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Canada Communicable Disease Report
Vol. 26 (ACS-2)
1 June 2000
An Advisory Committee Statement (ACS)
National Advisory Committee on Immunization (NACI)*
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STATEMENT ON INFLUENZA VACCINATION FOR THE 2000-2001
SEASON
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PREAMBLE
The National Advisory Committee on Immunization (NACI) provides Health
Canada with ongoing and timely medical, scientific, and public-health
advice relating to immunization. Health Canada acknowledges that the advice
and recommendations set out in this statement are based upon the best
current available scientific knowledge, and is disseminating this document
for information purposes. Persons administering or using the vaccine should
also be aware of the contents of the relevant product monograph(s). Recommendations
for use and other information set out herein may differ from that set
out in the product monograph(s) of the Canadian licensed manufacturer(s)
of the vaccine(s). Manufacturer(s) have only sought approval of the vaccine(s)
and provided evidence as to its safety and efficacy when used in accordance
with the product monographs.
INTRODUCTION
The antigenic components of the influenza vaccine have been updated
for the 2000-2001 season. The present statement also contains updated
information on pandemic planning, epidemiology, recommended recipients,
strategies for influenza control, and prophylaxis.
In Canada, two available measures can reduce the impact of influenza:
immunoprophylaxis with inactivated (killed-virus) vaccine and chemoprophylaxis
or therapy with an influenza-specific antiviral drug (amantadine). Vaccination
of persons at high risk each year before the influenza season is currently
the most effective measure for reducing the impact of influenza.
Influenza A viruses are classified into subtypes on the basis of two
surface antigens: hemagglutinin (H) and neuraminidase (N). Three subtypes
of hemagglutinin (H1, H2, and H3) and two subtypes of neuraminidase (N1
and N2) are recognized among influenza A viruses that have caused widespread
human disease. Immunity to these antigens - especially to the hemagglutinin -
reduces the likelihood of infection and lessens the severity of disease
if infection occurs. Infection with a virus of one subtype confers little
or no protection against viruses of other subtypes. Furthermore, over
time, antigenic variation (antigenic drift) within a subtype may be so
marked that infection or vaccination with one strain may not induce immunity
to distantly related strains of the same subtype. Although influenza B
viruses have shown more antigenic stability than influenza A viruses,
antigenic variation does occur. For these reasons, major epidemics of
respiratory disease caused by new variants of influenza continue to occur.
The 1999-2000 influenza season was characterized by a single peak of
influenza activity in early January, which appeared to spread rapidly
from west to east. Between 4 September 1999 and 22 April 2000, the Laboratory
Centre for Disease Control (LCDC) received reports on 51,439 laboratory
tests for influenza; 7,027 (14%) were positive, 6,961 (99.1%) were confirmed
as influenza type A, and 66 (0.9%) as influenza type B. The provincial
distribution of influenza A specimens was as follows: Newfoundland (71),
Nova Scotia (188), New Brunswick (98), Prince Edward Island (14), Quebec
(1,590), Ontario (2,898), Manitoba (253), Saskatchewan (431), Alberta
(1,126), and British Columbia (358). These results reflect influenza activity
and also local testing policies and resources. Isolates from the Yukon,
Northwest Territories, and Nunavut are included in provincial totals.
As of 30 March 2000, the Bureau of Microbiology, LCDC, has characterized
494 isolates; 437 (88.5%) were A/Sydney/5/97(H3N2)-like, 46 (9.3%) were
A/New Caledonia/20/99(H1N1)-like, and 11 (2.2%) were B/Beijing/184/93-like.
The provincial distribution of A/Sydney/5/97-like isolates was as follows:
Newfoundland (7), Nova Scotia (21), New Brunswick (6), Prince Edward Island
(4), Quebec (33), Ontario (260), Manitoba (10), Saskatchewan (37), Alberta
(32), and British Columbia (27). Of the 46 A/New Caledonia/20/99-like
isolates, 18 were from Nunavut, 20 were from Ontario, five were from Quebec,
two were from Alberta, and one was from Saskatchewan. Both Nunavut and
Ontario reported outbreaks of A/New Caledonia/20/99-like influenza. Of
note, there has been a substantial increase in H1N1 activity in Canada
this season as compared with the 1998-1999 season when only one H1N1(A/Bayern/7/95-like)
strain was detected.
Since October 1999, there has been influenza activity in both the northern
and southern hemispheres. Activity peaked in the northern hemisphere in
late December to mid January, with most countries reporting widespread
and regional influenza outbreaks. By February, influenza activity had
declined in North America and most of Europe, however Russia and pockets
in Europe were still reporting widespread influenza outbreaks. Between
October and February, most countries reporting in the southern hemisphere
indicated sporadic influenza activity throughout the season.
Since October 1999, 54 countries reported laboratory confirmed influenza
A to the World Health Organization (WHO), while only 32 countries reported
influenza B. Both subtypes of influenza A (H3N2 and H1N1) and influenza
B were detected on six continents (Africa, North America, South America,
Asia, Europe, and Oceania). Of the influenza A viruses, A/Sydney/5/97(H3N2)
appeared to be the predominant circulating strain world wide, including
Canada and the United States. Four other H3N2 strains were also in circulation:
A/Moscow/10/99, A/Panama/2007/99, A/Perugia/5/99, and A/Lyon/CHU/868/00.
These strains were detected in Europe and the eastern hemisphere this
season, but were not detected in North America and South America. Less
commonly detected were the H1N1 strains. The most commonly detected H1N1
strain was A/New Caledonia/20/99 which was detected in 14 countries on
four continents, including Canada and the United States. Two strains of
influenza B were detected: B/Beijing/184/93 and B/Yamanashi/166/98. B/Beijing/184/93
was the more common strain detected, isolated in 17 countries on five
continents, including Canada and the United States.
The antigenic characteristics of current and emerging influenza
virus strains provide the basis for selecting the strains included in
each year's vaccine. As suggested by WHO, NACI recommends that the
trivalent vaccine for the 2000-2001 season in the northern hemisphere
contain an A/Moscow/10/99(H3N2)-like virus, an A/New Caledonia/20/99(H1N1)-like
virus, and a B/Beijing/184/93-like virus. It should be noted that A/Panama/2007/99
is an A/Moscow/10/99(H3N2)-like virus, and the most widely used B/Beijing/184/93-like
vaccine strain virus is B/Yamanashi/166/98.
Annual immunization is required because there is always a change in
the vaccine in response to antigenic drift. As well, immunity declines
in the year following vaccination. Each 0.5 mL of vaccine will contain
15 µg of hemagglutinin of each antigen. The vaccine will be available
as a split-virus (chemically disrupted) preparation. Both humoral and
cell-mediated responses are thought to play a role in immunity to influenza.
The production and persistence of antibody after vaccination depends on
several factors, including age, prior and subsequent exposure to antigens,
and presence of immunodeficiency states. Humoral antibody levels which
correlate with vaccine protection are generally achieved by 2 weeks after
immunization. Immunity after the inactivated vaccine usually lasts < 1 year(1).
However, in the elderly, antibody levels may fall below protective levels
in <= 4 months. Data are not available to support the administration
of a second dose of influenza vaccine in elderly individuals in order
to boost immunity.
The recommended time for influenza immunization is the period from October
to mid-November. However, decisions regarding the exact timing of vaccination
of ambulatory and institutionalized individuals must be made based on
local epidemiology, recognition of the need to use patient contacts with
health-care providers as opportune moments for immunization, and program
issues. Further advice regarding the timing of influenza vaccination programs
may be obtained through consultation with local medical officers of health.
Health-care workers (HCWs) should use every opportunity to give vaccine
to any individual at risk who has not been immunized during the current
season, even after influenza activity has been documented in the community.
RECENT DEVELOPMENTS IN PANDEMIC PLANNING, INFLUENZA EPIDEMIOLOGY,
AND THERAPY
-
The Canadian Contingency Plan for Pandemic Influenza is being
revised as a result of input from several working groups and formal
consultation with the provinces and territories. Its purpose is to
enhance the capacity of Canada to respond to such an event and to
decrease associated mortality, morbidity, and societal disruption.
A memorandum of understanding between federal, provincial, and territorial
governments is being developed to address issues such as identified
roles and responsibilities, as well as choosing options for vaccine
and antiviral drug supply and related funding. A meeting to facilitate
contingency planning at provincial and territorial, and local levels
took place January 2000. At the time of this meeting, approximately
half of the provinces and territories had already commenced planning
activities.
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In a recently published study from California, the rate of hospitalization
during the influenza season for acute respiratory disease among children
who did not have conditions that put them at high risk for complications
of influenza, was approximately 12 times higher in those <
2 years of age compared to those 5 to 17 years of age(2).
Another study from Tennessee demonstrated hospitalization rates for
illness attributable to influenza, among healthy children < 1 year
of age, that were similar to rates for adults at high risk for influenza(3).
Influenza accounted for a substantial number of outpatient visits
and courses of antibiotics in Tennessee children of all ages.
-
Two neuraminidase inhibitors, zanamivir and oseltamivir, have been
licensed in Canada for therapy of infection due to either influenza
A or B virus. At the time of writing of this statement, neither have
been approved in Canada for prophylactic use. As NACI's mandate does
not encompass influenza therapy, this statement will not specifically
discuss the therapeutic use of these agents. Recently published reviews
are available for further information(4).
Recommendations for the prevention and control of influenza during the
2000-2001 influenza season follow.
RECOMMENDED RECIPIENTS
Current influenza vaccines licensed in Canada are immunogenic, safe,
and associated with minimal side effects (see "Adverse reactions"
and "Contraindications and precautions" below). Influenza vaccine
may be administered to any healthy child, adolescent, or adult for whom
contraindications are not present.
To reduce the morbidity and mortality associated with influenza and the
impact of illness in our communities, immunization programs should focus
on those at high risk for influenza-related complications, those capable
of transmitting influenza to individuals at high risk for complications,
and those who provide essential community services. However, significant
morbidity and societal costs are also associated with seasonal interpandemic
influenza illness and its complications occurring in healthy children
and adults(1). For this reason, healthy adults and their
children who wish to protect themselves from influenza should be encouraged
to receive the vaccine (see "Immunization of healthy persons"
below).
People at high risk for influenza-related complications
-
Adults and children with chronic cardiac or pulmonary disorders
(including bronchopulmonary dysplasia, cystic fibrosis, and asthma)
severe enough to require regular medical follow-up or hospital care.
Chronic cardiac and pulmonary disorders are by far the most
important risk factors for influenza-related death(5,6).
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People of any age who are residents of nursing homes and other
chronic care facilities. Such residents often have one or
more of the medical conditions outlined in the first group. In addition,
their institutional environment may promote spread of the disease.
Studies have shown that the use of vaccine in this setting will decrease
the occurrence of illness, hospital admission, pneumonia, and death(7,8).
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People >= 65 years of age. The risk
of severe illness and death related to influenza is moderately increased
in healthy people in this age group, but is not as great as in people
with chronic underlying disease. Vaccination is effective in preventing
hospital admission and death, and results in direct health-care cost
savings(9).
-
Adults and children with chronic conditions, such as diabetes
mellitus and other metabolic diseases, cancer, immunodeficiency, immunosuppression
(due to underlying disease and/or therapy), renal disease,
anemia, and hemoglobinopathy. Influenza vaccine is effective in
reducing hospital admissions in adults with diabetes(10).
The efficacy of the vaccine among children with chronic metabolic
and renal diseases is uncertain, but this uncertainty should not preclude
consideration of the vaccine. Immunosuppressed patients are at increased
risk for influenza infection, morbidity and mortality(11,12).
Although some immunosuppressed individuals may have a suboptimal immune
response, influenza vaccination is safe and can induce protective
antibody levels in a substantial proportion of adults and children,
including transplant recipients, those with proliferative diseases
of the hematopoietic and lymphatic systems, and HIV infected patients(13-17).
Among the latter, enhanced HIV replication may occur in those persons
who develop an immune response to the vaccine and are not receiving
suppressive anti-retroviral therapy. However the increase appears
to be transient and has not been shown to be associated with disease
progression(18,19). Influenza vaccination guidelines for
HIV-infected individuals which takes into account CD4+ T-lymphocyte
cell counts and anti-retroviral therapy, have been proposed by some
investigators(19), pending further studies in this population.
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Children and adolescents (age 6 months to 18 years)
with conditions treated for long periods with acetylsalicylic acid.
This therapy might increase the risk of Reye syndrome after influenza.
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People at high risk of influenza complications embarking on
travel to destinations where influenza is likely to be circulating.
Immunization with the most current available vaccine should be considered
for all individuals who wish to avoid influenza while travelling to
areas where influenza is likely to be circulating. There is insufficient
evidence at this time to advise in favour or against routine re-immunization
of travellers who were immunized in the fall, and who are subsequently
travelling to regions where influenza may be circulating in the late
spring and summer months. In the tropics, influenza can occur throughout
the year. In the southern hemisphere, peak activity occurs from April
through September. In the northern hemisphere, peak activity occurs
from November through March. Travel may expose individuals to situations
which facilitate the transmission of influenza(20,21).
The effectiveness of the influenza immunization for travellers may
vary depending on differences between influenza strains encountered
abroad and those included in the current vaccine.
People capable of transmitting influenza to those at high risk for
influenza-related complications
People who are potentially capable of transmitting influenza to those
at high risk should receive annual vaccination, regardless of whether
the high-risk person(s) is immunized.
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HCWs and other personnel who have significant contact with
people in the high-risk groups previously described (see
"Strategies for Reducing the Impact of Influenza" below).
The following groups should be vaccinated(8,20,22-25):
HWCs in long-term care facilities (LTCFs), hospitals, and outpatient
settings; employees of LTCFs who have patient contact; and those who
provide services within relatively closed settings to persons at high
risk (e.g. providers of home-care services, crew on ships that cater
to those at high risk).
-
Household contacts (including children) of people at high risk
who either cannot be vaccinated or may respond inadequately to vaccination.
Because low antibody responses to influenza vaccine may occur
in some people at high risk (e.g. the elderly, people with immunodeficiency),
annual vaccination of their household contacts may reduce the risk
of influenza exposure.
People who provide essential community services
Vaccination may be considered for these individuals in order to minimize
the disruption of routine activities in epidemics. Employers and their
employees should consider yearly influenza immunization for healthy working
adults as this has been shown to decrease work absenteeism from respiratory
and other illnesses(26-30).
Further comments regarding recommended recipients
-
Immunization of healthy persons. Any individual
who wishes to protect him/herself from influenza should be encouraged
to receive the vaccine, even if they are not in one of the aforementioned
priority groups. Several studies have shown that influenza immunization
of healthy adults and children may be cost-effective, under selected
circumstances(26-34). Assessment of the potential benefits
of influenza immunization in healthy adults and children depends on
numerous factors, including seasonal viral virulence and attack rates,
the match between vaccine and circulating viral strains, protective
immunity in previously infected individuals, vaccine side-effects,
and the costs of vaccination and of influenza-associated morbidity(32-35).
Among children, the effects of co-circulating viruses such as respiratory
syncytial virus must be separated from those of influenza(36).
Policy decisions regarding public funding of influenza vaccine for
healthy adults and children depends on modelling of these factors
within populations, as well as assessing health priorities, resources,
and pragmatic program issues(35-37).
The American Academy of Family Physicians and the Advisory Committee
on Immunization Practices (ACIP) have recommended lowering the age
of universal influenza vaccination of adults to 50 years of age(36,38).
The primary rationale is that many persons 50 to 64 years of age have
high-risk conditions such as diabetes mellitus, or heart disease,
yet the influenza immunization rate among American adults in this
age group who have high-risk chronic medical conditions is 24% to
32%(36,39). The low immunization rate is caused by persons
being unaware they have a high-risk condition, lack of health-care
access, or failure of HCWs to deliver immunization(40).
Age-based influenza guidelines may be more successful in reaching
individuals with medical conditions that put them at higher risk of
influenza complications, compared to previous guidelines based on
recognition of the specific high risk conditions. The cost-benefit
of this change in American guidelines has not been fully assessed.
At the present time, NACI suggests that program decisions in Canada
regarding how to access and immunize those listed under "Recommended
Recipients" (see above) are best made by agencies responsible
for the planning and implementation of such programs.
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Influenza vaccine in pregnancy. Influenza vaccine
is considered safe for pregnant women at all stages of pregnancy,
and for breastfeeding mothers. Vaccination is recommended for pregnant
and breastfeeding women who are characterized by any of the conditions
listed under "Recommended Recipients" (see above). The routine
immunization of otherwise healthy women in the second or third trimester
of pregnancy has been recommended by ACIP on the basis of case reports,
observational studies, and one retrospective case-control study of
a selected Tennessee population(36,41-46). Applying the
Tennessee study results to Canadian and European populations has been
questioned. The degree of morbidity due to influenza in Canadian women
who are pregnant has not been established, and the preventable fraction
of morbidity that could potentially be achieved through the use of
the influenza vaccine in this population is unknown. NACI concludes
that there is insufficient evidence at this time to recommend the
routine immunization of otherwise healthy Canadian women who are pregnant
during influenza season.
ADMINISTRATION OF INFLUENZA VACCINE
Dosage schedule
The recommended dosage schedule and type of influenza vaccine are presented
in Table 1. Split-virus vaccines are available in
Canada. Children < 9 years require two doses of the split-virus influenza
vaccine, with an interval of 4 weeks; however the second dose is not needed
if the child received one or more doses of vaccine prepared for a previous
season. In infants < 6 months of age, influenza vaccine is less immunogenic
than in infants and children aged 6 to 18 months. Therefore, immunization
with currently available influenza vaccines is not recommended for infants
< 6 months of age.
Table 1 Recommended influenza-vaccine dosage, by
age, 2000-2001
Age
|
Vaccine type
|
Dose (mL)
|
No. of doses
|
>= 9 years
|
split-virus
|
0.5
|
1
|
3-8 years
|
split-virus
|
0.5
|
1 or 2
|
6-35 months
|
split-virus
|
0.25
|
1 or 2
|
Intramuscular administration is preferred. The deltoid muscle is the
recommended site in adults and older children, the anterolateral thigh
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, especially in young adults who have received the
whole-virus vaccine and those receiving vaccine for the first time. Prophylactic
acetaminophen may decrease the frequency of some side effects in adults(47).
Healthy adults receiving the split-virus vaccine showed no increase in
the frequency of fever or other systemic symptoms compared to those receiving
placebo(48). 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 to occur in individuals
within 2 weeks of influenza vaccination(49,50). Influenza antigens
have not been identified in circulating immune complexes or in vessel
walls, and a causal relationship has not been proven.
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 1992-1993
and 1993-1994 seasons in four American states(51), 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
persons vaccinated against influenza. In comparison, the morbidity
and mortality associated with influenza are much greater.
In Canada the background incidence of GBS is estimated at just over
20 cases per million population in a study done in Ontario and Quebec(52).
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. It is also not known whether influenza
vaccination is causally associated with increased risk of recurrent GBS
in persons with a previous history of GBS. Avoiding subsequent influenza
vaccination of persons known to have developed GBS within 6 to 8 weeks
of a previous influenza vaccination appears prudent at this time.
Influenza vaccine is not known to predispose to Reye syndrome.
Please refer to the Canadian Immunization Guide(53)
for further details about administration of vaccine and management of
adverse events.
Contraindications and precautions
Influenza vaccine should not be given to people who had an anaphylactic
reaction to a previous dose or with known anaphylactic hypersensitivity
to eggs manifested as hives, swelling of the mouth and throat, difficulty
in breathing, hypotension, and shock.
Individuals with acute febrile illness usually should 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 The target groups
for influenza and pneumococcal vaccination overlap considerably. Health-care
providers should take the opportunity to vaccinate eligible persons against
pneumococcal disease when influenza vaccine is given. The concurrent administration
of the two vaccines at different sites does not increase the risk of side
effects. Pneumococcal vaccine, however, is usually given only once, whereas
influenza vaccine is given annually. Children at high risk may receive
influenza vaccine at the same time but at a different site from that used
for routine pediatric vaccines.
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, 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 illness in approximately 70% 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 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 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. Influenza vaccine programs should aim to vaccinate at least 90%
of eligible recipients. Nevertheless, only 70% of long-term care facility
(LTCF) residents and 20% to 40% of adults and children with medical conditions
listed previously receive vaccine annually(54,55). Studies
of HCWs in hospitals and LTCFs have shown vaccination rates of 26% to
61%(36,22-25,56,57).
This low rate of utilization is due both 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(56-58). 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. Educational efforts aimed
at physicians and the public should address common concerns about vaccine
effectiveness and adverse reactions. These include the beliefs of patients
at risk, HCWs, and other service providers that they rarely get influenza,
the fear of side effects from the vaccine, and doubt about the efficacy
of the vaccine.
The advice of a health-care provider is often a very important factor
affecting whether a person is immunized or not(59).
Most people at high risk are already under medical care and should
be vaccinated during regular fall visits. Strategies to improve coverage
include the following:
-
standing-order policies in institutions allowing nurses to administer
vaccine, and simultaneous immunization of staff and patients in nursing
homes and chronic care facilities (In a recent study of Canadian LTCFs,
increased vaccination rates were associated with a single non-physician
staff person organizing the program, having program aspects covered
by written policies, a policy of obtaining consent on admission that
was durable for future years, and automatically administering vaccine
to residents whose guardians could not be contacted for consent(57).)
-
vaccinating people at high risk who are being discharged from hospital
or visiting the emergency room in the autumn
-
promoting influenza vaccination in clinics which see high-risk groups
(e.g. cancer clinics, cardiac clinics, and pulmonary clinics)
-
using community newspapers, radio, television, flu-information lines,
and collaborating with pharmacists and specialist physicians to distribute
positively-framed information about the benefits and risks of immunization
-
issuing computer-generated reminders to physicians, mailing reminder
letters to patients, or using other recall methods to identify outpatients
at high risk
-
patient-carried reminder cards
-
increased accessibility of immunization clinics to staff in institutions
and community-based elderly, including implementation of mobile programs
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organized activities, such as vaccination fairs and competitions
between institutions
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working with multicultural groups to plan and implement effective
programs.
Vaccination of HCWs
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 on
antiviral prophylaxis.
Transmission of influenza between clinically or subclinically infected
HCWs and their vulnerable patients results in significant morbidity and
mortality(22,36). In the absence of contraindications, refusal
of HCWs to be immunized implies failure in their duty of care to their
patients. Studies have demonstrated that HCWs who are ill with influenza
frequently continue to work(22,24). In a recent British study,
59% of HCWs with serologic evidence of recent influenza infection could
not recall having influenza, suggesting that many HCWs experience subclinical
infection(60). These individuals continued to work, potentially
transmitting infection to their patients. In addition, absenteeism of
HCWs who are sick with influenza results in excess economic costs and
in some cases, potential endangerment of health-care delivery due to scarcity
of replacement workers.
Vaccination of HCWs in health-care facilities has been shown to reduce
total patient mortality, influenza-like illness, and serologically confirmed
influenza(23-25,36). 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(25,28,60-62).
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 for
therapy of patients with influenza is not discussed in this statement.
At the time of writing of this statement, 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 persons who take these drugs may still
develop immune responses that will protect them when they are exposed
to antigenically-related viruses in later years. However, amantadine
prophylaxis should not replace annual influenza vaccination in groups
for whom vaccine is recommended.
Three (1.3%) of 224 influenza A field isolates received by the Canadian
Science Centre for Human and Animal Health during the 1998-1999 season
were found to be amantadine resistant; two of the three resistant virus
isolates were from individuals who received amantadine (Dr.Y. Li, Bureau
of Microbiology, Canadian Centre for Human and Animal Health, Winnipeg:
personal communication, 2000). During the same season, a further 60 isolates
were obtained from individuals involved in outbreaks, 75% of whom were
given amantadine. Fifteen (25%) of the 60 isolates were amantadine resistant.
Increased prevalence of amantadine resistance has been reported in families
and within semi-closed settings including nursing homes(63-65).
Amantadine resistance is more likely to occur in populations where the
drug is used for both prophylaxis and treatment, as opposed to prophylaxis
alone(66). Failure to adequately 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(66).
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"
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 due to 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 is 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
persons 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.
-
For unvaccinated people who provide care for people at high
risk during an outbreak. Amantadine prophylaxis should
be continued until 2 weeks after the care provider has been vaccinated.
Factors including local epidemiology, potential side effects, concern
regarding emergence of viral resistance, adherence to medication regimens,
and cost may be considered in decisions regarding the duration of amantadine
prophylaxis(66-68).
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. 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
aged 10 to 64 years and in children weighing > 20 kg, who have normal
renal function, may be as effective as the recommended dose of 200 mg
daily(69-75).
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(76,77). A proposed new daily dosage
regimen, based on renal function, will be published this year in the Canadian
Journal of Infectious Diseases (Dr. A. McGeer, Mount Sinai
Hospital, Toronto: personal communication, 2000). 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 of this statement, neuraminidase inhibitors have been
used under study conditions for this purpose in institutional outbreaks(78-80).
Table 2 Recommended amantadine hydrochloride prophylactic
dosage by age and renal status
Age
|
Dosage
|
No renal impairment
|
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 impairement
|
Creatinine clearance (mL/min/1.73 m2)
|
Dosage for those 10-64 years
|
Dosage for those >= 65 years
|
>= 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 for
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/day 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:
|
|
(140 - age) x weight (kg)
serum creatinine (µmol/L) x 0.81
|
Female: CrCl mL/min
= 0.85 x CrCl (male)
|
Precautions
In otherwise healthy young adults given amantadine prophylactically,
5% to 10% report difficulty concentrating, insomnia, light-headedness,
and irritability. These side effects are usually mild and cease shortly
after the prophylaxis is stopped; however, they can be more frequent in
the older population unless a reduced dosage is used.
Serious side effects (e.g. marked behavioural changes, delirium, hallucinations,
agitation, seizures) have been associated with high plasma drug concentrations.
These have been observed most often 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(69).
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(81). It should be noted that the calculated
creatinine clearance is reasonably accurate for those with a creatinine
clearance > 40 mL/min, and those with a stable serum creatinine and
muscle mass. However the calculation becomes less accurate when these
conditions are not met. In particular, elderly persons with renal impairment
and low muscle mass may have a serum creatinine in the normal range and
an estimated creatinine clearance that is higher than the true value.
Physicians who prescribe amantadine must be familiar with the limitations
of formulas to estimate creatinine clearance, and make clinical decisions
regarding dosage adjustments based on these considerations.
Amantadine dosage should be reduced in people with a seizure disorder
in order to avoid the risk of increased frequency of seizures, and these
individuals should be closely observed.
Drug interactions have been noted during concurrent administration of
amantadine with triamterene and hydrochlorothiazide, trimethoprim-sulphamethoxazole,
quinine, and quinidine. The patient's age, weight, renal function, comorbid
conditions, current medications, as well as the indications for amantadine
use should all be considered prior to initiating this medication. Individuals
who are given amantadine should be carefully monitored for side effects.
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* Members: Dr. V. Marchessault (Chairperson),
Dr. J. Spika (Executive Secretary), N. Armstrong (Advisory Secretary),
Dr. I. Bowmer, Dr. G. De Serres, Dr. P. DeWals, Dr. J. Embree, Dr. I.
Gemmill, Dr. M. Naus, Dr. P. Orr, Dr. B. Ward, A. Zierler.
Liaison Representatives: Dr. J. Carsley (CPHA), Dr. G. Delage
(CPS), Dr. M. Douville-Fradet (ACE), Dr. T. Freeman (CFPC),
Dr. J. Livengood (CDC), Dr. A.E. McCarthy (ND), Dr. J. Salzman
(CATMAT), Dr. L. Samson (CIDS), Dr. J. Waters (CCMOH).
Ex-Officio Representatives: Dr. J. Calver (BBR), Dr. A. King (LCDC),
Dr. P. Riben (MSB).
+ This statement was prepared by Dr. P. Orr and approved by
NACI.
[Canada Communicable Disease Report]
|