Getting a jump on flu: New options in diagnosis and treatment

By John T. Benjamin MD

Widespread vaccination of children isn't yet a reality, but rapid diagnostic tests and new drugs are putting early, effective treatment of both influenza A and B within reach.

Epidemics of influenza occur nearly every year and are responsible for about 20,000 deaths a year in the United States.¹ The cornerstone of influenza control remains vaccination. At present, the Committee on Infectious Diseases of the American Academy of Pediatrics recommends giving the influenza vaccine primarily to children over 6 months of age with conditions that put them at high risk of contracting influenza, such as asthma, cardiac disease, immunosuppression, human immunodeficiency virus infection, sickle cell anemia, and diseases requiring long-term aspirin therapy.² Next year, an intranasal influenza vaccine should be available, which will make it easier to immunize larger numbers of children.³ In the absence of widespread immunization pediatricians need to be aware that they can identify influenza A and B in their office laboratories in a matter of minutes. Diagnosing influenza rapidly will enable them to treat infected patients and family members early with antiviral medications and avoid giving unnecessary antibiotics.

The symptoms of influenza are nonspecific--fever, myalgia, headache, sore throat, rhinitis, cough--making a specific diagnosis difficult. The influenza virus culture has been the diagnostic gold standard, but culture results may not be available for several days to several weeks. Since effective treatment requires beginning medication within 48 hours of the onset of symptoms, investigators have sought more rapid diagnostic techniques. Several newly developed rapid tests for influenza that can be done in the office laboratory are now available. Pediatricians will need to decide, based on their specific patient populations, whether such testing will be cost-effective in their practices. The cost-benefit reimbursement information provided here should be considered a guideline only since reimbursement varies considerably from state to state, and private reimbursement is higher than that provided by Medicaid.

The number of drugs available to treat influenza is also expanding. In addition to amantadine (Symmetrel, Symadine, others) and rimantadine (Flumadine), which are effective against influenza A, they include the promising new neuraminidase inhibitors, zanamivir (Relenza) and oseltamivir (Tamiflu), which can treat both influenza A and B.

Rapid influenza tests for the office

Table 1 lists rapid influenza tests that can be performed in the office laboratory. All of the tests are classified as moderately complex under the Clinical Laboratory Improvement Amendments (CLIA) regulations. The oldest of the rapid tests, Becton-Dickinson's Directogen Flu A, tests only for influenza A. It is marketed to hospital laboratories as well as office labs. Specimens can be collected by throat swab, nasopharyngeal swab, nasal aspirate, or nasopharyngeal wash. The test, which is based on an antigen-antibody reaction, takes 15 minutes to run. It has a sensitivity of 67% and a specificity of 92%, according the package insert, although a recent communication from the manufacturer claims 91% sensitivity and 95% specificity. The test requires nine reagents and about 10 minutes of hands-on time to complete the eight absorbing steps and the five-minute incubation. Because of the long hands-on time, many busy offices find it difficult to perform this test. Medicaid reimbursement is around $10 more per test than the cost if the test is charged under CPT code 85651.

Influenza B causes about 35% of influenza infections in children. These infections are indistinguishable clinically from those caused by influenza A. The advent of medications to treat both influenza A and B has created a need to develop office laboratory tests that will rapidly identify both types of influenza. Three such tests have been introduced in the past year: the ZstatFlu test by ZymeTx Inc., Flu OIA by Biostar, and, most recently, the QuickVue Influenza test by Quidel. Positive results from these tests indicate the presence of either influenza A or B but do not specifically identify which one.

The ZstatFlu test, which has a sensitivity of 62% and a specificity of 99%, is a neuraminidase assay that identifies the same active enzyme site on the surface of the virus that the new antiviral drugs target. It uses a throat swab specimen only. The test takes 30 minutes to complete, but the time will soon be shortened to 20 minutes. Unlike the Directogen Flu A test, it requires only one minute of hands-on time. The cost per test averages $16.50, and Medicaid reimbursement is only a few dollars more at $18.74, using CPT code 86710.

The Biostar Flu OIA (optical immunoassay) uses specimens obtained from nasal aspirates, nasal swabs, throat swabs, and sputum. Sensitivity and specificity for throat swab specimens are reported at 79.5% and 62% respectively. Sensitivities for specimens obtained from the nasopharynx, nasal aspirate, and sputum are 83%, 88%, and 81% respectively, while the specificities are 76.6%, 69%, and 51%. The test takes 15 minutes to perform and requires less than two minutes of hands-on time, according to the manufacturer. Cost and Medicaid reimbursement under CPT codes 87899 or 87449 are about the same: $16.50 and $16.58 per test respectively.

The QuickVue Influenza test by Quidel was approved by the FDA in September 1999, and test kits became available in November. Specimens for this test can be obtained from nasal swabs or nasal aspirates only, not throat swabs. Sensitivity and specificity are 73% and 95% to 99% respectively. The test takes 10 minutes to perform and involves less than one minute of hands-on time. The test costs $18.33, and Medicaid reimbursement under CPT code 87449 is $16.58.

Treating influenza in children

Amantadine and its close derivative rimantadine have been used effectively to treat influenza A in children for a number of years (Table 2). Both are available in liquid and pill form. In order to be effective, treatment must be started within 48 hours of onset of illness. Amantadine and rimantadine also can be used as prophylaxis against influenza A. Since neither drug has been tested in infants, these products are not recommended for children younger than 1 year. Dosages for both treatment and prophylaxis are 4 to 8 mg/kg/d, averaging 5 mg/kg/d up to 150 mg per day for children under 10 years of age and 200 mg per day in older children and adults. High-risk children should receive chemoprophylaxis with amantadine or rimantadine for two weeks after immunization against influenza to protect the patient while antibodies develop.² Neither medication interferes with the antibody response to the vaccine.

Side effects and adverse reactions are minimal with both amantadine and rimantadine. Nervousness, anxiety, difficulty concentrating, and lightheadedness are more common among persons taking amantadine than rimantadine. Concomitant administration of antihistamines or anticholinergic drugs can increase central nervous system side effects. Gastrointestinal side effects occur in 1% to 3% of patients. They disappear after discontinuation of the drug. Unfortunately increasing resistance of the influenza A virus to amantadine and rimantadine during treatment has been reported.⁴

In July 1999, the Food and Drug Administration approved zanamivir for treating influenza A and B. The drug selectively inhibits influenza A and B neuraminidases. These enzymes facilitate the spread of the influenza virus in several ways: They allow infected cells to release the virus, prevent formation of viral aggregates after release from cells, and may prevent viral inactivation and promote viral penetration into respiratory epithelial cells. According to one study, giving zanamivir within 30 hours of the onset of influenza symptoms reduces the number of days of illness from seven to four.⁵ Since insufficient data were obtained on children, the medication is approved only for persons over 12 years of age. It is given as an oral inhalation using a Diskhaler, which is a hand-held, breath-activated device. When the patient takes a breath, the Diskhaler delivers zanamivir directly to the surface of the respiratory tract. Treatment is twice a day for two days. Side effects were found to be no greater than those occurring with placebo.

As a prophylactic agent, zanamivir given one a day for four weeks was found to be 67% effective in protecting against laboratory-confirmed clinical influenza and 84% effective against laboratory-confirmed illness with fever.⁶

Oseltamivir, a neuraminidase inhibitor in pill form, received FDA approval for treating influenza A and B in October 1999. Even though Hayden and colleagues found the medication to be effective in preventing influenza,⁷ the FDA has approved it only for treatment in patients over 18 years of age at a dosage of 75 mg bid for five days. Side effects include nausea, vomiting, bronchitis, and trouble sleeping. Efficacy in patients with chronic cardiac or respiratory disease has not been established.

Oseltamivir has been tested only in adults so far. It is rapidly hydrolyzed to the active metabolite GS4071, which selectively interferes with the activity of neuraminidase. In a double-blind, placebo-controlled study, an osaltamivir-treated group infected with influenza improved at 52.6 hours vs. 94.8 hours for the placebo group.⁸ Preliminary studies also show that the drug is effective as a prophylactic agent against both influenza A and B.⁷

Faster diagnosis, earlier treatment

Controlling influenza depends primarily on protecting individuals at high risk by vaccination, but many children still become ill with the flu every year. By taking advantage of new diagnostic tests that identify influenza A and B rapidly and giving medications that are effective against both types, pediatricians can treat patients and their families early and avoid unnecessary use of antibiotics. Newly approved drugs also show promise of broadening the available options for preventing influenza.

THE AUTHOR is Professor of Pediatrics at the Medical College of Georgia, Augusta.

REFERENCES

1. Advisory Committee on Immunization Practices (ACIP): Prevention and control of influenza: Recommendations of the Advisory Committee on Immunization Practices. MMWR April 30, 1999;48(RR-04):1

2. Peter G (ed): 1997 Red Book: Report of the Committee on Infectious Diseases, ed 24. Elk Grove Village, IL, American Academy of Pediatrics, 1997, pp 307­315

3. Jackson LA, Holmes SJ, Mendelman PM, et al: Safety of a trivalent live attenuated intranasal influenza vaccine, FluMist, administered in addition to parenteral trivalent inactivated influenza vaccine to seniors with chronic medical conditions. Vaccine 1999;17:1905

4. Cox NJ, Hughes JM: New options for the prevention of influenza (editorial). N Engl J Med 1999;341:1387

5. Hayden FG, Osterhaus ADME, Treanor JJ, et al, for the GG167 Influenza Study Group: Efficacy and safety of the neuraminidase inhibitor Zanamivir in the treatment of influenza virus infections. N Engl J Med 1997;337:874

6. 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

7. Hayden FG, Atmar RL, Schilling M, et al: Use of the selective oral neuraminidase inhibitor oseltamivir to prevent influenza. N Engl J Med 1999;341:1336

8. Hayden FG, Lobo M, Treanor JJ, et al: Efficacy and tolerability of oral GS4104 for the early treatment of experimental influenza in humans. Abstract #LB-26. In 37th Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, Canada, Sept 28­Oct 1, 1999

John Benjamin. Getting a jump on flu: New options in diagnosis and treatment. Contemporary Pediatrics 2000;1:75.