalized cases (63.1%), and influenza B was identified in the remaining 36.9%; this appears consistent with the overall proportion of influenza A and B viruses detected by the Respiratory Virus Detection Surveillance System. The proportion of cases to date by influenza type and age group are as follows: influenza A – 28% were 0 to 5 months old, 25% 6 to 23 months old, 22% 2 to 4 years old, 15% 5 to 9 years old and 9.5% were 10 to 16 years old; influenza B – 9.5% were 0-5 months old, 26% 6 to 23 months old, 23% 2 to 4 years old, 31% 5 to 9 years old and 10% were 10 to 16 years old. Two influenza B-associated pediatric deaths were reported this season in Canada. Both children had underlying medical conditions.
Surveillance of antiviral resistance patterns of circulating influenza strains is now part of the routine surveillance program at the NML. From the start of the season until week 15, the NML tested 806 influenza A isolates (291 H3N2 and 515 H1N1) for amantadine resistance and found that 294 (36%) were resistant. The overall rate compared with previous seasons (76% in 2005-2006 and 27% in 2006-2007) in part reflects the proportionate mix of circulating H3N2 and H1N1 viruses. Of the 291 H3N2 isolates tested during the 2007-2008 season, 289 (99%) were resistant to amantadine, higher than the previous two seasons (92% and 37%, respectively). Of the 515 H1N1 isolates tested, five (1%) were resistant (compared with 1% and 2% in the previous two seasons).
At this time, there is no change to the PHAC recommendation, made in November 2006, that health care providers in Canada not prescribe amantadine for the treatment or prevention of influenza during the current influenza season(4).
On 25 January, 2008, the World Health Organization (WHO) was notified by the International Health Regulations National Focal Point about high rates of oseltamivir resistance among seasonal influenza A (H1N1) viruses detected through routine surveillance and testing in Norway. The NML had reported an influenza A (H1N1) oseltamivir-resistant strain from a child travelling from the Sudan just before the WHO notification. Further testing revealed that Canada also had an increase in oseltamivir resistance among influenza A (H1N1) isolates. In addition to Norway, several other countries in Europe and North America found an elevated rate of oseltamivir-resistant viruses during the first 15 weeks of this season. In Europe, the proportion of A (H1N1) resistant viruses varied significantly by country, with Norway still showing the highest proportion (66.5%) to date(5). Authorities in Norway have informed their health services and clinicians of this finding but have not announced any change to recommended treatments(6). The US Centers for Disease Control and Prevention is also reporting elevated rates of resistant viruses (10.4% of H1N1 viruses tested). Testing in the United States (U.S.) has shown that oseltamivir-resistant H1N1 viruses have to date retained their sensitivity to zanamivir(7). All oseltamivir-resistant strains were due to changes at position 274 in the viral neuraminidase gene (H274Y). At present, insufficient data are available to determine the full geographic scope, origins, or patterns of transmission of these oseltamivir-resistant H1N1 viruses, although evaluations are under way.
During 2006-2007, the NML developed a chemiluminescent neuraminidase assay to test influenza isolates for susceptibility to oseltamivir. In the 2006-2007 season the NML tested 1,048 isolates of which only one, an influenza A (H3N2) isolate (0.10%), was found to be resistant to oseltamivir.
For the 2007-2008 season up to 18 April, 2008, the NML tested 1,069 influenza isolates (454 A/H1N1, 146 A/H3N2 and 469 B) for oseltamivir resistance by enzyme inhibition assay and found that, overall, 107 of 1,069 isolates (10%) were resistant to oseltamivir. All resistant viruses belonged to the A (H1N1) subtype (107/454, 23.6%) and none to the H3N2 or B isolates. Of these 107 isolates resistant to oseltamivir 105 were characterized as A/Solomon Islands/3/06-like virus, well-matched to the 2007-2008 H1N1 vaccine component, and two of 107 were characterized as A/Brisbane/59/07-like (the recommended vaccine component for the 2008-2009 season(8)). All 107 oseltamivir-resistant viruses were sensitive to amantadine.
In an initial epidemiologic analysis of 43 oseltamivir-resistant cases, PHAC reported that the average age of cases was 27.6 years (range < 1 to 96 years). The proportion of cases by age group was as follows: 14% were between 0 and 4 years, 37% were 5 to 19 years, 40% were 20 to 49 years, 2% were 50 to 64 and 7% were ≥ 65 years. Males represented 55% of resistant H1N1 detections. Most cases recovered. There was one reported death in an LTCF, but the significance of this is uncertain in the context of expected background mortality rates in long-term care. Of the cases reviewed, one (2%) had received prophylaxis with oseltamivir and five (12%) reported receiving oseltamivir treatment.
On the basis of current findings related to antiviral resistance in 2007-2008, there is no change at present to the recommendations for the use of neuraminidase inhibitors. Recommendations may be updated as further information evolves or becomes available. Health care providers are advised to consult surveillance updates through public health and stay informed about influenza activity and resistance patterns during the 2008-2009 season.
International influenza surveillance
Between September 2007 and January 2008, influenza activity was generally low compared with the same periods in recent years(8). In the Northern Hemisphere, influenza activity began in Asia and North America in November and increased in December-January. In Europe, activity began in December and increased in January. In the Southern Hemisphere, mild influenza activity continued in September and declined in October. Influenza A (H1N1) viruses predominated in most parts of the Northern Hemisphere and were associated with outbreaks in some countries. Influenza A (H3N2) was sporadic in many countries, and outbreaks were reported in the U.S. Influenza B viruses circulated at low levels in most countries throughout that period.
In Europe, influenza activity first increased above baseline levels towards the end of 2007. While influenza activity was predominantly caused by the A (H1N1) influenza virus during most of the season, influenza B has dominated in Europe since week 09 of 2008. On the basis of characterization data from Europe this season (from 1 October, 2007, to 18 April, 2008), 62.3% of isolates were classified as A/Solomon Islands/3/2006 (H1N1)-like, 1.8% were A/New Caledonia/ 20/1999 (H1N1)-like, 0.5% were A/Brisbane/10/2007 (H3N2)-like, 0.6% were A/Wisconsin/67/2005 (H3N2)-like, 34.3% were B/Florida/4/2006 (Yamagata lineage)-like and 0.4% were B/Malaysia/2506/2004 (Victoria lineage)-like(9).
Influenza activity in the U.S. remained low until January, peaked in mid-February, and decreased thereafter. Influenza A (H1N1) viruses predominated through mid-January, but influenza A (H3N2) viruses have been more frequently identified since late January and have predominated overall. The majority of influenza A (H1N1) viruses were characterized as A/Solomon Islands/3/2006, the influenza A (H1N1) component of the 2007-2008 influenza vaccine for the Northern Hemisphere. To date, the majority of influenza A (H3N2) and influenza B viruses have been characterized as A/Brisbane/10/2007 and B/Florida/04/2006--respectively the recommended influenza A (H3N2) and influenza B components of the 2008-2009 influenza vaccine for the Northern Hemisphere. The highest proportion of strains characterized were influenza A (H1N1) viruses (46.8%) followed by influenza B and influenza A (H3N2) viruses in similar proportions (27.3% and 26.0% respectively). Of the 620 influenza viruses characterized, 32.3% were A/Solomon Islands/3/2006 (H1N1)-like, 3.2% showed somewhat reduced titres with antisera produced against A/Solomon Islands/3/2006, 11.3% were A/Brisbane/59/2007 (H1N1)-like, 18.5% were A/Brisbane/10/2007 (H3N2)-like, 5.6% were A/Wisconsin/67/2005 (H3N2)-like, 1.8% showed somewhat reduced titres with antisera produced against A/Wisconsin/67/2005 and A/Brisbane/10/2007, 1.0% were B/Ohio/01/2005 (Victoria lineage)-like, 0.3% showed somewhat reduced titres with antisera produced against B/Ohio/01/2005 and B/Malaysia/2506/2004, 25.2% were B/Florida/04/2006 (Yamagata lineage)-like and 0.8% showed a somewhat reduced titre with antiserum produced against B/Florida/04/2006(7).
Between 1 December, 2003, and 21 April, 2008, there have been a total of 381 human influenza A (H5N1) cases reported by the WHO in 14 countries (Azerbaijan, Cambodia, China, Djibouti, Egypt, Indonesia, Iraq, Lao People's Democratic Republic, Myanmar, Nigeria, Pakistan, Thailand, Turkey and Viet Nam). Of these 381 cases, 240 have died (overall case fatality of 63%). The largest proportions of cases were reported in Indonesia (35%) and Viet Nam (28%)(10). The highest incidence has been during the periods roughly corresponding to the winter and spring in the Northern Hemisphere(11).
Between 1 September, 2007, and 21 April, 2008, the WHO reported a total of 54 cases and 41 deaths (76% case fatality) in six countries (China, Egypt, Indonesia, Myanmar, Pakistan and Viet Nam), including the first reported cases in Myanmar and Pakistan. Fifty percent of the cases were from Indonesia.
The WHO has recently (January 2008) published an update in the New England Journal of Medicine summarizing the epidemiologic, clinical, pathogenic, laboratory, treatment and prevention aspects of human infection with avian influenza A (H5N1) virus(12). Despite widespread poultry outbreaks, avian influenza H5N1 infection in humans remains a rare disease(12,13). Most patients with influenza A (H5N1) were previously healthy. The median age of patients is cited as approximately 18 years, 90% of patients being 40 years of age or younger; older adults therefore appear underrepresented. The overall case fatality is 61%, highest among persons 10 to 19 years of age and lowest among persons ≥ 50 years of age.
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. Epidemiologic findings from outbreak investigations of family clusters in Thailand (September 2004(14)), Indonesia (May 2006(15)), China (December 2007(16)) and Pakistan (December 2007(17)) suggest that limited human-to-human transmission of the virus may have occurred. Handling of sick or dead poultry during the week before the onset of illness is the most commonly recognized risk factor for acquiring influenza A (H5N1) illness. To date, the WHO influenza pandemic preparedness level remains at Phase 3: a new influenza virus subtype is causing disease in humans, but without efficient or sustained spread(18).
Recommendations for the 2008-2009 influenza vaccine
The national goal of the influenza immunization program in Canada is to prevent serious illness caused by influenza and its complications, including death(19). In keeping with this, NACI 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, influenza vaccine is encouraged for all Canadians who have no contraindication.
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 2008-2009 season in the Northern Hemisphere contain an A/Brisbane/59/2007 (H1N1)-like virus, an A/Brisbane/10/2007 (H3N2)-like virus and a B/Florida/4/2006-like virus. Vaccine producers may use antigenically equivalent strains because of their growth properties.
All manufacturers of influenza vaccines in Canada have confirmed to the Biologics and Genetic Therapies Directorate that the vaccines to be marketed in Canada for the 2008-2009 influenza season contain the three WHO-recommended antigenic strains: A/Brisbane/59/2007(H1N1)-like, A/Uruguay/716/2007(H3N2)-like in place of the A/Brisbane/10/2007(H3N2)-like and B/Florida/4/2006.
Several characteristics of the trivalent influenza vaccine recommended for 2008-2009 should be noted. First, all three components of the 2008-2009 vaccine are changed from the 2007-2008 version. Second, despite similar names, the A/Brisbane/59/2007 (H1N1)-like virus and the A/Brisbane/10/2007 (H3N2)-like virus are not antigenically related. Finally, it should be noted that the B/Florida/4/2006-like virus belongs to the B/Yamagata lineage whereas the 2007-2008 B vaccine component belonged to the B/Victoria lineage.
Annual immunization against influenza is recommended for optimal protection. Continual antigenic drift of the influenza virus means that a new vaccine, updated yearly with the most current circulating strains, provides optimal protection against new infections. Protective antibody levels are generally achieved 2 weeks following immunization. Although initial antibody response may be lower to some influenza vaccine components among elderly recipients, a recent literature review identified no evidence for subsequent more rapid antibody decline in the elderly compared with younger age groups(20). In general, health care providers can begin offering vaccine soon after it becomes available and if possible by mid-October, given an influenza season typically spanning November to April in the Northern Hemisphere. Decisions regarding the precise timing of immunization in a given season, setting or geographic area should be made according to local epidemiologic factors (influenza activity, timing and intensity), opportune moments for immunization, as well as programmatic issues. Further advice regarding the timing of influenza vaccination programs may be obtained through consultation with local medical officers of health. Although vaccination before 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 individuals at risk who have 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, 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 in Canada. However, significant illness and associated societal costs also occur with seasonal influenza in people who may not be considered at high risk of complications (i.e. healthy people aged 2 to 64 years).
People at high risk of influenza-related complications or more likely to require hospitalization
People capable of transmitting influenza to those at high risk
Note: Healthy persons aged 2 to 64 years without contraindication are also encouraged to receive influenza vaccine even if they are not in one of the aforementioned priority groups.
People at high risk of influenza-related complications or more likely to require hospitalization
• Adults (including pregnant women) and children with the following chronic health conditions. A number of chronic health conditions 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 persons(21), and death rates increase with increasing age (22).
• Healthy children 6 to 23 months of age. 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 < 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(23,24). Risk is greatest in the very young. These rates of hospitalization are similar to or greater than those of persons ≥ 65 years of age, although comparison based on days of hospitalization and other severity indicators are not available and differences in the methods and setting for estimating influenza-attributable rates must also be taken into account. Influenza immunization of older children is efficacious(25,26,27), but few trials have specifically included children 6 to 23 months of age. NACI recognizes that both the number of studies and the number of participants in trials of influenza vaccine in children of this age are limited, that there are unanswered questions, including the uncertain efficacy of vaccine in unprimed children who have not had experience with the vaccine or infection and who receive a lower dose per injection than older children, and that there is uncertainty about the cost-effectiveness of routine immunization programs in this age group(28,29). NACI strongly encourages further research regarding these issues. However, on the basis of existing data indicating a high rate of influenza-associated hospitalization in healthy children < 24 months, NACI recommends the inclusion of children 6 to 23 months of age among high-priority recipients of influenza vaccine.
• Pregnant women. Women with the chronic health conditions indicated in Table 1 have a high risk of complications associated with influenza and are recommended by NACI as a high-priority group for immunization at any stage of pregnancy(30-33).
Several studies have described influenza-related risk in healthy pregnant women(34-36). Since surrogate outcomes for influenza (e.g. hospitalization for ILI and respiratory or cardiopulmonary outcomes) rather than laboratory-confirmed influenza have been reported, it is difficult to know the true influenza-attributable risk. In some studies it is also difficult to assess the contribution of underlying comorbidities since these are not always separately presented. More evaluation of the impact of seasonal influenza on the healthy pregnant woman and her fetus would be helpful.
All studies that have stratified analysis according to gestational age show that influenza-related risk is not evenly distributed across all trimesters of pregnancy(37-39). In these studies, the rate of influenza-related hospitalization is not significantly increased during the first trimester of healthy pregnancy but, rather, increases later in pregnancy, being highest in the third trimester(37-39). In Neuzil et al.'s frequently cited 1997 publication spanning almost 20 influenza seasons, the risk of cardiopulmonary hospitalization during the influenza season rose significantly above the non-pregnant rate only beyond 21 weeks' gestation(37). Dodds et al. (Canada) and Neuzil et al. (U.S.) reported excess influenza-related hospitalization rates of 40 and 100 per 100,000 women-months respectively in the third trimester, comparable to non-pregnant adults with comorbidities(37,38). Differences in the methods and setting for estimating influenza-attributable rates should be taken into account in making these comparisons.
The most robust epidemiologic evidence for increased influenza-related fatality in pregnancy comes from the major antigenic shifts of the 1918 and, to a lesser extent, the 1957 pandemics. Increased maternal mortality during subsequent antigenic shifts in 1968 and 1976 has not been described. With the exception of case reports and a single ecologic study in a single season in Great Britain(40), epidemiologic evidence has not shown increased maternal mortality associated with seasonal influenza(34,37,41-44).
The antibody response to TIV in pregnant women is not expected to differ from that of non-pregnant persons, although there are no randomized controlled trials of TIV efficacy in pregnancy, and evidence from other epidemiologic designs is similarly limited(34,45,46). Transplacental passage of maternal antibody is hypothesized to potentially protect the newborn, but epidemiologic studies to assess this have been inconclusive to date(34,47).
Passive surveillance has not identified concern related to serious adverse events following influenza immunization in pregnant women. Active studies to date have not shown evidence of harm to the mother or fetus associated with influenza immunization, but cumulative sample size to date has been small, especially during the first trimester(45,46,48-52). Further systematic evaluation would thus be informative.
Serious maternal morbidity (namely hospitalization) during seasonal influenza supports a recommendation for the immunization of healthy pregnant women, since rates of influenza-associated hospitalization increase with increasing length of gestation after the first trimester.
People capable of transmitting influenza to those at high risk of influenza-related complications or hospitalization
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 (have) been immunized. Immunization of care providers decreases their own risk of illness, as well as of death and other serious outcomes among the patients for whom they care(53-58). Immunization of care providers and residents is associated with decreased risk of ILI outbreaks(59). Individuals who are more likely to transmit influenza to those at risk of medical complications or hospitalization due to influenza include the following:
• Health care and other care providers in facilities and community settings. This group includes regular visitors, emergency response workers, those who have contact with residents of continuing care facilities or residences, those who provide home care for persons in high-risk groups, and students of related health care services.
• Household contacts (adults and children) of individuals at high risk of influenza complications, whether or not the individual at high risk has been immunized. These individuals include household contacts of individuals at high risk of influenza-related complications or hospitalization, as listed earlier, household contacts of infants < 6 months of age (who are at high risk of complications from influenza but for whom influenza vaccine is not approved) and members of a household expecting a newborn during the influenza season.
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).
• 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 during culling operations with poultry infected with avian influenza. These individuals may be at increased risk of avian influenza infection because of exposure during the culling operation(60-63). Influenza immunization on a yearly basis for these workers has been recommended in some countries(64) and provinces 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 influenza(65). 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 14 days. Antiviral prophylaxis should be used for at least 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.html (see also the section entitled Prophylactic use of Antivirals).
Further comments regarding influenza immunization
Immunization of healthy persons 2 to 64 years of age. 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 about 70% to 90% effective in preventing laboratory-confirmed influenza infection(25-27,66,67). A recent meta-analysis of randomized-controlled-trials since 1966 found a vaccine efficacy in young adults of 80% (95% confidence interval [CI] 56% to 91%) against laboratory-confirmed influenza when measured during select seasons of vaccine match and 50% (95% CI 27% to 65%) during select seasons of vaccine mismatch to circulating virus, although the amount of protection conferred is anticipated to vary with the degree of mismatch, the mix of circulating viruses and other factors(67).
In the U.S., the American Academy of Family Physicians and the Advisory Committee on Immunization Practices (ACIP) recommend routine annual influenza vaccination of adults ≥ 50 years of age. The prevalence of high risk conditions increases at 50 years of age, while the influenza immunization rate among U.S. adults with high-risk chronic medical conditions in this age group has been low. Age-based influenza guidelines may be more successful in reaching individuals with chronic medical conditions; in one analysis this approach has been considered cost-effective(68).
In 2004 the ACIP in the U.S. recommended annual influenza immunization for children 6 to 23 months of age and their household contacts, and in 2006 extended this to include children 24 to 59 months of age(69,70) on the basis of their increased risk of influenza-related clinic and emergency department visits. In February 2008, the ACIP also recommended annual vaccination for all children age 5 to 18 years beginning in the 2008-2009 influenza season if feasible, and no later than during the 2009-2010 influenza season on the basis of: (1) impact of influenza on school-age children and their household contacts (school absenteeism, antibiotic use, medical visits, parental work loss), (2) desire to improve coverage for high risk children and (3) potential for indirect protection extended to persons who have close contact with children and for reduced overall transmission within communities, given sufficient vaccination coverage(71). Epidemiologic evidence related to the latter rationale has varied and is mostly ecologic in nature.
Before making recommendations that may influence immunization programs nationally, NACI is committed to careful systematic review of the required and available evidence and interpretation in the context of goals and objectives previously established in Canada by a consensus process(19). As with other new vaccines, this process will be followed in considering population-based indications for expansion of influenza immunization programs. A summary of that analysis in relation to pediatric or other program expansion will be made available when concluded. Until then, NACI continues to encourage influenza vaccine for all Canadians.
• Travellers. Travellers with a chronic health condition or other factors that would make them recommended recipients of influenza vaccine should be immunized as previously discussed (Table 1), and healthy persons are also encouraged to receive vaccine as outlined earlier. Vaccine products/formulations prepared specifically for use in the Southern Hemisphere are not currently available in Canada, and the extent to which recommended vaccine components for the Southern Hemisphere may overlap with those in available Canadian formulations will vary. For further information on advising travellers about influenza prevention, the Committee to Advise on Tropical Medicine and Travel (CATMAT) statement should be consulted(72).
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 more limited cytotoxic T lymphocyte response. Both humoral and cell-mediated responses are thought to play a role in immunity to influenza. The antibody response after vaccination depends 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. For this reason the antigenic components of each year's vaccine change, and annual immunization is recommended.
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 confirmation(73). With a good match, influenza vaccination has been shown to prevent influenza illness in approximately 70% to 90% of healthy children and adults(25-27,66,67). Recent meta-analysis identified vaccine efficacy of 50% (95% CI 27% to 65%) during select seasons of vaccine mismatch, although mismatch is a relative term and the amount of cross-protection is expected to vary(67,74,75) . Systematic reviews have also demonstrated that influenza vaccine decreases the incidence of pneumonia, hospital admission and death in the elderly(76,77) and reduces exacerbations in persons with chronic obstructive pulmonary disease(78). In observational studies immunization reduces the number of physician visits, hospitalization and death in high-risk persons < 65 years of age(79), reduces hospitalizations for cardiac disease and stroke in the elderly(80) , and reduces hospitalization and deaths in persons with diabetes mellitus(81). The need for caution has recently been expressed in the interpretation of observational studies that use non-specific clinical outcomes and that do not take into account differences in health-related behaviors(82-87). Studies that assess vaccine protection against laboratory-confirmed influenza and its serious complications are needed.
The first time that children < 9 years of age receive influenza immunization, a two-dose schedule is required (Table 2)(88-90).
Allison et al. assessed vaccine effectiveness against outpatient visits for ILI for the period 1 November to 31 December, 2003, among children 6 to 21 months of age given two separate-season (fall 2002 + fall 2003) versus two same-season (fall 2003 + fall 2003) doses of TIV (no change in vaccine components between study years). Vaccine effectiveness against ILI of 62% (95% CI 49% to 72%) and 82% (95% CI 77% to 86%) were recorded for the separate-season and same-season schedules respectively(91). Although significantly different from each other, these vaccine effectiveness estimates are high given the non-specific clinical outcome that was used (ILI) and given that the vaccine was suboptimally matched to circulating virus in 2003-2004. Results from this study are therefore difficult to interpret in relation to same-versus separate-season scheduling of two-dose immunization.
Englund et al. conducted a randomized study of children 6 to 23 months of age comparing a two-dose TIV schedule given during separate seasons with two doses given during the same season. The authors reported similar immunogenicity whether two doses were given in the same or separate seasons without a change in vaccine formulation between seasons(92). In a non-randomized trial, the same group(93) compared a two-dose TIV schedule in children 6 to 23 months of age during another separate-season (Group 1: fall 2003 + fall 2004) versus same-season (Group 2: fall 2004 + fall 2004) design. Seroprotection rates were not significantly different between the two schedules for the H3N2 (minor vaccine strain change) and H1N1 (no vaccine change) components(93). However, 27% of healthy infants/toddlers in Group 1 had a seroprotective antibody response to the 2004-2005 influenza B component compared with 86% in Group 2. There was a major antigenic (lineage) change in the B component of the TIV vaccine between the 2003-2004 (B/Victoria) and 2004-2005 (B/Yamagata) vaccine formulations. In a randomized trial involving children 6 to 23 months of age by the same research group (Walter et al.) and using the same 2003-2004 and 2004-2005 vaccine formulations, similar findings were reported(94). In the 2007-2008 NACI influenza statement these immunogenicity data were interpreted in relation to whether doses were given in the same versus separate seasons. Another interpretation, however, is that children 6 to 23 months of age immunized against one B lineage may not be adequately primed to respond to a single dose of the other B lineage. On the basis of the sum total of evidence, NACI gives more weight to the latter interpretation, but further evaluation is required.
NACI thus continues to recommend two doses of TIV for all previously unvaccinated children who are < 9 years of age and receiving TIV for the first time. Because they are less likely to have had prior priming exposure to influenza virus and because they receive a lower per-injection dose of TIV, special effort is warranted to ensure that a two-dose schedule is followed for previously unvaccinated children 6 to 23 months of age. While data require further corroboration, recent studies suggest that when there is a major antigenic (B lineage) change in vaccine component (B/Victoria versus B/Yamagata) between sequential seasons, two doses may need to be considered in the second season for children 6 to 23 months of age(93,94). Studies to assess the extent to which this may also apply to older children are needed. Pending further evidence, eligible children < 9 years of age who have properly received one or more doses of TIV in the past are recommended to receive one dose per season thereafter. Readers should note that this is a change from the 2007-2008 NACI influenza statement(33). NACI encourages further research in this area, especially with respect to response to the B component.
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(95,96).
Administration of influenza vaccine: dosage and schedule
The recommended dosage schedule and type of influenza vaccine are presented in Table 2. Influenza vaccines in Canada are available as inactivated 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. InfluvacTM is a surface antigen, trivalent, inactivated subunit vaccine, which is currently approved for use in persons ≥ 18 years of age. For all TIV formulations, each 0.5 mL dose of vaccine contains 15 μg of hemagglutinin of each antigen.
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 ≥ 12 months of age. The anterolateral thigh is the recommended site in infants between 6 and 12 months of age.
Table 2. Recommended influenza vaccine dosage, by age, for the 2008-2009 season
No. of doses
1 or 2*
1 or 2*
≥ 9 years
≥ 18 years
subunit, or split virus
*Previously unvaccinated children < 9 years of age require two doses of the split-virus influenza vaccine, with an interval of 4 weeks. Eligible children < 9 years of age who have properly received one or more doses of TIV in the past are recommended to receive one dose per season thereafter. Additional considerations pertaining to the TIV schedule in young children are described in the section entitled Immunogenicity and Efficacy. See above text for details.
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(97). 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% of healthy children who are < 3 years of age. Post-vaccination fever may be observed in ≤ 12% of immunized children 1 to 5 years of age.
Several influenza vaccines that are currently marketed in Canada contain minute quantities of thimerosal, which is used as a preservative(98). One thimerosal-free vaccine (Influvac™, Solvay Pharma), approved for persons ≥ 18 years of age, is available in Canada(98). 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 a rare con-sequence 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 is consistent with a causal relation between the vaccine and GBS during that season(99). 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 1976(100).
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 Quebec(101). A variety of infectious agents, including Campylobacter jejuni , cytomegalovirus, Epstein-Barr virus and Mycoplasma pneumoniae , have been associated with GBS(102). A consistent finding in case series is the occurrence of an infection in the 6 weeks before GBS diagnosis in about two-thirds of patients(102). 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 to 2.8; p = 0.04) for GBS associated with influenza vaccination(103). 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 period 2 to 7 weeks after influenza vaccination, compared with the period 20 to 43 weeks after influenza vaccination, to be 1.45 (95% CI 1.05 to 1.99, p = 0.02)(104). These studies suggest that the absolute risk of GBS in the period following vaccination is about one excess case per 1 million vaccinees above the background GBS rate. The potential benefits of influenza vaccine (see Immunogenicity and Efficacy) 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 due to any cause. Avoiding subsequent influenza vaccination of persons known to have had GBS within 8 weeks of a previous influenza vaccination appears prudent at this time. 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)(105). 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 years(106,107). 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.
Please refer to the Canadian Immunization Guide(108) 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.
Persons 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, per the Canadian Immunization Guide (108).
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 cornerstone for preventing or attenuating influenza for those at high risk of serious illness or death from influenza infection and related complications. Despite this, influenza immunization rates among recommended recipients are suboptimal. The 2005 Canadian Community Health Survey reports coverage rates of influenza vaccination in the previous year of only 30.3% (95% CI 29.7 to 30.9, n = 22,693) for adults aged 18 to 64 years of age with a chronic medical condition(109). Results from the 2006 Adult National Immunization Coverage Survey on coverage for adults 18 to 64 years with a chronic medical condition are similarly low, at 38.2% (95% CI 33.3 to 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 to 75.7, n = 287) receiving 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%(110-112). Studies of HCWs in hospitals and LTCFs reveal influenza vaccination coverage rates of 26% to 61%. Coverage rates are higher among those in close contact with patients (69.7%, 95% CI 66.8 to 72.6, n = 727) (unpublished results from the 2006 Adult National Immunization Coverage Survey, Immunization and Respiratory Infections Division (IRID), PHAC).
Low rates of utilization may be 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. Educational efforts aimed at HCWs and the public should address common doubts about disease risk for HCWs, their families and patients, vaccine effectiveness and adverse reactions.
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, with having program aspects covered by written policies and with 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.
- Promoting influenza vaccination in clinics in which high-risk groups are seen (e.g. cancer clinics, cardiac clinics, pulmonary clinics, obstetrics clinics).
- Using community newspapers, radio, television, other media and influenza information lines, and collaborating with pharmacists and specialist physicians to distribute 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 the accessibility of immunization clinics for staff in institutions and for 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 HCWs
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 one study, 59% of HCWs with serologic evidence of recent influenza infection could not recall having influenza, suggesting that many HCWs experience subclinical infection(113). These individuals continued to work, potentially transmitting infection to their patients. In two other studies, HCWs reported 4 to 10 times as many days of respiratory illness as days absent from work due to respiratory illness, suggesting that many HCWs worked while they were ill and potentially able to transmit infection(114,115). 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 because of 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 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 with 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
Antiviral prophylaxis should not replace annual influenza vaccination. Vaccination remains our primary tool for the prevention of influenza infection and illness.
Antiviral treatment of influenza is not covered in this statement; recent Canadian treatment guidelines have been published(116).
Influenza antivirals are not effective against respiratory infections other than influenza. Therefore, it is important to base decisions about their use on appropriate epidemiologic, clinical and laboratory data about the etiology of prevalent infection(s).
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 (see earlier section on Amantadine Resistance).
NACI does not recommend amantadine for prophylaxis for the 2008-2009 season. This recommendation may be revised as new information becomes available. The rest of this report focuses on the use of neuraminidase inhibitors for the prevention of influenza. The 2005-2006 NACI statement contains additional information on amantadine(31).
The product monographs for oseltamivir and zanamivir should be consulted for detailed guidance related to their use for treatment or prevention(117,118).
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 (Tamiflu®) 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%(119) and 89%(120) for 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.
Although the emergence of oseltamivir-resistant virus during or after prophylactic use of this antiviral has not been reported, 0.33% to 18% of influenza isolates have been noted to be oseltamivir resistant during follow-up of children and adults in treatment studies. On 25 January, 2008, the WHO was notified by the International Health Regulations National Focal Point about high rates of oseltamivir resistance in seasonal influenza A (H1N1) viruses detected through routine surveillance and testing in Norway. All resistant strains were due to changes at position 274 in the viral neuraminidase gene (H274Y). For the 2007-2008 season collection period up to week 15, the NML tested 1,069 influenza isolates (454 A (H1N1), 146 A (H3N2) and 469 B) for oseltamivir resistance by enzyme inhibition assay and found that, overall, 107 (10%) were resistant. All resistant viruses belonged to the A/H1N1 subtype (107/434, 23.6%) and none to the H3N2 or B isolates. Of these 107 isolates resistant to oseltamivir, 105 were characterized as A/Solomon Islands/3/06-like virus, well-matched to the 2007-2008 H1N1 vaccine component, and two of the 107 were characterized as A/Brisbane/59/07-like (the recommended vaccine component for the 2008-2009 season(7)). All 107 oseltamivir-resistant viruses were sensitive to amantadine. Testing in the U.S. has shown that oseltamivir-resistant H1N1 viruses have to date retained their sensitivity to zanamivir(7).
On the basis of current findings related to antiviral resistance in 2007-2008, there is no change at present to recommendations for the use of neuraminidase inhibitors. Recommendations may be updated as further information evolves or becomes available. Influenza caused by current oseltamivir-resistant H1N1 viruses appears to be indistinguishable from illness caused by oseltamivir-sensitive viruses. Health care providers are advised to consult surveillance updates through public health and stay informed about influenza activity and resistance patterns during the 2008-2009 season. If oseltamivir resistance is detected or suspected in a facility outbreak setting (for example, if an outbreak appears poorly controlled despite proper antiviral use) or is reported to be widespread in the community, up-to-date advice of local and provincial health authorities should be sought for antiviral options.
Zanamivir (Relenza®) is a neuraminidase inhibitor that is administered by inhalation. It was recently approved for use for prophylaxis against influenza A and B in persons ≥ 7 years of age(121,122). Two trials of post-exposure prophylaxis showed a relative efficacy of 79%(121) and 81%(122)of zanamivir (absolute risk reduction of 10% and 15%) compared with placebo in preventing symptomatic, laboratory-confirmed influenza. Two trials of seasonal prophylaxis with zanamivir showed relative efficacy of 67% and 83% compared with placebo in preventing symptomatic, laboratory-confirmed influenza(123,124). 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)(125) and in the other they were not(126). 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 of influenza B in Japan, where neuraminidase inhibitors are widely used(127).
NACI recommends that neuraminidase inhibitors may be considered prophylactically in the following situations:
• For the control of influenza A or B outbreaks among high-risk residents of institutions. In this context, oseltamivir should be given as prophylaxis 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 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.
• 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.
• 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(128,129). 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 the start of the season 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 administration in the fall is preferred, influenza vaccine may be given through the winter months if the vaccination opportunity was previously missed.
• 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 6(130,131) to 8(132) weeks while influenza is circulating in the community, is currently an “off-label” use in Canada, although some evidence supports its use in that way. 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 officer of health. 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 effectiveness in years in which the appearance of new circulating strains may result in reduced vaccine protection. When considered for prolonged prophylaxis, patients should be informed of the product monograph specifications related to duration of use (see below separately for oseltamivir and zanamivir) and that longer duration may be clinically considered but constitutes “off-label” use in Canada.
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.
• For prophylaxis among individuals who have been or will be exposed to avian influenza. Consultation with the local medical officer of health is required. When prophylaxis is indicated, the decision regarding which antiviral agent to use and its duration should take into account the characteristics of the influenza strain(s), including antiviral susceptibility or resistance and the efficacy, potential toxicity, cost and ability to administer the antiviral within a particular population. 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 extended periods of time.
Oseltamivir administration Oseltamivir is available in 75 mg capsules and 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, 30 mg once a day; for children over 15 kg and up to and including 23 kg, 45 mg once a day; for children over 23 kg and up to and including 40 kg, 60 mg once a day; and for children > 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. The product monograph for oseltamivir (Tamiflu®) refers to use for up to 14 days for post-exposure prophylaxis(117).
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 to 30 mL/min, the dose of oseltamivir should be reduced to 75 mg every other day or 30 mg of suspension every day orally. For those with more significant renal impairment or those undergoing dialysis, expert consultation should be sought.
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 may lose its therapeutic effect if given with clopidogrel(133).
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 the use of oseltamivir in patients 10 to 19 years of age. When considering this information, it is important to remember that high fever or other complications of influenza can affect mental state, which in turn can lead to abnormal behaviour. As of 25 February, 2008, there have been no Canadian reports of deaths or psychiatric events, such as abnormal or suicidal behaviour, in children or teenagers taking Tamiflu®. In Canada, Tamiflu® is authorized for pediatric indications but is infrequently used in this population.
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 is inhaled. It is available as 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 post-exposure prophylaxis against influenza in persons ≥ 7 years of age is two 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. The product monograph for zanamivir (Relenza®) refers to two studies of seasonal prophylaxis with use for up to 28 days in association with community outbreaks(118).
At the therapeutic dose, bioavailability is low (10% to 20%), and as a result systemic exposure of patients to zanamivir is limited. This suggests that 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 involving 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 use inhaled bronchodilators should be advised to do so 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, laryngospasm, urticaria, serious skin rashes and anaphylaxis, have been reported. Zanamivir should be discontinued and immediate medical attention sought if these reactions occur.
There have been post-marketing reports (mostly from Japan) of delirium and abnormal behaviour leading to injury in patients with influenza who were receiving neuraminidase inhibitors, including zanamivir. These events were reported primarily among pediatric patients and often had an abrupt onset. As of 25 February, 2008, there has been one Canadian report of a non-serious psychiatric event in a teenager who took Relenza® for an influenza infection and developed nightmares. When considering this information, it is important to remember that high fever or other complications of influenza can affect mental state, which in turn can lead to abnormal behaviour.
The most common adverse events reported in post-exposure prophylaxis studies of zanamivir at doses of 10 mg once daily are headache, fatigue, nausea, cough, muscle pain, fever, chills and sore throat. However there were no differences between zanamivir and placebo in the incidence of these adverse events(118).
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Members: Dr. J. Langley (Chairperson), Dr. B. Warshawsky (Vice-Chairperson), Dr. S. Virani (Executive Secretary), Dr. S. Dobson, Ms. A. Hanrahan, Dr. J. Kellner, Dr. K. Laupland, Dr. A. McGeer, Dr. S. McNeil, Dr. M.-N. Primeau, Dr. B. Seifert, Dr. D. Skowronski, Dr. B. Tan
Liaison Representatives: Dr. B. Bell (Center for Disease Control and Prevention), Dr. P. Orr (Association of Medical Microbiology and Infectious Disease Canada), Ms. K. Pielak (Canadian Nursing Coalition for Immunization), Dr. S. Rechner (College of Family Physicians of Canada), Dr. M. Salvadori (Canadian Pediatric Society), Dr. D. Scheifele (Canadian Association for Immunization Research and Evaluation)
Ex-Officio Representatives: Ms. M. FarhangMehr, Dr. S. Desai, Dr. B. Law (Centre for Immunization and Respiratory Infectious Diseases), Major P. Laforce (Department of National Defence), Dr. R. Ramsingh (First National and Inuit Health Branch – Office of Community Medicine), Dr. H. Rode (Biologics and Genetic Therapies Directorate)
†This statement was prepared and approved by NACI with contribution from Samina Aziz and Francesca Reyes.
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