Recommendations of the Advisory Committee on
Immunization Practices (ACIP)
Advisory Committee on Immunization Practices Membership List, February 2001
CHAIRMAN
John F. Modlin, M.D.
Professor of Pediatrics and Medicine
Dartmouth Medical School
Lebanon, New Hampshire
EXECUTIVE SECRETARY
Dixie E. Snider, Jr., M.D., M.P.H.
Associate Director for Science
Centers for Disease Control and Prevention
Atlanta, Georgia
MEMBERS
Dennis A. Brooks, M.D., M.P.H.
Johnson Medical Center
Baltimore, Maryland
Richard D. Clover, M.D.
University of Louisville School of Medicine
Louisville, Kentucky
Jaime Deseda-Tous, M.D.
University of Puerto Rico School of Medicine
Hato Rey, Puerto Rico
Charles M. Helms, M.D., Ph.D.
University of Iowa Hospital and Clinics
Iowa City, Iowa
David R. Johnson, M.D., M.P.H.
Michigan Department of Community Health
Lansing, Michigan
Myron J. Levin, M.D.
University of Colorado School of Medicine
Denver, Colorado
Paul A. Offit, M.D.
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania
Margaret B. Rennels, M.D.
University of Maryland School of Medicine
Baltimore, Maryland
Natalie J. Smith, M.D., M.P.H.
California Department of Health Services
Berkeley, California
Lucy S. Tompkins, M.D., Ph.D.
Stanford University Medical Center
Stanford, California
Bonnie M. Word, M.D.
Monmouth Junction, New Jersey
EX-OFFICIO MEMBERS
James E. Cheek, M.D., M.P.H.
Indian Health Service
Albuquerque, New Mexico
Benedict M. Didiega, M.D., Col.
Department of Defense
Falls Church, Virginia
Geoffrey S. Evans, M.D.
Health Resources and Services Administration
Rockville, Maryland
Carole Heilman, M.D.
National Institutes of Health
Bethesda, Maryland
Karen Midthun, M.D.
Food and Drug Administration
Bethesda, Maryland
T. Randolph Graydon
Health Care Financing Administration
Baltimore, Maryland
Martin G. Myers, M.D.
National Vaccine Program Office
Atlanta, Georgia
Kristin Lee Nichol, M.D., M.P.H.
VA Medical Center
Minneapolis, Minnesota
LIAISON REPRESENTATIVES
American Academy of Family Physicians
Martin Mahoney, M.D., Ph.D.
Clarence, New York
Richard Zimmerman, M.D.
Pittsburgh, Pennsylvania
American Academy of Pediatrics
Larry Pickering, M.D.
Atlanta, GA
Jon Abramson, M.D.
Winston-Salem, North Carolina
American Association of Health Plans
Eric K. France, M.D.
Denver, Colorado
American College of Obstetricians and Gynecologists
Stanley A. Gall, M.D.
Louisville, Kentucky
American College of Physicians
Kathleen M. Neuzil, M.D., M.P.H.
Seattle, WA
American Hospital Association
William Schaffner, M.D.
Nashville, Tennessee
American Medical Association
H. David Wilson, M.D.
Grand Forks, North Dakota
Association of Teachers of Preventive Medicine
W. Paul McKinney, M.D.
Louisville, Kentucky
Canadian National Advisory Committee on Immunization
Victor Marchessault, M.D.
Cumberland, Ontario, Canada
Hospital Infection Control Practices Advisory Committee
Jane D. Siegel, M.D.
Dallas, Texas
Infectious Diseases Society of America
Samuel L. Katz, M.D.
Durham, North Carolina
London Department of Health
David M. Salisbury, M.D.
London, United Kingdom
National Immunization Council and Child Health Program, Mexico
Jose Ignacio Santos, M.D.
Mexico City, Mexico
National Medical Association
Rudolph E. Jackson, M.D.
Atlanta, Georgia
National Vaccine Advisory Committee
Georges Peter, M.D.
Providence, Rhode Island
Pharmaceutical Research and Manufacturers of America
Barbara J. Howe, M.D.
Collegeville, Pennsylvania
Members of the Influenza Working Group
Advisory Committee on Immunization Practices (ACIP)
Bonnie M. Word, M.D., Chairman
Richard D. Clover, M.D.
T. Randolph Graydon
Charles M. Helms, M.D., Ph.D.
Martin G. Myers, M.D.
Kristin Lee Nichol, M.D., M.P.H.
Margaret B. Rennels, M.D.
Natalie J. Smith, M.D.
ACIP
Jon Abramson, M.D.
American Academy of Pediatrics
Eric K. France, M.D.
American Association of Health Plans
Stanley A. Gall, M.D.
American College of Obstetricians and Gynecologists
Roland A. Levandowski, M.D.
Peter A. Patriarca, M.D.
Food and Drug Administration
Kathleen M. Neuzil, M.D., M.P.H.
American College of Physicians
Fred Ruben, M.D.
Pharmaceutical Research and Manufacturers of America
William Schaffner, M.D.
American Hospital Association
Mack Sewell, M.D., M.P.H.
New Mexico Department of Health
Richard Zimmerman, M.D.
American Academy of Family Physicians
Robert T. Chen, M.D.
Nancy J. Cox, Ph.D.
Keiji Fukuda, M.D., M.P.H.
James A. Singleton, M.S.
Marika Iwane, Ph.D., M.P.H.
Centers for Disease Control and Prevention
The following CDC staff members prepared this report:
Carolyn B. Bridges, M.D.
Keiji Fukuda, M.D., M.P.H.
Nancy J. Cox, Ph.D.
Division of Viral and Rickettsial Diseases
National Center for Infectious Diseases
James A. Singleton, M.S.
Division of Epidemiology and Surveillance
National Immunization Program
Summary
This report updates the 2000 recommendations by the Advisory
Committee on Immunization Practices (ACIP) on the use of influenza vaccine and
antiviral agents (MMWR 2000;49[No. RR-3]:1--38). The 2001 recommendations
include new or updated information regarding a) the cost-effectiveness of
influenza vaccination; b) the influenza vaccine supply; c) neuraminidase-inhibitor
antiviral drugs; d) the 2001--2002 trivalent vaccine virus strains, which are
A/Moscow/10/99 (H3N2)-like, A/New Caledonia/20/99 (H1N1)-like, and
B/Sichuan/379/99-like strains; and e) extension of the optimal time period for vaccination
through November. A link to this report and other information regarding influenza
can be accessed at the website for the Influenza Branch, Division of Viral
and Rickettsial Diseases, National Center for Infectious Diseases, CDC at
<http://www.cdc.gov/ncidod/diseases/flu/fluvirus.htm>.
INTRODUCTION
Epidemics of influenza typically occur during the winter months and
are responsible for an average of approximately 20,000 deaths per year in the
United States (1,2). Influenza viruses also can cause pandemics, during which rates of
illness and death from influenza-related complications can increase dramatically
worldwide. Influenza viruses cause disease among all age groups
(3--5). Rates of infection are highest among children, but rates of serious illness and death are highest
among persons aged >65 years and persons of any age who have medical conditions
that place them at increased risk for complications from influenza
(3,6--8).
Influenza vaccination is the primary method for preventing influenza and its
severe complications. In this report from the Advisory Committee on Immunization
Practices (ACIP), the primary target groups recommended for annual vaccination are a)
groups that are at increased risk for influenza-related complications (e.g., persons aged
>65 years and persons of any age with certain chronic medical conditions); b) the
group aged 50--64 years because this group has an elevated prevalence of certain
chronic medical conditions; and c) persons who live with or care for persons at high risk
(e.g., health-care workers and household members who have frequent contact with
persons at high risk and can transmit influenza infections to these persons at high
risk). Vaccination is associated with reductions in influenza-related respiratory illness
and physician visits among all age groups, hospitalization and death among persons
at high risk, otitis media among children, and work absenteeism among adults
(9--18). Although influenza vaccination levels have increased substantially,
further
improvements in vaccine coverage levels are needed, particularly among persons
at high risk aged <65 years. The ACIP recommends the use of strategies to
improve vaccination levels, including the use of reminder/recall systems and standing
orders programs (19,20).
Although influenza vaccination remains the cornerstone for the control
and treatment of influenza, updated information is also presented on antiviral
medications because these agents are an adjunct to vaccine.
Primary Changes in the Recommendations
These recommendations include five principal changes:
Information regarding the cost-effectiveness of influenza vaccination has
been added.
Information regarding the influenza vaccine supply has been added.
Information regarding neuraminidase-inhibitor antiviral drugs has been updated.
The 2001--2002 trivalent vaccine virus strains are A/Moscow/10/99
(H3N2)-like, A/New Caledonia/20/99 (H1N1)-like, and B/Sichuan/379/99-like strains.
The recommended optimal time period for vaccinating individuals is
October--November.
Influenza and Its Burden
Biology of Influenza
Influenza A and B are the two types of influenza viruses that cause epidemic
human disease (21). Influenza A viruses are further categorized into subtypes on the basis
of two surface antigens: hemagglutinin (H) and neuraminidase (N). Influenza B
viruses are not categorized into subtypes. Since 1977, influenza A (H1N1) viruses, influenza
A (H3N2) viruses, and influenza B viruses have been in global circulation. Both
influenza A and B viruses are further separated into groups on the basis of
antigenic characteristics. New influenza virus variants result from frequent antigenic
change (i.e., antigenic drift) resulting from point mutations that occur during viral
replication. Influenza B viruses undergo antigenic drift less rapidly than influenza A viruses.
A person's immunity to the surface antigens, especially hemagglutinin, reduces
the likelihood of infection and severity of disease if infection occurs
(22). Antibody against one influenza virus type or subtype confers limited or no protection against
another influenza virus type or subtype. Furthermore, antibody to one antigenic variant
of influenza virus might not protect against a new antigenic variant of the same type
or subtype (23). Frequent development of antigenic variants through antigenic drift is
the virologic basis for seasonal epidemics and the reason for the incorporation of one
or more new strains in each year's influenza vaccine.
Clinical Signs and Symptoms of Influenza
Influenza viruses are spread from person-to-person primarily through the
coughing and sneezing of infected persons
(21). The incubation period for influenza is 1--4
days, with an average of 2 days (24). Persons can be infectious starting the day
before
symptoms begin through approximately 5 days after illness onset; children can
be infectious for a longer period.
Uncomplicated influenza illness is characterized by the abrupt onset
of constitutional and respiratory signs and symptoms (e.g., fever, myalgia,
headache, severe malaise, nonproductive cough, sore throat, and rhinitis)
(25). Respiratory illness caused by influenza is difficult to distinguish from illness caused by other
respiratory pathogens on the basis of symptoms alone (see Role of Laboratory Diagnosis
section). Reported sensitivity and specificity of clinical definitions for influenza-like illness
that include fever and cough have ranged from 63% to 78% and 55% to 71%,
respectively, compared with viral culture
(26,27). Sensitivity and predictive value of
clinical definitions can vary, depending on the degree of co-circulation of other
respiratory pathogens and the level of influenza activity
(28).
Influenza illness typically resolves after several days for most persons,
although cough and malaise can persist for
>2 weeks. In some persons, influenza can exacerbate underlying medical conditions (e.g., pulmonary or cardiac disease), lead
to secondary bacterial pneumonia or primary influenza viral pneumonia, or occur as
part of a co-infection with other viral or bacterial pathogens
(29). Influenza infection has also been associated with encephalopathy, transverse myelitis, Reye
syndrome, myositis, myocarditis, and pericarditis
(29).
Hospitalizations and Deaths from Influenza
The risks for complications, hospitalizations, and deaths from influenza are
higher among persons aged >65 years, very young children, and persons of any age
with certain underlying health conditions than among healthy older children and
younger adults (1,30--33). Estimated rates of influenza-associated hospitalizations have
varied substantially by age group in studies conducted during different influenza
epidemics (Table 1).
Among children aged 0--4 years, hospitalization rates have ranged
from approximately 500/100,000 population for those with high-risk conditions to
100/100,000 population for those without high-risk conditions
(34,35). Within the 0--4 age group, hospitalization rates are highest among children aged 0--1 years and
are comparable to rates found among persons
>65 years (36,37) (Table 1).
During influenza epidemics from 1969--1970 through 1994--1995, the
estimated overall number of influenza-associated hospitalizations in the United States has
ranged from approximately 16,000 to 220,000/epidemic. An average of
approximately 114,000 influenza-related excess hospitalizations occurred per year, with 57% of
all hospitalizations occurring among persons aged <65 years. Since the 1968 influenza
A (H3N2) virus pandemic, the greatest numbers of influenza-associated
hospitalizations have occurred during epidemics caused by type A(H3N2) viruses, with an
estimated average of 142,000 influenza-associated hospitalizations per year
(38).
During influenza epidemics, influenza-related deaths can result from pneumonia
as well as from exacerbations of cardiopulmonary conditions and other chronic
diseases. In studies of influenza epidemics occurring from 1972--1973 through
1994--1995, excess deaths (i.e., the number of influenza-related deaths above a projected
baseline of expected deaths) occurred during 19 of 23 influenza epidemics
(39) (Influenza Branch, Division of Viral and Rickettsial Diseases [DVRD], National Center
for Infectious Diseases [NCID], CDC, unpublished data, 1998). During those 19
influenza seasons, estimated rates of influenza-associated deaths ranged from
approximately
30 to >150 deaths/100,000 persons aged
>65 years (Influenza Branch, DVRD, NCID, CDC, unpublished data, 1998). Older adults currently account for >90% of
deaths attributed to pneumonia and influenza
(40). From 1972--1973 through 1994--1995, >20,000 influenza-associated deaths were estimated to occur during each of
11 different U.S. epidemics, and >40,000 influenza-associated deaths were estimated
for each of 6 of these 11 epidemics (39) (Influenza Branch, DVRD, NCID, CDC,
unpublished data, 1998). In the United States, pneumonia and influenza deaths might be
increasing in part because the number of elderly persons is increasing
(41).
Options for Controlling Influenza
In the United States, the main option for reducing the impact of influenza
is immunoprophylaxis with inactivated (i.e., killed virus) vaccine (see
Recommendations for the Use of Influenza Vaccine). Vaccinating persons at high risk for
complications before the influenza season each year is the most effective means of reducing
the impact of influenza. Vaccination coverage can be increased by administering
vaccine to persons during hospitalizations or routine health-care visits before the
influenza season, making special visits to physicians' offices or clinics unnecessary.
When vaccine and epidemic strains are well-matched, achieving increased vaccination
rates among persons living in closed settings (e.g., nursing homes and other
chronic-care facilities) and among staff can reduce the risk for outbreaks by inducing herd
immunity (14). Vaccination of health-care workers and other persons in close contact
with persons in groups at high risk can also reduce transmission of influenza
and subsequent influenza-related complications.
The use of influenza-specific antiviral drugs for chemoprophylaxis or treatment
of influenza is an important adjunct to vaccine (see Recommendations for the Use
of Antiviral Agents for Influenza). However, antiviral medications are not a substitute
for vaccination.
Influenza Vaccine Composition
Influenza vaccine contains three strains (i.e., two type A and one type
B), representing the influenza viruses likely to circulate in the United States in
the upcoming winter. The vaccine is made from highly purified, egg-grown viruses
that have been made noninfectious (i.e., inactivated)
(42). Subvirion and purified surface-antigen preparations are available. Because the vaccine viruses are initially grown
in embryonated hens' eggs, the vaccine might contain small amounts of residual
egg protein. Influenza vaccine distributed in the United States might also
contain thimerosal, a mercury-containing compound, as the preservative
(43). Manufacturing processes differ by manufacturer. Certain manufacturers might use
additional compounds to inactivate the influenza viruses, and they might use an antibiotic
to prevent bacterial contamination. Package inserts should be consulted for
additional information.
The trivalent influenza vaccine prepared for the 2001--2002 season will include
A/Moscow/10/99 (H3N2)-like, A/New Caledonia/20/99 (H1N1)-like, and
B/Sichuan/379/99-like antigens. For the A/Moscow/10/99 (H3N2)-like antigen, manufacturers will use
the antigenically equivalent A/Panama/2007/99 (H3N2) virus; and for the
B/Sichuan/379/99-like antigen, they will use one of the antigenically equivalent viruses
B/Johannesburg/5/99, B/Victoria/504/2000, or B/Guangdong/120/2000. These viruses
will
be used because of their growth properties and because they are representative
of currently circulating A (H3N2) and B viruses.
Effectiveness of Inactivated Influenza Vaccine
The effectiveness of influenza vaccine depends primarily on the age
and immunocompetence of the vaccine recipient and the degree of similarity between
the viruses in the vaccine and those in circulation. Most vaccinated children and
young adults develop high postvaccination hemagglutination-inhibition antibody titers
(44,45). These antibody titers are protective against illness caused by strains similar to those
in the vaccine (45--47). When the vaccine and circulating viruses are antigenically
similar, influenza vaccine prevents influenza illness in approximately 70%--90% of
healthy persons aged <65 years (48). Vaccination of healthy adults also has resulted
in decreased work absenteeism and decreased use of health-care resources,
including the use of antibiotics, when the vaccine and circulating viruses are well-matched
(10--13,49,50). Other studies suggest that the use of trivalent inactivated influenza
vaccine decreases the incidence of influenza-associated otitis media and the use of
antibiotics among children (17,18).
Elderly persons and persons with certain chronic diseases might develop
lower postvaccination antibody titers than healthy young adults and thus can
remain susceptible to influenza-related upper respiratory tract infection
(51--53). However, among such persons, the vaccine can be effective in preventing
secondary complications and reducing the risk for influenza-related hospitalization and death
(14--16). Among elderly persons living outside of nursing homes or similar
chronic-care facilities, influenza vaccine is 30%--70% effective in preventing hospitalization
for pneumonia and influenza (16,54). Among elderly persons residing in nursing
homes, influenza vaccine is most effective in preventing severe illness,
secondary complications, and deaths. Among this population, the vaccine can be
50%--60% effective in preventing hospitalization or pneumonia and 80% effective in
preventing death, even though the effectiveness in preventing influenza illness often ranges
from 30% to 40% (55,56).
Cost-Effectiveness of Influenza Vaccine
Influenza vaccination can reduce both health-care costs and productivity
losses associated with influenza illness. Economic studies of influenza vaccination of
persons aged >65 years conducted in the United States have found overall societal
cost-savings and substantial reductions in hospitalization and death
(16,54,57). Studies of adults aged <65 years have shown that vaccination can reduce both direct
medical costs and indirect costs from work absenteeism
(9,11--13,49). Reductions of 34%--44% in physician visits, 32%--45% in lost work days
(11,13), and 25% in antibiotic use have been reported
(13). One cost-effectiveness meta-analysis estimated a cost
of approximately $60--$4,000/illness averted among healthy persons aged 18--64
years, depending on the cost of vaccination, the influenza attack rate, and
vaccine effectiveness against influenza-like illness
(49). Another cost-benefit economic model estimated an average annual savings of $13.66/person vaccinated
(58). In the second study, 78% of all costs prevented were costs from lost work productivity, whereas
the first study did not include productivity losses from influenza illness. Economic
studies specifically evaluating the cost-effectiveness of vaccinating persons aged 50--64
years are not available, and the number of studies that examine the economics of
routinely
vaccinating children are limited (9,59,60). However, in a study that included all
age groups, cost-utility improved with increasing age and among those with
chronic medical conditions (9). Among persons aged
>65 years, vaccination resulted in a net savings per
quality-adjusted-life-year (QALY) gained and resulted in costs of
$23--$256/QALY among younger age groups. Additional studies of the relative
cost-effectiveness and cost-utility of influenza vaccination among children and
among adults aged <65 years are needed and should be designed to account for
year-to-year variations in influenza attack rates, illness severity, and vaccine efficacy
when evaluating the long-term costs and benefits of annual vaccination.
Vaccination Coverage Levels
Among persons aged >65 years, influenza vaccination levels increased from
33% in 1989 (61) to 63% in 1997 and 1998
(62), surpassing the Healthy People 2000 goal
of 60% (63). Although influenza vaccination coverage increased through 1997
among black, Hispanic, and white populations, vaccination levels among blacks and
Hispanics continue to lag behind those among whites
(62,64). In 1998, the influenza vaccination rate among persons aged
>65 years were 66% among non-Hispanic whites,
46% among non-Hispanic blacks, and 50% among Hispanics
(62).
Possible reasons for the increase in influenza vaccination levels among
persons aged >65 years through 1997 include greater acceptance of preventive
medical services by practitioners, increased delivery and administration of vaccine by
health-care providers and sources other than physicians, new information regarding
influenza vaccine effectiveness, cost-effectiveness, and safety, and the initiation of
Medicare reimbursement for influenza vaccination in 1993
(9,15,16,55,56,65,66). Continued monitoring is needed to determine if vaccination coverage among persons aged
>65 years has reached a peak or plateau. The Healthy People 2010 objective is to
achieve vaccination coverage for 90% of persons aged
>65 years (67).
In 1997 and 1998, vaccination rate estimates among nursing home residents
were 64%--82% and 83%, respectively
(68,69). The Healthy People 2010 goal is to
achieve influenza vaccination of 90% of nursing home residents, an increase from the
Healthy People 2000 goal of 80% (63,67).
In 1998, the overall vaccination rate for adults aged 18--64 years with
high-risk conditions was 31%, far short of the Healthy People 2000 goal of 60%
(62,63). Among persons aged 50--64 years, 43% of those with chronic medical conditions and 29%
of those without chronic medical conditions received influenza vaccine. Only 23%
of adults younger than 50 years with high-risk conditions were vaccinated
(National Immunization Program [NIP], CDC, unpublished data, 2000).
Reported vaccination rates of children at high risk are low. One study
conducted among patients in health maintenance organizations found influenza vaccination
rates ranging from 9% to 10% among asthmatic children
(70), and a rate of 25% was found among children with severe-to-moderate asthma who attended an allergy
and immunology clinic (71). Increasing vaccination coverage among persons who
have high-risk conditions and are aged <65 years, including children at high risk, is
the highest priority for expanding influenza vaccine use.
Annual vaccination is recommended for health-care workers. Nonetheless,
the National Health Interview Survey found vaccination rates of only 34% and 37%
among health-care workers in the 1997 and 1998 surveys, respectively
(72; NIP, CDC, unpublished data, 2001). Vaccination of health-care workers has been associated
with
reduced work absenteeism (10) and fewer deaths among nursing home
patients (73,74).
Limited information is available regarding the use of influenza vaccine
among pregnant women. Among women aged 18--44 years without diabetes responding
to the 1999 Behavioral Risk Factor Surveillance Survey, those reporting they
were pregnant were less likely to report influenza vaccination in the past 12 months
(9.6%) than those not pregnant (15.7%). Vaccination coverage among pregnant women
did not significantly change during 1997--1999, whereas coverage among
nonpregnant women increased from 14.4% in 1997. Though not directly measuring
influenza vaccination among women who were past the second trimester of pregnancy
during influenza season, these data indicate low compliance with the ACIP
recommendations for pregnant women (75). In a study of influenza vaccine acceptance by
pregnant women, 71% offered the vaccine chose to be vaccinated
(76). However, a 1999 survey of obstetricians and gynecologists determined that only 39% gave influenza vaccine
to obstetric patients although 86% agree that pregnant women's risk for
influenza-related morbidity and mortality increased in the last two trimesters
(77).
RECOMMENDATIONS FOR THE USE OF INFLUENZA VACCINE
Influenza vaccine is strongly recommended for any person aged
>6 months who --- because of age or underlying medical condition --- is at increased risk for
complications of influenza. In addition, health-care workers and other individuals (including
household members) in close contact with persons at high risk should be vaccinated to
decrease the risk for transmitting influenza to persons at high risk. Influenza vaccine also can
be administered to any person aged >6 months to reduce the chance of
becoming infected with influenza.
Target Groups for Vaccination
Persons at Increased Risk for Complications
Vaccination is recommended for the following groups of persons who are
at increased risk for complications from influenza:
persons aged >65 years;
residents of nursing homes and other chronic-care facilities that house
persons of any age who have chronic medical conditions;
adults and children who have chronic disorders of the pulmonary
or cardiovascular systems, including asthma;
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 (including immunosuppression caused by medications or
by human immunodeficiency [HIV] virus);
children and teenagers (aged 6 months--18 years) who are receiving
long-term aspirin therapy and, therefore, might be at risk for developing Reye
syndrome after influenza infection; and
women who will be in the second or third trimester of pregnancy during
the influenza season.
Approximately 35 million persons in the United States are aged
>65 years; an additional 10--13 million adults aged 50--64 years, 15--18 million adults aged
18--49 years, and 8 million children aged 6 months--17 years have
>1 medical conditions that are associated with an increased risk of influenza-related complications (NIP,
CDC, unpublished data, 2000).
Persons Aged 50--64 Years
Vaccination is recommended for persons aged 50--64 years because this group
has an increased prevalence of persons with high-risk conditions. Approximately 41
million persons in the United States are aged 50--64 years, and 10--13 million
(24%--32%) have >1 high-risk medical conditions (NIP, CDC, unpublished data, 2000).
Influenza vaccine has been recommended for this entire age group to raise the low
vaccination rates among persons in this age group with high-risk conditions. Age-based
strategies have been more successful in increasing vaccine coverage than
patient-selection strategies based on medical conditions. Persons aged 50--64 years without
high-risk conditions also receive benefit from vaccination in the form of decreased rates
of influenza illness, decreased work absenteeism, and decreased need for medical
visits and medication, including antibiotics
(10--13). Further, 50 years is an age when
other preventive services begin and when routine assessment of vaccination and
other preventive services has been recommended
(78,79).
Persons Who Can Transmit Influenza to Those at High Risk
Persons who are clinically or subclinically infected can transmit influenza virus
to persons at high risk for complications from influenza. Decreasing transmission
of influenza from caregivers to persons at high risk might reduce influenza-related
deaths among persons at high risk. Evidence from two studies indicates that vaccination
of health-care workers is associated with decreased deaths among nursing
home patients (73,74). Vaccination of health-care workers and others in close contact
with persons at high risk, including household members, is recommended. The
following groups should be vaccinated:
physicians, nurses, and other personnel in both hospital and
outpatient-care settings, including emergency response workers;
employees of nursing homes and chronic-care facilities who have contact
with patients or residents;
employees of assisted living and other residences for persons in groups at
high risk;
persons who provide home care to persons in groups at high risk; and
household members (including children) of persons in groups at high risk.
Influenza Vaccine Supply
In 2000, difficulties with growing and processing the influenza A (H3N2)
vaccine strain and other manufacturing problems resulted in substantial delays in
the distribution of the 2000--2001 influenza vaccine
(80). In October 2000, ACIP recommended that persons at highest risk of influenza-related complications
(i.e., persons aged >65 years and those aged <65 years with high-risk medical
conditions) and health-care workers receive vaccine first. ACIP also recommended that
special efforts be made to vaccinate all persons aged 50--64 years, beginning in
December, and to continue efforts to vaccinate groups at high risk through December and
later (81). The possibility of future influenza vaccine delivery delays or vaccine
shortages remains. Steps to address such situations include identification and implementation
of ways to strengthen the influenza vaccine supply, to improve targeted delivery
of vaccine to groups at high risk, and to further encourage the administration of
vaccine throughout the influenza season.
Additional Information Regarding Vaccination of
Specific Populations
Pregnant Women
Influenza-associated excess deaths among pregnant women were
documented during the pandemics of 1918--1919 and 1957--1958
(82--85). Case reports and limited studies also suggest that pregnancy can increase the risk for serious
medical complications of influenza as a result of increases in heart rate, stroke volume,
and oxygen consumption; decreases in lung capacity; and changes in immunologic
function (86--89). A study of the impact of influenza during 17 interpandemic influenza
seasons demonstrated that the relative risk for hospitalization for selected
cardiorespiratory conditions among pregnant women enrolled in Medicaid increased from 1.4
during weeks 14--20 of gestation to 4.7 during weeks 37--42 in comparison with women
who were 1--6 months postpartum (90). Women in their third trimester of pregnancy
were hospitalized at a rate (i.e., 250/100,000 pregnant women) comparable with that
of nonpregnant women who had high-risk medical conditions. Using data from this
study, researchers estimated that an average of 1--2 hospitalizations could be prevented
for every 1,000 pregnant women vaccinated. Women who will be beyond the
first trimester of pregnancy (>14 weeks' gestation) during the influenza season should
be vaccinated. Pregnant women who have medical conditions that increase their risk
for complications from influenza should be vaccinated before the influenza
season, regardless of the stage of pregnancy.
Because currently available influenza vaccine is an inactivated vaccine,
experts consider influenza vaccination safe during any stage of pregnancy. A study of
influenza vaccination of >2,000 pregnant women demonstrated no adverse fetal
effects associated with influenza vaccine
(91). However, additional data are needed to
confirm the safety of vaccination during pregnancy. Some experts prefer to
administer influenza vaccine during the second trimester to avoid a coincidental association
with spontaneous abortion, which is common in the first trimester, and because
exposures to vaccines traditionally have been avoided during the first trimester.
Influenza vaccine distributed in the United States contains thimerosal, a
mercury-containing compound, as a preservative. This preservative has been used in
U.S. vaccines since the 1930s. No data or evidence exists of any harm caused by the
level of mercury exposure that might occur from influenza vaccination. Because
pregnant women are at increased risk for influenza-related complications and because
a substantial safety margin has been incorporated into the health guidance values
for organic mercury exposure, the benefit of influenza vaccine outweighs the
potential risks for thimerosal (92,93).
Persons Infected with HIV
Limited information is available regarding the frequency and severity of
influenza illness or the benefits of influenza vaccination among persons with HIV
infection (94,95). However, a retrospective study of young and middle-aged women enrolled
in Tennessee's Medicaid program found that the attributable risk for
cardiopulmonary hospitalizations among women with HIV infection was higher during influenza
seasons than during the peri-influenza periods. The risk for hospitalization was higher for
HIV-infected women than for women with other well-recognized high-risk
conditions, including chronic heart and lung diseases
(96). Another study estimated that the risk for influenza-related death was 9.4--14.6/10,000 persons with AIDS compared
with rates of 0.09--0.10/10,000 among all persons aged 25--54 years and
6.4--7.0/10,000 among persons aged >65 years
(97). Other reports demonstrate that
influenza symptoms might be prolonged and the risk for complications from influenza
increased for certain HIV-infected persons
(98,99).
Influenza vaccination has been shown to produce substantial antibody titers
against influenza in vaccinated HIV-infected persons who have minimal acquired
immuno-deficiency syndrome-related symptoms and high CD4+ T-lymphocyte cell counts
(100--103). A small, randomized, placebo-controlled trial found that influenza vaccine
was highly effective in preventing symptomatic, laboratory-confirmed influenza
infection among HIV-infected persons with a mean of 400 CD4+ T-lymphocyte
cells/mm3; a limited number of persons with CD4+ T-lymphocyte cell counts of <200 were
included in that study (95). Among patients who have advanced HIV disease and low CD4+
T-lymphocyte cell counts, influenza vaccine might not induce protective antibody
titers (102,103); a second dose of vaccine does not improve the immune response in
these persons (103,104).
One study found that HIV RNA levels increased transiently in one
HIV-infected patient after influenza infection
(105). Studies have demonstrated a
transient (i.e., 2--4-week) increase in replication of HIV-1 in the plasma or peripheral
blood mononuclear cells of HIV-infected persons after vaccine administration
(102,106). Other studies using similar laboratory techniques have not documented a
substantial increase in the replication of HIV
(107--109). Deterioration of CD4+ T-lymphocyte
cell counts or progression of HIV disease have not been demonstrated among
HIV-infected persons after influenza vaccination compared with unvaccinated persons
(103,110). Limited information is available concerning the effect of antiretroviral therapy
on increases in HIV RNA levels after either natural influenza infection or
influenza vaccination (94,111). Because influenza can result in serious illness and
because influenza vaccination can result in the production of protective antibody
titers, vaccination will benefit HIV-infected patients, including HIV-infected pregnant women.
Breastfeeding Mothers
Influenza vaccine does not affect the safety of mothers who are breastfeeding
or their infants. Breastfeeding does not adversely affect the immune response and is
not a contraindication for vaccination.
Travelers
The risk for exposure to influenza during travel depends on the time of year
and destination. In the tropics, influenza can occur throughout the year. In the
temperate regions of the Southern Hemisphere, the majority of influenza activity occurs
during April--September. In temperate climate zones of the Northern and
Southern Hemispheres, travelers also can be exposed to influenza during the
summer, especially when traveling as part of large organized tourist groups that
include persons from areas of the world where influenza viruses are circulating. Persons
at high risk for complications of influenza who were not vaccinated with influenza
vaccine during the preceding fall or winter should consider receiving influenza vaccine
before travel if they plan to
travel to the tropics;
travel with large organized tourist groups at any time of year; or
travel to the Southern Hemisphere during April--September.
No information is available regarding the benefits of revaccinating persons
before summer travel who were already vaccinated in the preceding fall. Persons at high
risk who received the previous season's vaccine before travel should be revaccinated
with the current vaccine in the following fall or winter. Persons aged
>50 years and others at high risk might wish to consult with their physicians before embarking on
travel during the summer to discuss the symptoms and risks for influenza and the
advisability of carrying antiviral medications for either prophylaxis or treatment of influenza.
General Population
In addition to the groups for which annual influenza vaccination is
recommended, physicians should administer influenza vaccine to any person who wishes to
reduce the likelihood of becoming ill with influenza (the vaccine can be administered
to children as young as age 6 months), depending on vaccine availability (see
Vaccine Supply). Persons who provide essential community services should be considered
for vaccination to minimize disruption of essential activities during influenza
outbreaks. Students or other persons in institutional settings (e.g., those who reside
in dormitories) should be encouraged to receive vaccine to minimize the disruption
of routine activities during epidemics.
Persons Who Should Not Be Vaccinated
Inactivated influenza vaccine should not be administered to persons known to
have anaphylactic hypersensitivity to eggs or to other components of the influenza
vaccine without first consulting a physician (see Side Effects and Adverse
Reactions). Prophylactic use of antiviral agents is an option for preventing influenza among
such persons. However, persons who have a history of anaphylactic hypersensitivity
to vaccine components but who are also at high risk for complications of influenza
can benefit from vaccine after appropriate allergy evaluation and
desensitization.
Information regarding vaccine components can be found in package inserts from
each manufacturer.
Persons with acute febrile illness usually should not be vaccinated until
their symptoms have abated. However, minor illnesses with or without fever do
not contraindicate the use of influenza vaccine, particularly among children with
mild upper respiratory tract infection or allergic rhinitis.
Timing of Annual Vaccination
The optimal time to vaccinate persons in groups at high risk is usually
during October--November. However, to avoid missed opportunities for vaccination,
influenza vaccine should be offered to persons at high risk when they are seen by
health-care providers for routine care or are hospitalized in September, provided that vaccine
is available. In addition, health-care providers should also continue to offer vaccine
to unvaccinated persons after November and throughout the influenza season even
after influenza activity has been documented in the community. In the United
States, seasonal influenza activity can begin to increase as early as November or
December but has not reached peak levels in the majority of recent seasons until late
December through early March (Table 2)
(81,112). Therefore, although the timing of
influenza activity can vary by region, vaccine administered after November is likely to
be beneficial in most influenza seasons. Adults develop peak antibody protection
against influenza infection 2 weeks after vaccination
(113,114).
Persons planning substantial organized vaccination campaigns might
consider scheduling these events after mid-October. Although influenza vaccine
generally becomes available by September, the availability of vaccine in any location cannot
be ensured consistently in the early fall. Scheduling campaigns after mid-October
will minimize the need for cancellations because vaccine is unavailable. In facilities
housing elderly persons (e.g., nursing homes), vaccination before October generally should
be avoided because antibody levels in such individuals can begin to decline within a
few months after vaccination (115,116). (For information regarding vaccination
of travelers, see Travelers.)
Dosage
Dosage recommendations vary according to age group (Table 3).
Among previously unvaccinated children aged <9 years, two doses administered
>1 months apart are recommended for satisfactory antibody responses. If possible, the
second dose should be administered before December. Among adults, studies have
indicated little or no improvement in antibody response when a second dose is
administered during the same season
(117--120). Even when the current influenza vaccine
contains one or more of the antigens administered in previous years, annual vaccination
with the current vaccine is necessary because immunity declines during the year
following vaccination (115,116). Vaccine prepared for a previous influenza season should not
be administered to provide protection for the current season.
Use of Inactivated Influenza Vaccine Among Children
Of the three influenza vaccines currently licensed in the United States,
two influenza vaccines (Flushield™, from Wyeth Laboratories, Inc., and
Fluzone® split, from
Aventis Pasteur, Inc.) are approved for use among persons aged
>6 months. One other influenza vaccine,
Fluvirin® (Evans Vaccines Ltd.), is labeled in the United States for
use only among persons aged >4 years because its efficacy among younger persons
has not been demonstrated. Providers should use influenza vaccine that has
been approved for vaccinating children aged 6 months--3 years.
Route
The intramuscular route is recommended for influenza vaccine. Adults and
older children should be vaccinated in the deltoid muscle. A needle length
>1 inches can be considered for these age groups because needles <1 inch might be of
insufficient length to penetrate muscle tissue in certain adults and older children
(121). Infants and young children should be vaccinated in the anterolateral aspect of the thigh
(122).
Side Effects and Adverse Reactions
When educating patients regarding potential side effects, clinicians
should emphasize that a) inactivated influenza vaccine contains noninfectious killed
viruses and cannot cause influenza; and b) coincidental respiratory disease unrelated
to influenza vaccination can occur after vaccination.
Local Reactions
In placebo-controlled blinded studies, the most frequent side effect of vaccination
is soreness at the vaccination site (affecting 10%--64% of patients) that lasts
<2 days (123--125). These local reactions generally are mild and rarely interfere with
the person's ability to conduct usual daily activities.
Systemic Reactions
Fever, malaise, myalgia, and other systemic symptoms can occur
following vaccination and most often affect persons who have had no prior exposure to
the influenza virus antigens in the vaccine (e.g., young children)
(126,127). These reactions begin 6--12 hours after vaccination and can persist for 1--2 days.
Recent placebo-controlled trials demonstrate that among elderly persons
and healthy young adults, administration of split-virus influenza vaccine is not
associated with higher rates of systemic symptoms (e.g., fever, malaise, myalgia, and
headache) when compared with placebo injections
(123,125).
Immediate --- presumably allergic --- reactions (e.g., hives, angioedema,
allergic asthma, and systemic anaphylaxis) rarely occur after influenza vaccination
(128). These reactions probably result from hypersensitivity to some vaccine
component; most reactions likely are caused by residual egg protein. Although current
influenza vaccines contain only a small quantity of egg protein, this protein can
induce immediate hyper-sensitivity reactions among persons who have severe egg
allergy. Persons who have developed hives, have had swelling of the lips or tongue, or
have experienced acute respiratory distress or collapse after eating eggs should consult
a physician for appropriate evaluation to help determine if vaccine should
be administered. Persons who have documented immunoglobulin E
(IgE)-mediated hypersensitivity to eggs ---
including those who have had occupational asthma or
other allergic responses to egg protein --- might also be at increased risk for
allergic
reactions to influenza vaccine, and consultation with a physician should be
considered. Protocols have been published for safely administering influenza vaccine to
persons with egg allergies (129,130).
Hypersensitivity reactions to any vaccine component can occur. Although
exposure to vaccines containing thimerosal can lead to induction of hypersensitivity,
most patients do not develop reactions to thimerosal when it is administered as
a component of vaccines, even when patch or intradermal tests for thimerosal
indicate hyper-sensitivity (131,132). When reported, hypersensitivity to thimerosal usually
has consisted of local, delayed-type hypersensitivity reactions
(131).
Guillain-Barré Syndrome
The 1976 swine influenza vaccine was associated with an increased frequency
of Guillain-Barré syndrome (GBS)
(133,134). Among persons who received the
swine influenza vaccine in 1976, the rate of GBS that exceeded the background rate was
<10 cases/1,000,000 persons vaccinated. Evidence for a causal relationship of GBS
with subsequent vaccines prepared from other influenza viruses is unclear.
Obtaining strong epidemiologic evidence for a possible small increase in risk is difficult for such
a rare condition as GBS, which has an annual incidence of 10--20 cases/1,000,000
adults (135), and stretches the limits of epidemiologic investigation. More definitive
data probably will require the use of other methodologies (e.g., laboratory studies of
the patho-physiology of GBS).
During three of four influenza seasons studied during 1977--1991, the
overall relative risk estimates for GBS after influenza vaccination were slightly elevated
but were not statistically significant in any of these studies
(136--138). However, in a study of the 1992--1993 and 1993--1994 seasons, the overall relative risk for GBS was
1.7 (95% confidence interval = 1.0--2.8; p = 0.04) during the 6 weeks after
vaccination, representing approximately 1 additional case of GBS/1,000,000 persons
vaccinated. The combined number of GBS cases peaked 2 weeks after vaccination
(139). Thus, investigations to date indicate no substantial increase in GBS associated with
influenza vaccines (other than the swine influenza vaccine in 1976) and that, if influenza
vaccine does pose a risk, it is probably slightly more than one additional case per
million persons vaccinated. Cases of GBS after influenza infection have been reported, but
no epidemiologic studies have documented such an association
(140,141). Substantial evidence exists that several infectious illnesses, most notably
Campylobacter jejuni, as well as upper-respiratory tract infections in general are associated with GBS
(135,142--144).
Even if GBS were a true side effect of vaccination in the years after 1976,
the estimated risk for GBS of approximately 1 additional case/1,000,000
persons vaccinated is substantially less than the risk for severe influenza, which could
be prevented by vaccination among all age groups, especially persons aged
>65 years and those who have medical indications for influenza vaccination (Table 1)
(see Hospitalizations and Deaths from Influenza). The potential benefits of
influenza vaccination in preventing serious illness, hospitalization, and death greatly
outweigh the possible risks for developing vaccine-associated GBS. The average
case-fatality ratio for GBS is 6% and increases with age
(135,145). No evidence indicates that the case-fatality ratio for GBS differs among vaccinated persons and those not vaccinated.
The incidence of GBS among the general population is low, but persons with
a history of GBS have a substantially greater likelihood of subsequently developing
GBS than persons without such a history
(136,146). Thus, the likelihood of
coincidentally developing GBS after influenza vaccination is expected to be greater among
persons with a history of GBS than among persons with no history of this syndrome.
Whether influenza vaccination specifically might increase the risk for recurrence of GBS is
not known; therefore, avoiding vaccinating persons who are not at high risk for
severe influenza complications and who are known to have developed GBS within 6
weeks after a previous influenza vaccination is prudent. As an alternative, physicians
might consider the use of influenza antiviral chemoprophylaxis for these persons.
Although data are limited, for most persons who have a history of GBS and who are at high
risk for severe complications from influenza, the established benefits of
influenza vaccination justify yearly vaccination.
Simultaneous Administration of Other Vaccines,
Including Childhood Vaccines
The target groups for influenza and pneumococcal vaccination
overlap considerably (147). For persons at high risk who have not previously been
vaccinated with pneumococcal vaccine, health-care providers should strongly
consider administering pneumococcal and influenza vaccines concurrently. Both vaccines
can be administered at the same time at different sites without increasing side
effects (148,149). However, influenza vaccine is administered each year,
whereas pneumococcal vaccine is not. A patient's verbal history is acceptable for
determining prior pneumococcal vaccination status. When indicated, pneumococcal vaccine
should be administered to patients who are uncertain regarding their vaccination
history (147). Children at high risk for influenza-related complications can receive
influenza vaccine at the same time they receive other routine vaccinations.
Strategies for Implementing These Recommendations
in Health-Care Settings
Successful vaccination programs combine publicity and education for
health-care workers and other potential vaccine recipients, a plan for identifying persons at
high risk, use of reminder/recall systems, and efforts to remove administrative and
financial barriers that prevent persons from receiving the vaccine
(19). Use of standing orders programs is recommended for long-term care facilities (e.g., nursing homes and
skilled nursing facilities) under the supervision of a medical director to ensure
the administration of recommended vaccinations for adults. Other settings (e.g.,
inpatient and outpatient facilities, managed care organizations, assisted living
facilities, correctional facilities, pharmacies, adult workplaces, and home health-care
agencies) are encouraged to introduce standing orders programs as well
(20). Persons for whom influenza vaccine is recommended can be identified and vaccinated in the
settings described in the following sections.
Outpatient Facilities Providing Ongoing Care
Staff in facilities providing ongoing medical care (e.g., physicians' offices,
public health clinics, employee health clinics, hemodialysis centers, hospital
specialty-care
clinics, and outpatient rehabilitation programs) should identify and label the
medical records of patients who should receive vaccination. Vaccine should be offered
during visits beginning in September and throughout the influenza season. The offer
of vaccination and its receipt or refusal should be documented in the medical
record. Patients for whom vaccination is recommended who do not have regularly
scheduled visits during the fall should be reminded by mail or telephone of the need
for vaccination.
Outpatient Facilities Providing Episodic or Acute Care
Acute health-care facilities (e.g., emergency rooms and walk-in clinics) should
offer vaccinations to persons for whom vaccination is recommended or provide
written information regarding why, where, and how to obtain the vaccine. This
written information should be available in languages appropriate for the populations
served by the facility.
Nursing Homes and Other Residential Long-Term Care Facilities
Vaccination should be routinely provided to all residents of chronic-care
facilities with the concurrence of attending physicians. Consent for vaccination should
be obtained from the resident or a family member at the time of admission to the
facility or anytime afterwards. All residents should be vaccinated at one time, preceding
the influenza season. Residents admitted during the winter months after completion of
the vaccination program should be vaccinated at the time of admission.
Acute-Care Hospitals
Persons of all ages (including children) with high-risk conditions and persons
aged >50 years who are hospitalized at any time during September--March should
be offered and strongly encouraged to receive influenza vaccine before they
are discharged. In one study, 39%--46% of patients hospitalized during the winter
with influenza-related diagnoses had been hospitalized during the preceding autumn
(150). Thus, the hospital serves as a setting in which persons at increased risk for
subsequent hospitalization can be identified and vaccinated. Use of standing orders in this
setting has been successful in increasing vaccination of hospitalized persons
(151).
Visiting Nurses and Others Providing Home Care
to Persons at High Risk
Nursing-care plans should identify patients for whom vaccination is
recommended, and vaccine should be administered in the home, if necessary. Caregivers and
other persons in the household (including children) should be referred for vaccination.
Other Facilities Providing Services to Persons Aged
>50 Years
Such facilities as assisted-living facilities, retirement communities, and
recreation centers should offer unvaccinated residents and attendees vaccine on site before
the influenza season. Staff education should emphasize the need for influenza vaccine.
Health-Care Workers
Before the influenza season, health-care facilities should offer
influenza vaccinations to all personnel, including night and weekend staff. Particular
emphasis should be placed on providing vaccinations for persons who care for members
of
groups at high risk. Efforts should be made to educate health-care workers
regarding the benefits of vaccination and the potential health consequences of influenza
illness for themselves and their patients. Measures should be taken to provide all
health-care workers convenient access to influenza vaccine at the work site, free of charge, as part
of employee health programs.
Evolving Developments Related to Influenza Vaccine
Potential New Vaccines
Intranasally administered, cold-adapted, live, attenuated, influenza virus
vaccines (LAIVs) are being used in Russia and have been under development in the
United States since the 1960s (152--156). The viruses in these vaccines replicate in the
upper respiratory tract and elicit a specific protective immune response. LAIVs have
been studied as monovalent, bivalent, and trivalent formulations
(155,156). LAIVs consist of live viruses that induce minimal symptoms (i.e., attenuated) and that replicate
poorly at temperatures found in the lower respiratory tract (i.e.,
temperature-sensitive). Possible advantages of LAIVs are their potential to induce a broad mucosal
and systemic immune response, ease of administration, and the acceptability of
an intranasal route of administration compared with injectable vaccines. In a 5-year
study that compared trivalent inactivated vaccine and bivalent LAIVs (administered by
nose drops) and that used related but different vaccine strains, the two vaccines were
found to be approximately equivalent in terms of effectiveness
(157). In a recent study of children aged 15--71 months, an intranasally administered trivalent LAIV was
93% effective in preventing culture-positive influenza A (H3N2) and B infections,
reduced otitis media among vaccinated children by 30%, and reduced otitis media
with concomitant antibiotic use by 35% compared with unvaccinated children
(158). In a follow-up study during the 1997--1998 season, the trivalent LAIV was 86% effective
in preventing culture-positive influenza among children, despite a poor match
between the vaccine's influenza A (H3N2) component and the predominant circulating
influenza A (H3N2) virus (159). A study conducted among healthy adults during the
same season found a 9%--24% reduction in febrile respiratory illnesses and
13%--28% reduction in lost work days (160). No study has directly compared the efficacy
or effectiveness of trivalent inactivated vaccine and trivalent LAIV.
Potential Addition of Young Children to Groups Recommended
for Vaccination
During 1998, the ACIP formed a working group to explore issues related to
the potential expansion of recommendations for the use of influenza vaccine. The
ACIP influenza working group is considering the impact of influenza among young
children as well as the potential safety issues and logistic and economic consequences
of recommending routine vaccination of young healthy children.
Studies indicate that rates of hospitalization are higher among young children
than older children when influenza viruses are in circulation
(34,36,37,161,162). The increased rates of hospitalization are comparable with rates for other groups at
high risk. However, the interpretation of these findings has been confounded
by cocirculation of respiratory syncytial viruses, which are a cause of serious
respiratory viral illness among children and which frequently circulate during the same time
as
influenza viruses (163--165). Recent studies have attempted to separate the effects
of respiratory syncytial viruses and influenza viruses on rates of hospitalization
among children aged <5 years who do not have high-risk conditions
(36,37). Both studies indicate that otherwise healthy children aged <2 years, and possibly children aged
2--4 years, are at increased risk for influenza-related hospitalization compared with
older healthy children (Table 1).
Because very young healthy children are at increased risk for
influenza-related hospitalization, the ACIP is studying the benefits, risks, economic consequences
and logistical issues associated with routine immunization of this age group.
Meanwhile, ACIP continues to support vaccination of healthy children aged
>6 months whose parents wish to decrease their child's risk for influenza infection, in addition
to vaccinating children with high-risk medical conditions.
RECOMMENDATIONS FOR THE USE OF ANTIVIRAL AGENTS FOR INFLUENZA
Antiviral drugs for influenza are an adjunct to influenza vaccine for the control
and prevention of influenza. However, these agents are not a substitute for
vaccination. Four currently licensed influenza antiviral agents are available in the United
States: amantadine, rimantadine, zanamivir, and oseltamivir.
Amantadine and rimantadine are chemically related antiviral drugs with
activity against influenza A viruses but not influenza B viruses. Amantadine was approved
in 1966 for prophylaxis of influenza A (H2N2) infection and was later approved in
1976 for the treatment and prophylaxis of influenza type A virus infections among
adults and children aged >1 years. Rimantadine was approved in 1993 for treatment
and prophylaxis of infection among adults and prophylaxis among children.
Although rimantadine is approved only for prophylaxis of infection among children,
certain experts in the management of influenza consider it appropriate for treatment
among children (see American Academy of Pediatrics, 2000 Red Book, in
Additional Information Regarding Influenza Infection Control Among Specific Populations).
Zanamivir and oseltamivir are neuraminidase inhibitors with activity against
both influenza A and B viruses. Both zanamivir and oseltamivir were approved in 1999
for the treatment of uncomplicated influenza infections. Zanamivir is approved
for treatment for persons aged >7 years, and oseltamivir is approved for treatment
for persons aged >1 years. In 2000, oseltamivir was approved for prophylaxis of persons
aged >13 years.
The four drugs differ in terms of their pharmacokinetics, side effects, and costs.
An overview of the indications, use, administration, and known primary side effects
of these medications is presented in the following sections. Information contained in
this report might not represent Food and Drug Administration approval or
approved labeling for the antiviral agents described. Package inserts should be consulted
for additional information.
Role of Laboratory Diagnosis
Appropriate treatment of patients with respiratory illness depends on accurate
and timely diagnosis. The early diagnosis of influenza can reduce the inappropriate use
of antibiotics and provide the option of using antiviral therapy. However, because
certain
bacterial infections can produce symptoms similar to influenza, bacterial
infections should be considered and appropriately treated if suspected. In addition,
bacterial infections can occur as a complication of influenza.
Influenza surveillance information as well as diagnostic testing can aid
clinical judgment and help guide treatment decisions. Influenza surveillance by state and
local health departments and CDC can provide information regarding the presence
of influenza viruses in the community. Surveillance can also identify the
predominant circulating types, subtypes, and strains of influenza.
Diagnostic tests available for influenza include viral culture, serology, rapid
antigen testing, and immunofluorescence (24). Sensitivity and specificity of any test
for influenza might vary by the laboratory that performs the test and by the type of
test used. As with any diagnostic test, results should be evaluated in the context of
other clinical information available to the physician.
Several commercial rapid diagnostic tests are available that can be used
by laboratories in outpatient settings to detect influenza viruses within 30
minutes (24,166). These rapid tests differ in the types of influenza virus they can detect
and whether or not they can distinguish between influenza types. Different tests can
detect a) only influenza A viruses; b) both influenza A and B viruses but not
distinguish between the two types, or c) both influenza A and B and distinguish between the
two. Sensitivity and specificity of rapid tests are lower than for viral culture and vary
by test. In addition, the types of specimens acceptable for use (i.e., throat swab,
nasal wash, or nasal swab) also vary. Package inserts and the laboratory performing
the test should be consulted for more details.
Despite the availability of rapid diagnostic tests, the collection of clinical
specimens for viral culture is critical, because only culture isolates can provide
specific information regarding circulating influenza subtypes and strains. This information
is needed to compare current circulating influenza strains with vaccine strains, to
guide decisions regarding influenza treatment and prophylaxis, and to formulate vaccine
for the coming year. Virus isolates also are needed to monitor the emergence of
antiviral resistance and the emergence of novel influenza A subtypes that might pose
a pandemic threat.
Indications for Use
Treatment
When administered within 2 days of illness onset to otherwise healthy
adults, amantadine and rimantadine can reduce the duration of uncomplicated influenza
A illness, and zanamivir and oseltamivir can reduce the duration of
uncomplicated influenza A and B illness by approximately 1 day
(49,167--180). More clinical data are available concerning the effectiveness of zanamivir and oseltamivir for treatment
of influenza A infection than for treatment of influenza B infection
(169,174--179,181--184). However, in vitro data
(185--190), studies of treatment among mice and
ferrets (186,187,191,192), and clinical studies have documented that zanamivir
and oseltamivir have activity against influenza B viruses
(173,177--179,183,184).
None of the four antiviral agents has been demonstrated to be effective
in preventing serious influenza-related complications (e.g., bacterial or viral
pneumonia or exacerbation of chronic diseases). Evidence for the effectiveness of these
four
antiviral drugs is based principally on studies of patients with uncomplicated
influenza (193). Data are limited and inconclusive concerning the effectiveness of
amantadine, rimantadine, zanamivir, and oseltamivir for treatment of influenza among persons
at high risk for serious complications of influenza
(167,169,170,172,173,180,194--197). Fewer studies of the efficacy of influenza antivirals have been conducted
among pediatric populations compared with adults
(167,170,176,177,196,198,199). One study of oseltamivir treatment documented a decreased incidence of otitis media
among children (177).
To reduce the emergence of antiviral drug-resistant viruses, amantadine
or rimantadine therapy for persons with influenza-like illness should be discontinued
as soon as clinically warranted, generally after 3--5 days of treatment or within
24--48 hours after the disappearance of signs and symptoms. The recommended duration
of treatment with either zanamivir or oseltamivir is 5 days.
Prophylaxis
Chemoprophylactic drugs are not a substitute for vaccination, although they
are critical adjuncts in the prevention and control of influenza. Both amantadine
and rimantadine are indicated for the prophylaxis of influenza A infection, but are
not effective against influenza B. Both drugs are approximately 70%--90% effective
in preventing illness from influenza A infection
(49,167,196). When used as prophylaxis, these antiviral agents can prevent illness while permitting subclinical infection and
the development of protective antibody against circulating influenza viruses.
Therefore, certain persons who take these drugs will develop protective immune responses
to circulating influenza viruses. Amantadine and rimantadine do not interfere with
the antibody response to the vaccine (167). Both drugs have been studied
extensively among nursing home populations as a component of influenza outbreak
control programs, which can limit the spread of influenza within chronic care
institutions (167,195,200--202).
Among the neuraminidase inhibitor antivirals, zanamivir and oseltamivir,
only oseltamivir has been approved for prophylaxis, but community studies of
healthy adults indicate that both drugs are similarly effective in preventing febrile,
laboratory-confirmed influenza illness (efficacy: zanamivir, 84%; oseltamivir, 82%)
(203,204). Both antiviral agents have also been reported to prevent influenza illness among
persons given chemoprophylaxis after a household member was diagnosed with
influenza (183,205). Experience with prophylactic use of these agents in institutional settings
or among patients with chronic medical conditions is limited
(179,206--211). One 6-week study of oseltamivir prophylaxis among nursing home residents found a
92% reduction in influenza illness (179,212). Use of zanamivir has not been reported
to impair the immunologic response to influenza vaccine
(178,213). Data are not available on the efficacy of any of the four antiviral agents in preventing
influenza among severely immune compromised persons.
When determining the timing and duration for administering influenza
antiviral medications for prophylaxis, factors related to cost, compliance, and potential
side effects should be considered. To be maximally effective as prophylaxis, the drug
must be taken each day for the duration of influenza activity in the community. However,
to be most cost-effective, one study of amantadine or rimantadine prophylaxis
reported
that the drugs should be taken only during the period of peak influenza activity in
a community (214).
Persons at High Risk Who Are Vaccinated After Influenza Activity Has
Begun. Persons at high risk for complications of influenza still can be vaccinated after
an outbreak of influenza has begun in a community. However, the development
of antibodies in adults after vaccination can take as long as 2 weeks
(118,119). When influenza vaccine is given while influenza viruses are circulating,
chemoprophylaxis should be considered for persons at high risk during the time from vaccination
until immunity has developed. Children who receive influenza vaccine for the first time
can require as long as 6 weeks of prophylaxis (i.e., prophylaxis for 4 weeks after the
first dose of vaccine and an additional 2 weeks of prophylaxis after the second dose).
Persons Who Provide Care to Those at High
Risk. To reduce the spread of virus to persons at high risk during community or institutional outbreaks,
chemoprophylaxis during peak influenza activity can be considered for unvaccinated persons who
have frequent contact with persons at high risk. Persons with frequent contact
include employees of hospitals, clinics, and chronic-care facilities, household members,
visiting nurses, and volunteer workers. If an outbreak is caused by a variant strain of
influenza that might not be controlled by the vaccine, chemoprophylaxis should be
considered for all such persons, regardless of their vaccination status.
Persons Who Have Immune Deficiency. Chemoprophylaxis can be considered
for persons at high risk who are expected to have an inadequate antibody response
to influenza vaccine. This category includes persons infected with HIV, especially
those with advanced HIV disease. No published data are available concerning
possible efficacy of chemoprophylaxis among persons with HIV infection or interactions
with other drugs used to manage HIV infection. Such patients should be monitored closely
if chemoprophylaxis is administered.
Other Persons. Chemoprophylaxis throughout the influenza season or during
peak influenza activity might be appropriate for persons at high risk who should not
be vaccinated. Chemoprophylaxis can also be offered to persons who wish to
avoid influenza illness. Health-care providers and patients should make this decision on
an individual basis.
Control of Influenza Outbreaks in Institutions
The use of antiviral drugs for treatment and prophylaxis of influenza is
an important component of institutional outbreak control. In addition to the use of
antiviral medications, other outbreak control measures include instituting droplet
precautions and establishing cohorts of patients with confirmed or suspected influenza,
re-offering influenza vaccinations to unvaccinated staff and patients, restricting staff
movement between wards or buildings, and restricting contact between ill staff or visitors
and patients (215--217). (For additional information regarding outbreak control in
specific settings, refer to additional references in Additional Information Regarding
Influenza Infection Control Among Specific Populations.)
Most published reports on the use of antiviral agents to control
institutional influenza outbreaks are based on studies of influenza A outbreaks among
nursing home populations where amantadine or rimantadine were used
(167,195,200--202). Less information is available concerning the use of oseltamivir in influenza A or
B
institutional outbreaks (210,212). When confirmed or suspected outbreaks of
influenza occur in institutions that house persons at high risk, chemoprophylaxis should
be started as early as possible to reduce the spread of the virus. In these
situations, having preapproved orders from physicians or plans to obtain orders for
antiviral medications on short notice is extremely useful.
When institutional outbreaks occur, chemoprophylaxis should be administered
to all residents --- regardless of whether they received influenza vaccinations during
the previous fall --- and should continue for
>2 weeks or until approximately 1 week
after the end of the outbreak. The dosage for each resident should be
determined individually. Chemoprophylaxis also can be offered to unvaccinated staff who
provide care to persons at high risk. Prophylaxis should be considered for all
employees, regardless of their vaccination status, if the outbreak is caused by a variant strain
of influenza that is not well-matched by the vaccine.
In addition to nursing homes, chemoprophylaxis also can be considered
for controlling influenza outbreaks in other closed or semiclosed settings (e.g.,
dormitories or other settings where persons live in close proximity). For
example, chemoprophylaxis with rimantadine has been used successfully to control an
influenza A outbreak aboard a large cruise ship
(218).
To limit the potential transmission of drug-resistant virus during
institutional outbreaks, whether in chronic or acute-care settings or other closed
settings, measures should be taken to reduce contact as much as possible between
persons taking anti-viral drugs for treatment and other persons, including those
taking chemoprophylaxis (see Antiviral Drug-Resistant Strains of Influenza).
Dosage
Dosage recommendations vary by age group and medical conditions (Table 4).
Children
Amantadine. The use of amantadine among children aged <1 year has not
been adequately evaluated. The Food and Drug Administration-approved dosage
for children aged 1--9 years for treatment and prophylaxis is 4.4--8.8 mg/kg/day, not
to exceed 150 mg/day. Although further studies are needed to determine the
optimal dosage for children aged 1--9 years, physicians should consider prescribing only 5
mg/kg/day (not to exceed 150 mg/day) to reduce the risk for toxicity. The approved
dosage for children aged >10 years is 200 mg/day (100 mg twice a day); however, for
children weighing <40 kg, prescribing 5 mg/kg/day, regardless of age, is advisable
(219).
Rimantadine. Rimantadine is approved for prophylaxis among children aged
>1 years and for treatment in children aged
>13 years. Although rimantadine is
approved only for prophylaxis of infection among children, certain experts in the management
of influenza consider it appropriate for treatment among children (see
American Academy of Pediatrics, 2000 Red Book, in Additional Information Regarding
Influenza Infection Control Among Specific
Populations). The use of rimantadine among
children aged <1 year has not been adequately evaluated. Rimantadine should be
administered in one or two divided doses at a dosage of 5 mg/kg/day, not to exceed 150 mg/day
for children aged 1--9 years. The approved dosage for children aged
>10 years is 200 mg/day (100 mg twice a day); however, for children weighing <40 kg, prescribing 5
mg/kg/day, regardless of age, is recommended
(220).
Zanamivir. Zanamivir is not approved for use among children aged <7 years.
The recommended dosage of zanamivir for treatment of influenza among persons aged
>7 years is two inhalations (one 5-mg blister per inhalation for a total dose of 10
mg) twice daily (approximately 12 hours apart)
(178).
Oseltamivir. Oseltamivir is not approved for use among persons aged <1
year. Recommended treatment doses for children vary by the weight of the child: the
dose recommendation for children who weigh
<15 kg is 30 mg twice a day; for
children weighing >15--23 kg, the dose is 45 mg twice a day; for those weighing >23--40 kg,
the dose is 60 mg twice a day; and for children weighing >40 kg, the dose is 75 mg twice
a day. The treatment dosage for persons
>13 years is 75 mg twice daily. For children
>13 years, the recommended dose for prophylaxis is 75 mg once a day
(179).
Persons Aged >65 Years
Amantadine. The daily dose of amantadine for persons aged
>65 years should not exceed 100 mg for prophylaxis or treatment, because renal function declines
with increasing age. For certain elderly persons, the dose should be further reduced.
Rimantadine. Among elderly persons, the incidence and severity of
central nervous system (CNS) side effects are substantially lower among those
taking rimantadine at a dosage of 100 mg/day than among those taking amantadine
at dosages adjusted for estimated renal clearance
(221). However, chronically ill elderly persons have had a higher incidence of CNS and gastrointestinal symptoms
and serum concentrations two to four times higher than among healthy, younger
persons when rimantadine has been administered at a dosage of 200 mg/day
(167).
For elderly nursing home residents, the dosage of rimantadine should be
reduced to 100 mg/day for prophylaxis or treatment. For other elderly persons, further
studies are needed to determine the optimal dosage. However, a reduction in dosage to
100 mg/day should be considered for all persons aged
>65 years who experience side effects when taking a dosage of 200 mg/day.
Zanamivir and Oseltamivir. No reduction in dosage is recommended on the basis
of age alone.
Persons with Impaired Renal Function
Amantadine. A reduction in dosage is recommended for patients with
creatinine clearance <50
mL/min/1.73m2. Guidelines for amantadine dosage on the basis
of creatinine clearance are found in the package insert. Because recommended
dosages on the basis of creatinine clearance might provide only an approximation of
the optimal dose for a given patient, such persons should be observed carefully
for adverse reactions. If necessary, further reduction in the dose or discontinuation of
the drug might be indicated because of side effects. Hemodialysis contributes minimally
to amantadine clearance (222).
Rimantadine. A reduction in dosage to 100 mg/day is recommended for
persons with creatinine clearance <10 mL/min. Because of the potential for accumulation
of rimantadine and its metabolites, patients with any degree of renal
insufficiency, including elderly persons, should be monitored for adverse effects, and either
the dosage should be reduced or the drug should be discontinued, if
necessary. Hemodialysis contributes minimally to drug clearance
(223).
Zanamivir. Limited data are available regarding the safety and efficacy
of zanamivir for patients with impaired renal function. Among patients with renal
failure
who were administered a single intravenous dose of zanamivir, decreases in
renal clearance, increases in half-life, and increased systemic exposure to zanamivir
were observed (178,224). However, a small number of healthy volunteers who
were administered high doses of intravenous zanamivir tolerated systemic levels
of zanamivir that were much higher than those resulting from administration of
zanamivir by oral inhalation at the recommended dose
(225,226). On the basis of these considerations, the manufacturer recommends no dose adjustment for
inhaled zanamivir for a 5-day course of treatment for patients with either mild-to-moderate
or severe impairment in renal function (178).
Oseltamivir. Serum concentrations of oseltamivir carboxylate (GS4071), the
active metabolite of oseltamivir, increase with declining renal function
(182,179). For patients with creatinine clearance of 10--30 mL/min
(179), a reduction of the treatment dose of oseltamivir to 75 mg once daily and in the prophylaxis dose to 75 mg every other
day is recommended. No treatment or prophylaxis dosing recommendations are
available for patients undergoing routine renal dialysis treatment.
Persons with Liver Disease
Amantadine. No increase in adverse reactions to amantadine has been
observed among persons with liver disease. Rare instances of reversible elevation of
liver enzymes among patients receiving amantadine have been reported, although
a specific relationship between the drug and such changes has not been
established (227).
Rimantadine. A reduction in dosage to 100 mg/day is recommended for
persons with severe hepatic dysfunction.
Zanamivir and Oseltamivir. Neither of these medications has been studied
among persons with hepatic dysfunction.
Persons with Seizure Disorders
Amantadine. An increased incidence of seizures has been reported among
patients with a history of seizure disorders who have received amantadine
(228). Patients with seizure disorders should be observed closely for possible increased seizure
activity when taking amantadine.
Rimantadine. Seizures (or seizure-like activity) have been reported among
persons with a history of seizures who were not receiving anticonvulsant medication
while taking rimantadine (229). The extent to which rimantadine might increase
the incidence of seizures among persons with seizure disorders has not been
adequately evaluated.
Zanamivir and Oseltamivir. Seizure events have been reported
during postmarketing use of zanamivir and oseltamivir, although no epidemiologic
studies have reported any increased risk for seizures with either zanamivir or oseltamivir use.
Route
Amantadine, rimantadine, and oseltamivir are administered orally.
Amantadine and rimantadine are available in tablet or syrup form, and oseltamivir is available
in capsule or oral suspension form (178,179). Zanamivir is available as a dry powder
that is self-administered via oral inhalation by using a plastic device included in
the
package with the medication. Patients will benefit from instruction and
demonstration of correct use of this device
(178).
Pharmacokinetics
Amantadine
Approximately 90% of amantadine is excreted unchanged in the urine
by glomerular filtration and tubular secretion
(200,230--233). Thus, renal clearance of amantadine is reduced substantially among persons with renal insufficiency,
and dosages might need to be decreased (see Dosage) (Table 4).
Rimantadine
Approximately 75% of rimantadine is metabolized by the liver
(196). The safety and pharmacokinetics of rimantadine among persons with liver disease have
been evaluated only after single-dose administration
(196,234). In a study of persons with chronic liver disease (most with stabilized cirrhosis), no alterations in liver
function were observed after a single dose
(175,217). However, for persons with severe
liver dysfunction, the apparent clearance of rimantadine was 50% lower than that
reported for persons without liver disease
(220).
Rimantadine and its metabolites are excreted by the kidneys. The safety
and pharmacokinetics of rimantadine among patients with renal insufficiency have
been evaluated only after single-dose administration
(196,223). Further studies are needed to determine multiple-dose pharmacokinetics and the most appropriate dosages
for patients with renal insufficiency. In a single-dose study of patients with anuric
renal failure, the apparent clearance of rimantadine was approximately 40% lower, and
the elimination half-life was approximately 1.6-fold greater than that among
healthy persons of the same age (223). Hemodialysis did not contribute to drug clearance.
In studies of persons with less severe renal disease, drug clearance was also
reduced, and plasma concentrations were higher than those among control patients
without renal disease who were the same weight, age, and sex
(220,235).
Zanamivir
In studies of healthy volunteers, approximately 7%--21% of the orally
inhaled zanamivir dose reached the lungs, and 70%--87% was deposited in the
oropharynx (236,237). Approximately 4%--17% of the total amount of orally inhaled zanamivir
is systemically absorbed. Systemically absorbed zanamivir has a half-life of
2.5--5.1 hours and is excreted unchanged in the urine. Unabsorbed drug is excreted in
the feces (178,226).
Oseltamivir
Approximately 80% of orally administered oseltamivir is absorbed
systemically (182). Absorbed oseltamivir is metabolized to oseltamivir carboxylate, the
active neuraminidase inhibitor, primarily by hepatic esterases. Oseltamivir carboxylate has
a half-life of 6--10 hours and is excreted in the urine by glomerular filtration and
tubular secretion via the anionic pathway
(179,238). Unmetabolized oseltamivir also
is excreted in the urine by glomerular filtration and tubular secretion
(238).
Side Effects and Adverse Reactions
When considering the use of influenza antiviral medications (i.e., choice of
antiviral drug, dose, and duration of therapy), clinicians must consider the patient's age,
weight, and renal function (Table 4); presence of other medical conditions; indications for
use (i.e., prophylaxis or therapy); and the potential for interaction with other medications.
Amantadine and Rimantadine
Both amantadine and rimantadine can cause CNS and gastrointestinal side
effects when administered to young, healthy adults at equivalent dosages of 200
mg/day. However, incidence of CNS side effects (e.g., nervousness, anxiety,
difficulty concentrating, and lightheadedness) is higher among persons taking amantadine
than among those taking rimantadine (239). In a 6-week study of prophylaxis
among healthy adults, approximately 6% of participants taking rimantadine at a dosage of
200 mg/day experienced >1 CNS symptoms, compared with approximately 13% of
those taking the same dosage of amantadine and 4% of those taking placebo
(239). A study of elderly persons also demonstrated fewer CNS side effects associated
with rimantadine compared with amantadine
(221). Gastrointestinal side effects (e.g., nausea and anorexia) occur in approximately 1%--3% of persons taking either
drug, compared with 1% of persons receiving the placebo
(239).
Side effects associated with amantadine and rimantadine are usually mild
and cease soon after discontinuing the drug. Side effects can diminish or disappear
after the first week, despite continued drug ingestion. However, serious side effects
have been observed (e.g., marked behavioral changes, delirium, hallucinations,
agitation, and seizures) (228). These more severe side effects have been associated with
high plasma drug concentrations and 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 dosage of
200 mg/day (200). Clinical observations and studies have indicated that lowering
the dosage of amantadine among these persons reduces the incidence and severity
of such side effects (Table 4). In acute overdosage of amantadine, CNS, renal,
respiratory, and cardiac toxicity, including arrhythmias, have been reported
(219). Because rimantadine has been marketed for a shorter period than amantadine, its
safety among certain patient populations (e.g. chronically ill and elderly persons) has
been evaluated less frequently.
Zanamivir
In a study of zanamivir treatment of influenza-like illness among persons
with asthma or chronic obstructive pulmonary disease where study medication
was administered after the use of a b2-agonist, 13% of patients receiving zanamivir
and 14% of patients who received placebo (inhaled powdered lactose vehicle)
experienced a >20% decline in forced expiratory volume in 1 second (FEV1) after
treatment (178,180). However, in a phase I study of persons with mild or moderate asthma
who did not have influenza-like illness, 1 of 13 patients experienced
bronchospasm following administration of zanamivir
(178). In addition, during postmarketing surveillance, cases of respiratory function deterioration following inhalation
of zanamivir have been reported. Certain patients had underlying airways disease
(e.g., asthma or chronic obstructive pulmonary disease). Because of the risk for
serious
adverse events and because the efficacy has not been demonstrated in
this population, zanamivir is generally not recommended for treatment for patients
with underlying airway disease (178). If physicians decide to prescribe zanamivir to
patients with underlying chronic respiratory disease after carefully considering potential
risks and benefits, the drug should be used with caution under conditions of
proper monitoring and supportive care, including the availability of
short-acting bronchodilators (193). Patients with asthma or chronic obstructive pulmonary
disease who use zanamivir are advised to a) have a fast-acting inhaled
bronchodilator available when inhaling zanamivir and b) stop using zanamivir and contact
their physician if they develop difficulty breathing
(178). No clear evidence is available regarding the safety or efficacy of zanamivir for persons with underlying
respiratory or cardiac disease or for persons with complications of acute influenza
(193).
In clinical treatment studies of persons with uncomplicated influenza,
the frequencies of adverse events were similar for persons receiving inhaled
zanamivir and those receiving placebo (i.e., inhaled lactose vehicle alone)
(168--173,178,236). The most common adverse events reported by both groups were diarrhea;
nausea; sinusitis; nasal signs and symptoms; bronchitis; cough; headache; dizziness; and
ear, nose, and throat infections
(150,151,153,154,191). Each of these symptoms
was reported by <5% of persons in the clinical treatment studies combined
(178).
Oseltamivir
Nausea and vomiting were reported more frequently among adults
receiving oseltamivir for treatment (nausea without vomiting, approximately 10%;
vomiting, approximately 9%) than among persons receiving placebo (nausea without
vomiting, approximately 6%; vomiting, approximately 3%)
(174,175,179,240). Among children treated with oseltamivir, 14.3% had vomiting compared with 8.5% of
placebo recipients. Overall, 1% discontinued the drug secondary to this side effect
(177), whereas a limited number of adults enrolled in clinical treatment trials of
oseltamivir discontinued treatment because of these symptoms
(179). Similar types and rates of adverse events were found in studies of oseltamivir prophylaxis
(179). Nausea and vomiting might be less severe if oseltamivir is taken with food
(179,240).
Use During Pregnancy
No clinical studies have been conducted regarding the safety or efficacy
of amantadine, rimantadine, zanamivir, or oseltamivir for pregnant women; only
two cases of amantadine use for severe influenza illness during the third trimester
have been reported (89,241). However, both amantadine and rimantadine have
been demonstrated in animal studies to be teratogenic and embryotoxic when
administered at very high doses (219,220). Because of the unknown effects of influenza
antiviral drugs on pregnant women and their fetuses, these four drugs should be used
during pregnancy only if the potential benefit justifies the potential risk to the embryo or
fetus (see package inserts [178,179,219,220]).
Drug Interactions
Careful observation is advised when amantadine is administered concurrently
with drugs that affect CNS, especially CNS stimulants. Concomitant administration
of
antihistamines or anticholinergic drugs can increase the incidence of adverse
CNS reactions (167). No clinically significant interactions between rimantadine and
other drugs have been identified.
Clinical data are limited regarding drug interactions with zanamivir. However,
no known drug interactions have been reported, and no clinically important
drug interactions have been predicted on the basis of in vitro data and data from studies
of rats (178,242).
Limited clinical data are available regarding drug interactions with
oseltamivir. Because oseltamivir and oseltamivir carboxylate are excreted in the urine
by glomerular filtration and tubular secretion via the anionic pathway, a potential
exists for interaction with other agents excreted by this pathway. For
example, coadministration of oseltamivir and probenecid resulted in reduced clearance
of oseltamivir carboxylate by approximately 50% and a corresponding
approximate twofold increase in the plasma levels of oseltamivir carboxylate
(179,238).
No published data are available concerning the safety or efficacy of
using combinations of any of these four influenza antiviral drugs. For more
detailed information concerning potential drug interactions for any of these influenza
antiviral drugs, package inserts should be consulted.
Antiviral Drug-Resistant Strains of Influenza
Amantadine-resistant viruses are cross-resistant to rimantadine and vice
versa (243). Drug-resistant viruses can appear in approximately one third of patients
when either amantadine or rimantadine is used for therapy
(199,244). During the course of amantadine or rimantadine therapy, resistant influenza strains can replace
sensitive strains within 2--3 days of starting therapy
(244,245). Resistant viruses have been isolated from persons who live at home or in an institution where other residents
are taking or have recently taken amantadine or rimantadine as therapy
(246,247); however, the frequency with which resistant viruses are transmitted and their
impact on efforts to control influenza are unknown. Amantadine- and
rimantadine-resistant viruses are not more virulent or transmissible than sensitive viruses
(248). The screening of epidemic strains of influenza A has rarely detected amantadine-
and rimantadine-resistant viruses
(244,249,250).
Persons who have influenza A infection and who are treated with
either amantadine or rimantadine can shed sensitive viruses early in the course of
treatment and later shed drug-resistant viruses, especially after 5--7 days of therapy
(199). Such persons can benefit from therapy even when resistant viruses emerge.
Resistance to zanamivir and oseltamivir can be induced in influenza A and
B viruses in vitro (251--258), but induction of resistance requires several passages in
cell culture. By contrast, resistance to amantadine and rimantadine in vitro can be
induced with fewer passages in cell culture
(259,260). Development of viral resistance
to zanamivir and oseltamivir during treatment has been identified but does not appear
to be frequent (179,261--264). In clinical treatment studies using oseltamivir, 1.3%
of posttreatment isolates from patients aged
>13 years and 8.6% among patients aged 1--12 years had decreased susceptibility to oseltamivir
(179). No isolates with reduced susceptibility to zanamivir have been reported from clinical trials, although the
number of posttreatment isolates tested is limited
(265), and the risk for emergence of zanamivir resistant isolates cannot be quantified
(178). Only one clinical isolate with
reduced susceptibility to zanamivir, obtained from an immunocompromised child
on prolonged therapy, has been reported
(262). Currently available diagnostic tests
are not optimal for detecting clinical resistance, and better tests as well as more
testing are needed before firm conclusions can be reached
(265). Postmarketing surveillance for neuraminidase inhibitor-resistant influenza viruses is being conducted.
SOURCES OF INFORMATION REGARDING INFLUENZA AND ITS SURVEILLANCE
Information regarding influenza surveillance is available through the CDC
Voice Information System (influenza update) at (888) 232-3228; CDC Fax
Information Service at (888) 232-3299; or website for the Influenza Branch, DVRD, NCID, CDC
at <http://www.cdc.gov/ncidod/diseases/flu/weekly.htm>. During October--May,
the information is updated at least every other week. In addition, periodic
updates regarding influenza are published in the weekly
MMWR. State and local health departments should be consulted regarding availability of influenza vaccine, access
to vaccination programs, information regarding state or local influenza activity, and
for reporting influenza outbreaks and receiving advice regarding outbreak control.
ADDITIONAL INFORMATION REGARDING INFLUENZA INFECTION CONTROL AMONG SPECIFIC POPULATIONS
Each year, the ACIP provides general, annually updated information regarding
the control and prevention of influenza. Other documents on the control and prevention
of influenza among specific populations (e.g., immunocompromised persons,
health-care workers, hospitals, and travelers) are also available in the following publications:
Garner JS. Hospital Infection Control Practices Advisory Committee.
Guideline for isolation precautions in hospitals. Infect Control Hosp
Epidemiol 1996;17: 53--80.
Tablan OC, Anderson LJ, Arden NH, et al., Hospital Infection Control
Practices Advisory Committee. Guideline for prevention of nosocomial pneumonia.
Infect Control Hosp Epidemiol 1994;15:587--627.
Bolyard EA, Tablan OC, Williams WW, et al., Hospital Infection Control
Practices Advisory Committee. Guideline for infection control in health care personnel.
Am J Infect Control 1998;26:289--354.
Bradley SF, The Long-Term--Care Committee of the Society for
Healthcare Epidemiology of America. Prevention of influenza in long-term care
facilities. Infect Control Hosp Epidemiol 1999;20:629--37.
Sneller V-P, Izurieta H, Bridges C, et al. Prevention and control of
vaccine-preventable diseases in long-term care facilities. J Am Med Directors
Assoc 2000;1(Suppl):S2--37.
American Academy of Pediatrics. 2000 red book: report of the Committee
on Infectious Diseases. 25th ed. Elk Grove Village, IL: American Academy
of Pediatrics, 2000.
CDC. 1999 USPHS/IDSA Guidelines for the prevention of opportunistic
infections in persons infected with human immunodeficiency virus. MMWR
1999;48(No. RR-10):1--59.
CDC. General recommendations on immunization: recommendations of
the Advisory Committee on Immunization Practices (ACIP). MMWR 1994;43(No.
RR-1):1--38.
Bodnar UR, Maloney SA, Fielding KL, et al. Preliminary guidelines for
the prevention and control of influenza-like illness among passengers and
crew members on cruise ships. Atlanta, GA: US Department of Health and
Human Services, CDC, National Center for Infectious Diseases, 1999.
CDC. General recommendations for preventing influenza A infection
among travelers. Atlanta, GA: US Department of Health and Human Services,
CDC, 2001. Available at <http://www.cdc.gov/travel/feb99.htm>. Accessed March
19, 2001.
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