Antiviral Drugs in Healthy Children



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Am Fam Physician. 1998 Mar 1;57(5):1073-1077.

Several antiviral agents are available to treat viral illnesses in healthy children. In some children, treatment with acyclovir is an alternative to vaccination for the treatment and prevention of chickenpox. Acyclovir also can be useful in the treatment or prevention of herpes simplex infections in neonates. Ribavirin, once recommended as routine therapy for high-risk infants with respiratory syncytial virus disease, is now reserved for use in selected children. Amantadine and rimantidine are effective against influenza type A and can be used to protect children from influenza, as well as to lessen the duration and severity of illness in those who are already ill.

Viral infections in neonates, infants and children range from the common cold to the extremely rare, but deadly, herpes simplex meningitis. Although not much can be done to prevent or treat colds, antiviral agents can shorten the duration of some viral diseases.

In this review, the current status of antiviral drugs in the treatment of varicella (chicken-pox), herpes simplex virus infections and respiratory syncytial virus infections, as well as the prevention and treatment of influenza infection, is briefly outlined. The complex needs of immunocompromised children are beyond the scope of this paper.

Varicella

Varicella infection (chickenpox) occurs in about 3 to 4 million children per year. However, this incidence should drop drastically as a result of the recent approval of the varicella vaccine (Varivax) and the recommendation for its widespread use by the Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention.1,2

In addition to the constitutional manifestations of varicella, the most frequent adverse effects associated with the infection are days lost from school (on average, 8.7 days) and work days lost by parents (on average, 0.5 days) who must stay home with their child.3 Serious complications in children, such as pneumonia and encephalitis, are rare, although about 50 deaths occur each year. Groups at greatest risk of complications include infants less than one year of age, adolescents, pregnant women and patients taking high-dose corticosteroids. Older patients with the disease have a more severe clinical course.

Acyclovir (Zovirax) is approved for the acute management of varicella in children and adults. When acyclovir is given within the first 24 hours of the onset of rash in children, constitutional symptoms and pruritus are diminished. The number of lesions and the time until crusting are also reduced. Defervescence occurs more quickly on average in treated children (day 1 versus day 2). However, by the third day, all treated children and 75 percent of untreated children are afebrile.4 When acyclovir therapy is started 24 or more hours after the onset of rash, no benefit is conferred.

Currently, no data indicate that treating varicella with acyclovir hastens the return of children to school or parents to work; the rate of development of complications has not been diminished by active therapy.

Adverse effects attributable to acyclovir are uncommon. Gastrointestinal problems occur infrequently. The immune response following varicella is not affected by acyclovir therapy. No effect has been shown on the subsequent development of varicella zoster in children treated with acyclovir.

The dosage of oral acyclovir is 20 mg per kg per dose, four times a day, up to 800 mg per dose. Acyclovir therapy is not indicated in pregnant women or in infants less than two years of age. Therapy is continued for five days and costs between $70 and $80.

Acyclovir also has been used to prevent the development of chickenpox following household exposure. In one unblinded, nonrandomized study,5 exposed children were given acyclovir starting seven to nine days following exposure and continuing for seven days. Varicella developed in 16 percent of treated children, compared with 100 percent of untreated children. Seroconversion, a marker of subclinical infection, occurred in 85 percent of the children receiving acyclovir.

A second study6 also found that acyclovir prophylaxis, given in the second week following exposure, allowed seroconversion without the development of symptoms. This protection did not occur in all of the study subjects, so it is still not known whether acyclovir is a suitable alternative to varicella zoster immune globulin for postexposure protection.

The American Academy of Pediatrics7 (AAP) recommends against the routine use of acyclovir in cases of uncomplicated varicella in otherwise healthy children. It recommends acyclovir treatment for susceptible nonpregnant adolescents. Acyclovir therapy also may be considered in children over 12 months of age who are receiving long-term salicylate therapy (because of the risk of Reye's syndrome), in those with chronic pulmonary or skin problems, and in those receiving aerosolized corticosteroids. However, the benefits of therapy in these groups has not been proved.

Immunocompromised children, including those receiving oral corticosteroids in dosages of 2 or more mg per kg per day, should receive intravenous acyclovir to prevent or treat disseminated varicella. The dosage is 500 mg per m2 every eight hours. In children less than 12 months of age, the dosage is 30 mg per kg per day in three divided doses. Therapy is continued for seven to 10 days.8(p635)

Two other antiviral agents, famciclovir (Famvir) and valacyclovir (Valtrex), are available for the treatment of herpes zoster and recurrent genital herpes. Neither of these agents is labeled for use in the treatment of varicella in children, and no studies have evaluated the use of these agents in children with zoster.

In summary, acyclovir therapy can slightly decrease the severity and duration of acute varicella. To be effective, therapy must be started within 24 hours of the onset of rash, which may be difficult. Its effect on the subsequent development of zoster is not known. With the marketing of the varicella vaccine, few children should require treatment of acute varicella infection.

Herpes Simplex Virus

Herpes simplex virus most commonly causes “cold sores” (herpes labialis) in infants and children and genital herpes in adolescents. Herpes simplex virus is also responsible for eye infections in children and for lesions on the distal parts of fingers (herpetic whitlow) and at other sites.

The most dramatic results of the use of antiviral therapy in healthy children have been seen with the use of acyclovir in the treatment of herpes simplex gingivostomatitis. A recent trial9 of 72 children receiving acyclovir, 15 mg per kg five times a day for seven days, showed a marked benefit with treatment compared with placebo. Intraoral lesions cleared significantly more quickly (four days versus 10 days) with the use of acyclovir. Other signs and symptoms disappeared significantly more quickly with treatment: fever (one versus three days), eating difficulties (four versus seven days), drinking difficulties (three versus six days) and the presence of lesions around the mouth (zero versus five and one-half days).

A much greater concern is herpes simplex virus infection in newborn infants. The virus is most frequently transmitted to infants from the mother during vaginal delivery or, sometimes, via ascending infection.

Transmission is much more likely to occur during a vaginal birth in a mother who is having a first episode of genital herpes. In such cases, the rate of transmission may be 33 to 50 percent. Unfortunately, in most cases, infected neonates are born to women in whom neither the history nor the physical examination suggests active infection.8(p268)

Herpes simplex infection in newborns can range from a local infection of the skin, eyes and mouth to a generalized systemic infection or a localized infection of the central nervous system. Neonatal meningitis is extremely rare: A recently published survey10 of all causes of neonatal meningitis in England and Wales during the years 1975 to 1991 found only 10 cases that were due to herpes simplex virus among 26,090 reported cases. For this reason, the AAP8(p272) does not recommend empiric treatment of infants born to mothers with active primary or recurrent genital herpes infections unless cultures are positive or manifestations of herpes simplex virus infection occur.

Infants with documented herpes simplex virus infections, whether localized, systemic or involving the central nervous system, should be treated with acyclovir. The usual dosage is 30 mg per kg per day, given intravenously in three divided doses. Patients should receive treatment for at least 14 days and up to 21 days.

Ribavirin for Respiratory Syncytial Virus

Ribavirin (Virazole) has been approved since the early 1980s for the treatment of respiratory syncytial virus infection. It is administered as an aerosol, generally via an oxygen tent, head box or mask, using a specific small-particle aerosol generator. Initial dosing consists of continuous inhalation, 12 to 20 hours per day for four to five days. The drug also may be given in high dosages for two hours three times a day.

Recent research about the effectiveness of ribavirin has contradicted previous findings. As a result, the AAP8(p445),11 has changed its recommendation for the use of ribavirin in infants at high risk for serious respiratory syncytial disease. The previous recommendation that ribavirin “should be used” has been changed in the latest report to a less definitive “is a consideration.”

Two recent studies12,13 have failed to confirm the effectiveness of ribavirin. One study12 compared length of hospital stay, the number of days of oxygen therapy and the number of patients requiring mechanical ventilation in one hospital that used ribavirin and one hospital that did not. No difference in these outcomes was seen between the two groups. A second, randomized trial13 comparing ribavirin with a saline placebo also failed to show benefit as measured by these same standards. Two meta-analyses have confirmed the lack of benefit of ribavirin on mortality, respiratory deterioration or length of hospitalization.14 As a result of this new information, the AAP recommends that ribavirin may be considered for use in infants with severe heart or lung disease or immunosuppression, or in those who are severely ill.

The use of ribavirin is being replaced by immunization with intravenous respiratory syncytial virus immune globulin (RespiGam) in children who are at risk for developing respiratory syncytial virus infection. Use of immune globulin has been shown to reduce the incidence of hospital admissions and the duration of hospitalization for respiratory syncytial virus infections or other respiratory infections.15 It is given once per month during the respiratory syncytial virus season to children less than two years of age with bronchopulmonary dysplasia who have received or are receiving oxygen therapy. It also is used in infants born prematurely (less than 35 weeks of gestation).16

Influenza Prevention and Treatment

Yearly vaccination with influenza vaccine is the preferred method of protecting children against influenza, especially those who are at high risk for complications. The vaccine is inexpensive, easy to administer and effective against both type A and type B influenza viruses (providing they are chosen to be included in the vaccine). The oral antiviral agents—amantadine (Symmetrel) and rimantadine (Flumadine)—are effective only against type A influenza viruses. However, they are 70 to 90 percent effective in preventing illness caused by these viruses, and their onset of protection is quicker than vaccination, making them a useful alternative, especially during type A influenza epidemics.

Amantadine and rimantadine are approved for prophylaxis of type A influenza in children one year of age or older.17 These medications may be given to children who receive influenza vaccine for the first time, since adequate antibody levels take six weeks to develop. The oral agents do not affect antibody response to the vaccine.

Amantadine, but not rimantadine, is also labeled for the treatment of type A influenza in children. Prompt treatment within 48 hours of the onset of symptoms reduces the severity and shortens the duration of illness. The effect of treatment on the development of complications is not known.

The dosages of amantadine and rimantadine for the treatment and prevention of type A influenza are listed in Table 1. Both agents are available in liquid and tablet or capsule forms. Typical costs for one week of therapy are $10 for amantadine syrup and $12 for rimantadine syrup.

TABLE 1

Recommended Dosages for Amantadine (Symmetrel) and Rimantadine (Flumadine) Treatment and Prophylaxis

Antiviral agent 1 to 9 years and <40 kg (88 lb) 10 to 18 years and ≥ 40 kg (88 lb) Duration of therapy

Amantadine

Treatment

5 mg per kg per day, up to 150 mg in two doses

100 mg twice daily

Until 24 to 48 hours after resolution of symptoms (usually seven days total)

Prophylaxis

5 mg per kg per day, up to 150 mg in two doses

100 mg twice daily

Up to six weeks (four weeks if the patient is concurrently immunized)

Rimantadine

Treatment

Not applicable

Prophylaxis

5 mg per kg per day, up to 150 mg in two doses

100 mg twice daily

Up to six weeks (four weeks if the patient is concurrently immunized)


Reprinted from Centers for Disease Control and Prevention. Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 1997;46(RR-9):1-25.

TABLE 1   Recommended Dosages for Amantadine (Symmetrel) and Rimantadine (Flumadine) Treatment and Prophylaxis

View Table

TABLE 1

Recommended Dosages for Amantadine (Symmetrel) and Rimantadine (Flumadine) Treatment and Prophylaxis

Antiviral agent 1 to 9 years and <40 kg (88 lb) 10 to 18 years and ≥ 40 kg (88 lb) Duration of therapy

Amantadine

Treatment

5 mg per kg per day, up to 150 mg in two doses

100 mg twice daily

Until 24 to 48 hours after resolution of symptoms (usually seven days total)

Prophylaxis

5 mg per kg per day, up to 150 mg in two doses

100 mg twice daily

Up to six weeks (four weeks if the patient is concurrently immunized)

Rimantadine

Treatment

Not applicable

Prophylaxis

5 mg per kg per day, up to 150 mg in two doses

100 mg twice daily

Up to six weeks (four weeks if the patient is concurrently immunized)


Reprinted from Centers for Disease Control and Prevention. Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 1997;46(RR-9):1-25.

The incidence of side effects is higher in patients treated with amantadine than in those treated with rimantadine. Both agents can cause nausea and anorexia. Central nervous system side effects can range from nervousness and lightheadedness to delirium, hallucinations and seizures. These adverse effects are dose-related.

The Authors

Katherine L. Margo, m.d., is medical director of the Harrisburg Family Practice Center and associate residency director of the Harrisburg Family Practice Residency Program, Harrisburg, Pa. She is also clinical associate professor in the department of family medicine of the Allegheny University of the Health Sciences, Philadelphia. Dr. Margo received her medical degree from the State University of New York Health Science Center at Syracuse Medical School and served a residency in family practice at St. Joseph's Hospital, Syracuse.

Allen F. Shaughnessy, pharm.d., is director of research in the Harrisburg Family Practice Residency Program. A graduate of the Temple University School of Pharmacy, Philadelphia, he received a doctorate from the Medical University of South Carolina College of Pharmacy, where he also completed a faculty development fellowship. He is clinical associate professor in the department of family medicine of the Allegheny University of the Health Sciences.

Address correspondence to Allen F. Shaughnessy, Pharm.D., Harrisburg Family Practice Residency Program, P.O. Box 8700, 205 S. Front St., Harrisburg, PA 17105-8700. Reprints are not available from the authors.

REFERENCES

1. Centers for Disease Control and Prevention. Prevention of varicella: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep. 1996;45(RR-11):1–36.

2. American Academy of Pediatrics Committee on Infectious Diseases. Recommended childhood immunization schedule. Pediatrics. 1996;98:158–60.

3. Sullivan-Bolyai JZ, Yin EK, Cox P, Marchand A, Meissinger J, Venerable L, et al. Impact of chicken-pox on households of healthy children. Pediatr Infect Dis J. 1987;6:33–5.

4. Dunkle LM, Arvin AM, Whitley RJ, Rotbart HA, Feder HM Jr, Feldman S, et al. A controlled trial of acyclovir for chickenpox in normal children. N Engl J Med. 1991;325:1539–44.

5. Asano Y, Yoshikawa T, Suga S, Kobayashi I, Nakashima T, Yazaki T, et al. Postexposure prophylaxis of varicella in family contact by oral acyclovir. Pediatrics. 1993;92:219–22.

6. Suga S, Yoshikawa T, Ozaki T, Asano Y. Effect of oral acyclovir against primary and secondary viraemia in incubation period of varicella. Arch Dis Child. 1993;69:639–43.

7. American Academy of Pediatrics Committee on Infectious Diseases. The use of oral acyclovir in otherwise healthy children with varicella. Pediatrics. 1993;91:674–6.

8. American Academy of Pediatrics Committee on Infectious Diseases. 1997 Red Book: report of the Committee on Infectious Diseases. 24th ed. Elk Village, Ill.: American Academy of Pediatrics, 1997.

9. Amir J, Harel L, Smetana Z, Varsano I. Treatment of herpes simplex gingivostomatitis with aciclovir in children: a randomised double blind placebo controlled study. BMJ. 1997;314:1800–3.

10. Synnott MB, Morse DL, Hall SM. Neonatal meningitis in England and Wales: a review of routine national data. Arch Dis Child. 1994;71:F75–80.

11. American Academy of Pediatrics Committee on Infectious Diseases. Reassessment of the indications for ribavirin therapy in respiratory syncytial virus infections. Pediatrics. 1996;97:137–40.

12. Wheeler JG, Wofford J, Turner RB. Historical cohort evaluation of ribavirin efficacy in respiratory syncytial virus infection. Pediatr Infect Dis J. 1993;12:209–13.

13. Meert KL, Sarnaik AP, Gelmini MJ, Lieh-Lai MW. Aerosolized ribavirin in mechanically ventilated children with respiratory syncytial virus lower respiratory tract disease: a prospective, double-blind, randomized trial. Crit Care Med. 1994;22:566–72.

14. Randolph AG, Wang EE. Ribavirin for respiratory syncytial virus lower respiratory tract infection. In: Douglas R, Bridges-Webb C, Glasziou P, Lozano J, Steinhoff M, Wang E, eds. Acute Respiratory Infections Module of the Cochrane Database of Systematic Reviews [database on disk, CD-ROM and online; updated 03 June 1997]. The Cochrane Collaboration; Issue 3. Oxford: Update Software, 1997.of Systematic Reviews database on disk, CD-ROM and online; updated

15. The PREVENT Study Group. Reduction of respiratory syncytial virus hospitalization among premature infants and infants with bronchopulmonary dysplasia using respiratory syncytial virus immune globulin prophylaxis. Pediatrics. 1997;99:93–9.

16. American Academy of Pediatrics Committee on Infectious Diseases, Committee on Fetus and Newborn. Respiratory syncytial virus immune globulin intravenous: indications for use. Pediatrics. 1997;99:645–50.

17. Centers for Disease Control and Prevention. Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep. 1997;46(RR-9):1–25.

Richard W. Sloan, M.D., R.PH., coordinator of this series, is chairman and residency program director of the Department of Family Medicine at York (Pa.) Hospital and clinical associate professor in family and community medicine at the Milton S. Hershey Medical Center, Pennsylvania State University, Hershey, Pa.



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