The Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention (CDC) has issued recommendations on the prevention and control of influenza for the 2001–2002 influenza season. This report updates the 2000 recommendations by ACIP on the use of influenza vaccine and antiviral agents.

According to ACIP, influenza epidemics typically occur during the winter months and cause an average of 20,000 deaths per year in the United States. Rates of infection are highest among children, but rates of serious illness and death from influenza are highest among persons 65 years of age and older and persons of any age with medical conditions that place them at increased risk of complications from influenza. The ACIP states that vaccination against influenza is the primary method of prevention, but that antiviral medications are also important as an adjunct to vaccine.

Primary changes in the recommendations include new or updated information about the cost-effectiveness of influenza vaccination; the influenza vaccine supply; neuraminidase-inhibitor antiviral drugs; the 2001–2002 trivalent vaccine virus strains, which are A/Moscow/10/99 (H3N2)-like, A/New Caledonia/20/99 (H1N1)-like, and B/Sichuan/379/99-like strains; and extension of the optimal time period for vaccination through November.

The recommendations appear in the April 20, 2001 issue of the recommendations and reports series of Morbidity and Mortality Weekly Report. This report can be accessed at the Web site of the Influenza Branch, Division of Viral and Rickettsial Diseases, National Center for Infectious Diseases, CDC, athttp://www.cdc.gov/ncidod/diseases/flu/fluvirus.htm.

Recommendations for the Use of Influenza Vaccine

TARGET GROUPS

Groups at high risk for influenza-related complications include (1) persons 65 years of age and older; (2) residents of nursing homes and other chronic care facilities that house persons of any age who have chronic medical conditions; (3) adults and children who have chronic disorders of the pulmonary or cardiovascular systems, including asthma; (4) adults and children who have required regular medical follow-up or hospitalization during the preceding year because of chronic metabolic diseases (including diabetes mellitus), renal dysfunction, hemoglobinopathies or immunosuppression (including immunosuppression caused by medications or by human immunodeficiency virus [HIV]); (5) persons six months to 18 years of age who are receiving long-term aspirin therapy and, therefore, might be at risk of developing Reye syndrome after influenza infection; and (6) women who will be in the second or third trimester of pregnancy during the influenza season.

SPECIFIC POPULATIONS

Specific populations such as pregnant women, breast-feeding mothers, persons with HIV infection and travelers should also be considered for influenza vaccination. According to the ACIP, pregnant women who will be beyond the first trimester of pregnancy during the influenza season should be vaccinated, and pregnant women who have medical conditions that increase their risk of complications from influenza should be vaccinated before the influenza season, regardless of the stage of pregnancy. Influenza vaccine does not affect the safety of mothers or infants who are breastfeeding.

Persons with HIV infection, including HIV-infected pregnant women, should receive influenza vaccine because influenza can result in serious illness and vaccination can produce protective antibody titers. Persons at high risk for complications of influenza who did not receive influenza vaccine during the preceding fall or winter season should consider vaccination before travel if they plan to travel to the tropics, with large organized tourist groups at any time of year, or to the Southern Hemisphere during April to September.

PERSONS WHO SHOULD NOT BE VACCINATED

Persons with known anaphylactic hypersensitivity to eggs or to other components of the influenza vaccine should not be vaccinated without first consulting a physician. In such persons, prophylactic use of antiviral agents may be considered. However, persons who are hypersensitive to vaccine components but who are also at high risk of complications of influenza can benefit from vaccination after appropriate allergy evaluation and desensitization.

Persons with acute febrile illness usually should not be vaccinated until their symptoms have abated.

INFLUENZA VACCINE SUPPLY

Difficulties with growing and processing the influenza A (H3N2) vaccine strain and manufacturing problems resulted in substantial delays in the distribution of the 2000–2001 influenza vaccine. Because future influenza vaccine shortages are possible, the ACIP recommends steps to address the situation. These include identification and implementation of ways to strengthen the influenza vaccine supply, to improve targeted delivery of vaccine to groups at high risk and to further encourage the administration of vaccine throughout the influenza season.

TIMING OF ANNUAL VACCINATION

The optimal time to vaccinate persons in high-risk groups is usually during October and November. To avoid missed opportunities for vaccination, influenza vaccine should also be offered to persons at high risk during routine office visits or hospitalization in September, provided that vaccine is available. Health care professionals should continue to offer vaccine to unvaccinated persons after November and throughout the influenza season even after influenza activity has been documented in the community.

DOSING

Dosage recommendations vary according to age group (Table 1). The ACIP recommends that two intramuscular doses administered one month or more apart be given to previously unvaccinated children younger than nine years of age. If possible, the second dose should be given before December. However, a second dose of vaccine during the same influenza season has not been shown to improve antibody response among adults.

SIDE EFFECTS AND ADVERSE REACTIONS

The most common side effect of the influenza vaccine is soreness at the vaccination site. Fever, malaise, myalgia and other systemic symptoms can occur, but most often affect persons who have had no previous exposure to the influenza virus antigens in the vaccine. Allergic reactions are rare.

According to the ACIP, a rare link between influenza vaccine and Guillain-Barré syndrome has been suggested, but is unclear. Therefore, in persons with a history of Guillain-Barré syndrome, physicians might consider the use of influenza antiviral chemoprophylaxis instead of vaccine.

Recommendations for the Use of Antiviral Agents for Influenza

Antiviral drugs for influenza have been used as an adjunct to influenza vaccine. However, these agents are not a substitute for vaccination. Four currently licensed influenza antiviral agents are available in the United States: amantadine, rimantadine, zanamivir and oseltamivir.

Amantadine and rimantadine are chemically related antiviral drugs with activity against influenza A viruses, but not influenza B viruses. Both drugs are administered orally. Amantadine was approved in 1966 for prophylaxis of influenza A (H2N2) infection and in 1976 for the treatment and prophylaxis of influenza type A virus infections among adults and children one year of age and older.

Rimantadine was approved in 1993 for the treatment and prophylaxis of infection among adults and prophylaxis among children. Although rimantadine is approved only for prophylaxis of infection among children, some influenza experts consider it to be appropriate for treatment among children.

Zanamivir and oseltamivir are neuraminidase inhibitors with activity against both influenza A and B viruses. Both zanamivir and oseltamivir were approved in 1999 for the treatment of uncomplicated influenza infections. Zanamivir is approved for treatment of persons seven years of age and older, and oseltamivir is approved for treatment of persons one year of age and older. In 2000, oseltamivir was approved for prophylaxis of persons 13 years of age and older. Oseltamivir is administered orally, while zanamivir is administered via oral inhalation.

DIAGNOSIS

Accurate and timely diagnosis of viral respiratory illness is important when determining the appropriate treatment regimen. Early diagnosis of influenza can help to reduce the inappropriate use of antibiotics and offers patients the option of using antiviral therapy. Information obtained from influenza surveillance and diagnostic testing can help guide treatment decisions. Diagnostic tests available for influenza include viral culture, serology, rapid antigen testing and immunofluorescence.

TREATMENT

Amantadine and rimantadine can reduce the duration of uncomplicated influenza A illness when administered within two days of illness onset in otherwise healthy adults, and zanamivir and oseltamivir can reduce the duration of uncomplicated influenza A and B illness by approximately one day. None of the four antiviral agents has been shown to be effective in preventing serious influenza-related complications.

To reduce the emergence of antiviral drug-resistant viruses, use of amantadine or rimantadine in persons with influenza-like illness should be discontinued as soon as clinically warranted, usually after three to five days of treatment or within 24 to 48 hours after the disappearance of signs and symptoms. The recommended duration of treatment with zanamivir or oseltamivir is five days.

PROPHYLAXIS

Amantadine and rimantadine are approximately 70 to 90 percent effective in preventing illness from influenza A infection. When used as prophylaxis, these antiviral agents can prevent illness while permitting subclinical infection and the development of protective antibody against circulating influenza viruses.

When determining timing and duration of administering influenza antiviral medications for prophylaxis, factors related to cost, compliance and potential side effects should be considered. For maximal efficacy, the drug must be taken each day for the duration of influenza activity in the community.

DOSING

Dosing recommendations vary by age group and medical conditions (Table 2). These guidelines outline dosing recommendations for children, persons 65 years and older, persons with impaired renal function, persons with liver disease and persons with seizure disorders.

• Children. The use of amantadine among children younger than one year of age has not been adequately evaluated. For treatment and prophylaxis in children one to nine years of age, the U.S. Food and Drug Administration has approved a dosage of 4.4 to 8.8 mg per kg per day, not to exceed 150 mg per day. However, to reduce the risk for toxicity, the ACIP recommends prescribing only 5 mg per kg per day. For children 10 years and older, the approved dosage is 100 mg twice a day. Children who weigh less than 40 kg (88 lb) should take 5 mg per kg per day, regardless of age. TABLE 2

  	Age groups
  Antiviral agent	One to six years	Seven to nine years	10 to 12 years	13 to 64 years	65 years and older
  Amantadine*
  Treatment	5 mg per kg per day up to150 mg in two divided doses†	5 mg per kg per day up to 150 mg in two divided doses†	100 mg twice daily‡	100 mg twice daily‡	100 mg or less per day
  Prophylaxis	5 mg per kg per day up to150 mg in two divided doses†	5 mg per kg per day up to 150 mg in two divided doses†	100 mg twice daily‡	100 mg twice daily‡	100 mg or less per day
  Rimantadine§
  Treatment‖	NA	NA	NA	100 mg twice daily‡	100 or 200¶ mg per day
  Prophylaxis	5 mg per kg per day up to 150 mg in two divided doses†	5 mg per kg per day up to 150 mg in two divided doses†	100 mg twice daily‡	100 mg twice daily‡	100 or 200¶ mg per day
  Zanamivir#**
  Treatment	NA	10 mg twice daily	10 mg twice daily	10 mg twice daily	10 mg twice daily
  Oseltamivir
  Treatment††	Dose varies by child's weight‡‡	Dose varies by child's weight‡‡	Dose varies by child's weight‡‡	75 mg twice daily	75 mg twice daily
  Prophylaxis	NA	NA	NA	75 mg per day	75 mg per day

  NA = not applicable.

  *—The drug package insert should be consulted for dosage recommendations for administering amantadine to persons with creatinine clearance of 50 mL or less per min per 1.73m² .

  †—5 mg per kg of amantadine or rimantadine syrup = 1 tsp/22 lb.

  ‡—Children 10 years of age or older who weigh less than 40 kg (88 lb) should be administered amantadine or rimantadine at a dosage of 5 mg per kg per day.

  §—A reduction in dosage to 100 mg per day of rimantadine is recommended for persons who have severe hepatic dysfunction or those with creatinine clearance of 10 mL or less per min. Other persons with less severe hepatic or renal dysfunction taking 100 mg per day of rimantadine should be observed closely, and the dosage should be reduced or the drug discontinued, if necessary.

  ‖—Only approved for treatment in adults.

  ¶—Elderly residents of nursing homes should be administered only 100 mg per day of rimantadine. A reduction in dosage of 100 mg per day should be considered for all persons 65 years of age or older if they experience side effects when taking 200 mg per day.

  #—Zanamivir is administered via inhalation by using a plastic device included in the package with the medication. Patients will benefit from instruction and demonstration of correct use of the device.

  **—Zanamivir is not approved for prophylaxis.

  ††—A reduction in the dose of oseltamivir is recommended for persons with creatinine clearance of less than 30 mL per min.

  ‡‡—The dose recommendation for children who weigh less than 15 kg (33 lb) is 30 mg twice a day; for children weighing 15 to 23 kg (33 to 50.6 lb), the dose is 45 mg twice a day; for children weighing 23 to 40 kg (50.6 to 88 lb), the dose is 60 mg twice a day; and for children weighing more than 40 kg (88 lb), the dose is 75 mg twice a day.

  Reprinted from MMWR Morb Mortal Wkly Rep April 20, 2001;50(RR-4):1–44.

Rimantadine is approved for prophylaxis in children one year and older and for treatment in children 13 years and older. Rimantadine should be administered in one or two divided doses at a dosage of 5 mg per kg per day, not to exceed 150 mg per day for children one to nine years of age. In children 10 years and older, the approved dosage is 100 mg twice daily. Children who weigh less than 40 kg should receive 5 mg per kg per day, regardless of age.

Zanamivir is not approved for use in children younger than seven years. The recommended dosage for treatment of influenza in children seven years and older is two inhalations (one 5-mg blister per inhalation for a total dose of 10 mg) twice daily (approximately 12 hours apart).

Oseltamivir is not approved for use in infants younger than one year. Recommended treatment dosages vary by the weight of the child. For children who weigh 15 kg (33 lb) or less, the dosage is 30 mg twice a day; for children who weigh more than 15 to 23 kg (33 to 50.6 lb), the dosage is 45 mg twice a day; for children who weigh more than 23 to 40 kg (50.6 to 88 lb), the dosage is 60 mg twice a day; and for children who weigh more than 40 kg (88 lb), the dosage is 75 mg twice a day. For persons 13 years and older, the treatment dosage is 75 mg twice a day and the prophylaxis dosage is 75 mg once a day.

• Persons 65 years and older. According to the ACIP, the daily dose of amantadine for persons 65 years and older should not exceed 100 mg for prophylaxis or treatment, because renal function declines with increasing age. Among elderly persons taking 100 mg per day of rimantadine, the incidence and severity of central nervous system side effects are substantially lower than among those taking amantadine at dosages adjusted for renal clearance. A reduction in dosage to 100 mg per day should be considered for all persons 65 years and older who experience side effects when taking a dosage of 200 mg per day. There is no reduction in dosage recommended for zanamivir and oseltamivir based on age alone.

SIDE EFFECTS AND ADVERSE REACTIONS

When considering the use of influenza antiviral agents, clinicians must consider the patient's age, weight and renal function; presence of other medical conditions; indications for use; and the potential for interaction with other medications.

Amantadine and rimantadine can cause central nervous system and gastrointestinal side effects when given to young, healthy adults at dosages of 200 mg per day. The incidence of central nervous system side effects is higher in persons taking amantadine than in those taking rimantadine. Side effects are usually mild and cease soon after use is discontinued.

In clinical studies, the frequency of adverse events was similar for persons taking zanamivir and persons taking placebo. The most common adverse effects in both groups were diarrhea, nausea, sinusitis, nasal signs and symptoms, bronchitis, cough, headache, dizziness and infections of the ear, nose and throat.

Caution should be used if zanamivir is prescribed for persons with underlying chronic respiratory disease. In a study of zanamivir treatment of influenza-like illness among persons with asthma or chronic obstructive pulmonary disease, 13 percent of patients who used zanamivir and 14 percent of patients who received placebo experienced a greater than 20 percent decline in forced expiratory volume in one second or peak expiratory flow rates after treatment.

Because of the risk of serious adverse events and because the efficacy has not been demonstrated in patients with underlying airway disease, zanamivir is generally not recommended for treatment in this population. If, after fully considering the potential risks and benefits, physicians choose to prescribe zanamivir to patients with underlying chronic respiratory disease, patients should be advised to have a fast-acting inhaled bronchodilator available when inhaling zanamivir and to contact their physician if they develop difficulty breathing.

Studies showed that nausea and vomiting were reported more often among adults being treated with oseltamivir than among persons receiving placebo. These symptoms might be lessened if oseltamivir is taken with food.

Sources of Information

Information about influenza surveillance is available through the CDC Voice Information System (influenza update) at 888-232-3228; CDC Fax Information Service at 888-232-3299; or the Influenza Branch Web site at http://www.cdc.gov/ncidod/diseases/flu/fluvirus.htm. The American Academy of Family Physicians has issued an updated policy statement on distribution of influenza vaccine. The policy statement can be viewed at https://www.aafp.org/policy/comp/27.html.