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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 1918–1919. The last major pandemic occurred in 1968–1969, 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. I Vol. 7, No. 2 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. JCOM February 2000 63 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 Reye’s 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):1–28. 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 worker’s 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 [6–8]. 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 [6–9]. 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 [6,7,11–13] 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 Vol. 7, No. 2 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 Reye’s 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]. Vol. 7, No. 2 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 Minneapolis–St. Paul area in the 1994–1995 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. JCOM February 2000 65 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):1–15. • 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. Nichol’s 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 patient’s 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 “I’ve never had the flu so I don’t want to rock the boat.” Now, she calls her PCP’s office and tells the triage nurse that she has had a temperature of 101°F, myalgias, and headache Vol. 7, No. 2 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 patient’s 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 [34–37]. 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 physician’s 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 [41–44]. 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 JCOM February 2000 67 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 nausea—should 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? Vol. 7, No. 2 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 individual’s 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 CDC’s 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 provider’s 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):1–28. 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 CDC’s influenza surveillance Web site and confirms that epidemic levels of influenza activity are present in the patient’s locale. Since the patient’s 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 family’s chance of becoming infected. • What is the role of antiviral agents in influenza prophylaxis? JCOM February 2000 69 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 HMO’s 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 patient’s employer may benefit the most from the patient’s 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 [email protected]. Dr., Chenoweth and Dr. Fendrick: 3116 Taubman Center, Box 0376, Ann Arbor, MI 48109. References 1. Atkinson W, Furphy L, Humiston S, Pollard B, Nelson R, Wolfe C, editors. Epidemiology and prevention of vaccinepreventable diseases. Washington (DC): Department of Health and Human Services; 1997. 2. Meltzer MI, Cox NJ, Fukuda K. 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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. A B C D 2. A B C D 3. A B C D 4. A B C D 5. A B C D Please answer the following questions: 1. In general, how do you rate the information presented in the case study? ❏ excellent ❏ good ❏ fair ❏ poor 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: State: ________________________ Zip: __________________ Phone: ( ) ______________________________________ Social Security #:______________________________________ Medical specialty: ____________________________________ Note: CME credit letter and correct responses will be sent to the above-named person. Wayne State University School of Medicine is accredited by the Accreditation Council for Continuing Medical Education to sponsor continuing medical education for physicians. The Wayne State University School of Medicine designates this continuing medical education activity for 1 credit hour of the Physician’s 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