ABSTRACT: When influenza is present in the community, clinical symptoms are as accurate as rapid point-of-care tests for making the diagnosis; in this setting, the combination of cough and fever (temperature, 37.7°C [100°F] or higher) of acute onset has a positive predictive value of 77% to 79%. Accurate diagnosis ensures timely administration of antiviral agents and prevents unnecessary antibiotic use. In elderly persons, vaccination reduces illness severity, incidence of complications, and mortality. An intranasal vaccine is a new option for persons aged 5 to 49 years who are at risk for complications and refuse injection. Chemoprophylaxis with amantadine, rimantadine, or a neuraminidase inhibitor is a useful adjunct to vaccination in certain groups, such as nursing-home residents. Antiviral therapy started within 24 to 48 hours of symptom onset can reduce the duration of illness by 1 to 1.5 days and ameliorate symptoms in patients with uncomplicated influenza. However, treatment is expensive and does not prevent complications.
Influenza viruses cause nearly 20 million respiratory infections each year in the United States. Between 30% and 50% of persons younger than 18 years are affected, as well as 10% of all adults and up to 25% of adults older than 65 years. More than 150,000 hospitalizations and 20,000 deaths are caused by influenza annually; of these, 90% occur in patients older than 65 years.1
The risk of complications is highest in elderly and very young patients, as well as those with chronic illnesses, such as diabetes and cardiovascular disease. In the last 20 years, influenza deaths among elderly persons have increased dramatically2-a fact that underscores the need for improved preventive measures.
In this article, I address current issues in diagnosis, treatment, and prevention. I will also discuss the newly approved intranasal vaccine.
The symptoms of influenza are listed in Table 1. Influenza is generally diagnosed clinically; however, the advent of new antiviral agents has heightened the need for rapid and reliable diagnostic methods. Accurate diagnosis of influenza also helps prevent unnecessary antibiotic use.
Three recent studies have shown that clinical manifestations alone have a high positive predictive value (PPV) for influenza, compared with viral culture and polymerase chain reaction (PCR) testing.3-5When influenza is present in the community, the combination of acute onset of cough and temperature of 37.7°C (100°F) or higher (37.2°C [99°F] or higher in those older than 65 years) has a PPV of 77% to 79%.4 The more severe the cough or fever, the higher the PPV. Sore throat was more commonly associated with noninfluenza respiratory illnesses.3 A PPV of 75% was found for the combination of headache and fever of acute onset, cough, and lack of influenza vaccination.5
The gold standard of laboratory testing has been viral culture, although influenza viruses are difficult to grow in the laboratory and results take 5 to 10 days when respiratory samples are sent to a reference laboratory. Newer techniques are being developed. Reverse transcriptase PCR testing may replace viral culture because it is more specific and yields results in 1 to 2 days.3 Serologic testing using paired acute and convalescent serum samples takes 1 to 2 weeks. This analysis is typically reserved for confirmatory testing. Immunofluorescence and enzyme immunoassay testing are quicker than culture or serologic testing but still require 2 to 4 hours, which is impractical for point-of-care results.
Rapid tests for influenza A and B are described in Table 2; results are available in 30 minutes or less. However, the reported sensitivity of these tests (which ranges up to about 80%, with a specificity of over 90%) is not significantly better than that of the combination of the clinical symptoms of cough and fever of acute onset.
Consider using these tests when influenza is suspected at a time remote from community outbreaks; confirm the results with periodic viral cultures. You may also wish to consider rapid tests in sicker patients who may benefit from antiviral medications.
Vaccination is appropriate in the general population; it can be used to prevent and control influenza epidemics. Chemoprophylaxis may be helpful in certain groups of at-risk patients.
Vaccination. Inactivated intramuscular vaccines are available as whole virus, split product, or neuraminidase/hemagglutinin subunit formulations. These are developed yearly to match predicted strains of influenza for the coming season. The optimal timing for administration in the northern hemisphere is October through mid-November. The protection afforded by the vaccine lasts 4 to 6 months.6 Its efficacy ranges from 30% to 80% depending on the population, the end points measured, and the match between vaccine and circulating virus.6
In young healthy adults, vaccination is 70% to 90% effective. It is somewhat less effective in elderly persons and those with chronic illnesses but nevertheless reduces illness severity and incidence of complications. Studies indicate that vaccination reduces hospitalizations by 70% and mortality by 85% in elderly community-dwelling persons. It reduces hospitalizations by 50%, risk of pneumonia by 60%, and mortality by 80% in elderly nursing-home residents.7
The evidence strongly supports influenza vaccination, especially in elderly persons. The number needed to treat (NNT) to prevent hospitalization in older adults ranged from 65 to 115 in observational studies.6 Cost savings of $5 million during a 3-year period have been reported. In persons older than 65 years, the net savings of vaccination per quality-adjusted-life-year (QALY) gained was $10 to $117 per vaccination.7
Young healthy adults are at higher risk for influenza than elderly persons; however, they are much less likely to suffer complications. The NNT to prevent an upper respiratory tract infection in young persons is 13. However, vaccination is not cost-effective in this group; one study showed a net cost of $66 per vaccination per QALY gained.8
The CDC has specific recommendations regarding candidates for vaccination (Table 3). However, in general, any person older than 6 months who has no contraindications may be vaccinated. The most appropriate candidates are persons at increased risk for complications of influenza.
An intranasal vaccine recently became available (Box).
Chemoprophylaxis. This is not a substitute for vaccination but an adjunct for prevention and control of influenza in special populations, such as nursing-home residents (Table 4). Patients at high risk for influenza-related morbidity who are vaccinated after an epidemic has begun, as well as high-risk contacts of a known case, might also benefit from short-term prophylaxis. The most commonly used chemoprophylactic agents, amantadine and rimantadine, are approximately 70% to 90% effective in preventing illness from influenza A-but not influenza B-virus infection.7These agents have been studied extensively in nursing homes and other chronic-care institutions. Amantadine is associated with neurologic side effects (agitation and difficulty in concentration) in 10% of patients.
The neuraminidase inhibitors oseltamivir and zanamivir, which were originally developed for treatment, are also effective chemoprophylactic agents. Only oseltamivir has been approved for this indication, but zanamivir has similar efficacy. Community studies show these agents to be 80% to 85% effective (NNT, 25 to 30).11,12 They also prevent influenza in household contacts of a patient with the disease. Only limited data are available on the use of these medications in chronic-care settings and among persons who are severely immunocompromised.
Chemoprophylaxis is recommended during the period of peak influenza activity only; timing and length of administration depend on cost, compliance, and side effects.
For maximum effectiveness, all medications must be started within 2 days of symptom onset. Studies have shown that influenza medications can reduce the duration of illness by 1 to 1.5 days and relieve symptoms.13-15 However, none of these agents prevent serious influenza-related complications. All studies involved healthy patients with uncomplicated influenza. Amantadine and rimantadine are effective only against influenza A. Rimantadine is better tolerated than amantadine, which has a high incidence of CNS side effects.16
Oseltamivir and zanamivir are effective against both influenza A and B. They decrease the duration of illness by 1 to 1.5 days and decrease symptom scores.13-15 Higher rates of side effects were noted with oseltamivir, but there was no increase in withdrawal because of these effects.14Because these agents are expensive and do not prevent complications, their use is best reserved forpatients who present within 48 hours of illness and have the typical clinical signs and symptoms of influenza.
Antipyretics are sometimes used in influenza; acetaminophen and ibuprofen are the recommended agents. However, a recent observational study indicated that acetaminophen might prolong the duration of illness in patients with influenza A.17
REFERENCES:1. Newton DW, Treanor JJ, Menegus MA. Clinical and laboratory diagnosis of influenza virus infections. Am J Manag Care. 2000;6(suppl 5):S265-S275.
2. Thompson WW, Shay DK, Weintraub E, et al. Mortality associated with influenza and respiratory syncytial virus in the United States. JAMA. 2003;289: 179-186.
3. Zambon M, Hays J, Webster A, et al. Diagnosis of influenza in the community: relationship of clinical diagnosis to confirmed virological, serologic, or molecular detection of influenza. Arch Intern Med. 2001;161:2116-2122.
4. Monto AS, Gravenstein S, Elliott M, et al. Clinical signs and symptoms predicting influenza infection. Arch Intern Med. 2000;160:3243-3247.
5. van Elden LJ, van Essen GA, Boucher CA, et al. Clinical diagnosis of influenza virus infection: evaluation of diagnostic tools in general practice. Br J Gen Pract. 2001;51:630-634.
6. Cifu A, Levinson W. Influenza. JAMA. 2000;284: 2847-2849.
7. Zimmerman RK, Ruben FL, Ahwesh ER. Influenza, influenza vaccine, and amantadine/rimantadine. J Fam Prac. 1997;45:107-124.
8. Cram P, Blirz S, Monto A, Fendrick AM. Influenza: costs of illness and considerations in the economic evaluation of new and emerging therapies. Pharmacoeconomics. 2001;19:223-230.
9. Nichol KL, Mendelman PM, Mallon KP, et al. Effectiveness of live, attenuated intranasal influenza virus vaccine in healthy working adults: a randomized controlled trial. JAMA. 1999;282:182-184.
10. Luce BR, Zangwill KM, Palmer CS, et al. Cost-effectiveness analysis of an intranasal influenza vaccine for the prevention of influenza in healthy children. Pediatrics. 2001;108:e24.
11. Welliver R, Monto AS, Carewicz O, et al. Effectiveness of oseltamivir in preventing influenza in household contacts: a randomized controlled trial. JAMA. 2001;285:748-754.
12. Monto AS, Robinson DP, Herlocher ML, et al. Zanamivir in the prevention of influenza among healthy adults: a randomized controlled trial. JAMA. 1999;282:31-35.
13. Montalto NJ, Gum KD, Ashley JV. Updated treatment for influenza A and B. Am Fam Physician. 2000;62:2467-2476.
14. Treanor JJ, Hayden FG, Vrooman PS, et al. Efficacy and safety of the oral neuraminidase inhibitor oseltamivir in treating acute influenza: a randomized controlled trial. JAMA. 2000;283:1016-1024.
15. Monto AS, Flemin DM, Henry D, et al. Efficacy and safety of the neuraminidase inhibitor zanamivir in the treatment of influenza A and B virus infections. J Infect Dis. 1999;180:254-261.
16. Wintermeyer SM, Nahata MC. Rimantadine: a clinical perspective. Ann Pharmacother. 1995;29: 299-310.
17. Plaisance KI, Kudaravalli S, Wasserman SS, et al. Effect of antipyretic therapy on the duration of illness in experimental influenza A, Shigella sonnei, and Rickettsia rickettsii infections. Pharmacotherapy. 2000;20:1417-1422.
18. Centers for Disease Control and Prevention. Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices. MMWR. 2003;(RR-08):53. Also available at: www.cdc.gov.ncidod/diseases/flu/fluvirus.htm. Accessed September 4, 2003.