search text   Advanced Search

This Article Abstract Full Text (PDF) P3Rs: Submit a response Alert me when this article is cited Alert me when P3Rs are posted Alert me if a correction is posted Citation Map Services E-mail this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My File Cabinet Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Search for Related Content PubMed PubMed Citation Related Collections Infectious Disease & Immunity

Antiviral Therapy and Prophylaxis for Influenza in Children

	ABSTRACT

TOP ABSTRACT INTRODUCTION ANTIVIRAL DRUGS FOR EPIDEMIC... INDICATIONS FOR THERAPY AND... ANTIVIRAL THERAPY IN PANDEMIC... Committee on Infectious... Liaisons Ex Officio Consultant Staff APPENDIX: INFANTS AND CHILDREN... REFERENCES

 
Antiviral agents are available that are safe and effective for the treatment and prophylaxis of influenza virus infections in children. The neuraminidase inhibitors (oseltamivir [Tamiflu] and zanamivir [Relenza]) are preferred agents because of current widespread resistance to the adamantanes (amantadine [Symmetrel] and rimantadine [Flumadine]). Therapy should be provided to children with influenza infection who are at high risk of severe infection and to children with moderate-to-severe influenza infection who may benefit from a decrease in the duration of symptoms. Prophylaxis should be provided (1) to high-risk children who have not yet received immunization and during the 2 weeks after immunization, (2) to unimmunized family members and health care professionals with close contact with high-risk unimmunized children or infants who are younger than 6 months, and (3) for control of influenza outbreaks in unimmunized staff and children in an institutional setting. Testing of current H5N1 avian influenza virus isolates, the potential agents of pandemic influenza, suggests susceptibility to oseltamivir and zanamivir. Because no prospective data exist on the efficacy of these agents in humans for H5N1 strains, the dosage and duration of therapy in adults and children may differ from those documented to be effective for epidemic influenza strains.

Key Words: influenza • children • influenza antiviral • oseltamivir • zanamivir • amantadine • rimantadine • ribavirin

Abbreviations: NAI—neuraminidase inhibitor • FDA—Food and Drug Administration • CNS—central nervous system

	INTRODUCTION

TOP ABSTRACT INTRODUCTION ANTIVIRAL DRUGS FOR EPIDEMIC... INDICATIONS FOR THERAPY AND... ANTIVIRAL THERAPY IN PANDEMIC... Committee on Infectious... Liaisons Ex Officio Consultant Staff APPENDIX: INFANTS AND CHILDREN... REFERENCES

 
Antiviral agents for treatment and prophylaxis of influenza are safe and effective in children. Annual immunization against influenza is the preferred strategy for prevention of infection, but certain situations exist in which the use of antiviral agents is beneficial.

The morbidity and mortality of epidemic influenza in unimmunized children is substantial, particularly in those younger than 2 years.^1–5 The purpose of this report is to offer guidance regarding antiviral treatment and prophylaxis to clinicians caring for children during yearly influenza epidemics and to provide resources for information on antiviral treatment in the event of an influenza pandemic, because no prospective human data currently exist on which to base recommendations for treatment of infections caused by potential H5N1 pandemic influenza virus strains.

	ANTIVIRAL DRUGS FOR EPIDEMIC AND PANDEMIC INFLUENZA

TOP ABSTRACT INTRODUCTION ANTIVIRAL DRUGS FOR EPIDEMIC... INDICATIONS FOR THERAPY AND... ANTIVIRAL THERAPY IN PANDEMIC... Committee on Infectious... Liaisons Ex Officio Consultant Staff APPENDIX: INFANTS AND CHILDREN... REFERENCES

 
Two classes of antiviral medications are currently available for treatment or prophylaxis of influenza infections: neuraminidase inhibitors (NAIs) (oseltamivir [Tamiflu; Roche Laboratories, Nutley, NJ] and zanamivir [Relenza; GlaxoSmithKline, Research Triangle Park, NC]) and the adamantanes (amantadine [Symmetrel; Endo Pharmaceuticals, Chads Ford, PA] and rimantadine [Flumadine; Forest Pharmaceuticals, St Louis, MO]). Guidelines for the use of these 4 antiviral agents are summarized in Table 1. Little is currently known about the efficacy of antiviral agents against H5N1 strains of influenza A virus that may ultimately cause an influenza pandemic. Current concerns about widespread resistance to the adamantanes limit the usefulness of this class of agents for both epidemic strains and H5N1 strains of influenza A virus.

With all antiviral medications, treatment earlier in the course of infection is likely to offer maximum benefit. Treatment starting as early as 12 hours after onset of symptoms has the greatest impact on disease resolution.¹³ Most studies have been performed in otherwise healthy children who had symptoms for less than 48 hours, with the reported improvement in outcomes being most profound in those children who were provided early therapy. Although study populations may not accurately reflect the diverse patient population seen by health care professionals, the longer symptoms extend beyond 48 hours before starting treatment, the less likely the child will benefit from antiviral therapy.

The antiviral agents discussed below that are approved for treatment and/or prophylaxis of influenza are active only against influenza viruses. Exposing children to antiviral therapy for noninfluenza infections results in unnecessary toxicity and cost and may deplete the supply of antiviral agents. Testing for influenza is encouraged if available and expected to influence clinical management, particularly at the onset of the influenza season.⁵ The sensitivity and specificity of rapid diagnostic tests for influenza have been reviewed recently.⁹

NAIs
Background
There are 2 NAIs approved by the US Food and Drug Administration (FDA): oseltamivir and zanamivir. Oseltamivir is available in tablet and liquid forms, but zanamivir is only available in an aerosol formulation.

Infection of the cell by influenza virus is initiated when viral hemagglutinin binds to sialic acid–containing glycoproteins on the cell surface. After the virus enters the cell and viral proteins and nucleic acid subsequently are produced, new viral particles assemble at the cell surface. The viral neuraminidase cleaves the virus from the host cell membrane attachment site, thus freeing the virus to infect other cells. The NAI antiviral agents inhibit productive infection by preventing release of infectious virus from host cell membranes and promote clumping of viral particles via binding to glycoproteins that are present in respiratory mucus.^{10, 12}

Oseltamivir Treatment
Oseltamivir has been investigated in a prospective, randomized, blinded, placebo-controlled study in children 1 to 12 years of age.¹⁴ A 5-day treatment course was associated with a median reduction in overall clinical illness of 36 hours and a reduction in fever of 25 hours in oseltamivir-treated children compared with placebo recipients. Furthermore, the incidence of acute otitis media (assessed by tympanometry and physician-prescribed antimicrobial therapy) was reduced by 44% compared with placebo recipients. A significant decrease in viral shedding was also noted in treated children, with few children still shedding virus on day 4 of therapy. The most common adverse drug effects noted were gastrointestinal tract disturbances, with vomiting in 14% of oseltamivir-treated children compared with 8% of children who were given placebo.

In studies of unimmunized children with asthma 6 to 12 years of age who received oseltamivir or placebo, no difference in the median time to freedom from illness was demonstrated, but a significant improvement in pulmonary function was noted on day 6 after treatment.¹⁵ For oseltamivir-treated children whose therapy was started within 24 hours of onset, a more dramatic difference in alleviation of all symptoms was noted, compared with those who were started on therapy after 24 to 48 hours of symptoms.

Although earlier therapy may lead to a more profound treatment effect, it is also possible that earlier treatment may impair the host immunologic response to influenza infection. An impaired immune response could leave the host susceptible on reexposure to the virus, as has been reported in 2 children with influenza B virus infections.¹⁶

Oseltamivir is not approved for therapy in children younger than 12 months because of concerns of central nervous system (CNS) toxicity seen in infant rats.¹⁷ Limited data on safety and efficacy of oseltamivir exist in this young age group, although no specific drug-attributable toxicities have been observed to date.^{18, 19}

Oseltamivir may be taken with or without food and is eliminated entirely by glomerular filtration and tubular secretion. The dose of oseltamivir should be decreased by 50% for children with decreased renal function associated with a creatinine clearance of between 10 and 30 mL/minute.

Unpublished safety data on oseltamivir were recently reviewed by the FDA on the basis of reports of neuropsychiatric events associated with patients treated for influenza with oseltamivir (www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4254b_09_01_Tamiflu%20AE%20Review%202006%20Redacted_D060309_092.pdf). Although 92%of the most recent cases were reported from Japan, a country with approximately 4 times more courses of oseltamivir prescribed than in the United States, package labeling was changed in the United States in 2006 to alert physicians to the possibility of these rare and unusual clinical findings. Accurate data on the incidence of these events are not available, but they seem to be in the range of 1 in 10000 to 100000 treatment courses. On the basis of the FDA review, it is not known whether the spontaneous reports of neuropsychiatric behavior reflect a true adverse event caused by oseltamivir, perhaps with a greater incidence in populations with a certain genetic background; a result of CNS infection caused by influenza virus; or a combination of both drug and virus in the CNS. There are no reports of neuropsychiatric events in adults or children receiving oseltamivir prophylaxis for influenza infection.

Zanamivir Treatment
Zanamivir is administered by aerosol twice daily for 5 days. In a study of children 4 to 12 years of age, the mean duration of symptomatic illness was reduced by 1.25 days in children who received zanamivir, compared with those who received placebo.²⁰ In 3 trials in subjects 12 years and older, zanamivir treatment decreased symptoms by 1 to 2.5 days in influenza-positive subjects.^21–24 In a multicenter prospective study of subjects whose therapy was started within 30 hours of the onset of symptoms, resolution of major symptoms occurred 3 days earlier in the treatment group compared with that in controls.²⁴

Reported adverse effects in otherwise healthy children and adults were similar between those treated with zanamivir and those given placebo. However, concerns by the FDA regarding bronchospasm and decreased pulmonary function after inhalation of zanamivir in patients with underlying reactive airways disease, including asthma and chronic obstructive pulmonary disease, prompted warnings about use of zanamivir in this population. Potential risks and benefits should be carefully weighed before treatment of these children. Monitoring of respiratory function should be considered if treatment is given.²⁵

Zanamivir is minimally absorbed from the respiratory tract mucosa. No dosing changes are required for renal failure.

Prophylaxis With Oseltamivir and Zanamivir
Postexposure prophylaxis with oseltamivir has been reported in a multicenter study in North America and Europe for family contacts who were at least 1 year of age after identification of a documented index case within the family.²⁶ In this setting, in which the index case was also treated with oseltamivir, the protective efficacy against proven influenza for individual contacts was 68%.²⁶ In a similar multicenter study for household contacts 12 years and older, oseltamivir was 89% effective in the prevention of laboratory-confirmed symptomatic influenza infection when used within 48 hours of contact with an index case who had not been treated.²⁷ Adverse events reported in treated subjects in this study, including gastrointestinal tract symptoms, were not different from those in controls.²⁷

Zanamivir was investigated as postexposure prophylaxis for family members 5 years and older, at a dosage of 10 mg, inhaled once daily for 10 days, with the index case also receiving treatment. After exposure to a virus-positive index case, the number of families with a clinically symptomatic member decreased 72%.²⁸

Antiviral Resistance
Development of resistance to NAIs while on therapy occurs less often than resistance to adamantanes.²⁹ In a multicenter study in the United States, only 5% of children who received oseltamivir therapy developed in vitro resistance in influenza isolates cultured during therapy.¹⁴ In contrast, a study from Japan documented resistance of 18% in isolates cultured from 50 oseltamivir-treated children.^{12, 30} Fortunately, oseltamivir-resistant isolates from children do not seem to be as capable of sustaining infection as wild-type strains as assessed in animal models of influenza infection.^{31, 32} However, when generated entirely in vitro, some mutants are just as capable of infectivity as the parent strain,³³ which indicates that the possibility still exists for the development and spread of oseltamivir-resistant strains among children. Zanamivir resistance was not reported in the published large-scale clinical trials.

Adamantanes
Background
Amantadine and rimantadine are approved for children 12 months and older. Amantadine, the first antiviral agent available against influenza, was approved by the FDA in 1966; rimantadine was approved in 1993. Antiviral activity is mediated by binding these agents to the M2 protein ion channels on the viral envelope, preventing acidic conditions within the virus that are required for uncoating and subsequent release of viral nucleic acid into the host cell.³⁴ Only influenza A virus contains the M2 protein. A different envelope protein that does not bind to the adamantanes provides a similar function in influenza B virus; amantadine and rimantadine are not active against influenza B. The effectiveness of adamantanes has been limited by the emergence of widespread resistance in H3N2 strains isolated in the 2005–2006 influenza season.³⁵ Recommendations for adamantane antiviral use in subsequent years will be based on the resistance patterns documented in strains circulating during those influenza seasons.

Amantadine Treatment
Placebo-controlled, randomized clinical trials have documented that amantadine treatment decreases the duration of fever and other influenza-attributable symptoms in influenza caused by adamantane-susceptible strains by approximately 1 day in children 1 year and older.^36–40 However, many of the earlier placebo-controlled studies that included children did not report age-specific response or adverse-event rates. Adverse events have been most accurately assessed and reported in adults. The most commonly occurring (5%–10%) adverse events are nausea, lightheadedness, and insomnia. Those that occur infrequently (1%–5%) include anxiety, nervousness, irritability, dry mouth, headache, fatigue, and diarrhea.⁴¹ The incidence of CNS adverse effects noted above is twofold higher in those taking amantadine than in those taking rimantadine. Gastrointestinal adverse effects are equivalent between the 2 agents. These effects are dosage related and are usually mild, resolving when the agent is discontinued. Serious adverse effects have been reported in adults and are often associated with either high plasma drug concentrations in patients with renal insufficiency or in those with an underlying psychiatric or seizure disorder.⁴²

Although no prospective studies have been published on the treatment of children with encephalitis as a complication of influenza, data on cerebrospinal fluid concentrations of amantadine suggest a high degree of cerebrospinal fluid penetration, with concentrations that may provide antiviral activity.⁴³

Amantadine is well absorbed orally and is excreted almost entirely by the kidneys with variable metabolism before elimination. The dose should be decreased 50% in children with creatinine clearance between 30 and 50 mL/minute per 1.73 m². Additional reductions are required for more profound renal failure.

Rimantadine Treatment
Rimantadine was evaluated in prospective studies of children using acetaminophen-treated controls between 1 and 12 years of age⁴⁴ and 1 and 15 years of age.⁴⁵ In a study by Thompson et al,⁴⁴ no differences were recorded in the reduction of symptoms between the 2 groups, although the amount of virus shed was less during the first 2 days of therapy for the treatment group. Of concern, the virus shed by those who continued to have positive culture results on the fourth day of treatment was often resistant to rimantadine. Hall and colleagues⁴⁵ noted a significant reduction in severity of disease, including fever. However, a high rate of rimantadine resistance occurred in treated children, with almost half of the strains noted to be resistant when isolated from children who were still shedding virus at the end of the 7-day treatment course. In addition, it is concerning that rimantadine-treated children were more likely to be shedding virus at the end of therapy than were controls. No differences in adverse-event rates were noted between children treated with rimantadine and those treated with acetaminophen. In controlled studies in adults, no drug-attributable adverse effects occurred in more than 5% of the study subjects, with the most commonly reported events being insomnia and dizziness.⁴⁶

Rimantadine is also well absorbed orally but, unlike amantadine, undergoes extensive hepatic metabolism with subsequent renal elimination. Dose adjustment should be made for severe hepatic dysfunction or renal failure.

Prophylaxis With Amantadine and Rimantadine
Early studies on the prevention of influenza with amantadine were conducted in home or institutional settings during the influenza season using prospective, double-blind trial designs and documented a statistically significant benefit by reducing the attack rate of influenza A.^47–50 However, as with the early amantadine treatment studies, age-specific data are lacking.

Studies on the use of rimantadine as prophylaxis for children within families were conducted during influenza seasons in which the predominant circulating strains were H1N1⁵¹ and H3N2.⁵² In both studies, prophylaxis reduced the number of symptomatic influenza cases in children relative to an attack rate of 15% to 20% among placebo recipients. Prophylaxis in children also reduced the number of cases of symptomatic influenza in adult family members. Of note, cases of asymptomatic influenza infection as documented by throat culture or fourfold increase in influenza antibody titers did occur in a small number of children who received rimantadine prophylaxis.

Antiviral Resistance
Amantadine or rimantadine resistance develops in approximately one third of patients who receive antiviral therapy.⁵³ The development of resistance has implications for therapeutic failure for (1) the child, if resistance develops early in therapy, (2) household or close contacts, because resistance in the index case determines which therapy is likely to be effective in those exposed to the index case, and (3) communities, in which resistance may be so widespread to a particular agent that empiric therapy with that agent may no longer be recommended.

Resistance to adamantanes occurs rapidly, often within the first 3 days of therapy. Mutations lead to structural changes at predictable, specific sites on the M2 protein. These changes are relatively stable, with little reversion to wild-type susceptible virus after stopping the adamantane. Appreciable differences in virulence or transmissibility between resistant and susceptible viruses have not been noted.

In a recent study, nasal swabs, nasal aspirates, or throat cultures were obtained from hospitalized children before, during, and after a 3- to 5-day course of amantadine, and 80% of isolates from treated children demonstrated amantadine resistance.⁵⁴ Shedding of resistant strains was not associated with persistent or relapsing clinical disease, which is felt to reflect an adequate host immunologic response that develops as resistant strains are emerging. For the high-risk child with a poor immunologic response to infection, persistent disease or relapse is a concern.

Close contacts of an amantadine- or rimantadine-treated child who subsequently develop influenza infection are at high risk of infection caused by an adamantane-resistant influenza virus. If such patients require treatment or prophylaxis, an NAI should be used. During the 2005–2006 influenza season, data collected on widespread resistance to adamantanes in circulating influenza A strains in the United States led the Centers for Disease Control and Prevention to recommend against the use of these agents for either treatment or prophylaxis of influenza A infections.⁵⁵

Ribavirin
Ribavirin has in vitro activity against influenza virus but is not currently approved for treatment of influenza infection. Limited studies have been performed with aerosolized ribavirin in the treatment of influenza in children.⁵⁶ For life-threatening influenza infection requiring parenteral therapy, intravenous ribavirin may be obtained as an investigational product through the FDA, as supplied by the manufacturer. No prospective, controlled data currently exist on the safety or efficacy of parenteral ribavirin for severe, invasive influenza infection, although limited data on pharmacokinetics of parenteral ribavirin exist for adults.⁵⁷

	INDICATIONS FOR THERAPY AND PROPHYLAXIS

TOP ABSTRACT INTRODUCTION ANTIVIRAL DRUGS FOR EPIDEMIC... INDICATIONS FOR THERAPY AND... ANTIVIRAL THERAPY IN PANDEMIC... Committee on Infectious... Liaisons Ex Officio Consultant Staff APPENDIX: INFANTS AND CHILDREN... REFERENCES

 
Therapy

• Influenza infection of any severity in high-risk children (see Appendix) regardless of immunization status
  
• Any otherwise healthy child with moderate-to-severe influenza infection who may benefit from the decrease in duration of clinical symptoms documented to occur with therapy
  

Prophylaxis

• High-risk children during the 2 weeks after influenza immunization, if influenza is active in the community
  
• High-risk children for whom influenza vaccine is contraindicated
  
• Family members or health care providers who are unimmunized and are likely to have ongoing, close exposure to (1) high-risk, unimmunized children or (2) infants who are younger than 6 months
  
• Control of influenza outbreaks for unimmunized staff and children in a closed institutional setting with high-risk pediatric residents (eg, extended-care facilities)
  
• As a supplement to immunization among high-risk children
  
• Postexposure prophylaxis in a family setting
  
• High-risk children and their family members and close contacts, as well as health care workers, when circulating strains of influenza virus in the community are not matched with vaccine strains
  

	ANTIVIRAL THERAPY IN PANDEMIC INFLUENZA

TOP ABSTRACT INTRODUCTION ANTIVIRAL DRUGS FOR EPIDEMIC... INDICATIONS FOR THERAPY AND... ANTIVIRAL THERAPY IN PANDEMIC... Committee on Infectious... Liaisons Ex Officio Consultant Staff APPENDIX: INFANTS AND CHILDREN... REFERENCES

 
Antiviral therapy may play a major role in both treatment and prophylaxis during a pandemic.^{58, 59} Pandemic influenza is likely to occur sometime within the next decade. Recent observations document the spread of an epidemic of H5N1 strain of avian influenza A virus in both wild and domestic bird species from southeast Asia to Indonesia, Europe, and Africa, with further spread felt likely to occur. As of October 16, 2006, 256 adult and pediatric cases of H5N1 influenza infection have been documented worldwide, associated with a mortality rate of 59%.⁶⁰ These infections have occurred most often in those with close, direct contact with poultry. Efficient transmission of the virus between humans, an event that is required before a human pandemic can occur, has not been documented to date with any of the currently identified H5N1 strains.

Intense planning for the possibility of an influenza pandemic with a virulent strain of H5N1 or another influenza virus subtype is ongoing at international, national, state, and local levels. The American Academy of Pediatrics and other professional organizations and stakeholders have had important input into the Pandemic Influenza Strategic Plan of the US Department of Health and Human Services, which was released in late 2005.⁶¹ Interim priorities for antiviral therapy and vaccine are included as part of the plan and reflect a need to treat and protect those most at risk of severe and fatal influenza and to preserve critical societal infrastructure (eg, law enforcement, medical facilities, government). Efforts are currently underway to stockpile adequate supplies of antiviral drugs to address both health care and societal requirements. The Strategic National Stockpile currently includes oseltamivir and rimantadine. Although most strains of H5N1 are susceptible only to the NAIs, some are susceptible to the adamantanes. The dose and duration of therapy for H5N1 infections may be different from those for currently circulating H3N2 or H1N1 infections. In the case of a pandemic, the Centers for Disease Control and Prevention, the American Academy of Pediatrics, and state and local health departments will provide current recommendations for therapy and prophylaxis.

	Committee on Infectious Diseases, 2006–2007

TOP ABSTRACT INTRODUCTION ANTIVIRAL DRUGS FOR EPIDEMIC... INDICATIONS FOR THERAPY AND... ANTIVIRAL THERAPY IN PANDEMIC... Committee on Infectious... Liaisons Ex Officio Consultant Staff APPENDIX: INFANTS AND CHILDREN... REFERENCES

 
Joseph A. Bocchini, Jr, MD, Chairperson

Robert S. Baltimore, MD

Henry H. Bernstein, DO

John S. Bradley, MD

Michael T. Brady, MD

Penelope H. Dennehy, MD

Margaret C. Fisher, MD

Robert W. Frenck, Jr, MD

David W. Kimberlin, MD

Sarah S. Long, MD

Julia A. McMillan, MD

Lorry G. Rubin, MD

	Liaisons

TOP ABSTRACT INTRODUCTION ANTIVIRAL DRUGS FOR EPIDEMIC... INDICATIONS FOR THERAPY AND... ANTIVIRAL THERAPY IN PANDEMIC... Committee on Infectious... Liaisons Ex Officio Consultant Staff APPENDIX: INFANTS AND CHILDREN... REFERENCES

 
Richard D. Clover, MD

American Academy of Family Physicians

Marc A. Fischer, MD

Centers for Disease Control and Prevention

Richard L. Gorman, MD

National Institutes of Health

R. Douglas Pratt, MD

Food and Drug Administration

Anne Schuchat, MD

Centers for Disease Control and Prevention

Benjamin Schwartz, MD

National Vaccine Program Office

Jeffrey R. Starke, MD

American Thoracic Society

Jack Swanson, MD

Practice Action Group

	Ex Officio

TOP ABSTRACT INTRODUCTION ANTIVIRAL DRUGS FOR EPIDEMIC... INDICATIONS FOR THERAPY AND... ANTIVIRAL THERAPY IN PANDEMIC... Committee on Infectious... Liaisons Ex Officio Consultant Staff APPENDIX: INFANTS AND CHILDREN... REFERENCES

 
Larry K. Pickering, MD

Red Book Editor

Carol J. Baker, MD

Red Book Associate Editor

	Consultant

TOP ABSTRACT INTRODUCTION ANTIVIRAL DRUGS FOR EPIDEMIC... INDICATIONS FOR THERAPY AND... ANTIVIRAL THERAPY IN PANDEMIC... Committee on Infectious... Liaisons Ex Officio Consultant Staff APPENDIX: INFANTS AND CHILDREN... REFERENCES

 
Edgar O. Ledbetter, MD

	Staff

TOP ABSTRACT INTRODUCTION ANTIVIRAL DRUGS FOR EPIDEMIC... INDICATIONS FOR THERAPY AND... ANTIVIRAL THERAPY IN PANDEMIC... Committee on Infectious... Liaisons Ex Officio Consultant Staff APPENDIX: INFANTS AND CHILDREN... REFERENCES

 
Alison Siwek, MPH

	APPENDIX: INFANTS AND CHILDREN AT HIGH RISK OF COMPLICATIONS FROM INFLUENZA INCLUDE THOSE WITH:

TOP ABSTRACT INTRODUCTION ANTIVIRAL DRUGS FOR EPIDEMIC... INDICATIONS FOR THERAPY AND... ANTIVIRAL THERAPY IN PANDEMIC... Committee on Infectious... Liaisons Ex Officio Consultant Staff APPENDIX: INFANTS AND CHILDREN... REFERENCES

 

• Ages between 6 and 24 months (no antiviral agent is currently approved for infants younger than 12 months)
  
• Asthma or other chronic pulmonary diseases such as cystic fibrosis
  
• Hemodynamically significant cardiac disease
  
• Immunosuppressive disorders or therapy
  
• HIV infection
  
• Sickle cell anemia and other hemoglobinopathies
  
• Diseases requiring long-term aspirin therapy, such as rheumatoid arthritis or Kawasaki disease
  
• Chronic renal dysfunction
  
• Chronic metabolic disease such as diabetes mellitus
  
• Neuromuscular disorders, seizure disorders, or cognitive dysfunction that may compromise the handling of respiratory secretions
  

	FOOTNOTES

 
All clinical reports from the American Academy of Pediatrics automatically expire 5 years after publication unless reaffirmed, revised, or retired at or before that time.

The guidance in this report does not indicate an exclusive course of treatment or serve as a standard of medical care. Variations, taking into account individual circumstances, may be appropriate.

	REFERENCES

TOP ABSTRACT INTRODUCTION ANTIVIRAL DRUGS FOR EPIDEMIC... INDICATIONS FOR THERAPY AND... ANTIVIRAL THERAPY IN PANDEMIC... Committee on Infectious... Liaisons Ex Officio Consultant Staff APPENDIX: INFANTS AND CHILDREN... REFERENCES

 

1. American Academy of Pediatrics, Committee on Infectious Diseases. Reduction of the influenza burden in children. Pediatrics. 2002;110 :1246 –1252[Abstract/Free Full Text]
2. Izurieta HS, Thompson WW, Kramarz P, et al. Influenza and the rates of hospitalization for respiratory disease among infants and young children. N Engl J Med. 2000;342 :232 –239[Abstract/Free Full Text]
3. Neuzil KM, Mellen BG, Wright PF, Mitchel EF Jr, Griffin MR. The effect of influenza on hospitalizations, outpatient visits, and courses of antibiotics in children. N Engl J Med. 2000;342 :225 –231[Abstract/Free Full Text]
4. Bhat N, Wright JG, Broder KR, et al. Influenza-associated deaths among children in the United States, 2003–2004. N Engl J Med. 2005;353 :2559 –2567[Abstract/Free Full Text]
5. Poehling KA, Edwards KM, Weinberg GA, et al. The underrecognized burden of influenza in young children. N Engl J Med. 2006;355 :31 –40[Abstract/Free Full Text]
6. Oxford JS, Bossuyt S, Balasingam S, Mann A, Novelli P, Lambkin R. Treatment of epidemic and pandemic influenza with neuraminidase and M2 proton channel inhibitors. Clin Microbiol Infect. 2003;9 :1 –14[CrossRef][ISI][Medline]
7. Cooper NJ, Sutton AJ, Abrams KR, Wailoo A, Turner D, Nicholson KG. Effectiveness of neuraminidase inhibitors in treatment and prevention of influenza A and B: systematic review and meta-analyses of randomised controlled trials. BMJ. 2003;326 :1235[Abstract/Free Full Text]
8. Turner D, Wailoo A, Nicholson K, Cooper N, Sutton A, Abrams K. Systematic review and economic decision modelling for the prevention and treatment of influenza A and B. Health Technol Assess. 2003;7:iii–iv, xi–xiii ,1 –170[Medline]
9. Uyeki TM. Influenza diagnosis and treatment in children: a review of studies on clinically useful tests and antiviral treatment for influenza. Pediatr Infect Dis J. 2003;22 :164 –177[CrossRef][ISI][Medline]
10. Matheson NJ, Symmonds-Abrahams M, Sheikh A, Shepperd S, Harnden A. Neuraminidase inhibitors for preventing and treating influenza in children. Cochrane Database Syst Rev. 2003;(3) :CD002744
11. Schmidt AC. Antiviral therapy for influenza: a clinical and economic comparative review. Drugs. 2004;64 :2031 –2046[CrossRef][ISI][Medline]
12. Moscona A. Oseltamivir-resistant influenza? Lancet. 2004;364 :733 –734[CrossRef][ISI][Medline]
13. Aoki FY, Macleod MD, Paggiaro P, et al. Early administration of oral oseltamivir increases the benefits of influenza treatment. J Antimicrob Chemother. 2003;51 :123 –129[Abstract/Free Full Text]
14. Whitley RJ, Hayden FG, Reisinger KS, et al. Oral oseltamivir treatment of influenza in children [published correction appears in Pediatr Infect Dis J. 2001;20:421]. Pediatr Infect Dis J. 2001;20 :127 –133[ISI][Medline]
15. Johnston SL, Ferrero F, Garcia ML, Dutkowski R. Oral oseltamivir improves pulmonary function and reduces exacerbation frequency for influenza-infected children with asthma. Pediatr Infect Dis J. 2005;24 :225 –232[CrossRef][ISI][Medline]
16. Ijichi S, Ijichi N. Too early cure of influenza: recurrence in oseltamivir-treated children. J Paediatr Child Health. 2003;39 :480 –481[ISI][Medline]
17. BPCA executive summary NDA 21-087/NDA 21-246: Tamiflu capsules and for oral suspension. Available at: www.fda.gov/cder/foi/esum/2004/21087,21246_Tamiflu_clinical_BPCA.pdf. Accessed September 20, 2006
18. Okamoto S, Kamiya I, Kishida K, Shimakawa T, Fukui T, Morimoto T. Experience with oseltamivir for infants younger than 1 year old in Japan. Pediatr Infect Dis J. 2005;24 :575 –576[CrossRef][ISI][Medline]
19. Tamura D, Miura T, Kikuchi Y. Oseltamivir phosphate in infants under 1 year of age with influenza infection. Pediatr Int. 2005;47 :484[CrossRef][ISI][Medline]
20. Hedrick JA, Barzilai A, Behre U, et al. Zanamivir for treatment of symptomatic influenza A and B infection in children five to twelve years of age: a randomized controlled trial. Pediatr Infect Dis J. 2000;19 :410 –417[CrossRef][ISI][Medline]
21. The MIST (Management of Influenza in the Southern Hemisphere Trialists) Study Group. Randomised trial of efficacy and safety of inhaled zanamivir in treatment of influenza A and B virus infections [published corrections appear in Lancet. 1999;353:504; and Lancet. 1999;353:1104]. Lancet. 1998;352 :1877 –1881[CrossRef][ISI][Medline]
22. Makela MJ, Pauksens K, Rostila T, et al. Clinical efficacy and safety of the orally inhaled neuraminidase inhibitor zanamivir in the treatment of influenza: a randomized, double-blind, placebo-controlled European study. J Infect. 2000;40 :42 –48[CrossRef][ISI][Medline]
23. Monto AS, Fleming DM, Henry D, et al. Efficacy and safety of the neuraminidase inhibitor zanamivirin the treatment of influenza A and B virus infections. J Infect Dis. 1999;180 :254 –261[CrossRef][ISI][Medline]
24. Hayden FG, Osterhaus AD, Treanor JJ, et al. Efficacy and safety of the neuraminidase inhibitor zanamivir in the treatment of influenzavirus infections. GG167 Influenza Study Group. N Engl J Med. 1997;337 :874 –880[Abstract/Free Full Text]
25. Relenza [package insert]. Research Triangle Park, NC: GlaxoSmithKline, 2006. Available at: www.fda.gov/cder/foi/label/2006/021036s008lbl.pdf. Accessed September 20, 2006
26. Hayden FG, Belshe R, Villanueva C, et al. Management of influenza in households: a prospective, randomized comparison of oseltamivir treatment with or without postexposure prophylaxis. J Infect Dis. 2004;189 :440 –449[CrossRef][ISI][Medline]
27. Welliver R, Monto AS, Carewicz O, et al. Effectiveness of oseltamivir in preventing influenza in household contacts: a randomized controlled trial. JAMA. 2001;285 :748 –754[Abstract/Free Full Text]
28. Hayden FG, Gubareva LV, Monto AS, et al. Inhaled zanamivir for the prevention of influenza in families. Zanamivir Family Study Group. N Engl J Med. 2000;343 :1282 –1289[Abstract/Free Full Text]
29. Hayden FG. Antiviral resistance in influenza viruses: implications for management and pandemic response. N Engl J Med. 2006;354 :785 –788[Free Full Text]
30. Kiso M, Mitamura K, Sakai-Tagawa Y, et al. Resistant influenza A viruses in children treated with oseltamivir: descriptive study. Lancet. 2004;364 :759 –765[CrossRef][ISI][Medline]
31. Carr J, Ives J, Kelly L, et al. Influenza virus carrying neuraminidase with reduced sensitivity to oseltamivir carboxylate has altered properties in vitro and is compromised for infectivity and replicative ability in vivo. Antiviral Res. 2002;54 :79 –88[CrossRef][ISI][Medline]
32. Ives JA, Carr JA, Mendel DB, et al. The H274Y mutation in the influenza A/H1N1 neuraminidase active site following oseltamivir phosphate treatment leave virus severely compromised both in vitro and in vivo. Antiviral Res. 2002;55 :307 –317[CrossRef][ISI][Medline]
33. Yen HL, Herlocher LM, Hoffmann E, et al. Neuraminidase inhibitor-resistant influenza viruses may differ substantially in fitness and transmissibility. Antimicrob Agents Chemother. 2005;49 :4075 –4084[Abstract/Free Full Text]
34. Jefferson T, Deeks JJ, Demicheli V, Rivetti D, Rudin M. Amantadine and rimantadine for preventing and treating influenza A in adults. Cochrane Database Syst Rev. 2004;(3) :CD001169
35. Bright RA, Shay DK, Shu B, Cox NJ, Klimov AI. Adamantane resistance among influenza A viruses isolated early during the 2005–2006 influenza season in the United States. JAMA. 2006;295 :891 –894[Abstract/Free Full Text]
36. Kitamoto O. Therapeutic effectiveness of amantadine hydrochloride in influenza A2: double blind studies. Jpn J Tuberc Chest Dis. 1968;15 :17 –26[Medline]
37. Kitamoto O. Therapeutic effectiveness of amantadine hydrochloride in naturally occurring Hong Kong influenza: double-blind studies. Jpn J Tuberc Chest Dis. 1971;17 :1 –7[Medline]
38. Galbraith AW, Oxford JS, Schild GC, Potter CW, Watson GI. Therapeutic effect of 1-adamantanamine hydrochloride in naturally occurring influenza A2-Hong Kong infection: a controlled double-blind study. Lancet. 1971;2(7716) :113 –115
39. Galbraith AW, Schild GC, Potter CW, Watson GI. The therapeutic effect of amantadine in influenza occurring during the winter of 1971–2 assessed by double-blind study. J R Coll Gen Pract. 1973;23 :34 –37[Medline]
40. Galbraith AW. Experiences from planning and execution of a controlled therapeutic trial in new cases of epilepsy. Acta Neurol Scand Suppl. 1975;60 :75 –76[Medline]
41. Symmetrel [package insert]. Chadds Ford, PA: Endo Pharmaceuticals Inc; 2003. Available at: www.endo.com/PDF/symmetrel_pack_insert.pdf. Accessed September 20, 2006
42. Advisory Committee on Immunization Practices; Smith NM, Bresee JS, et al. Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP) [published correction appears in MMWR Morb Mortal Wkly Rep. 2006;55:800]. MMWR Recomm Rep. 2006;55(RR-10) :1 –42
43. Geskey JM, Thomas NJ. Amantadine penetration into cerebrospinal fluid of a child with influenza A encephalitis. Pediatr Infect Dis J. 2004;23 :270 –272[CrossRef][ISI][Medline]
44. Thompson J, Fleet W, Lawrence E, Pierce E, Morris L, Wright P. A comparison of acetaminophen and rimantadine in the treatment of influenza A infection in children. J Med Virol. 1987;21 :249 –255[CrossRef][ISI][Medline]
45. Hall CB, Dolin R, Gala CL, et al. Children with influenza A infection: treatment with rimantadine. Pediatrics. 1987;80 :275 –282[Abstract/Free Full Text]
46. Flumadine [package insert]. St Louis, MO: Forest Pharmaceuticals Inc; 2000. Available at: www.fda.gov/cder/foi/label/2001/19650S4lbl.pdf. Accessed September 20, 2006
47. Galbraith AW, Oxford JS, Schild GC, Watson GI. Protective effect of 1-adamantanamine hydrochloride on influenza A2 infections in the family environment: a controlled double-blind study. Lancet. 1969;2(7629) :1026 –1028
48. Galbraith AW, Oxford JS, Schild GC, Watson GI. Study of 1–adamantanamine hydrochloride used prophylactically during the Hong Kong influenza epidemic in the family environment. Bull World Health Organ. 1969;41 :677 –682[ISI][Medline]
49. Schapira M, Oxford JS, Galbraith AW. A study of 1-adamantamine hydrochloride during the 1970 Hong Kong influenza epidemic. J R Coll Gen Pract. 1971;21 :695 –697[Medline]
50. Finklea JF, Hennessy AV, Davenport FM. A field trial of amantadine prophylaxis in naturally-occurring acute respiratory illness. Am J Epidemiol. 1967;85 :403 –412[Free Full Text]
51. Clover RD, Crawford SA, Abell TD, Ramsey CN Jr, Glezen WP, Couch RB. Effectiveness of rimantadine prophylaxis of children within families. Am J Dis Child. 1986;140 :706 –709[Abstract]
52. Crawford SA, Clover RD, Abell TD, Ramsey CN Jr, Glezen P, Couch RB. Rimantadine prophylaxis in children: a follow-up study. Pediatr Infect Dis J. 1988;7 :379 –383[ISI][Medline]
53. De Clercq E. Antiviral drugs in current clinical use. J Clin Virol. 2004;30 :115 –133[CrossRef][ISI][Medline]
54. Shiraishi K, Mitamura K, Sakai-Tagawa Y, Goto H, Sugaya N, Kawaoka Y. High frequency of resistant viruses harboring different mutations in amantadine-treated children with influenza. J Infect Dis. 2003;188 :57 –61[CrossRef][ISI][Medline]
55. Centers for Disease Control and Prevention. High levels of adamantane resistance among influenza A (H3N2) viruses and interim guidelines for use of antiviral agents: United States, 2005–06 influenza season. MMWR Morb Mortal Wkly Rep. 2006;55 :44 –46[Medline]
56. Rodriguez WJ, Hall CB, Welliver R, et al. Efficacy and safety of aerosolized ribavirin in young children hospitalized with influenza: a double-blind, multicenter, placebo-controlled trial. J Pediatr. 1994;125 :129 –135[CrossRef][ISI][Medline]
57. Hayden FG, Sable CA, Connor JD, Lane J. Intravenous ribavirin by constant infusion for serious influenza and parainfluenzavirus infection. Antivir Ther. 1996;1 :51 –56[Medline]
58. Hayden FG. Pandemic influenza: is an antiviral response realistic? Pediatr Infect Dis J. 2004;23(11 suppl) :S262 –S269
59. Hayden FG. Perspectives on antiviral use during pandemic influenza. Philos Trans R Soc Lond B Biol Sci. 2001;356 :1877 –1884[CrossRef][ISI][Medline]
60. World Health Organization. Cumulative number of confirmed human cases of avian influenza A/(H5N1) reported to WHO. Available at: www.who.int/csr/disease/avian_influenza/country/cases_table_2006_10_16/en/index.html. Accessed October 24, 2006
61. Department of Health and Human Services. Pandemic flu Web site. Available at: www.pandemicflu.gov. Accessed October 24, 2006

This article has been cited by other articles:

				Committee on Infectious Diseases Prevention of Influenza: Recommendations for Influenza Immunization of Children, 2007-2008 Pediatrics, April 1, 2008; 121(4): e1016 - e1031. [Abstract] [Full Text] [PDF]

				H. H. Bernstein CDC issues guidance for 2007-'08 flu season AAP News, September 1, 2007; 28(9): 1 - 2. [Full Text] [PDF]

				Advice on using antivirals for influenza AAP News, April 1, 2007; 28(4): 8 - 8. [Full Text] [PDF]

This Article Abstract Full Text (PDF) P3Rs: Submit a response Alert me when this article is cited Alert me when P3Rs are posted Alert me if a correction is posted Citation Map Services E-mail this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My File Cabinet Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Search for Related Content PubMed PubMed Citation Related Collections Infectious Disease & Immunity

	Home | My Pediatrics | Journal Information | Current Issue | Past Issues | Subscriptions & Services | Contact Us Click here for faster international access © 2007 American Academy of Pediatrics. All rights reserved.