Recommendations of the Immunization Practices Advisory Committee
Prevention and Control of Influenza
These recommendations update information on the vaccine and
antiviral agent available for controlling influenza during the
1988-89
influenza season (superseding MMWR 1987;36:373-80,385-7). Changes
include statements about 1) updating of the influenza strains in
the
trivalent vaccine for 1988-89, 2) increased emphasis on the need
for
vaccination of health-care workers, 3) prevention of influenza in
persons with human immunodeficiency virus (HIV) infection, and 4)
dosage considerations for amantadine.
INTRODUCTION
Influenza A viruses are classified into subtypes on the basis
of
two antigens: hemagglutinin (H) and neuraminidase (N). Three
subtypes
of hemagglutinin (H1, H2, H3) and two subtypes of neuraminidase
(N1,
N2) are recognized among influenza A viruses that have caused
widespread human disease. Immunity to these antigens, especially
the
hemagglutinin, reduces the likelihood of infection and the
severity of
disease if infection occurs. However, over time there may be
enough
antigenic variation (antigenic drift) within the same subtype 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 antigenic characteristics of current strains provide
the
basis for selecting virus strains included in each year's vaccine.
Typical influenza illness is characterized by abrupt onset of
fever, sore throat, and nonproductive cough. Unlike many other
common
respiratory infections, it can cause extreme malaise lasting
several
days. More severe illness can result if influenza virus invades
the
lungs (primary viral pneumonia) or if secondary bacterial
pneumonia
occurs. High attack rates of acute illness and
lower-respiratory-tract
complications during influenza epidemics usually result in
dramatic
increases in visits to physicians' offices, walk-in clinics, and
emergency rooms by persons of all ages.
Elderly persons and those with underlying health problems are
at
increased risk for complications of influenza infection. Such
high-risk persons are more likely than the general population to
require hospitalization if infected. One recent study showed that,
during major epidemics, hospitalization rates for high-risk adults
increased twofold to fivefold, depending on age group. Previously
healthy children and younger adults occasionally are hospitalized
for
influenza-related complications, but the relative increase in
their
hospitalization rates is much less than that for high-risk groups.
A significant increase in mortality further indicates the
impact
of influenza epidemics. This increase is a direct result not only
of
pneumonia, but also of cardiopulmonary or other chronic diseases
that
can be exacerbated by influenza infection. Ten thousand or more
excess
deaths have been documented in each of 19 different epidemics
during
the years 1957-1986; more than 40,000 excess deaths occurred in
each
of several recent epidemics. Approximately 80%-90% of the excess
deaths attributed to pneumonia and influenza were among persons
greater than or equal to65 years of age; however,
influenza-associated
deaths have also been reported among children or previously
healthy
adults less than 65 years of age during major epidemics.
Because the proportion of elderly persons in the U.S.
population
is increasing, and because age and its associated chronic diseases
are
risk factors for severe influenza illness, the toll from influenza
can
be expected to increase unless control measures are used more
vigorously. The number of younger persons at high risk for
infection-
related complications is also increasing for various reasons, such
as
the success of neonatal intensive-care units, better management of
diseases such as cystic fibrosis, better survival rates for
organ-transplant recipients, and the spread of HIV infection.
OPTIONS FOR THE CONTROL OF INFLUENZA
Two measures are available in the United States to reduce the
impact of influenza: immunoprophylaxis with inactivated
(killed-virus)
vaccine and chemoprophylaxis or therapy with the antiviral drug
amantadine. Vaccination of high-risk persons each year before the
influenza season is the single most important measure for reducing
the
impact of influenza. Vaccination can be highly cost-effective 1)
when
it is aimed at individuals who experience the most severe
consequences
and who have a higher- than-average risk of infection and 2) when
it
is administered to high-risk individuals during routine
health-care
visits before the influenza season, making special visits to
physicians' offices or clinics unnecessary. Recent reports
indicate
that, when there is a good match between vaccine and epidemic
strains
of virus, achieving high vaccination rates in closed populations
can
reduce the risk of outbreaks by inducing herd immunity. When
outbreaks
of influenza A do occur in closed populations, they can be stopped
by
chemoprophylaxis for all residents.
Other indications for prophylaxis (whether with vaccine or
amantadine) include the strong desire of any person to avoid an
influenza infection, reduce the severity of disease, or reduce the
chances of transmitting influenza to high-risk persons with whom
they
have frequent contact. Unlike vaccine, which protects against
influenza types A and B, amantadine is effective only against
influenza A.
Amantadine therapy is most likely to benefit persons who seek
medical attention shortly after the abrupt onset of an acute
respiratory infection during an influenza A epidemic. Early
amantadine
therapy may reduce the severity and duration of illness in
high-risk
individuals who have not been vaccinated or who were not protected
by
vaccination.
Influenza is known to be transmitted in medical settings.
Measures
such as using isolation precautions for ill patients individually
or
in groups, limiting visitors, and avoiding elective admissions and
surgery during an influenza outbreak may limit further
transmission of
virus within hospitals and other institutions. However, unlike
amantadine prophylaxis, these measures have not been shown to be
effective in controlling outbreaks. Likewise, the effectiveness of
closing schools or classrooms during explosive outbreaks has not
been
established.
INACTIVATED VACCINE FOR INFLUENZA A AND B
Influenza vaccine is made from highly purified, egg-grown
viruses
that have been rendered noninfectious (inactivated). Most vaccines
distributed in the United States have been chemically treated
(split-virus preparations) to reduce the incidence of febrile
reactions in children. Influenza vaccine currently contains three
virus strains (two type A and one type B) representing influenza
viruses recently circulating worldwide and believed likely to
circulate in the United States the following winter. The potency
of
the present vaccine is such that it causes minimal systemic or
febrile
reactions. Most vaccinated young adults develop
hemagglutination-inhibition antibody titers that are likely to
protect
them against infection by strains like those in the vaccine and,
often, by related variants that may emerge. Elderly persons and
persons with certain chronic diseases may develop lower
postvaccination antibody titers than healthy young adults and,
thus,
may be more susceptible to upper-respiratory-tract infection.
Nevertheless, influenza vaccine can still be effective in
preventing
lower- respiratory-tract involvement or other complications,
thereby
reducing the risk of hospitalization and death.
RECOMMENDATIONS FOR USE OF INACTIVATED INFLUENZA VACCINE
Influenza vaccine is recommended for 1) high-risk persons
greater
than or equal to6 months of age and their medical-care providers
or
household contacts; 2) children and teenagers receiving long-term
aspirin therapy who, therefore, may be at increased risk of
developing
Reye syndrome after an influenza virus infection; and 3) other
persons
who wish to reduce their chances of acquiring influenza. Vaccine
composition and dosages for the 1988-89 season are given in Table
1.
Guidelines for the use of vaccine among different groups are given
below.
Remaining 1987-88 vaccine should not be used.
Although the current influenza vaccine often contains one or
more
antigens used in previous years, immunity declines in the year
following vaccination. Therefore, annual vaccination is required.
During the past decade, data on influenza vaccine
immunogenicity
and side effects have generally been obtained when vaccine has
been
administered intramuscularly. Because there has been no adequate
evaluation of recent influenza vaccines administered by other
routes,
the intramuscular route should be used. Adults and older children
should be vaccinated in the deltoid muscle, and infants and young
children, in the anterolateral aspect of the thigh.
TARGET GROUPS FOR SPECIAL VACCINATION PROGRAMS
Groups at greatest risk of influenza-related complications:
Adults and children with chronic disorders of the pulmonary or
cardiovascular systems requiring regular medical follow-up or
hospitalization during the preceding year, including children
with
asthma.
Residents of nursing homes and other chronic-care facilities
housing patients of any age with chronic medical conditions.
Groups at moderate risk of influenza-related complications:
Otherwise healthy persons greater than or equal to65 years
old.
Adults and children who have required regular medical
follow-up or
hospitalization during the preceding year because of chronic
metabolic diseases (including diabetes mellitus), renal
dysfunction, hemoglobinopathies, or immunosuppression.
Children and teenagers (aged 6 months-18 years) who are
receiving
long-term aspirin therapy and, therefore, may be at risk of
contracting Reye syndrome after an influenza infection.
Groups potentially capable of nosocomial transmission of
influenza
to high-risk persons. Individuals attending high-risk persons can
transmit influenza infections to them while they are themselves
incubating infection, undergoing subclinical infection, or working
despite the existence of symptoms. Some high-risk persons (e.g.,
the
elderly, transplant recipients, or persons with acquired
immunodeficiency syndrome (AIDS)) can have relatively low antibody
responses to influenza vaccine. Efforts to protect them against
influenza may be improved by reducing the chances that their care
providers may expose them to influenza. Therefore, the following
groups should be vaccinated:
Physicians, nurses, and other personnel who have extensive
contact
with high-risk patients (e.g., primary-care and certain
specialty
clinicians and staff of chronic-care facilities and
intensive-care
units, particularly neonatal intensive- care units).
Providers of home care to high-risk persons (e.g., visiting
nurses, volunteer workers) as well as all household members of
high-risk persons, including children, whether or not they
provide
care.
VACCINATION OF OTHER GROUPS
General Population: Physicians should administer influenza
vaccine
to any person who wishes to reduce his/her chances of acquiring
influenza infection. Persons who provide essential community
services
may be considered for vaccination to minimize the disruption of
essential activities during severe epidemics.
Pregnant Women: Pregnancy has not been shown to be a risk
factor
for severe influenza infection, except in the largest pandemics of
1918-19 and 1957-58. However, pregnant women who have medical
conditions that increase their risks of complications from
influenza
should be vaccinated, as the vaccine is considered safe for
pregnant
women. Administering the vaccine after the first trimester is a
reasonable precaution to minimize any concern over the theoretical
possibility of teratogenicity. However, it is undesirable to delay
vaccination of pregnant women with high-risk conditions who will
still
be in the first trimester of pregnancy when the influenza season
begins.
Persons infected with human immunodeficiency virus (HIV):
Increases in infections and complications caused by various
respiratory pathogens have been observed in persons infected with
HIV.
However, similar increases due to influenza have not been reported
during recent epidemics. Nevertheless, because influenza may
result in
serious illness and complications in some HIV-infected persons,
vaccination is a prudent precaution.
PERSONS WHO SHOULD NOT BE VACCINATED
Inactivated influenza vaccine should not be given to persons
who
have an anaphylactic hypersensitivity to eggs (see Side Effects
and
Adverse Reactions below). Persons with acute febrile illnesses
normally should not be vaccinated until their temporary symptoms
have
abated.
TIMING OF INFLUENZA VACCINATION ACTIVITIES
Influenza vaccine should be offered beginning in September.
Except
in years of pandemic influenza (e.g., 1957 and 1968), high levels
of
influenza activity generally do not occur in the contiguous 48
states
before December. Therefore, organized vaccination campaigns where
high-risk persons are routinely accessible are optimally
undertaken in
November. In facilities such as nursing homes, it is particularly
important to avoid administering vaccine too far in advance of the
influenza season because antibody can begin to decline within a
few
months. Such vaccination programs may be undertaken in September
or
October if regional influenza activity is expected to begin
earlier
than normal.
Children less than or equal to12 years of age who have not
been
vaccinated previously require two doses with at least 1 month
between
doses. The second dose should be given before December. Vaccine
can be
given to both children and adults up to and even after influenza
virus
activity is documented in a region.
STRATEGIES FOR IMPLEMENTING INFLUENZA VACCINE RECOMMENDATIONS
More effective programs are needed for giving influenza
vaccine to
high-risk persons, their health-care providers, and their
household
contacts. Programs for administering vaccine in nursing homes and
other chronic-care facilities, physicians' offices, health
maintenance
organizations, hospitals, and employee health clinics must be
carefully planned. High-risk adults and children who do not live
in
nursing homes or other chronic-care facilities should be offered
influenza vaccine at their last regular medical appointment before
the
influenza season (i.e., before December). If they do not have a
regular medical appointment scheduled in the fall, they should be
notified by their health-care providers to come in specifically to
receive influenza vaccine. From September through February,
hospital
discharge procedures should include influenza vaccination of
high-risk
patients. Medical-care personnel and support staff should ensure
that
no high-risk patient resides in or leaves a medical- care facility
in
the fall without being offered and urged to receive influenza
vaccine.
Equally important, administrators and infection-control staff of
health-care facilities should establish procedures for offering
vaccine to patient-care staff that take into account barriers to
vaccination. More staff members will be vaccinated if vaccine is
readily available at the worksite (e.g., on patient-care units
during
all shifts rather than at an employee health clinic).
Educational materials about influenza and its control are
available from a variety of sources. For information on sources of
educational materials and a selected bibliography, contact the
Centers
for Disease Control, Center for Prevention Services, Technical
Information Services, 1600 Clifton Road, N.E., Atlanta, Georgia
30333.
SIDE EFFECTS AND ADVERSE REACTIONS
Because influenza vaccine contains only noninfectious viruses,
it
cannot cause influenza. Occasional cases of respiratory disease
following vaccination represent coincidental illnesses unrelated
to
influenza vaccination. The most frequent side effect of
vaccination is
soreness around the vaccination site for up to 1 or 2 days; this
occurs in less than one-third of vaccinees.
In addition, the following two types of systemic reactions
have
occurred:
Fever, malaise, myalgia, and other systemic symptoms occur
infrequently and most often affect persons who have had no
exposure to the influenza virus antigens in the vaccine (e.g.,
young children). These reactions begin 6-12 hours after
vaccination and can persist for 1 or 2 days.
Immediate, presumably allergic, reactions such as hives,
angioedema, allergic asthma, or systemic anaphylaxis occur
extremely rarely after influenza vaccination. These reactions
probably result from hypersensitivity to some vaccine
component--most likely residual egg protein. Although current
influenza vaccines contain only a small quantity of egg
protein,
they are presumed capable of inducing immediate
hypersensitivity
reactions in persons with severe egg allergy, and such persons
should not be given influenza vaccine. This includes persons
who
develop hives, have swelling of the lips or tongue, or
experience
acute respiratory distress or collapse after eating eggs.
Persons
with a documented immunoglobulin E (IgE)-mediated
hypersensitivity
to eggs, including those who have experienced occupational
asthma
or other allergic responses from occupational exposure to egg
protein, may also be at increased risk of reactions from
influenza
vaccine.
Unlike the 1976 swine influenza vaccine, subsequent vaccines
prepared from other virus strains have not been associated with an
increased frequency of Guillain-Barre syndrome. Although influenza
vaccination can inhibit the clearance of warfarin and
theophylline,
clinical studies have consistently failed to show any adverse
effects
attributable to these drugs in patients receiving influenza
vaccine.
SIMULTANEOUS ADMINISTRATION OF OTHER VACCINES,
INCLUDING CHILDHOOD VACCINES
The target groups for influenza and pneumococcal vaccination
overlap considerably. Both vaccines can be given at the same time
at
different sites without increasing side effects. However,
influenza
vaccine is given annually, and it is currently recommended that
pneumococcal vaccine be given only once. Detailed immunization
records
should be provided to each patient to record the date when
pneumococcal vaccine was given.
High-risk children usually see a health professional to
receive
routine pediatric vaccines. These visits provide a good
opportunity to
administer influenza vaccine simultaneously but in a different
site.
Although studies have not been conducted, simultaneous
administration
should not diminish immunogenicity or increase adverse reactions.
ANTIVIRAL AGENTS FOR INFLUENZA A
Two antiviral drugs have specific activity against influenza A
viruses: amantadine hydrochloride and rimantadine hydrochloride.
Currently, only amantadine is approved for marketing in the United
States.
Both amantadine and rimantadine interfere with the replication
cycle of type A influenza viruses, although the specific
mechanisms of
their antiviral activity are not completely understood. Both drugs
are
70%-90% effective in preventing illnesses caused by naturally
occurring strains of type A influenza viruses. However, they are
not
effective against type B influenza. When administered within 24-48
hours after the onset of illness, they can reduce the duration of
fever and other systemic symptoms, allowing the patient to return
more
rapidly to routine daily activities. Since these drugs may not
prevent
infection itself, persons who take them can still develop immune
responses that will protect them when they are subsequently
exposed to
antigenically related viruses.
Increasing the availability of rapid viral diagnostic tests
and
improving the dissemination of information about areas where
influenza
A virus infections have been confirmed will allow for more
efficient
and appropriate use of antiviral agents. Such information is
reported
throughout the influenza season in the MMWR and is also available
by
computer telecommunication through the Public Health Foundation.
AMANTADINE PROPHYLAXIS RECOMMENDATIONS
Amantadine is recommended under certain circumstances,
particularly for control of presumed influenza A outbreaks in
institutions housing high-risk persons. Chemoprophylaxis should
begin
as early as possible after the outbreak is recognized. Contingency
planning is needed in chronic-care facilities to establish
specific
steps for rapidly administering amantadine to residents and staff
when
influenza outbreaks occur. For outbreak control, amantadine should
be
administered to all residents of the institution whether or not
they
received influenza vaccine the previous fall. Amantadine should
also
be offered to unvaccinated staff who provide care to high-risk
patients. For prophylaxis, the antiviral drug should be taken each
day
for the duration of influenza activity in the community.
Amantadine prophylaxis is also recommended in the following
situations:
As an adjunct to late vaccination of high-risk persons. It is
not
too late to vaccinate even when influenza A is known to be in
the
community. However, because the development of an antibody
response following vaccination takes about 2 weeks, amantadine
should be used during this period. Amantadine does not
interfere
with the antibody response to the vaccine.
To reduce the spread of infection and to maintain care for
high-risk persons in the home. Unvaccinated persons who
provide
home care for high-risk persons (e.g., household members,
visiting
nurses, volunteer workers) should also receive amantadine
prophylaxis during the period when influenza A outbreaks
occur.
For immunodeficient persons. As a supplement to the protection
afforded by vaccination, amantadine prophylaxis is indicated
for
high-risk patients who may have a poor antibody response to
influenza vaccine, such as persons with AIDS. Whereas adults
with
AIDS can be expected to have some residual immunity to
influenza
from prior infections, children with AIDS may have little or
no
immunity to the virus. Therefore, amantadine prophylaxis
against
influenza should be considered during influenza epidemics,
especially for children with AIDS. The potential benefits
should
be evaluated on a case-by-case basis, taking into account the
potential risks of side effects, especially in patients with
central nervous system involvement.
For persons for whom influenza vaccine is contraindicated (see
Side Effects and Adverse Reactions above).
Amantadine can also be used prophylactically in other
situations
(e.g., for unimmunized members of the general population who wish
to
avoid influenza A illness). This decision should be made on an
individual basis.
AMANTADINE THERAPY
Although amantadine has been shown to reduce the severity and
shorten the duration of influenza A illness in healthy adults and
children, no well-controlled clinical studies have examined the
efficacy of amantadine therapy in preventing complications of
influenza A in high-risk persons. Nevertheless, because of the
potential benefits, amantadine should be considered for high-risk
patients who contract an illness compatible with influenza during
a
period of known or suspected influenza A activity in the
community.
The drug should be given within 24-48 hours after onset of illness
and
should be continued until 48 hours after signs and symptoms
resolve.
DOSAGE CONSIDERATIONS FOR AMANTADINE
The following information should be considered in determining
the
appropriate dosage of amantadine:*
In controlled studies, 5%-10% of healthy young adults taking
amantadine at the standard adult dosage of 200 mg per day have
reported side effects including nausea, dizziness, insomnia,
nervousness, and impaired concentration. Data suggest that a
daily
prophylactic dosage of 100 mg may provide protection
comparable to
that of 200 mg/day but with fewer side effects. No studies
have
compared the efficacy of amantadine at daily dosages of 100 mg
and
200 mg for treatment of influenza A infection.
Amantadine is not metabolized and is excreted unchanged in the
urine by glomerular filtration and tubular secretion. Because
renal function declines with aging, the daily dosage for
persons
greater than or equal to65 years of age should not exceed 100
mg
for prophylaxis or treatment. When amantadine is administered
to
patients with impaired renal function, the dosage should be
further reduced (see package insert). Because recommended
dosages
for persons with renal impairment provide only a rough
estimate of
the optimal dosage for a given patient, such individuals
should be
closely observed so that adverse reactions can be recognized
promptly and the dosage reduced or the drug discontinued if
necessary.
Persons with active seizure disorders may be at increased risk
for
seizures when given amantadine at a dosage of 200 mg daily.
Data
suggest that the risk of seizures in such persons might be
reduced
by using a lower dose of the drug.
The use of amantadine in children less than 1 year of age has
not
been adequately evaluated. The approved dosage for children
1-9
years of age is 4.4 mg/kg/day, not to exceed 150 mg/day.
Although
further studies would be desirable to determine the optimal
dosage
for children, physicians should consider prescribing 4.4
mg/kg/day
to reduce the risk of toxicity. For children greater than or
equal
to10 years weighing less than 45 kg, it may also be advisable
to
prescribe 4.4 mg/kg/day. The dose for treatment should not
exceed
150 mg for children aged 1-9 years and 200 mg for children
greater
than or equal to10 years of age. As for adults, a maximum
dosage
of 100 mg daily should be effective for prophylaxis (see #1
above).
*Further information is available from DuPont Pharmaceuticals, one
of
the manufacturers of amantadine, by calling (800)441-9861.
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