CASE-BASED REVIEW

Developments in the Care of Influenza Patients:

Priorities and Perspectives
Introduction and Case Study, Susan G. Blitz, MD, MPH
Commentary, Susan G. Blitz, MD, MPH, Carol Chenoweth, MD, and A. Mark Fendrick, MD

INSTRUCTIONS
JCOM The following case study, Developments in the
CME Care of Influenza Patients: Priorities and Perspectives, is accompanied by a continuing medical education
(CME) evaluation that consists of 5 multiple-choice questions. After reading the case study, carefully consider each
of the questions in the CME evaluation on page 73. Then,
circle your selected answer to each question on the CME
evaluation form on page 74. In order to receive 1 CME
credit, at least 3 of the 5 questions must be answered correctly. The estimated time for this CME activity is 1 hour.
OBJECTIVES
JCOM After participating in the CME activity, primary
CME care physicians should be able to:
1. Appreciate the clinical and economic burden of influenzal disease in the United States
2. Understand the importance of vaccination for various
patient populations
3. Be familiar with the diagnostic tests available and the
relative advantages and disadvantages of the various
methods
4. Be familiar with the drugs available for treatment and
prophylaxis of influenza
INTRODUCTION
nfluenza is such a familiar disease that we refer to it by a
diminutive, though not affectionate, term. Indeed, the
flu has been around for ages, the name influenza originating in 15th-century Italy from an epidemic attributed to
influence of the stars [1]. Outbreaks can be severe: The devastating human toll exacted by World War I was dwarfed by
the number of people affected by the worldwide pandemic of
Spanish flu in 19181919. The last major pandemic occurred in 19681969, but many authorities consider another
pandemic to be highly likely, if not inevitable [2]. This disease,
although commonplace and unexciting, has been treated to a
recent resurgence in publicity with the availability of new
drug treatments and the expected introduction of a live, attenuated vaccine with a more convenient delivery system.

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This case study discusses some of the promises and pitfalls of

innovations in the care of influenza.
Influenza viruses are single-stranded RNA viruses of the
Orthomyxoviridae family. Influenza A and B are the types
of influenza virus that are associated with epidemics in
humans. Type C is rarely reported as a cause of human illness. Subtypes of influenza A virus are determined by the
surface antigens hemagglutinin and neuraminidase. Hemagglutinin antigens have a role in the attachment of the influenza virus to host cells, while neuraminidase aids in viral penetration into cells [1,3]. These surface antigens undergo
constant antigenic variation, called drift, so that different
strains may predominate in each influenza season. Periodically, the virus undergoes antigenic shift, a dramatic change
in antigens that leaves entire populations susceptible to infection and may result in worldwide pandemics [1,4]. Influenza is spread directly and indirectly through infected respiratory secretions. It has a seasonal occurrence in temperate
climates, peaking between December and March, although
cases may be identified as early as mid-November and as
late as the end of April [1,3].
Annual excess mortality in the United States from influenza ranges from 20,000 to 40,000 depending on the severity of outbreaks and the degree of immunity in the population [3]. The major causes of death are pneumonia and
exacerbation of underlying cardiopulmonary disorders.

Susan G. Blitz, MD, MPH, Clinical Assistant Professor, Division of

General Internal Medicine, Department of Internal Medicine,
University of Michigan School of Medicine, Medical Director,
Mworks Occupational Health Program, University of Michigan
Health System, Ann Arbor, MI; Carol Chenoweth, MD, Clinical
Assistant Professor, Division of Infectious Diseases, Department of
Internal Medicine, University of Michigan School of Medicine,
Medical Director of Infection Control, University of Michigan
Hospitals and Health Centers, Ann Arbor, MI; and A. Mark
Fendrick, MD, Associate Professor, Departments of Internal Medicine
and Health Management and Policy, University of Michigan School
of Medicine and University of Michigan School of Public Health, CoDirector, Consortium for Health Outcomes Innovation and CostEffectiveness Studies (CHOICES), Ann Arbor, MI.

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INFLUENZA
Table 1. Target Groups for Vaccination
Persons at high risk for influenza-related complications
Persons aged 65 years
Residents of nursing homes and other chronic care facilities
Persons with chronic disorders of the pulmonary or cardiovascular
systems, including asthma
Persons with chronic diseases such as diabetes mellitus, renal dysfunction, hemoglobinopathies, or immunosuppression (including
immunosuppression caused by medications)
Persons infected with HIV
Children and teenagers receiving long-term aspirin therapy (risk
of Reyes syndrome)
Women who will be in the second or third trimester of pregnancy
during the influenza season
Persons who can transmit influenza to those at high risk
Physicians, nurses, and other personnel in hospital and outpatient
care settings
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
high-risk groups
Persons who provide home care to persons in high-risk groups
Household members (including children) of persons in high-risk
groups
Adapted from Prevention and control of influenza: recommendations of
the Advisory Committee on Immunization Practices (ACIP). MMWR
Morb Mortal Wkly Rep 1999;48(RR-4):128.

Primary influenza viral pneumonia is an uncommon complication but has a high fatality rate; secondary bacterial
pneumonia is the most frequent complication [1]. Determining the full extent of the medical and economic impact of
influenza is problematic because only a minority of persons
with influenza seeks medical attention. The economic impact of a future pandemic in the United States has been estimated at between $71 and $166 billion, excluding disruptions to commerce and society [2].
CASE STUDY
Initial Presentation
A 35-year-old woman presents to her primary care
physician (PCP) in October for a health maintenance
examination.
History
The patient has no major medical problems, does not take
medications on a regular basis, and is a nonsmoker. Her family history is significant for diabetes in her mother and coronary artery disease in her father. The patient works as an
engineer for a computer software manufacturer and lives
with her husband, 3 school-aged children, and her widowed
64 JCOM February 2000

mother. During the history, the patient mentions that she had
received information from her health maintenance organization (HMO) about adult immunization and asks whether
she should receive a flu shot.

Who should receive an influenza vaccination?

Dr. Chenoweth:
Influenza contributes to excess medical morbidity and mortality as well as to excess costs related to medical care and
loss of productivity [5]. Vaccination remains the primary
method of preventing infection with influenza. Because of
antigenic drift, influenza vaccine must be administered annually. Vaccine efficacy varies between 70% and 90%,
depending on the match between circulating strains and
vaccine composition, but is lower in the elderly and in individuals with chronic diseases [3]. For individuals with medical conditions that predispose to influenza complications,
vaccination has been shown to decrease medical costs, hospitalizations for respiratory illnesses, and excess deaths attributable to complications of influenza [6]. In a healthy population in whom morbidity and mortality from influenza
are low, the measurable benefits are mostly economic
reducing lost workdays attributable to the workers illness
or caring for an ill dependent.
Vaccine Use in High-Risk Patients
Historically, vaccination campaigns have been directed at
increasing immunization rates in persons at highest risk
(Table 1). One group at high risk for the development of
complications or death from influenza is the elderly: 90% to
95% of deaths due to influenza occur in persons older than
65 years [68]. Although influenza vaccination may not uniformly prevent infection, vaccination in the elderly has
several benefits, including reducing physician visits, hospitalizations, and deaths in this population [69]. In a placebocontrolled trial, influenza vaccination in elderly persons
resulted in a 58% decrease in serologic or clinical influenza
[10]. In addition, vaccination of elderly patients has been
associated with a 30% to 57% reduction in hospitalizations
due to influenza or pneumonia [6,7,1113] and a 27% to 75%
decrease in deaths from all causes [6,11,13]. Among elderly
residents in long-term care facilities, influenza vaccination
has been associated with a 50% reduction in hospitalizations
and a 68% reduction in death during influenza season [8,9].
Elderly patients with underlying chronic illnesses, such as
cardiopulmonary disease, are at particularly high risk for
complications due to influenza [3,6,7].
During influenza epidemics, patients with chronic
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CASE-BASED REVIEW
pulmonary disease have a higher rate of admission for acute
respiratory disease. Asthma, bronchitis, chronic obstructive
pulmonary disease (COPD), and emphysema account for
82% of the pulmonary diagnoses associated with acute respiratory disease [14]. In a recent study of influenza vaccination
in elderly members of a managed care organization who had
chronic lung disease, vaccination was associated with a 52%
reduction in hospitalizations and a 70% reduction in deaths
from influenza or pneumonia during influenza season [6].
Patients with chronic renal disease, especially nephrotic
syndrome, appear to be at higher risk for influenza; however, the actual risk in this group is unknown [3]. Diabetes mellitus appears to be another risk factor for death and complications due to influenza. Based on cumulative data from
the National Medical Registration in the Netherlands during
influenza seasons between 1976 and 1979, patients with diabetes mellitus were at increased risk for influenza, pneumonia, diabetic ketoacidosis, and death during influenza epidemic years [15].
Immunocompromised patients, especially those who
have received a solid organ or bone marrow transplantation,
are at risk for complications from influenza [3,16]. Although
the majority of infections occur in the first 2 years following
transplantation, there is an increased risk for the duration
that the patient remains on immunosuppressive medications. Heart transplant recipients had a fourfold reduction in
response to influenza vaccination when compared with
healthy controls [16]. In HIV-infected patients, influenza
may cause prolonged symptoms and increase the risk of
pneumonia; however, it does not appear to be a significant
cause of mortality in this patient population [3,17]. In
1 recent study, influenza vaccination had a 100% protective
efficacy for laboratory-confirmed influenza in HIV-infected
individuals and had no effect on CD4+ cell counts or quantitative viral load [17].
Other groups that should be targeted for influenza vaccine include children receiving high-dose aspirin therapy
(eg, in the treatment of Kawasaki disease and acute rheumatic fever) because of the risk of Reyes syndrome associated
with influenza infection. Women in their second and third
trimesters of pregnancy are at increased risk for complications due to influenza [3,18]. Women in their third trimester
of pregnancy were found to be hospitalized for influenza at
a rate of 250 per 100,000 pregnant women, a rate similar to
that for nonpregnant women with other high-risk medical
conditions [18]. Because it is an inactivated vaccine, many
experts consider influenza vaccination safe at any stage of
pregnancy, but many health care providers choose to delay
vaccination until after the first trimester to avoid administering the vaccine during the period when coincidental spontaneous abortions are most likely to occur [3].

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Although health care workers are not considered a population at high risk for morbidity and mortality from
influenza, vaccinating health care workers is an important
public health strategy. Although well-designed studies
demonstrating a decrease in nosocomial influenza from vaccinating health care workers have not been published, a
trend of increasing employee vaccination and decreased
incidence of serologically proven nosocomial influenza was
noted in 1 study [19]. The Centers for Disease Control and
Prevention (CDC) endorse influenza vaccination for personnel in both hospital and outpatient care settings, employees
of nursing homes and chronic care facilities, employees of
assisted living and other residences for persons in high-risk
groups, home care providers for persons at high risk, and
household members of persons in high-risk groups [3].
Dr. Blitz:
Vaccine Use in the General Population
Vaccinating the general population not only protects immunized individuals from influenza but is essential for the development of herd immunity, the resistance of a population
to invasion and spread of an infectious agent. In addition,
influenza vaccination programs geared toward healthy
adults have demonstrated decreases in medical costs and
reductions in lost productivity [20,21]. The cost-effectiveness
of a vaccination program for a working population will
depend on the level of influenza activity and vaccine efficacy in any given year.
A randomized, double-blind, placebo-controlled trial [20]
of vaccination in a population of healthy, working adults in
the MinneapolisSt. Paul area in the 19941995 influenza
season demonstrated the cost-effectiveness of influenza vaccination. The primary outcome measures were episodes of
upper respiratory illnesses, physician visits for such illnesses, and absenteeism from work because of upper respiratory
illnesses. Influenza vaccination reduced the frequency of
upper respiratory illnesses by 25% and reduced physician
visits for upper respiratory illnesses by 44%. Lost workdays
for upper respiratory illnesses decreased from 122 days to
70 days per 100 workers, a 43% reduction [20]. Taking direct
and indirect costs into account, the authors concluded that
the vaccination program resulted in an estimated net savings
of $46.85 per vaccinee (in 1994 dollars). A prospective, nonrandomized study [21] looked at the effect of influenza vaccination on the occurrence and cost of self-reported febrile,
respiratory illnesses (influenza-like illness) in a working
population in North Carolina. Among vaccinated patients,
20% reported illness and 11% reported missed workdays
because of an influenza-like illness, compared with rates of
64% and 24% among unvaccinated patients. The cost per
saved workday was $22.36.

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INFLUENZA
Table 2. Selected Interventions to Increase Vaccination
Coverage
Increasing community demand for vaccinations
Client reminder/recall systems
Multicomponent interventions that include education (used with at
least 1 other activity to improve vaccination rates)
Enhancing access to vaccination services
Reducing out-of-pocket costs (free vaccinations, providing
insurance coverage, reducing copayments)
Expanding access in clinical settings (reducing distance from
setting to population, expanded hours, drop-in service)
Provider-based interventions
Provider reminder/recall
Assessment and feedback for vaccination providers
Standing orders
Adapted from Vaccine-preventable diseases: improving vaccination
coverage in children, adolescents, and adults. A report on recommendations from the Task Force on Community Preventive Services. MMWR
Morb Mortal Wkly Rep 1999;48(RR-8):115.

When is the optimal time for influenza vaccination?

Dr. Chenoweth:
The timing of the influenza vaccine is important to optimize
protection of high-risk patients. The antibody response to
influenza vaccine develops between 10 to 14 days following
vaccination. Protective antibodies, however, may begin to
decline after a few months [3,22]. Since most outbreaks of
influenza peak between late December and March, the optimum time to give the vaccine is October through midNovember [3]. However, to maximize the number of persons vaccinated, influenza vaccine should be offered to
high-risk patients during routine office visits or during hospitalization beginning in September [3]. Vaccination after
December for individuals who have not received it earlier
should not be denied.

What strategies can be used to increase immunization

rates?

Dr. Blitz:
Increasing Compliance with Vaccination
Immunization of adults older than 65 has been steadily
increasing [23]. In 1997, 65.6% of persons in this age-group
received vaccination, a rate that exceeds the Healthy People
66 JCOM February 2000

2000 target rate of 60%. Vaccination rates for high-risk

adults, however, have not reached this level. Since advanced
age and chronic illness appear to reduce the immunologic
response to influenza vaccine, vaccination rates well beyond
60% may be necessary to achieve desired outcomes from a
public health perspective. In 1999, the American Academy of
Family Physicians lowered the recommended age to begin
annual influenza vaccination from 65 years to 50 years [24].
The higher rates achieved in the elderly may reflect the
greater efficiency and acceptance of a universal vaccination
policy as opposed to a program that depends on identifying
and targeting patients with risk factors.
Nichols 10-year study [25] examining the impact of a program to increase immunization rates among a population of
high-risk veterans suggests several factors critical to increasing vaccine acceptance and delivery. These include provider
recommendations, systems to identify at-risk populations, an
efficient and comprehensive delivery process, and performance assessment. A strong recommendation from a patients personal medical provider is critical for the adoption of
several healthy lifestyle decisions, including smoking cessation and immunization [26,27]. Although timed mailings
from a medical clinic or health insurer may raise awareness
of the benefits of vaccination, a discussion regarding the epidemiology, risk factors, and effectiveness of the vaccine and
an explicit recommendation for vaccination is often the key
factor in acceptance.
In addition to discussing the benefits of vaccination,
physicians must address patients fears regarding vaccine
side effects. Patients often cite fear of vaccine side effects as a
deterrent to vaccination [28,29]. The frequency of adverse
effects of the vaccine has been investigated in several welldesigned studies. The only difference found between
influenza and a saline placebo injection was a higher frequency of local soreness at the influenza injection site
[28,30,31].
A comprehensive report on recommendations for improving vaccination coverage prepared by the Task Force on
Community Preventive Services [29] evaluated 17 interventions for increasing vaccination coverage. Based on an extensive literature review, the specific interventions were rated
for effectiveness. Strategies to improve vaccination rates
should be directed toward the root causes of undervaccination; specific interventions found to be effective are listed in
Table 2.
Two Months Later
Two months ago, at her previous visit, the patient
decided against the influenza vaccination, stating
that Ive never had the flu so I dont want to rock the boat.
Now, she calls her PCPs office and tells the triage nurse that
she has had a temperature of 101F, myalgias, and headache
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CASE-BASED REVIEW
for the past 36 hours. She is in the midst of a major project at
work, and she and her colleagues are dismayed that she had
to miss work today. She says that she saw a television advertisement for a new medicine that will cure the flu and asks
that the doctor call in a prescription.

Can influenza be diagnosed based on this patients

signs and symptoms?
Which tests can confirm the diagnosis of influenza?

Dr. Blitz:
Clinical Diagnosis
The clinical picture most often associated with influenza is
the sudden onset of fever accompanied by myalgias, lethargy, cough, and headache [32]. None of these signs and symptoms, however, effectively differentiate influenza from other
common respiratory diseases that occur during the winter
and early spring months (eg, parainfluenza, respiratory syncytial virus, adenovirus, mycoplasma or even pneumococcal
pneumonia). The likelihood of influenza being the etiologic
agent for an upper respiratory infection is proportional to its
prevalence in a particular community during a specific time
period. This epidemiologic diagnosis of disease has been
considered by some authorities to be adequate for empiric
treatment when influenza prevalence is high [33].
The diagnostic performance of typical symptom complexes has been evaluated in comparison with a variety of
laboratory diagnostic methods [3437]. The precise positive
predictive value of the presence of fever with some combination of myalgias, fatigue, and upper respiratory symptoms depends on the specific symptoms, the laboratory
method for confirming infection with influenza, and the
presence or absence of an influenza outbreak during the
study period. The range generally falls between 30% and
70%. In a study of the safety and efficacy of zanamivir [37],
57% of study participants with an influenza-like illness had
culture-proven influenza. Of participants who were febrile
on entry into the study, 74% had culture-proven influenza.
This suggests that fever early in the course of the infection
may be a marker for influenza. In contrast, in individuals
with acute rhinorrhea, nasal congestion, and/or sore throat
without fever (ie, symptoms of the common cold), rhinovirus was the most common pathogen found (52.5%) and
influenza accounted for only 6% of the cases [38].
Laboratory Testing
The ideal method for diagnosing influenza would have high
sensitivity and specificity for identification of infection, be
relatively simple and inexpensive to administer, and allow
Vol. 7, No. 2

for diagnosis early in the course of disease when antiviral

medication is effective [39]. At the present time, a diagnostic
method that fulfills all these criteria has yet to be developed,
but there are innovations that may bring us closer to the
ideal test.
Viral culture is costly, and there is a lengthy interval of
3 to 20 days until isolation is completed, but this method has
been considered the gold standard for diagnosis. The use
of viral culture is critical for characterizing circulating subtypes and strains, information that is necessary for assessing
the match between vaccine strains and current circulating
viruses and helping to determine the vaccine composition
for the coming year [3]. New technology involving viral
amplification, such as reverse transcription polymerase
chain reaction (PCR), has recently been evaluated for its utility in detection of influenza. The sensitivity of PCR appears
to exceed that of viral culture, with no decrease in specificity
[40]. Although currently PCR is fairly labor intensive and
therefore expensive, further automation of the technology
should result in decreased cost as well as faster turnaround
than the existing 2- to 4-day time frame.
Currently, several commercial assays that can detect
influenza antigens in the respiratory secretions are available
for use in a clinic or physicians office as well as in a more
conventional laboratory setting. These methods have the
advantage of being relatively simple to administer and yield
rapid results, often in less than 1 hour. The most widely
employed rapid tests use fluorescent antibody (direct and
indirect) or enzyme immunoassay techniques. They are relatively inexpensive, but several require a Clinical Laboratory
Improvement Act (CLIA)approved laboratory, which may
prove a barrier to wide introduction into the office setting.
No published study has directly compared the sensitivity,
specificity, and positive and negative predictive value of
these rapid assays, but sensitivities in the 70% to 90% range
have been reported, with specificities slightly higher [4144].
To optimize the sensitivity of most of the rapid diagnostic
tests, specimens of nasopharyngeal aspirates should be
used. Obtaining this specimen is more time consuming and
less acceptable to patients than a simple throat swab.

What agents are used for treatment of influenza?

Dr. Blitz:
Older Antivirals
Amantadine and rimantadine have been demonstrated to be
effective for both treatment and prophylaxis of influenza A
[33]. Their mechanism of action appears to be inhibition of
viral replication by blocking the viral M2 protein ion channel
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INFLUENZA
Table 3. Drugs for Treatment of Influenza in Adults
Drug

Dosage

Cost*

Amantadine

100 mg bid 5 days

0$3.65

Rimantadine

100 mg bid 5 days

$17.47

Zanamivir

2 inhalations (10 mg) bid 5 days

$44.10

Oseltamivir

75 mg bid 5 days

$53.00

Comments
Rapid emergence of viral resistance; gastrointestinal and central
nervous system toxicity, particularly in elderly populations
Rapid emergence of viral resistance; reduce dosage with hepatic and
renal dysfunction
Respiratory irritation reported; use with caution in patients with
bronchospasm
Reduce dosage in renal disease; can cause nauseashould be taken
with food

*1999 average wholesale price.

[45]. The utility of these drugs is limited for several reasons.

For one, they are effective only against influenza A virus.
Although influenza A is the major subtype implicated in epidemic influenza, the relative proportion of subtypes causing
disease will vary by influenza season, and treatment that is
effective against only 1 subtype makes empiric therapy
based on clinical diagnosis less acceptable. To be effective,
these drugs must be started within 48 hours of symptom
onset. Adverse effects, which include nausea, anorexia, and
central nervous disturbances such as disorientation and
lightheadedness, are frequent, particularly in older individuals where decreased elimination leads to higher plasma
levels. A major limitation is the propensity of both drugs to
induce viral resistance, a significant problem when low-risk
patients receiving treatment develop resistant strains that
can be transmitted to high-risk contacts [33].
Neuraminidase Inhibitors
A new generation of antiviral agents for treatment and prophylaxis of influenza ushered in this millennial influenza
season. Inhaled zanamivir (Relenza, Glaxo Wellcome) and
oral oseltamivir (Tamiflu, Roche) are the first in a class of
neuraminidase inhibitors, agents that address some of the
limitations of amantadine and rimantadine. Neuraminidase
is one of the glycoproteins on the surface of both influenza A
and influenza B viruses and is used in the typing scheme of
the myriad of strains of influenza. Neuraminidase is essential for viral replication and for the release of virus particles
from cells and prevents inactivation of influenza virus by
respiratory mucous [46]. The new drugs bind neuraminidase and have been demonstrated in several recent studies
to be effective for the treatment, as well as prophylaxis, of
influenza A and B.
Zanamivir reduces the median number of days to alleviation of major symptoms by 1 to 1.5 days and reduces the
time to resumption of normal activity and the use of
symptom-relief medications. The effect appears to be great-

68 JCOM February 2000

est in febrile and more symptomatic patients. The drug is

generally well tolerated, although reports of respiratory irritation from the inhaled drug have been reported [37,47].
Treatment with oseltamivir demonstrated similar findings
in symptom reduction and time to symptom resolution. In
addition, viral titers and viral shedding were reduced in a
group of treated patients compared with a placebo-treated
group. Transient mild to moderate nausea after dosing was
observed, which was largely prevented by ingestion with
food [48]. Although treatment with either drug has been
demonstrated to be effective if initiated within 48 hours
after onset of symptoms, effectiveness is improved if therapy is begun even earlier in the course of the disease
(30 hours or less) [49]. The efficacy studies of zanamivir and
oseltamivir have been conducted in populations with a limited number of high-risk and older individuals. Whether
they will prove as effective in those populations is yet to be
determined.
Emergence of drug-resistant strains associated with use
of the older antivirals has not been noted in the neuraminidase inhibitor studies. Only 1 instance of resistance has been
found, and this occurred when zanamivir was given for a
prolonged period to an immunosuppressed child [50].
Further experience in using these drugs may provide more
information regarding resistance.
No studies have directly compared the effectiveness of
the 4 drugs currently available for treatment of influenza A
(Table 3), but the available information indicates that the
agents are roughly comparable in shortening the duration of
symptomatic illness. However, none of the drugs has been
shown to decrease serious morbidity from influenza [46].

What factors must be considered in the management of

patients with influenza symptoms?

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CASE-BASED REVIEW
Dr. Fendrick:
Factors That Affect Decision Making
Management options for patients with influenza symptoms include empiric treatment with an antiviral agent, treatment after
rapid testing is positive for influenza, or use of symptomatic
over-the-counter treatments. The best approach can be determined only by well-designed studies that consider the relevant
epidemiologic, clinical, and economic issues. In the meantime,
direct-to-consumer advertising campaigns by manufacturers
of the neuraminidase inhibitors are pressing providers to consider their approach to the flu-suffering patient.
The decision-making process should include consideration of the likelihood of influenza in a particular patient; the
medical, economic, and social costs of the individuals disease;
the effectiveness of treatment options; the potential adverse
effects of the treatment; and treatment costs. During an influenza outbreak, the likelihood of correctly diagnosing
influenza based on the presence of an acute, febrile respiratory illness may be comparable to the sensitivity and specificity
of the rapid, in-office laboratory kits [51]. Providers who
choose to treat patients empirically should be familiar with the
influenza statistics in their area. The CDC publishes weekly
influenza surveillance on its Web site at www.cdc.gov/
ncidod/diseases/flu/weekly.htm. The surveillance methodology is detailed on the Web site at www.cdc.gov/ncidod/
diseases/flu/flusurv.htm. In addition to the CDCs service,
local and state health departments are a good source of information on the prevalence of influenza in a particular community. Providers who prefer to test for influenza prior to making
treatment decisions should understand the sensitivity and
specificity of the test being used and must ensure that testing
will not delay initiation of treatment beyond the recommended 48-hour time frame. Systems for triaging patients phone
calls, expediting appointments, and ensuring timely test
results must be in place to optimize outcomes resulting from
the providers decision.
Benefits to be gained from antiviral therapy include
maintaining the productivity of the work force; decreasing
the social disruption and stress experienced by ill individuals, caregivers, and dependents; and improving the quality
of life for individuals with influenza. An indirect benefit of
effective antiviral therapy may be a reduction in inappropriately prescribed antibiotics [47]. Influenza vaccine has been
demonstrated to decrease secondary bacterial infections in
children [52]; antiviral therapy that ameliorates the disease
may have that effect as well.
As previously mentioned, the cost of lost workdays and
over-the-counter drugs for a population of individuals who are
ill but do not seek medical treatment in a future influenza pandemic in the United States has been estimated to range
between $71 and $166 billion (in 1995 dollars), depending on

Vol. 7, No. 2

Table 4. Indications for Consideration of Chemoprophylaxis

Protection of high-risk individuals
Persons at high risk who are vaccinated after influenza activity
has begun
Unvaccinated persons who provide care for those at high risk
Persons who are expected to have poor response to vaccine
Persons at high risk for whom vaccine is contraindicated
Control of influenza outbreaks in institutions
Residents of facilities where outbreak is suspected or evident
Unvaccinated staff who provide care for persons at high risk
Adapted from Prevention and control of influenza: recommendations of
the Advisory Committee on Immunization Practices (ACIP). MMWR
Morb Mortal Wkly Rep 1999;48(RR-4):128.

the gross attack rate. Although it is clear that disability due to

influenza has a significant impact on the U.S. economy, treatment to ameliorate the disease has not been advocated except
for those individuals at highest risk of morbidity. Concerns
regarding toxicity and the rapid development of viral resistance are the most significant factors limiting the use of the
older antivirals, and these issues have, until recently, rendered
immaterial the question of treatment for low-risk individuals
with influenza. The introduction of the neuraminidase
inhibitors, well-tolerated and effective drugs for both influenza A and influenza B, has elevated the question of treatment to
one that must be answered by well-designed and rigorous
cost-effectiveness analyses.
Diagnosis and Prescription of Therapy
The physician checks the CDCs influenza surveillance Web site and confirms that epidemic levels of
influenza activity are present in the patients locale. Since the
patients clinical history is compatible with influenza, the
prevalence of influenza in the area is high, and the patient is
insistent that she cannot miss work, the physician decides to
empirically treat her for influenza. He calls in a prescription
for one of the neuraminidase inhibitors.
When the nurse calls the patient with this information,
the patient states that she is concerned that her children may
catch her flu and miss school. She is also worried about
her diabetic mother, even though her mother receives
influenza vaccination yearly. She asks if there is any way to
decrease her familys chance of becoming infected.

What is the role of antiviral agents in influenza prophylaxis?

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INFLUENZA
Dr. Chenoweth:
The importance of vaccination as the primary means of
reducing the incidence of influenza cannot be overstated.
Under certain circumstances, prophylactic drugs may be
complementary to the vaccine (Table 4). Amantadine and
rimantadine, currently the only drugs approved by the U.S.
Food and Drug Administration for influenza A prophylaxis,
are approximately 70% to 90% effective in preventing illness
from the infection [3]. Zanamivir and oseltamivir have been
demonstrated to be equal in effectiveness to amantadine and
rimantadine and are effective against both influenza A and
influenza B but have not been approved for prophylaxis
[37,48,53]. Prophylaxis is indicated for high-risk patients
who may not respond to vaccine; high-risk patients in whom
vaccine is contraindicated or who are vaccinated after
influenza activity has begun; and patients in institutions (eg,
long-term care facilities and hospitals) during influenza outbreaks. Further studies are needed to examine the benefits
and costs of prophylaxis for family members of patients with
influenza. Cost-effectiveness will likely be greatest in prophylaxis of high-risk patients, such as the mother of the
patient in this case and residents in long-term care facilities.
Cost of Treatment
When the patient goes to the pharmacy to pick up
her prescription, she is told that the drug is not part
of her HMOs formulary and she will have to pay the $55
price out of pocket. Since her supervisor has insisted that the
patient is urgently needed at work, she contemplates asking
her employer for reimbursement.

Who will pay for antiviral therapy for influenza?

Dr. Fendrick:
The benefits and costs of any innovation in health care can be
considered from several perspectives. Indeed, in this case,
the patients employer may benefit the most from the patients early return to function. Who will benefit, who will
pay, and what information will be included in the influenza
practice guidelines have yet to be clarified. What is apparent
is that the renewed interest in influenza prevention and
treatment generated by the introduction of new interventions should prove a positive step in further reducing the
burden of this preventable disease.
The authors thank Bonita Kothe for assistance in preparation of
the manuscript.

70 JCOM February 2000

Author addresses: Dr. Blitz: C380 Med Inn 380, 1500 E. Medical
Center Dr., Ann Arbor, MI 48109, e-mail sblitz@umich.edu.
Dr., Chenoweth and Dr. Fendrick: 3116 Taubman Center, Box
0376, Ann Arbor, MI 48109.

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Copyright 2000 by Turner White Communications Inc., Wayne, PA. All rights reserved.

72 JCOM February 2000

Vol. 7, No. 2

JCOM

CME
EVALUATION FORM: Developments in the Care of Influenza Patients: Priorities and Perspectives

DIRECTIONS: Each of the questions or incomplete statements below is followed by four possible answers or completions of the statement. Select the ONE lettered answer that is BEST in each case and circle the corresponding letter
on the answer sheet.

1. Influenza is responsible for an estimated annual excess

mortality in the United States of
(A) 2000 to 5000
(B) 10,000 to 20,000
(C) 20,000 to 40,000
(D) 100,000 to 200,000
2. All of the following groups are at high-risk for influenza
complications EXCEPT
(A) Pregnant women in the third trimester
(B) Individuals with diabetes mellitus
(C) Persons with HIV
(D) Health care workers
3. Which of the following statements about influenza vaccine is true?
(A) Efficacy is dependent upon the match between circulating antigens and vaccine composition
(B) Vaccine efficacy generally ranges between 50% to
70%
(C) Vaccine should not be used in pregnant women
(D) Adverse reactions to the vaccine are frequent

Vol. 7, No. 2

4. An advantage of the culture method for identifying

influenza is that
(A) It is inexpensive
(B) Results are available within 24 hours
(C) It allows for early treatment
(D) It helps in determining the antigen composition of
the vaccine for the coming year
5. Which of the following statements about the neuraminidase inhibitors is true?
(A) They are more effective than rimantadine and
amantadine against influenza A
(B) They have no side effects
(C) They have less potential to induce viral resistance
(D) They are less expensive than rimantadine and
amantadine

JCOM February 2000 73

JCOM

CME
EVALUATION FORM: Developments in the Care of Influenza Patients: Priorities and Perspectives

To receive CME credit for this case study, read the case study
and then answer the multiple-choice questions on page 73.
Circle your answers below. Also, please respond to the
four questions that follow. Then, detach the evaluation form
and mail or FAX to:

JCOM CME Evaluation

Wayne State University
University Health Center, 5E
4201 St. Antoine
Detroit, MI 48201
Phone: (313) 577-1453 FAX: (313) 577-7554

Please print clearly:

Name: ______________________________________________
Address: ____________________________________________

Circle your answer to the CME questions below:

1.

2.

3.

4.

5.

Please answer the following questions:

1.

In general, how do you rate the information presented

in the case study?
excellent
good
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2.

Do you find the information presented in this case study

to be fair, objective, and balanced?
yes
no

3.

Name three clinical conditions that, in your experience,

lead to less than optimal patient outcomes:

Condition 1: ________________________________________
Condition 2: ________________________________________

4.

Name three clinical topics you would like explored in

future JCOM case studies:

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Medical specialty: ____________________________________

Note: CME credit letter and correct responses will be sent

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The Wayne State University School of Medicine
designates this continuing medical education activity for 1 credit hour of the Physicians Recognition
Award of the American Medical Association.

Cut along the dotted line

Condition 3: ________________________________________

City: ________________________________________________

Topic 1: ____________________________________________
Topic 2: ____________________________________________
Topic 3: ____________________________________________

74 JCOM February 2000

The credit designation for this activity

will expire on February 28, 2001.

Vol. 7, No. 2