Treatment of Viral Infections in Healthy Children
PEDIATRIC UPDATE
By Louis M. Bell, MD, FAAP
Fortunately, viral infections in childhood are most often benign, requiring symptomatic treatment only. However, there are circumstances in which antiviral drugs are available to treat these ubiquitous pathogens, either to prevent serious sequelae or severe infection. The purpose of this article is to review the antiviral drugs available for the treatment of infections in healthy children. The use of antiviral agents for infected immunocompromised children or retroviral agents used in those with HIV/AIDS will not be discussed.
Acyclovir
Acyclovir is a synthetic nucleoside analogue that inhibits the growth of herpes simplex virus-1 (HSV), HSV-2, and varicella-zoster Virus (VZV). Acyclovir is converted to its active form within infected cells by virus encoded thymidine kinase. The active form inhibits viral DNA synthesis by competing with deoxguanosine triphosphate as a substrate for viral DNA polymerase thereby terminating viral DNA synthesis.1
Two related antiviral agents, famciclovir (the prodrug of penciclovir) and valacidovir (the prodrug of acyclovir), were recently approved for treatment of VZV infections. Experience with these agents in infants and children is limited, although less frequent dosing intervals is one potential benefit of these newly released agents.
Experience with acyclovir has shown it to be safe with few adverse effects. Reversible renal dysfunction has been reported but is uncommon.1
Genital Herpes. In persons with primary genital HSV infection, oral or intravenous acyclovir therapy significantly reduces the duration of viral shedding, decreases pain, and hastens resolution of ulcers.2 (See Table.) Treatment does not reduce future recurrences. In recurrent disease, treatment within 24 hours of onset shortens viral shedding and time to resolution by only one day.3
Primary Herpes Stomatitis and Herpes Labialis. Primary herpes stomatitis in young children, usually caused by HSV-1, may be severe with elevated temperature and severe mouth pain-often resulting in dehydration. Occasionally, hospitalization is required for parenteral fluid therapy. Amir and associates in a well controlled study compared oral acyclovir (15 mg/kg 5 times daily) with placebo in children with primary herpes stomatitis. The acyclovir group showed more rapid clearing of mouth lesions, a shorter duration of fever, and improved fluid intake.4
Recurrent cold sores or herpes labialis is an irritating reactivation of HSV-1 often occurring at the vermillion border of the lips. Topical use of acyclovir is not helpful.1 Oral acyclovir does not significantly alter the course of illness either by reducing pain or time to healing.
Herpes Simplex Eye Disease. Herpes simplex eye disease is a leading cause of corneal opacification and infection related to loss of vision. It has recently been reported that long-term (12 months) prophylaxis with acyclovir (400 mg bid) reduces the rate of recurrent ocular disease-orofacial HSV disease-by more than 50% compared to placebo.5
Neonatal HSV Infections. HSV infections in neonates are classified into three categories: 1) localized to the skin, eyes, and mouth, 2) involving the central nervous system with or without skin, eye and mouth involvement or, 3) disseminated. Any newborn with culture proven or suspected HSV should be given IV Acyclovir at a dose of 30-60 mg/kg per day. Treatment should be continued for 14-21 days. Approximately 50% of infected newborns will have recurrent skin lesions within the first month of life.1 Reactivation in the skin may indicate a subclinical reactivation in the brain as well as insidious, unrecognized encephalitis and subsequent neurological impairment.6,7 Some experts consider oral acyclovir treatment for the first 6 months of life in infants with disease localized to skin, eyes, and mouth to prevent recurrences and possibly improve neurological outcome.
Infants born through an infected birth canal either in a woman with evidence of active recurrent genital disease or with proven primary disease have a high incidence of disease. Therefore, empiric therapy should be considered. (See Table.)
Herpes Simplex Encephalitis. Herpes simplex encephalitis can be a devastating disease with high mortality and morbidity, especially if the patient is not treated early in the course of illness. Parenteral acyclovir therapy at 10 mg/kg every eight hours for 10-14 days is the treatment of choice.
Chickenpox (VZV). Chickenpox, until recently, was considered a childhood rite of passage. With the approval of a new vaccine, chickenpox cases will hopefully decline making treatment unnecessary. Of the current vaccine preventable diseases, chickenpox has the highest mortality. Complications from chickenpox, including pneumonia and secondary bacterial infections, increase with age. Oral acyclovir, if begun early enough, decreases new lesion formation, reduces the total number of lesions, and reduces systemic symptoms.8 The Redbook recommends that treatment with oral acyclovir be instituted within 24 hours of the appearance of rash for those older than 12 years (500 mg/m2 every 8 hours for 10 days). The use of acyclovir routinely for treatment of varicella in healthy children is not recommended. However, for adolescents in whom the disease may be more severe, treatment may be prudent. For household contacts, prophylaxis with acyclovir beginning 7-9 days after exposure seems reasonable since the second case of varicella in a household is often more severe, but no controlled data are available.
Neonatal Varicella. Infants are at risk for life-threatening varicella infection if born to women who develop chickenpox from two days before delivery until five days after delivery. Mortality in infants with neonatal varicella has been reported to be as high as 30%.11 When the infant is born, varicella-zoster immune globulin should be administered intramuscularly. If the infant develops varicella infection within the first 4 weeks of life, acyclovir should be given (500 mg/m2 intravenously every 8 hours) for 5-7 days or until no new lesions are noted and crusting of the lesions occurs.9
Herpes Zoster. In general, acyclovir is not indicated for the treatment of shingles in immunocompetent children. If there is eye involvement or neurologic abnormalities associated with the development of the rash, IV acyclovir is recommended. (See Table.)
Ribavirin
Ribavirin is a synthetic nucleoside analog that resembles guanosine and inosine and interferes with the expression of messenger RNA and inhibits viral protein synthesis. It is active against respiratory syncytial virus (RSV), the major cause of lower respiratory tract disease in infants and young children.
Indications for use of Ribavirin
RSV Bronchiolitis. Since its approval in 1986, ribavirin has not proven to have a major therapeutic effect on clinical RSV disease in otherwise healthy infants.7 However, in infants who require mechanical ventilation, ribavirin may be beneficial. A randomized, double-blind, placebo-controlled evaluation comparing ribavirin to sterile water in infants requiring tracheal intubation and mechanical ventilation showed that infants receiving aerosolized ribavirin required shorter duration of mechanical ventilation (4.9 vs 9.9 days), supplemental oxygen (8.7 vs 13.5 days), and hospital stay (9.0 vs 15.3 days).10 Ribavirin therapy should be reserved for those rare infants at high risk for severe disease (bronchopulmonary dysplasia) or those requiring mechanical ventilation.11 Use of ribavirin in patients requiring mechanical ventilation should be undertaken with caution because the drug can accumulate within the ventilator resulting in pulmonary dysfunction. Fortunately, immunoprophylaxis with RSV immune globulin for RSV disease in children is available. Its use is to be considered in infants and children younger than 24 months of age with severe bronchopulmonary dysplasia or infants with a gestational age of younger than 32 weeks.
Table
Acyclovir dosing
| Herpes Simplex Virus Infection |
|
Recommended Dosage and Length of Therapy |
| Primary Genital |
|
200 mg 5 times daily for 5-7 days |
| Primary Herpes Stomatitis |
|
15 mg/kg 5 times daily for 5-7 days |
| Prophylaxis of Recurrent |
|
800 mg bid X 12 months eye infections |
| Proven Neonatal Disease1 |
|
10 to 20 mg/kg q8° for 14 to 21 days |
| Prophylaxis of Neonates at risk for HSV2 |
|
10 mg/kg q8° for 10 days |
| Herpes Encephalitis |
|
10 mg/kg q8° for 10-14 days |
| Varicella Zoster Virus Infection |
|
|
| Neonatal Varicella3 |
|
500 mg/m2 q8° for 5-7 days or until crusting |
| Adolescent Varicella (> 12 yrs) |
|
20 mg/kg q6° for 5-7 days (max. dose 3200 mg/d) |
| Shingles4 |
|
500 mg/m2 q8° for 7-10 days |
1For preterm infants 10 mg/kg q 12° for 14-21 days.
2 "At risk for HSV" is defined as babies born to women with evidence of active recurrent genital disease or with proven primary infection.
3Indicated for infants with chickenpox in the first month of life.
4Indicated if neurological or eye involvement is suspected in those older than 1 year of age.
Amantadine and Rimantadine
Influenza A. Amantadine and the related analogue rimantadine are approved by the FDA for prophylaxis against influenza A in children (> 1 year of age) and adults. The FDA has approved only amantadine for treatment of Influenza A infection in children. When administered within 48 hours of onset of symptoms, both drugs appear to diminish the severity of the influenza A disease.11
Chemoprophylaxis is not usually indicated in healthy children, although it can be used in conjunction with the influenza vaccine for those who are at high risk of severe influenza A disease, who are vaccinated during the influenza A season.12
A decision to treat active influenza A cases should be made on a case-by-case basis. Treatment should be continued for 48 hours after the child is asymptomatic.
The dose of amantadine for treatment is 5 mg/kg/d (maximum 150 mg/d) in one or two divided doses for those 1-9 years of age. For older children who weigh less than 40 kg, the dose is 5 mg/kg/d in one or two divided doses. For those who weigh more than 40 kg, the dose is 200 mg/d in one or two divided doses. The dosages for prophylaxis are the same as those for treatment. Side effects are dose-related and include nausea and vomiting. (Dr. Bell is Associate Professor of Pediatrics [Infectious Diseases], University of Pennsylvania School of Medicine, Philadelphia.)
References
1. Whitley RJ, et al. Acyclovir and HSV infections in children. Semin Pediatr Infect Dis 1997;8:196-204.
2. Bryson YJ, et al. Treatment of first episodes of genital herpes simplex virus infection with oral acyclovir. N Engl J Med 1983;308:916-921.
3. Reichman, et al. Treatment of recurrent genital herpes simplex infections with oral acyclovir. JAMA 1984; 251:2103-2107.
4. Amir J, et al. Treatment of herpes simplex gingivostomatitis with aciclovir in children: A randomized double blind placebo controlled study. BMJ 1997;314: 1800-1803.
5. Acyclovir for the prevention of recurrent herpes simplex virus eye disease. Herpetic eye disease study group. N Engl J Med 1998;339:300-306.
6. Whitley RJ, et al. A controlled trial comparing vidarabine with acyclovir in neonatal herpes simplex virus infection. N Engl J Med 1991;324:444-449.
7. Kimberlin DW, et al. Application of the polymerase chain reaction to the diagnosis and management of neonatal herpes simplex virus disease. J Infect Dis 1996;174:1162-1167.
8. Balfour HH, et al. Acyclovir treatment of varicella in otherwise healthy adolescents. The collaborative acyclovir varicella study group. J Pediatr 1992;120: 627-633.
9. Wald ER, et al. In re ribavirin: A case of premature adjudication? J Pediatr 1988;12:154-158.
10. Smith DW, et al. A controlled trial of aerosolized ribavirin in infants receiving mechanical ventilation for severe respiratory syncytial virus infection. N Engl J Med 1991;325:24-29.
11. Peter G, ed. Redbook: Report of the Committee on Infectious Diseases. 24th ed. Elk Grove Village, IL: American Academy of Pediatrics, 1997:309.
12. Centers for Disease Control and Prevention. Prevention and Control of Influenza. MMWR Morb Mortal Wkly Rev 1997;46(RR-9):1-25.
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