|
Canada Communicable Disease Report
Volume 31 ACS-6 15 June 2005 An Advisory Committee Statement (ACS) Statement on Influenza Vaccination
|
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 |
Influenza vaccine should be administered intramuscularly. The deltoid muscle is the recommended site in adults and children age 12 months. The anterolateral thigh is the recommended site in infants age < 12 months.
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(41). Healthy adults receiving the split-virus vaccine showed 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, occurs in 7% of healthy children who are age < 3 years. Postvaccination fever may be observed in 12% of immunized children age 1 to 5 years.
Several influenza vaccines which are marketed in Canada contain minute quantities of thimerosal, which is used as a preservative(42). Retrospective cohort studies of large health databases have demonstrated that there is no association between childhood vaccination with thimerosal-containing vaccines and neurodevelop-mental outcomes, including autistic-spectrum disorders(43,44). Nevertheless, in response to public concern, influenza vaccine manufacturers in Canada are working toward production and marketing of thimerosal-free influenza vaccines.
Allergic responses to influenza vaccine are rare and are probably a consequence of hypersensitivity to some vaccine component, such as residual egg protein, which is present in minute quantities.
Guillain-Barré syndrome (GBS) occurred in adults in association with the 1976 swine influenza vaccine, and evidence favours the existence of a causal relation between the vaccine and GBS during that season(45). In an extensive review of studies since 1976, the United States Institute of Medicine concluded that the evidence is inadequate to accept or reject a causal relation between GBS in adults and influenza vaccines administered subsequent to the swine influenza vaccine program in 1976(45,46).
In Canada the background incidence of GBS is estimated at just over 20 cases per million population in a study from Ontario and Quebec(47). Various infectious agents, such as Campylobacter jejuni, have been associated with GBS. It is unknown whether influenza virus infection itself is associated with GBS. It is also unknown whether influenza vaccination is causally associated with increased risk of recurrent GBS in persons with a previous history of GBS. Avoiding subsequent influenza vaccination of persons known to have developed GBS within 6 to 8 weeks of a previous influenza vaccination appears prudent at this time.
Influenza vaccine is unknown to predispose to Reye syndrome.
Conjunctivitis and/or respiratory symptoms following influenza immunization were reported sporadically prior to 2000 in Canada, the United States, and Europe(48,49). However, during the 2000-2001 influenza season, Health Canada received an increased number of reports of vaccine- associated symptoms and signs that were subsequently described as oculorespiratory syndrome (ORS)(47). 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(50). 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.
Subsequent to the 2000-2001 influenza season, fewer ORS cases have been reported to Health Canada(50). Surveillance for all vaccine-associated adverse events, including ORS, is ongoing.
Approximately 5% to 34% of patients who have previously experienced ORS may experience a recurrence that is attributable to the vaccine(50-56). Most recurrences, however, are less severe than the previous episode. Persons who experience a recurrence of ORS upon revaccination do not necessarily experience further episodes of ORS associated with further vaccination.
Individuals who have experienced mild or moderate ORS symptoms or severe ORS consisting of non-lower respiratory symptoms (bilateral red eyes, cough, sore throat, hoarseness, facial swelling) may be safely re-immunized with influenza vaccine. 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.
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, difficult swallowing) that raise concern about the safety of re-immunization. This advice may be obtained from local medical officers of health or other experts in infectious disease, allergy/immunology, and/or public health. Health care providers who are unsure whether an individual previously experienced ORS versus an IgE-mediated hypersensitivity immune response should seek 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.
The Canadian Immunization Guide(57) provides further details about administration of vaccine and management of adverse events.
Influenza vaccine should not be given to people who have had an anaphylactic reaction to a previous dose or who have known IgE-mediated hypersensitivity to eggs manifested as hives, swelling of the mouth and throat, difficulty in breathing, hypotension, or shock.
Adults with serious acute febrile illness usually should not be vaccinated until their symptoms have abated. Those with mild non-serious febrile illness (such as mild upper respiratory tract infections) may be given influenza vaccine. Opportunities for immunization should not be lost due to inappropriate deferral of immunization.
Although influenza vaccination can inhibit the clearance of war-farin and theophylline, clinical studies have not shown any adverse effects attributable to these drugs in those who receive the 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.
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 pneumo-coccal disease when influenza vaccine is given.
Influenza vaccine should be stored at 2° C to 8° C and should not be frozen.
The effectiveness of influenza vaccine varies, depending upon the age and immunocompetence of the vaccine recipient, the degree of similarity between the virus strain included, and the characteristics of the strain of circulating virus during influenza season. With a good match, influenza vaccination has been shown to prevent laboratory-confirmed influenza illness in approximately 70% or more of healthy individuals. Under these circumstances, studies have also shown influenza vaccination to be 70% effective in preventing hospitalization for pneumonia and influenza among elderly persons living in the community. Studies among elderly persons residing in nursing homes have shown influenza vaccination to be 50% to 60% effective in preventing hospitalization and pneumonia and up to 85% effective in preventing death, even though efficacy in preventing influenza illness may be as low as 30%.
Vaccination is recognized as the single most effective way of preventing or attenuating influenza for those at high risk of serious illness or death from influenza infection and related complications. Influenza vaccine programs should aim to vaccinate at least 90% of eligible recipients. Nevertheless, only 70% to 91% of long-term care facility (LTCF) residents and 20% to 40% of adults and children with medical conditions listed previously receive vaccine annually(58-62). Studies of HCWs in hospitals and LTCFs have shown vaccination rates of 26% to 61%(59-61,63).
This low rate of utilization is due to failure of the health care system to offer the vaccine and to refusal by persons who fear adverse reactions or mistakenly believe that the vaccine is either ineffective or unnecessary. HCWs and their employers have a duty to actively promote, implement, and comply with influenza immunization recommendations to decrease the risk of infection and complications in vulnerable populations for which they provide care(64). Educational efforts aimed at HCWs and the general public should address common concerns about vaccine effectiveness and adverse reactions. These include beliefs of patients at risk, HCWs and other service providers - that they rarely get influenza, they fear side effects, and they doubt the efficacy of the vaccine.
The advice of a health care provider is an important factor affecting whether a person accepts immunization. Most people at high risk are already under medical care and should be vaccinated during regular fall visits. Strategies to improve coverage include the following:
Person-to-person transmission of influenza virus occurs primarily through respiratory droplets generated by sneezing, coughing, or talking. Adults may spread influenza to others during a period ranging from 1 day before to 7 days after the onset of symptoms. Children may shed virus for 1 day prior to symptoms to 10 to 14 days after illness onset.
Transmission of influenza between infected HCWs and their vulnerable patients results in significant morbidity and mortality(65). 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(66). 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(65). 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 owing to the scarcity of replacement workers.
Vaccination of HCWs in health care facilities has been shown to reduce total patient mortality, influenza-like illness, and serologically confirmed influenza(66). Influenza vaccination programs for HCWs may also result in cost savings and reduced work absenteeism, depending on factors including disincentives to take sick days, strain virulence, and the match between infecting strain and vaccine(67-69).
For the purposes of this document, we define HCW as a person who provides direct patient care and as an individual who provides health services in an indirect fashion, such as one who performs administrative activities. The latter may still come into close contact with patients by sharing 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 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 influenza prevention for the protection of their patients. HCWs who have direct patient contact should consider that their responsibility is to provide the highest standard of care, which includes undergoing annual influenza vaccination. In the absence of contraindications, HCWs who have direct patient contact and their refusal to be immunized for influenza implies failure in their duty to patient care.
To protect vulnerable patients in an outbreak situation, it is reasonable to exclude from direct patient contact HCWs who develop confirmed or presumed influenza and unvaccinated HCWs who are not taking antiviral prophylaxis. Health care organizations should have policies in place to deal with this issue.
This section discusses the prophylactic use of antiviral agents against influenza. Antiviral therapy against influenza is not discussed in this statement.
Antiviral prophylaxis should not replace annual influenza vaccination. Vaccination remains our primary tool for the prevention of influenza infection and illness.
Amantadine hydrochloride is an antiviral agent that interferes with the replication cycle of influenza A virus through the blocking of ion channels of the cell membrane. It is not effective against influenza B.
Rimantadine is a related adamantanamine antiviral agent that is not licensed in Canada. It will not be discussed in this statement.
Randomized trials in healthy adults suggest that amantadine prevents 23% of clinical influenza cases and 63% of serologically confirmed influenza A illness(70,71). A non-blind randomized trial of amantadine versus placebo during an influenza outbreak in healthy boys age 13 to 19 years living in a boarding school showed 91% efficacy against culture confirmed influenza illness and 86% efficacy against clinical influenza illness(72). A non-randomized trial in boys age 12 to 18 years showed 70% efficacy of amantadine, compared with placebo, in preventing influenza illness(73).
In non-randomized controlled trials, amantadine prophylaxis used for periods varying from 9 days to 16 weeks interrupted influenza A outbreaks and reduced mortality in populations at increased risk for influenza complications, including disabled children, hospitalized adults, elderly residents of nursing homes, and prison populations(74-76). Postexposure prophylaxis with amantadine provides protection (protective efficacy 74%) in families when the index case does not receive antiviral therapy(74,77). Amantadine does not provide protection from influenza A in household contacts when it is also used to treat the index case, likely owing to the spread of resistant virus within the household(74,78,79). Amantadine resistance is more likely to occur in populations, such as families and within semi-closed settings, including nursing homes where the drug is used for prophylaxis and treatment, as opposed to prophylaxis alone. Simultaneous use of amantadine for prophylaxis and therapy within a family, facility, or institution is not advised because of the increased risk of the emergence of viral resistance. Failure to ade quately isolate institutional patients on amantadine therapy also increases the probability of transmission of any resistant virus that may emerge, which in turn may result in prolongation of an epidemic or a second epidemic wave(80,81).
Neuraminidase inhibitors prevent the replication of both type A and B influenza viruses by inhibiting influenza virus neuramini-dase. Neuraminidase promotes the release of virus from infected cells by preventing virions from self-aggregating and binding to the surface of infected cells. Oseltamivir is a neuraminidase inhibitor, licensed for pre- and post-exposure prophylaxis against influenza A and/or B in persons age 13 years(82-84).
Zanamivir is a neuraminidase inhibitor that has not been approved by Health Canada for prophylactic use, although it has been used off-label for this purpose. Zanamivir will not be discussed further in this statement.
A review of randomized placebo-controlled trials in healthy adults reports that neuraminidase inhibitors are 74% effective in preventing naturally occurring cases of clinically defined influenza and 60% effective in preventing laboratory confirmed influenza(85-87). Sufficient data are not available to assess the efficacy of neuraminidase inhibitors used prophylactically in healthy children age < 13 years, and they are not licensed for prophylactic use in this age group(88). Oseltamivir was 92% effective in preventing laboratory-confirmed clinical influenza illness in a randomized multicentre controlled trial of prophylaxis among elderly individuals in residential care; however, residents with significant renal disease, hepatic dysfunction, cardiac failure, cancer, HIV Infection, and history of alcohol/drug abuse were excluded(82). The efficacy of oseltamivir in preventing influenza in immunocompromised persons has not been established. Oseltamivir has been successfully used as prophylaxis, along with vaccination and infection control measures, to control outbreaks of influenza in nursing homes and long-term care facilities(83,84). In a randomized controlled trial, oseltamivir was efficacious in protecting healthy household contacts of index influenza cases that were not treated(89). Households with pregnant or breastfeeding women, or individuals with cancer, immunosuppression, HIV infection, chronic liver or renal disease were excluded from this study.
The emergence of oseltamivir-resistant virus during or after pro-phylactic use of this antiviral has not yet been noted(87). However, 0.33% to 18% of influenza isolates have been noted to be oseltamivir resistant during follow-up of children and adults in treatment studies(90-92).
Because antiviral agents taken prophylactically may prevent illness but not subclinical infection, some persons who take these drugs may still develop immune responses that provide protection when they are exposed to antigenically related viruses in later years. However, as previously indicated, antiviral prophy-laxis should not replace annual influenza vaccination.
Amantadine and oseltamivir are ineffective in providing prophylaxis for respiratory infections other than influenza. Therefore, it is critically important to base decisions about their prophylactic use on appropriate epidemiologic, clinical, and laboratory data regarding the etiology of prevalent infec-tion(s).
NACI recommends using influenza antivirals (amantadine or oseltamivir) prophylactically in the following situations:
The diagnosis of influenza in the index case should be based on laboratory confirmation (e.g. using a rapid diagnostic test) or clinical parameters that have high positive predictive value in the setting of prevalent infection in the community. Studies suggest that when influenza is circulating in a community, patients with an influenza-like illness who exhibit cough and fever within 48 hours of symptom onset are likely to have influenza(96,97). The presence of sore throat suggests a diagnosis other than influenza.
Despite the availability of antiviral agents for postexposure prophylaxis within households, the use of influenza vaccine for pre-exposure prophylaxis at season onset remains the recommended protective strategy of choice. Influenza vaccine provides protection against illness that may result from exposure within the family and community over a more prolonged period of time.
Note that these recommendations encompass off-label (outside of licensed indications) use of oseltamivir.
When prophylaxis is indicated, deciding which antiviral agent to use should consider the type of influenza strain circulating and
the efficacy, potential toxicity, cost, and ability to administer the agent within a particular population.
Factors such as local epidemiology, potential side effects, concern regarding emergence of viral resistance, adherence to medication regimens, and cost may be considered when determining the duration of antiviral prophylaxis.
Table 3 presents the amantadine dosage recommendations for prophylaxis of influenza A infection, but read the package insert for complete information. Any adjustments for renal function should be made in addition to adjustments for age. Pay particular attention to dosages in those age > 65 years, among whom some degree of renal impairment is common. Dosages may be adjusted according to calculated or laboratory-confirmed creatinine clearance. In care facilities for the elderly, serum creatinine levels measured up to 12 months previously can be safely used to estimate creatinine clearance(98,99). Note that, although Table 3 presents the recommended dosage schedule for amantadine prophylaxis, a few studies suggest that a prophylactic dose of 100 mg daily may be as effective as the recommended dose of 200 mg daily in those age 10 to 64 years and in children weighing > 20 kg who have normal renal function(74).
Although the use of this dosing schedule, when properly adhered to, has been effective in controlling institutional influenza A outbreaks, the intermittent dosages may be confusing. Table 4 shows an alternative - once daily dosage regimen for persons age > 65 years - based on renal function (99). This new dosage regimen is based on pharmokinetic modelling, suggesting that it should be as effective and safe as the standard regimen presented in Table 3. HCWs and influenza program planners will need to assess the advantages and disadvantages of the two different schedules when selecting a regimen for their patients.
Amantadine was given for 10 days in studies of postexposure pro-phylaxis among household contacts of index cases with influenza(77). Amantadine has been given for up to 16 weeks in pre-exposure prophylaxis studies(74,75).
In otherwise healthy young adults who were 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 occur more frequently in the older population unless a reduced dosage is used.
Serious side effects (e.g. marked behavioural changes, delirium, hallucinations, agitation, seizures) have been associated with high plasma drug concentrations. These have been observed most often among persons who have renal insufficiency, seizure disorders, or certain psychiatric disorders, and among elderly persons who have been taking amantadine as prophylaxis at a dose of 200 mg/day. Lowering the dosage among these persons is effective in reducing the severity of such side effects.
Amantadine is eliminated from plasma wholly by renal tubular secretion and glomerular filtration; it is not metabolized by the liver. For this reason, for those with reduced renal function, particularly the elderly, toxic levels can occur if the dosage is not reduced. Tables 3 and 4 provide the recommended prophylac-tic dosages by age and renal function. In patients with dialysis-dependent renal failure, the half-life of amantadine is 200 36 hours(100). For patients with a creatinine clearance < 10 ml/min who are not on dialysis, an amantadine dose of 100 mg orally every 3 weeks is recommended [F. Aoki, personal communication, September 14, 2004](101).
Note, the calculated creatinine clearance is reasonably accurate for those with a creatinine clearance > 40 ml/min and for those with a stable serum creatinine and muscle mass. The calculation, however, becomes less accurate when these conditions are not met. Specifically, elderly persons with renal impairment and low muscle mass may have a serum creatinine in the normal range and an estimated creatinine clearance that is higher than the true value. Physicians who prescribe amantadine must be familiar with the limitations of formulas to estimate creatinine clearance and make clinical decisions on dosage adjustments based on these considerations.
To avoid the risk of increased frequency of seizures, reduce amantadine dosage in individuals who suffer from seizure disorder, and observe closely.
Drug interactions have been noted during concurrent administration of amantadine with triamterene and hydrochlorothiazide, trimethoprim-sulphamethoxazole, quinine, and quinidine. The patient's age, weight, renal function, comorbid conditions, and current medications, as well as the indications for amantadine use, should all be considered prior to initiating this medication. Individuals who are given amantadine should be carefully monitored for side effects.
Oseltamivir is available in 75 mg capsules, as well as a powder that can be reconstituted into an oral suspension at 12 mg/mL. The recommended oral dose of oseltamivir for prevention of influenza in persons age 13 years is 75 mg once daily. For postexposure prophylaxis, oseltamivir should begin within 48 hours of exposure. The duration of household postexposure pro-phylaxis used in a randomized controlled trial was 7 days(89). 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, because these persons may continue to shed virus for up to 14 days after onset of their illness.
No dose adjustment is necessary with a creatinine clearance above 30 mL/min. A recent serum creatinine or creatinine clearance result based on a 24-hour urine collection is not required before starting oseltamivir prophylaxis, unless there is reason tosuspect significant renal impairment. For those with a creatinine clearance of 10 to 30 mL/min, reduce the dosage of oseltamivir to 75 mg every other day, or 30 mg of suspension every day orally. No dosing recommendation is available for patients with a creatinine clearance < 10 mL/min and for those undergoing hemodialysis and peritoneal dialysis.
Oseltamivir is converted to oseltamivir carboxylate by esterases located predominantly in the liver. The safety and efficacy of oseltamivir in those with hepatic impairment has not been established.
Oseltamivir should be used during pregnancy and lactation only if the potential benefit justifies the potential risk to the fetus or nursing infant. Insufficient data are available regarding possible toxic effects on the fetus. It is unknown whether oseltamivir or its active metabolite are excreted in human milk.
Oseltamivir should not be given to children age < 1 year. Oseltamivir is licensed by Health Canada for prophylactic use only for children age ≥ 13 years.
Oseltamivir is contraindicated in persons with known hypersensitivity to any components of the product.
Co-administration of probenecid results in a two-fold increase in exposure to oseltamivir carboxylate, the active metabolite of oseltamivir, as a result of increased active amniotic tubular secretion in the kidney.
The most common adverse events reported in oseltamivir prevention studies using doses of 75 mg once daily are headache, fatigue, nausea, cough, diarrhea, vomiting, abdominal pain, insomnia, and vertigo. However, the difference in incidence between oseltamivir and placebo was > 1% only for headache, nausea, vomiting, and abdominal pain(90).
NACI gratefully acknowledges the assistance of Samina Aziz, Karen Ellison, Theresa Tam, and Jill Sciberras in the preparation of this manuscript.
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___________________________________
*Members: Dr. M. Naus (Chairperson), Dr. T. Tam (Executive Secretary), Dr. I. Bowmer, Dr. S. Dobson, Dr. B. Duval, Dr. J. Embree, Ms. A. Hanrahan, Dr. J. Langley, Dr. A. McGeer, Dr. P. Orr, Dr. M-N Primeau, Dr. B. Tan, Dr. B. Warshawsky, A. Zierler.
Liaison Representatives: S. Callery (CHICA), Dr. J. Carsley (CPHA), Dr. L. Chapman (CDC), Dr. A. Gruslin (SOGC), A. Honish (CNCI), Dr. B. Larke (CCMOH), Dr. B. Law (ACCA), Dr. M. Salvadori (AMMI Canada), Dr. S. Rechner (CFPC), Dr. J. Salzman (CATMAT), Dr. L. Samson (CPS), Dr. D. Scheifele (CAIRE).
Ex-Officio Representatives: Dr. S. Deeks (CIDPC), Dr. H. Rode (BGTD), Dr. M. Lem (FNIHB), Dr. M. Tepper (DND).
This statement was prepared by Dr. P. Orr and approved by NACI and the Public Health Agency of Canada.
[Canada Communicable Disease Report]
Last Updated: 2005-09-23 |