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Canada Communicable Disease Report
Volume 29  ACS-415 August 2003 An Advisory Committee Statement (ACS)
STATEMENT ON INFLUENZA VACCINATION
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Age |
Vaccine type |
Dose (mL) |
No. of doses |
|
6-35 months |
split virus |
0.25 |
1 or 2* |
|
3-8 years |
split virus |
0.5 |
1 or 2* |
|
>= 9 years |
split virus |
0.5 |
1 |
* See text for criteria
Intramuscular administration is preferred. The deltoid muscle is the recommended site in adults and children > 18 months of age. The anterolateral thigh is the recommended site in infants and young children.
Adverse reactions
Influenza vaccination cannot cause influenza because the vaccine does not contain live virus. Soreness at the injection site lasting up to 2 days is common but rarely interferes with normal activities. Fever, malaise, and myalgia may occur within 6 to 12 hours after vaccination and last 1 to 2 days. Prophylactic acetaminophen may decrease the frequency of some side effects in adults. Healthy adults receiving the split-virus vaccine have shown no increase in the frequency of fever or other systemic symptoms compared with those receiving placebo. In children aged 2 to 12 years, fever and local reactions are no more frequent after administration of split-virus vaccine than after placebo injections. In those < 24 months of age, fever occurs more often but is seldom severe.
Allergic responses are rare and are probably a consequence of hypersensitivity to some vaccine component, most likely residual egg protein, which is present in minute quantities.
Rare cases of systemic vasculitis have been reported in individuals after influenza vaccination, but a causal relation has not been proven(45,46).
A case report postulated that influenza vaccination may have caused a significant increase in carbamazepine blood levels in a 14-year-old child(47).
Guillain-Barré syndrome (GBS) associated with influenza vaccination has been observed in a minority of influenza seasons over the last two decades. Apart from the 1976-1977 swine ‘flu season, the risk of GBS associated with influenza vaccination is small. In a retrospective study of the 1992-93 and 1993-94 seasons in four U.S. states(48), the relative risk of GBS occurring within 6 weeks after influenza vaccination, adjusted for age and sex, was 1.7 (95% confidence intervals 1.0, 2.8; p = 0.04), suggesting slightly more than one additional case of GBS per million people vaccinated against influenza. In comparison, the morbidity and mortality associated with influenza are much greater.
In Canada the background incidence of GBS was estimated at just over 20 cases per million population in a study done in Ontario and Quebec(49). A variety of infectious agents, such as Campylobacter jejuni, have been associated with GBS. It is not known whether influenza virus infection itself is associated with GBS, or whether influenza vaccination is causally associated with increased risk of recurrent GBS in people with a previous history of GBS. Avoiding subsequent influenza vaccination of people known to have developed GBS within 6 to 8 weeks of a previous influenza vaccination appears prudent at this time.
Influenza vaccine is not known to predispose to Reye's syndrome.
Conjunctivitis and/or respiratory symptoms following influenza immunization were reported sporadically before 2000 in Canada, the United States, and Europe(50,51). However, during the 2000-2001 influenza season, Health Canada received an increased number of vaccine-associated symptoms and signs, which were subsequently described as oculorespiratory syndrome (ORS)(50). The case definition (revised in 2001) is as follows: the onset of bilateral red eyes and/or respiratory symptoms (cough, wheeze, chest tightness, difficulty breathing, difficulty swallowing, hoarseness or sore throat) and/or facial swelling occurring within 24 hours of influenza immunization(52). Assessment of the severity of ORS symptoms is based on the perception of the individual: mild (easily tolerated; present but not problematic), moderate (interferes with activities of daily living; bothersome, requires activity changes and possibly medication), or severe (prevents activities of daily living; unable to work or sleep).
The pathophysiologic mechanism underlying ORS remains unknown. Initial attention focused on the potential role of large aggregates of unsplit virions in vaccine products(52). Studies suggest that ORS is not the manifestation of an anaphylactic allergic response(53). Potential etiologic hypotheses have been discussed in recent publications(52-57).
After the 2000-2001 influenza season, fewer cases of ORS cases were reported to Health Canada(52). Those reported have occurred in association with both influenza vaccines marketed in Canada(58). Surveillance for all vaccine-associated adverse events (VAAE), including ORS, is ongoing.
Approximately 5% to 25% of patients who have previously experienced ORS may have a recurrence attributable to the vaccine(52,56-59). However, most recurrences are less severe than the previous episode(52,55,56). People who experience a recurrence of ORS upon revaccination do not necessarily have further episodes of ORS associated with future vaccinations(57).
Individuals who have experienced mild or moderate ORS symptoms, or severe ORS without lower respiratory symptoms (bilateral red eyes, cough, sore throat, hoarseness, facial swelling), may be safely re-immunized with influenza vaccine. Data on clinically significant adverse events do not support the preference of one vaccine product over another when those who have previously experienced ORS are revaccinated(57,58).
Expert review of the risks and benefits of vaccination should be sought for those who have previously had severe lower respiratory symptoms (wheeze, chest tightness, difficulty breathing) within 24 hours of influenza vaccination. Expert review should also be sought for those experiencing severe difficulty in swallowing or symptoms that are not listed in the ORS case definition (e.g. severe throat constriction) but that raise concern regarding the safety of re-immunization. This advice may be obtained from the local Medical Officers of Health or other experts in infectious disease, allergy/immunology, and/or public health. Health care providers who are unsure whether an individual previously experienced ORS or had an IgE-mediated hypersensitivity immune response should seek consultative advice. In view of the considerable morbidity and mortality associated with influenza, a diagnosis of influenza vaccine allergy should not be made without confirmation (which may involve skin testing) from an allergy/immunology expert.
Please refer to the Canadian Immunization Guide(60) 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 or who have known anaphylactic hypersensitivity to eggs manifested as hives, swelling of the mouth and throat, difficulty in breathing, hypotension and shock.
Adults with acute febrile illness should usually not be vaccinated until their symptoms have abated.
Although influenza vaccination can inhibit the clearance of warfarin and theophylline, clinical studies have not shown any adverse effects attributable to these drugs in people receiving influenza vaccine.
Simultaneous administration of other vaccines
Influenza vaccine may be given at the same time as other vaccines, provided different sites and administration sets (needle and syringe) are used.
The target groups for influenza and pneumococcal vaccination overlap considerably. Health care providers should take the opportunity to vaccinate eligible people against pneumococcal disease when influenza vaccine is given.
Storage
Influenza vaccine should be stored at 2o C to 8o C and should not be frozen.
Strategies for reducing the impact of influenza
The effectiveness of influenza vaccine varies, depending upon the age and immunocompetence of the vaccine recipient, and the degree of similarity between the virus strain included and the strain of circulating virus during the influenza season. With a good match, influenza vaccination has been shown to prevent laboratory-confirmed influenza illness in approximately 70% to 90% of healthy children and adults. Under these circumstances, studies have also shown influenza vaccination to be approximately 70% effective in preventing hospitalization for pneumonia and influenza among elderly people living in the community. Studies of elderly people residing in nursing homes have shown influenza vaccination to be 50% to 60% effective in preventing hospitalization and pneumonia and up to 85% effective in preventing death, even though the efficacy in preventing influenza illness may often be in the range of 30% to 40% among the frail elderly.
Vaccination is recognized as the single most effective way of preventing or attenuating influenza for those at high risk of serious illness or death from influenza infection and related complications. Influenza vaccine programs should aim to vaccinate at least 90% of eligible recipients. Nevertheless, only 70% to 91% of long-term care facility (LTCF) residents and 20% to 40% of adults and children with medical conditions listed previously receive vaccine annually(61-64). Studies of HCWs in hospitals and LTCFs have shown vaccination rates of 26% to 61%(62-65).
This low rate of utilization is due both to failure of the health care system to offer the vaccine and to refusal by people who fear adverse reactions or mistakenly believe that the vaccine is either ineffective or unnecessary. HCWs and their employers have a duty to actively promote, implement and comply with influenza immunization recommendations in order to decrease the risk of infection and complications in the vulnerable populations they care for(19-21). Educational efforts aimed at HCWs and the public should address common concerns about vaccine effectiveness and adverse reactions. These include the beliefs of patients at risk, health care workers, and other service providers that they rarely get influenza, the fear of side effects from the vaccine, and doubt about the efficacy of the vaccine(66).
The advice of a health care provider is often a very important factor
affecting whether a person is immunized or not. Most people at high
risk are already under medical care and should be vaccinated during regular
fall visits. Strategies to improve coverage include the following:
standing order policies in institutions to allow 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, establishing a policy of obtaining consent on admission that is durable for future years, and automatically administering vaccine to residents whose guardians cannot be contacted for consent;
vaccination of people at high risk who are being discharged from hospital or are visiting the emergency department in the autumn;
promotion of influenza vaccination in clinics where high-risk groups are seen (e.g. cancer clinics, cardiac clinics, and pulmonary clinics);
use of community newspapers, radio, television, and 'flu-information lines, and collaboration with pharmacists and specialist physicians to distribute positively framed information about the benefits and risks of influenza immunization;
computer-generated reminders to HCWs, mailed reminder letters to patients, or use of other recall methods to identify outpatients at high risk;
patient-carried reminder cards;
increased accessibility of immunization clinics to staff in institutions and community-based elderly, including implementation of mobile programs;
organized activities, such as vaccination fairs and competitions between institutions;
work with multicultural groups to plan and implement effective programs;
incorporation of influenza vaccination within the provision of home health care.
Immunization of HCWs
Person-to-person transmission of influenza virus occurs primarily through small-particle aerosols (< 10 µm in mass median diameter) created by sneezing, coughing, and talking. The virus can also be spread by direct contact with infected people or contaminated surfaces. Adults may spread influenza to others during a period ranging from 1 day before to 7 days after the onset of symptoms(67).
Transmission of influenza between clinically or subclinically infected HCWs and their vulnerable patients results in significant morbidity and mortality(22). Studies have demonstrated that HCWs who are ill with influenza frequently continue to work(17). 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(22). These individuals continued to work, potentially transmitting infection to their patients. In addition, absenteeism of HCWs who are sick with influenza results in excess economic costs and, in some cases, potential endangerment of health care delivery due to scarcity of replacement workers.
Vaccination of HCWs in health care facilities has been shown to reduce total patient mortality, ILI, and serologically confirmed influenza(17,18). Influenza vaccination programs for HCWs may also result in cost savings and reduced work absenteeism, depending on factors such as disincentives to take sick days, strain virulence, and the match between infecting strain and vaccine(18,29,68-70).
For the purposes of this document, we may define “direct patient care” as activities that allow opportunities for influenza transmission between HCWs and patient. NACI considers the provision of influenza vaccination for HCWs involved in direct patient care to be an essential component of the standard of care for influenza prevention(19-21). HCWs involved in direct patient care should consider it their responsibility to provide the highest standard of care, which includes undergoing annual influenza vaccination. In the absence of contraindications, refusal of HCWs who are involved in direct patient care to be immunized against influenza implies failure in their duty of care to their patients.
In order to protect vulnerable patients in an outbreak situation, it is reasonable to exclude from direct patient care 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.
Recommendations for the prophylactic use of amantadine
Amantadine hydrochloride is an antiviral agent that interferes with the replication cycle of type A (but not type B) influenza viruses. The following are recommendations for its use in prophylaxis. Use of amantadine as therapy for influenza is not discussed in this statement.
At the time of writing, the only drug currently approved in Canada for the specific prophylaxis of influenza virus infections is amantadine hydrochloride. It is 70% to 90% effective in preventing illness caused by type A influenza viruses but is ineffective against type B strains. Because antiviral agents taken prophylactically may prevent illness but not subclinical infection, some people who take these drugs may still develop immune responses that will protect them when they are exposed to antigenically related viruses in later years. However, amantadine prophylaxis should not replace annual influenza vaccination in groups for whom vaccine is recommended.
During influenza outbreaks, increased prevalence of amantadine resistance has been reported in families and within semi-closed settings, including nursing homes. Amantadine resistance is more likely to occur in populations in which the drug is used for both prophylaxis and treatment, as opposed to prophylaxis alone(71). Failure to adequately isolate institutional patients receiving amantadine therapy also increases the probability of transmission of any resistant virus that may emerge, which in turn may result in prolongation of an epidemic or a second epidemic wave(71).
Amantadine prophylaxis may be used as follows:
For the control of influenza A outbreaks among high-risk
residents of institutions.
Consultation with the local
Medical Officer of Health is important in order to confirm that the
circulating strain is type A. Amantadine should
be given to all residents who are not already ill with influenza, whether
previously vaccinated or not, and to unvaccinated staff (see Precautions section
below). Prophylaxis should also be considered for HCWs, regardless of vaccination
status, during outbreaks caused by influenza A strains that are not well
matched by the vaccine. Prophylaxis should be given for a minimum of 2
weeks, or until 1 week after the end of the outbreak.
As the sole agent for prophylaxis in people at high risk during an outbreak when vaccine is unavailable, contraindicated, or unlikely to be effective because of a shift in the antigenic composition of the outbreak strain. In this case, prophylactic amantadine must be taken each day for the duration of influenza A activity in the community.
As an adjunct to late vaccination of people at high risk. Amantadine should be continued for 2 weeks after appropriate vaccination has been completed. For those who require two doses of vaccine (e.g. previously unvaccinated children) amantadine should be continued for 2 weeks after the second dose. Amantadine does not interfere with the antibody response to the vaccine.
As a supplement to vaccination in people at high risk expected to have an impaired immune response to vaccine. This includes people with HIV infection, especially those with advanced HIV disease. No data are available on possible interactions with other drugs used in the management of patients with HIV infection. Such patients should be monitored closely if amantadine is administered.
Factors to be considered in decisions about the duration of amantadine prophylaxis include local epidemiologic factors, potential side effects, concern regarding emergence of viral resistance, adherence to medication regimens, and cost(70-72).
Dosage recommendations for prophylaxis of influenza A infection with amantadine are presented in Table 2, but the package insert should be read for complete information. Any adjustments for renal function should be made in addition to adjustments for age. Particular caution should be paid to dosages in those > 65 years of age, among whom some degree of renal impairment is common. Dosages may be adjusted according to calculated or laboratory-confirmed creatinine clearance. A recent Canadian study performed in a care facility for the elderly determined that serum creatinine levels measured up to 12 months previously could be safely used to estimate creatinine clearance(73). It should be noted that although Table 2 presents the recommended dosage schedule for amantadine prophylaxis, a few studies suggest that a prophylactic dose of 100 mg daily in those 10 to 64 years of age and in children weighing > 20 kg who have normal renal function may be as effective as the recommended dose of 200 mg daily(72).
While use of this dosing schedule, when properly adhered to, has been effective in controlling institutional influenza A outbreaks, the intermittent dosages may be confusing. An alternative, once daily dosage regimen for people > 65 years of age, based on renal function, is shown in Table 3(74). This new dosage regimen is based on pharmokinetic modelling, which suggests that it should be as effective and safe as the standard regimen presented in Table 2. HCWs and influenza program planners will need to assess the advantages and disadvantages of the two different schedules when selecting a regimen for their patients.
Although they have not been licensed for prophylactic use in Canada at the time of writing, neuraminidase inhibitors have been used under study conditions for this purpose. During institutional outbreaks of influenza, situations in which neuraminidase inhibitors may be indicated as prophylactic agents under appropriate study (off-licence) conditions include outbreaks of influenza B, outbreaks involving amantadine-resistant strains of influenza A as well as illness among residents who are at risk of serious side effects from amantadine.
Table 2. Recommended amantadine hydrochloride prophylactic dosage by age and renal status
|
Age |
Dosage |
|
|
No renal impairment |
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1-9 yearsa |
5 mg/kg once daily, or divided twice daily, total daily dose not to exceed 150 mg |
|
|
10-64 years |
200 mg once daily, or divided twice dailyb,c |
|
|
>= 65 years |
100 mg once dailyd |
|
|
Renal impairment |
||
|
Creatinine clearance (mL/min/1.73m2) |
Dosage for those 10-64 years |
Dosage for those |
|
>= 80 mL/min |
100 mg twice daily |
100 mg once daily |
|
60-79 mL/min |
Alternating daily doses of 200 mg and 100 mg |
Alternating daily doses of 100 mg and 50 mg |
|
40-59 mL/min |
100 mg once daily |
100 mg every 2 days |
|
30-39 mL/min |
200 mg twice weekly |
100 mg twice weekly |
|
20-29 mL/min |
100 mg three times/week |
50 mg three times/week |
|
10-19 mL/min |
Alternating weekly doses of 200 mg and 100 mg |
Alternating weekly doses of 100 mg and 50 mg |
a Use in children < 1 year of age
has not been evaluated adequately.
b Reduction of dosage to 100 mg/day
is recommended for people with a seizure disorder, because they may be
at risk of more frequent seizures when the dosage is 200 mg/day.
c For children who are > 10 years
of age but who weigh < 40 kg, a dosage of 5 mg/kg daily is advised
regardless of age.
d The reduced dosage
is recommended to minimize the risk of toxic effects, because renal function
generally
declines with age and because side effects have been reported more frequently
in the elderly.
Calculation of estimated creatinine clearance:
Male: |
CrCl mL/min = |
(140 - age) x weight (kg) |
Female: |
CrCl mL/min = |
0.85 x CrCl (male) |
Table 3. Proposed once daily dosing schedule for amantadine solution (10 mg/mL) in people over the age of 65 years*
|
Creatinine clearance |
Initial dose |
Subsequent doses (starting day 2) |
|
80 mL/min or greater |
100 mg |
100 mg/day (10 mL) |
|
60-79 mL/min |
100 mg |
75 mg/day (7.5 mL) |
|
40-59 mL/min |
100 mg |
50 mg/day (5 mL) |
|
20-39 mL/min |
100 mg |
25 mg/day (2.5 mL) |
|
10-19 mL/min |
100 mg |
‡ |
* Table reproduced with permission of McGeer et al(74) and the Canadian Journal of Infectious Diseases. Daily dosing increments set at 2.5 mL to permit the use of medicine cups marked at 2.5 mL.
‡ No daily dose; if outbreak continues, repeat 100 mg dose every 7 days during the outbreak.
Precautions
Of otherwise healthy young adults given amantadine prophylactically, 5% to 10% report difficulty concentrating, insomnia, light-headedness, and irritability. These side effects are usually mild and cease shortly after the prophylaxis is stopped; however, they can be more frequent in the older population unless a reduced dosage is used.
Serious side effects (e.g. marked behavioural changes, delirium, hallucinations, agitation, seizures) have been associated with high plasma drug concentrations. These have been observed most often among people who have renal insufficiency, seizure disorders, or certain psychiatric disorders, and among elderly people who have been taking amantadine as prophylaxis at a dose of 200 mg/day. Lowering the dose among these people is effective in reducing the severity of such side effects.
Amantadine is eliminated from plasma wholly by renal tubular secretion and glomerular filtration; it is not metabolized by the liver. Therefore, in people with reduced renal function, particularly the elderly, toxic levels can occur if the dosage is not reduced. Recommended prophylactic dosages by age and renal function are shown in Table 2. In patients with dialysis-dependent renal failure, the half-life of amantadine is 200 ± 36 hours(75). It should be noted that the calculated creatinine clearance is reasonably accurate for those with a creatinine clearance of > 40 mL/min and those with a stable serum creatinine and muscle mass. However, the calculation becomes less accurate when these conditions are not met. In particular, elderly people with renal impairment and low muscle mass may have a serum creatinine in the normal range and an estimated creatinine clearance that is higher than the true value. Physicians who prescribe amantadine must be familiar with the limitations of formulas to estimate creatinine clearance, and make clinical decisions regarding dosage adjustments on the basis of these considerations.
Amantadine dosage should be reduced in people with a seizure disorder in order to avoid the risk of increased frequency of seizures, and these individuals should be closely observed.
Drug interactions have been noted during concurrent administration of amantadine and triamterene and hydrochlorothiazide, trimethoprim-sulphamethoxazole, quinine and quinidine. The patient's age, weight, renal function, comorbid conditions, current medications as well as the indications for amantadine use should all be considered before this medication is initiated. Individuals who are given amantadine should be carefully monitored for side effects.
Members: Dr. M. Naus (Chairperson), Dr. A. King (Executive Secretary), |
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This statement was prepared by Dr. Pamela Orr and approved by NACI. |
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Last Updated: 2003-08-27 |  |
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