December 2000
CHICAGO - Influenza is a significant problem for children as well as adults.
"It's more common in children than in adults," said Frederick G. Hayden, MD, professor of internal medicine and pathology at the University of Virginia Health System in Charlottesville, Va. "The attack rates are about threefold that of adults, and there is a high rate of complications." Additionally, children often serve as vectors for transmitting the virus to adults.
For these reasons, effective treatment and prophylaxis may be helpful.
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M2 protein inhibitors are indicated for children as young as 1 year. Amantadine may be used for treatment or prophylaxis. Rimantadine (Flumadine, Forest) is indicated for prophylaxis only, although it has been shown to be effective for treatment as well.
M2 protein inhibitors have several limitations. "Their antiviral spectrum is limited to the A viruses," Hayden said. "They have relatively modest in vivo antiviral potency," and they do not reduce complications for influenza when used for treatment.
Hayden cited a study from the middle 1980s comparing rimantadine with acetaminophen in 69 previously healthy 1- to 15-year-old children. After two days of treatment, 55% of children taking rimantadine still had recoverable virus, compared with 85% of children taking acetaminophen. However, researchers also found that more children in the rimantadine group shed virus after completing treatment, compared with children in the acetaminophen group.
"Subsequent analysis found that overall 27% of these children shed a rimantadine-resistant virus," said Hayden, who spoke here at the American Academy of Pediatrics 2000 Annual Meeting. "And of those still shedding virus after termination of therapy, 43% had a resistant virus."
The biggest concern is the possibility of shedding resistant virus to healthy contacts. He cited four studies in which family members received either rimantadine or amantadine prophylaxis. Two studies found prophylaxis to be effective; two others did not. Hayden noted that in those studies, index cases were treated with the same agent that family members received for prophylaxis. "There is rapid emergence of drug resistance in index cases that spreads to their healthy household contacts, causing failures for prophylaxis." Resistance "comes on rapidly, after two to four days of treatment." And "the mutations are quite specific to close contacts."
Neuraminidase inhibitors cover both influenza A and B.
Although indicated only for adults and children older than 12 years, zanamivir (Relenza, Glaxo Wellcome) may be beneficial for younger children as well. However, because the inhalation device requires some skill to use, the drug will probably not be used in children younger than 5.
Hayden cited results of a study recently published in the Pediatric Infectious Disease Journal of inhaled zanamivir in children. Children ages 5 to 12 received either 10 mg of zanamivir twice daily (BID) for five days or matching placebo. Entry criteria included duration of illness of <36 hours, having visited the doctor for fever and influenza circulating in the community. Children were excluded if they had a suspected bacterial component. The average age was 8.5 years.
Just more than 7% of children in both groups had laboratory confirmed influenza infection. About two-thirds of infections were due to influenza A, and one-third were due to influenza B. Median symptom duration prior to treatment was 20 hours.
Of confirmed cases of influenza, children taking placebo were symptomatic for 5.25 days, compared with four days for children taking zanamivir. For influenza A, there was a one-day difference in symptom duration between the two groups; for influenza B, there was a two-day difference in symptom duration. Children taking zanamivir also returned to normal activities one day sooner than children taking placebo.
However, the difference in complications leading to antibiotic use was not great, 12% in the zanamivir group, compared with 15% in the placebo group.
Hayden cited another study in which investigators placed families on surveillance until influenza was known to be circulating in the community. When someone came home with an influenza-like illness, all members of the family were placed either on inhaled zanamivir or placebo within 36 hours of symptom onset. Patients with influenza received 10 mg BID for five days, and healthy contacts received the same dose once daily for 10 days.
Researchers found that 19% of contacts in the placebo group contracted influenza, compared with 4% in the zanamivir group. Additionally, they did not note any drug-resistant variants.
Oseltamivir (Tamiflu, Hoffman-La Roche) is another neuraminidase inhibitor. Although it is indicated only for adults, the drug "is going to have much greater use in the pediatric population," he said. A liquid formulation will allow children as young as age 1 to take it.
Hayden cited a study of approximately 500 children ages 1 and older. Enrollment criteria included fever and at least one respiratory symptom for <48 hours. Children were excluded if respiratory syncytial virus screening came back positive. Children were randomized to 2 mg/kg of oseltamivir in a liquid formulation or placebo BID for five days.
Researchers compared time to resolution of illness and return to usual activities, as well as the occurrence of secondary complications, including antibiotic use. About two-thirds of influenza infections were due to influenza A, and about one-third of infections were due to influenza B. Children in the placebo group were symptomatic for 28 hours before treatment was started, compared with 27 hours in the oseltamivir group.
Children were symptomatic for 137 hours in the placebo group, compared with 101 hours in the oseltamivir group. Breaking down by types of virus, researchers found a 35-hour reduction of symptoms among children with influenza A taking oseltamivir, compared with a 40-hour reduction for children with influenza B taking oseltamivir.
Researchers also found that oseltamivir reduced complications (28% in the placebo group, compared with 17% in the oseltamivir group).
For more information:
- Hayden F. New options for treating pediatric infections. Session H352. Presented at the American Academy of Pediatrics 2000 Annual Meeting. Oct. 28-Nov. 1, 2000. Chicago.
- Gubareva LV, Kaiser L, Hayden FG. Influenza virus neuraminidase inhibitors. Lancet. 2000;355:827-835.
- American Academy of Pediatrics. Influenza. In: Pickering LK, ed. 2000 Red Book: Report of the Committee on Infectious Diseases. 25th ed. Elk Grove Village, Ill. American Academy of Pediatrics;2000:351-359.
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