Influenza Update: Focus on Children

Authors: Ann M. Dietrich, MD, FAAP, FACEP, Associate Clinical Professor, The Ohio State University, Columbus; Attending Physician, Columbus Children’s Hospital; Associate Pediatric Medical Director, MedFlight, Columbus, OH; and Leslie Mihalov, MD, FAAP, Assistant Professor of Clinical Pediatrics, Department of Pediatrics, The Ohio State University, Columbus; Chief, Section of Emergency Medicine, Children’s Hospital Department of Pediatrics, Columbus, OH.

Peer Reviewer: Steven M. Winograd, MD, FACEP, Attending Physician, Department of Emergency Medicine, St. Joseph Hospital, Reading, PA.

From October 2003 to Jan. 9, 2004, the Centers for Disease Control and Prevention (CDC) received reports of 93 influenza-associated deaths among children younger than 18 years. The demands the annual flu season places on emergency department (ED) and urgent care facilities and the voracity of the current year’s epidemic have overwhelmed many physicians. High-risk adults long have been the focus of public health programs and early diagnostic and therapeutic interventions. Influenza is responsible for significant morbidity and mortality in infants and young children, with influenza-associated hospitalization rates similar to those in adults with chronic medical conditions.1,2

During influenza epidemics, a diagnostic test that provides an accurate diagnosis in infants younger than 6 months of age with fever enables the clinician to provide the family with specific expectations for the disease process and minimizes unnecessary use of antibiotics.

This article reviews the current status of diagnostic testing, vaccine indications, and antiviral therapies for pediatric patients with influenza infections. The Editor

Epidemiology

Children account for nearly two-thirds of diagnosed cases of influenza during a typical season, with more than 30% of children living in affected communities.3 Adults contract the illness from children, and infection rates dramatically increase in households with school-age children.

Two population-based studies highlight the direct effect of influenza on children. Evaluation of hospitalization rates in Group Health Seattle and Kaiser Northern California indicated dramatically increased rates of hospitalization in healthy children younger than 2 years of age.1 Analysis of Tennessee Medicaid patients indicated hospitalization rates of children younger than age 2 that were similar to high-risk adults with substantive excess use of antibiotics.2

Influenza strikes hard in Japan. The population is long-lived, and many elderly live in homes with schoolchildren present. From 1962 to 1987, most Japanese schoolchildren were vaccinated against influenza. The vulnerable elderly were considered secondary targets for immunization. Excess influenza and pneumonia deaths dropped 40%, with 37,000-49,000 excess deaths per year averted. The laws mandating this effort were relaxed in 1987 and repealed in 1994. Subsequent vaccination rates dropped to low levels, leading to a sharply rising number of deaths.4

Similar findings are emerging from a study of immunizing schoolchildren with attenuated live intranasal influenza vaccine in a Texas community. Immunization rates of 50% have demonstrated the ability to prevent community epidemics and dramatically reduce excess mortality in the elderly. Immunization of schoolchildren was shown to be cost-effective when considering indirect costs of illness.5 In another, less recent study by Monto and colleagues in Tecumseh, MI, school-age immunization reached 85%, and the incidence of influenza-like illness was one-third that of neighboring communities.6

Prior to the 2003-2004 influenza season, laboratory-confirmed influenza illnesses and deaths were not nationally reportable conditions. Due to an increased concern about the morbidity (especially encephalitis cases) and mortality associated with influenza in pediatrics, the CDC requested that all influenza-associated deaths be reported to state and local health departments in the 2003-2004 season. Since October 2003, a total of 93 influenza-associated deaths in children have been reported. The median age of the 93 children was 4 years, with 26% between 6 months and 23 months of age and 59% of the children younger than 5 years of age.7 Although 38% of the children were reported to have a chronic underlying medical condition, 44% had no report of any pre-existing conditions. Another series reported that an underlying medical condition (asthma, neurologic deficits, or malignancy) was documented in 25% of children hospitalized with influenza A or B.8

Clinical Picture and Diagnosis

The clinical picture of influenza in young children often is subtle, with signs and symptoms mimicking other common childhood diseases. A series evaluating the prevalence of influenza in children 0-11 months of age, during the peak of an influenza epidemic, found that every third patient seen in a pediatric ED had virologically confirmed influenza infection.9 The younger the child, the more difficult it is to distinguish influenza from other febrile illnesses.8 In one series, the most common symptoms of influenza included fever, cough, and rhinorrhea, all nonspecific symptoms.

A retrospective 20-year review of pediatric patients with nasopharyngeal aspirates that were positive for influenza A or B, conducted in Finland, characterized the diversity of presentations. The majority of children had high fevers, and febrile seizures occurred in 12% of the children with influenza A and 9% with influenza B. Rhinorrhea and cough were present in 60% of the children and gastrointestinal symptoms (vomiting and diarrhea) were documented in 24% of the children. The classic adult symptoms of influenza (myalgias, headache, and malaise) are challenging to elicit from children younger than 3 years, secondary to normal developmental limitations. In assessments of children older than 3 years of age, 25% conveyed the presence of a headache and only 6% reported myalgias.8

Further confounding the ability of the clinician to make an accurate diagnosis is the diversity of clinical syndromes that may be caused by influenza. Croup, bronchiolitis, a febrile disease mimicking bacterial sepsis, and encephalitis all have been reported in association with influenza. Differentiation from parainfluenza or respiratory syncytial virus (RSV) infections requires culture or immunoassay. In addition, the young infant may require significant laboratory testing and procedures to assure a nonbacterial focus of infection.8,10-12

In the past, the lack of effective treatment coupled with delayed laboratory confirmation limited the ability of practitioners to develop a timely, specific diagnosis. The viral diagnosis paradigm was simply an exclusion of treatable bacterial illness in the differential diagnosis. The emergence of effective diagnostic techniques and antiviral therapy mandates a reconsideration of the evaluation of children with potential influenza-associated illnesses.

Complications

Influenza may be severe and may even lead to death, especially in children with underlying medical conditions. Secondary infections, including pneumonia and otitis media, may complicate influenza. One series reported 24% of the children developed otitis media, and pneumonia occurred in approximately 9% of the patients.8 Pneumonia was reported in 25 of the 93 fatal cases reported for the 2003-2004 influenza season, and 15 of the children had an invasive bacterial co-infection.7 Severe presentations and complications also have been associated with influenza and include encephalitis, Guillain-Barré type polyradiculopathy, and myositis.8

Diagnostic Testing

Exclusively pediatric studies comparing the accuracy of a clinical diagnosis to laboratory-confirmed influenza virus infections have not been conducted. Studies consisting primarily of adult patients have shown the highest predictive value of any case definition for influenza was 40% when compared with viral culture.13 Immunofluorescence staining may be performed on respiratory specimens (nasopharyngeal swabs, aspirate, or nasal swab with adequate epithelial cells) for the detection of influenza viruses.

Direct immunofluorescence antibody (DFA) tests and indirect immunofluorescence antibody (IFA) tests may be performed on respiratory samples to detect influenza viruses. These tests usually can be performed at a hospital or reference lab within 2-4 hours, but the specimen quality (adequate number of epithelial cells in the specimen) and technician experience are important. Three studies of the use of DFA for influenza A (compared to viral culture), revealed a median sensitivity of 62% (range 45-65%) and the median specificity was 98% (range 92-99.7%).14-17 Three studies that compared IFA for influenza A and B to viral culture revealed a median sensitivity of 73.9% (range 59.8-90%) and a median specificity of 97% (range 93-97%).17-19 Both IFA and DFA only are available to hospital-based physicians, have a high rate of false negative results, and require a minimum of 2-4 hours for test results.

The availability of CLIA (Clinical Laboratories Improvement Act) made rapid diagnostic kits for influenza available for diagnosis and timely intervention. Rapid influenza testing is reasonably accurate for detecting influenza infections in pediatric patients. (See Table 1.) False negative results may occur, but false positives are infrequent. Therefore, if the diagnosis of influenza is suspected in a moderately to severely ill child, more definitive testing may be indicated.

The development of a selective strategy for the use of the rapid influenza test is pragmatic. Each patient is not necessarily tested; rather, the test is used to calibrate the clinician’s clinical acumen and to provide confirmation of local disease presence. In certain situations, use of the rapid test may confirm a specific viral diagnosis; avert unnecessary diagnostic testing; provide for early, effective antiviral treatment; and reassure concerned parents about the lack of indication for antibiotics.

The use of diagnostic tests has led to a significant decrease in the unnecessary use of antibiotics, and logically should lead to a reduction in the emergence of antibiotic resistance.20,21 The use of laboratory and radiographic testing also has been shown to be significantly reduced through the use of the rapid influenza tests, leading to decreased patient charges.10,21 Especially in infants and younger children, a positive influenza test has been shown to decrease the number of complete blood counts, blood cultures, urine cultures, cerebral spinal fluid studies, and chest radiographs.10 In addition, the use of rapid diagnostic testing has been shown to decrease the length of stay in the ED for patients with a positive rapid test for influenza.10

Treatment

Currently, three antiviral drugs—amantadine, oseltamivir, and zanamivir—are approved for the treatment of influenza in children, and two other drugs—rimantadine and ribavirin—have been used. (See Table 2.)

Amantadine. About 30 years ago, specific antiviral therapy of influenza began with the introduction of amantadine, a drug that targets the M2 membrane protein of influenza A. The drug has not been studied in an exclusively pediatric population, but two studies have shown a reduction in the mean duration of fever.22,23 It also has been shown to decrease the frequency of headaches and gastrointestinal symptoms (nausea and vomiting)22,23 and to reduce the duration of uncomplicated influenza A and B illness by one day when compared to placebo. Amantadine has not been demonstrated to be effective for the prevention of serious influenza-related complications, and the majority of the studies have been conducted in patients with uncomplicated illnesses. Although the development of amantadine resistance has not been adequately assessed, a trend toward a rapid emergence of resistance and lack of activity against influenza type B reduces its usefulness.

It also is effective as a prophylactic agent during epidemics in both adults and children older than 1 year.24 Neurologic and gastrointestinal side effects may be significant in very young and elderly patients. Resistance has been documented within single households, with treated index cases transmitting resistant virus to other family members.25

Rimantadine. Although rimantadine currently only is approved for chemoprophylaxis of influenza type A infections among children, some experts consider it acceptable treatment for the illness. Rimantadine, similar to amantadine, has been shown to decrease the duration of uncomplicated influenza A illness when administered within 48 hours of the onset of illness.26 Resistance has been shown to develop rapidly with the use of rimantadine, and one study demonstrated a prolonged viral excretion in children treated with rimantadine.26 Rimantadine has been shown to have a decreased incidence of central nervous system (CNS) side effects when compared to amantadine.

Zanamivir. Zanamivir is a neuraminidase inhibitor and has activity against both influenza A and B. Clinical studies in experimental and natural infection demonstrated decreased length of viral shedding, symptoms, and severity in both type A and B influenza illnesses.27,28 Ongoing studies of the neuraminidase inhibitors have shown efficacy in childhood. A double-blind, placebo-controlled study of zanamivir in the 1998-1999 northern hemisphere flu season recruited 471 children with flu-like symptoms. Three hundred forty-six had culture-proven influenza, and inhaled diskhaler therapy significantly shortened time to alleviation of symptoms and time to resumption of normal activity. The treatment group also used less relief medications and there was a reduction in associated complications (16%) and antibiotic use (12%).29

Questions were raised regarding respiratory function deterioration in patients with existing chronic obstructive pulmonary disease (COPD) and asthma. Bronchospasm has occurred in patients with asthma.28,30 The package insert contains important precautionary information regarding the use of zanamivir with underlying airway disease. The drug is taken as a five-day course using a proven diskhaler design. It is indicated for patients ages 7 and older who have signs and symptoms of influenza A and B of fewer than 48 hours duration.

Oseltamivir. The desire for an orally active drug led to the development of oseltamivir (Tamiflu). Oseltamivir is a neuraminidase inhibitor that has activity against both influenza A and B. Oseltamivir has been approved for treating uncomplicated influenza infections in children older than 1 year and also has been approved for use as a chemoprophylaxis agent in children older than 13 years.

A study of 695 patients ages 1-12 years showed a 36-hour, or 26%, reduction in duration of influenza. The incidence of otitis media was reduced by 44%.31 Specific efficacy was demonstrated with influenza B infection in other studies, with a decrease of symptom duration by 25%.30,32 Oseltamivir was well-tolerated in clinical trials, with no safety issues raised. In adult, adolescent, and child studies, nausea was reported, with a greater incidence of emesis over placebo of 5.8%. The recipients described the gastrointestinal symptoms as transient and mild.33,34 Discontinuation of medication due to adverse events was 1.8% in the oseltamivir group vs. 1.1% with placebo.31 Prior studies with adolescents and adults indicate significant reduction of gastrointestinal symptoms with concomitant consumption of food.33 Resistant strains were uncommon and represented viruses with limited infectivity in humans.

Ribaviron. Minimal information is available regarding the use of ribaviron for the treatment of influenza in children. Two randomized controlled studies compared ribaviron to the use of placebo in children with influenza. Aerosolized ribaviron, given to hospitalized children who had fewer than 48 hours of symptoms reduced the mean duration of fever.35 Oral ribaviron was evaluated in a single double-blinded controlled study in girls 8-16 years of age and found significantly reduced symptoms 24 hours after starting the medication and decreased viral shedding. Neither study reported any significant adverse effects.36

Prophylaxis. Chemoprophylactic drugs are an adjunct to vaccination in the prevention and control of influenza. The neuroaminidase inhibitors have been shown effective for prevention of influenza infection. Zanamivir once a day was 79% effective for the prevention of influenza transmission within families with a confirmed index case.37 Orally administered oseltamivir 75 mg once a day protected close family contacts against influenza by 92% and interrupted transmission within households by 89%.38,39 Post-exposure, the placebo group had a 12% incidence of influenza, compared with a 1% incidence in the prophylaxis group. The U.S. Food and Drug Administration (FDA) has indicated oseltamivir for prophylaxis in adolescents and adults ages 13 and older.

It has been suggested that use of family prophylaxis after treatment of the index case may be the most effective use of the medication. It not only protects familial contacts but also can serve to reduce community exposure. Family physicians are in a unique position to treat the whole family when an index case is identified. Pediatricians will need to form effective alliances with internists and family physicians to effectively reach the parents of children with influenza.

Reducing Complications and Antibiotic Use

The serious complications of influenza include bacterial pneumonias, Reye syndrome, and prolonged recovery of high-risk patients. The increased frequency of otitis media and other respiratory infections in children with influenza is under-appreciated. With proper antiviral treatment of influenza, a substantive reduction of antibiotic usage has been demonstrated. This reflects a real decrease in otitis media occurrence, as well as the desired reduction in the overuse of antibiotics for primary viral infection.

In the oseltamivir trials in children ages 1-12 years, 21% of placebo recipients and only 12% of treated subjects had documented otitis media.30 The 44% reduction in clinical diagnosis was paralleled by a 40% reduction in antibiotic usage.31 The zanamivir trials of children ages 5-12 years showed a 30% reduction in bacterial complications, with a 20% reduction in antibiotic use.29 Effective treatment of primary viral infections can reduce otitis morbidity and antibiotic usage.

In pivotal clinical trials, the neuraminidase inhibitors showed efficacy with one- to two-day decreases in time to alleviation of all significant symptoms of influenza. Early FDA examination and subsequent professional commentary questioned this apparent marginal benefit from therapy. Health maintenance organizations and other third-party payers also questioned utility, and frequently excluded the medications from their panels. This marginality of efficacy contrasted strongly with clinical observations of patients, physicians, and investigators using the medications. In an effort to reconcile clinical impressions in practice with clinical trial data, investigators followed 1408 patients using prescribed zanamivir in Australia during the 1999 flu season.

Symptom relief was reported by more than 50% of patients within 24 hours and by 77% within 48 hours.40 Of the 400 elderly patients, 78% were satisfied with their treatment, with 59% experiencing symptom relief within 24 hours.41 The survey concluded that zanamivir was associated with an early return to normal activities. The investigators also noted that patients with influenza had a protracted cough. Even in treated influenza patients, the cough persisted after systemic symptoms of fever, headache, myalgia, and malaise had resolved. They speculated that residual cough prolonged the end point in the clinical studies and, thus, caused an underestimation of the clinical effect of treatment.

The identification and treatment of primary viral infections remains a significant challenge to pediatric medicine. It also represents a significant opportunity to reduce an ongoing burden of illness. The technology for effectively preventing, diagnosing, and treating influenza has been demonstrated. Outpatient clinics, emergency rooms, and urgent care centers, as well as private physician offices, need to organize specifically to meet the challenge of early intervention in influenza epidemics. Telephone triage systems need to efficiently screen those with classic symptoms of influenza and promptly direct them to where they can be evaluated and treated with minimal delay. Specific time slots dedicated to prompt evaluation and treatment of infectious disease must be set aside during anticipated flu seasons.

The widespread implementation of influenza prevention and treatment in pediatric populations would provide benefit not only to the index cases but also to household contacts and vulnerable fragile elderly in the community. The antiviral treatment and chemoprophylaxis of contacts of influenza victims will serve as a model for treatment of other specific viral illness as newer antiviral agents that are readily visible in the drug pipeline become available to the practitioner.

Immunization. The U.S. Advisory Committee on Immunization Practices (ACIP) has issued its recommendations for the 2004-2005 influenza season. ACIP has recommended that all children 6-23 months of age be vaccinated annually against influenza beginning in the fall of 2004. Children younger than 9 years of age who previously have been unvaccinated should receive two doses one month apart. ACIP continues to strongly recommend vaccination of children with chronic medical problems. The recommendation to vaccinate healthy children in the 6-23 month age group is based on studies that showed that previously healthy young children account for the majority of hospitalizations for pediatric influenza.42 Cost calculations have suggested that, for healthy children, vaccination against influenza would be cost-effective5 and would decrease influenza-associated morbidity and mortality in the adult population because of the important role of children in the dissemination of influenza.4 Vaccination programs should start in October and target adults older than 50 years, children 6-23 months of age, high-risk patients of any age and their household contacts, and health care workers. The attenuated live intranasal vaccine (FluMist) is an expensive option ($55.20/dose) for healthy individuals 5-49 years of age who do not have contact with immunocompromised patients. Children 6-35 months may receive 0.25mL/dose of Fluzone, and patients older than 35 months may receive 0.50 mL/dose of Fluvirin or Fluzone.

Future Directions and Considerations

The use of real-time influenza reporting systems enables clinicians to either include or exclude the possibility of influenza through community epidemiology. The use of quick diagnostic kits makes a positive diagnosis of the viral infection possible, and increased usage may prevent many needless exposures to unnecessary antibiotics.

With proper local epidemiologic surveillance and available laboratory tests, more precise diagnosis will be facilitated, and enhanced use of antiviral agents promoted. More than ever, precision in defining the etiologic agents is not only desirable, but also necessary.

(The authors wish to acknowledge the contributions of Katalin Koranyi, MD, Professor of Clinical Pediatrics, Section of Infectious Disease, Department of Pediatrics, College of Medicine, The Ohio State University, Columbus.)

References

1. 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.

2. Neuzil KM, Mellen BG, Wright PF, et al. The effect of influenza on hospitalization, outpatient visits, and courses of antibiotics in children. N Engl J Med 2000;342:225-231.

3. National Institute of Allergy and Infectious Diseases. Fact Sheet: Flu. December 1997.

4. Reichert TA, Sugaya N, Fedson DS, et al. The Japanese experience with vaccinating schoolchildren against influenza. N Engl J Med 2001;344:889-892.

5. White T, Lavoie S, Nettleman MD. Potential cost savings attributable to influenza vaccination of school-aged children. Pediatrics 1999;103:e6.

6. Monto AS, Davenport FM, Napier JA, et al. Modification of an outbreak of influenza in Tecumseh, Michigan by vaccination of schoolchildren. J Infect Dis 1970;122:16-25.

7. Center for Disease Control and Prevention. Update: Influenza-associated deaths reported among children age < 18 Years—United States, 2003-2004 influenza season. MMWR Morb Mortal Wkly Rep 2004;52:1286-1288.

8. Peltola V, Ziegler T, Ruuskanenn O. Influenza A and B virus infections in children. CID 2003:36 (1 February):299-305.

9. Ploin D, Liberas S, Thouvenot, D, et al. Influenza burden in children newborn to eleven months of age in a pediatric emergency department during the peak of an influenza epidemic. Pediatr Infect Dis J 2003;22:218-222.

10. Bonner AB, Monroe KW, Talley LI, et al. Impact of the rapid diagnosis of influenza on physician decision-making and patient management in the pediatric emergency department: Results of a randomized, prospective, controlled trial. Pediatrics 2003;112: 363-367.

11. Henderson F. Viral Respiratory Infection. In: Rudolph A, Hoffman J, Rudolph C. Rudolph’s Pediatrics. 20th ed. Stamford: Appleton & Lange;1996:1.

12. Glezen W, Cherry J. Influenza Viruses. In: Feigin RD, Cherry J, eds. Textbook of Pediatric Infectious Diseases. 3rd ed. Philadelphia: Saunders; 1992:1688-1704.

13. Carrat F, Tachet A, Rouzioux C, et al. Evaluation of clinical case definitions of influenza: Detailed investigation of patients during the 1995-1996 epidemic in France. Clin Infect Dis 1999;28: 283-290.

14. Dominguez EA, Taber LH, Couch RB. Comparison of rapid diagnostic techniques for respiratory syncytial and influenza A virus respiratory infections in young children. J Clin Microbiol 1993; 31:2286-90.

15. Stout C, Murphy MD, Lawrence S, Julian S. Evaluation of a monoclonal antibody pool for rapid diagnosis of respiratory viral infections. J Clin Microbiol 989;27:448-452.

16. Higazi Z, Pacsa A, Eisa S, et al. Laboratory diagnosis of acute lower respiratory tract viral infections in children. J Trop Pediatr 1996;42:276-280.

17. Uyeki TM. Influenza diagnosis and treatment in children: A review of studies on clinically useful tests and antiviral treatment for influenza. Pediatr Infect Dis 2003;22:164-177.

18. Spada B, Biehler K, Chegas P, et al. Comparison of rapid immunofluorescence assay to cell culture isolation for the detection of influenza A and B viruses in nasopharyngeal secretions from infants and children. J Virol Methods 1991;33:305-310.

19. Noyola DE, Clark B, O’Donnell FT, et al. Comparison of a new neuramidinase detection assay with an enzyme immunoassay, immunofluorescence, and culture for the rapid detection of influenza A and B viruses in nasal wash specmens. J Clin Microbiol 2000; 38:1161-1165.

20. Noyola D, Demmler GJ. Effect of rapid diagnosis on management of Influenza A infections. Pediatr Infect Dis J 2000;19:303-307.

21. Sharma V, Dowd D, Slaughter AJ, et al. Effect of rapid diagnosis of influenza virus type A on the emergency department management of febrile infants and toddlers. Arch Pediatr Adolesc Med 2002; 156:41-43.

22. Kitamoto O. Therapeutic effectiveness of amantadine hydrochloride in influenza A2: Double blind studies. Jpn J Tuberc Chest Dis 1968; 15:17-26.

23. 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.

24. Amantadine: Does it have a role in the prevention and treatment of influenza? NIH Consens Statement 1979 Oct 15-16;2:51-56.

25. Hayden FG, Belshe RB, Clover RD, et al. Emergence and apparent transmission of rimantadine-resistant influenza A virus in families. N Eng J Med 1989;321:1696-1702.

26. Hall CB, Dolin R, Gala CL, et al. Children with influenza A infection: Treatment with rimantadine. Pediatrics 1987;80:275-282.

27. Boivin G, Goyette N, Aoki F, et al. Clinical and virological efficacy of zanamivir in the treatment of influenza A virus infections during the 1997-1998 flu season. Poster Session ICAAC, 1999.

28. Hayden FG, Osterhaus AD, Treanor JJ, et al. Efficacy and safety of the neuraminidase inhibitor zanamivir in the treatment of influenza virus infections. N Engl J Med 1997;337:874-880.

29. Hedrick J, Barzilai A, Behre U. 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: 410-417.30.

30. Monto A, Fleming D, Henry D, et al. Efficacy and safety of the neuraminidase inhibitor zanamivir in the treatment of influenza A and B virus infections. J Infect Dis 1999;180:254-261.

31. Whitley RJ, Hayden FG, Reisinger KS, et al. Oral oseltamivir treatment of influenza in children. Pediatr Infect Dis J 2001;20:127-133.

32. Hayden F, Robson R, Jennings L, et al. Efficacy of oseltamivir in experimental human influenza B virus infection, Poster 670. ICAAC 2000.

33. Hayden FG, Atmar RL, Schilling M, et al. Safety and efficacy of a selective oral neuraminidase inhibitor (oseltamivir) to prevent influenza. N Engl J Med 1999;341:1336-1343.

34. Hayden FG, Treanor JT, Fritz RS, et al. Use of the oral neuraminidase inhibitor oseltamivir in experimental human influenza: Randomized controlled trials for prevention and treatment. JAMA 1999;282:1240-1246.

35. Rodriguez WJ, Hall CB, Welliver R, et al. Efficacy and safety of aerosolized ribavirin in young children hoespitalized with influenza: A double-blind, multicenter, placebo-controlled trial. J Pediatr 1994;125:129-135.

36. Salido-Rengell F, Nasser-Quinones H, Briseno-Garcia B. Clinical evaluation of 1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide (ribavirin) in a double-blind study during an outbreak of influenza. Ann NY Acad Sci 1977;284:272-277.

37. Monto A, Robinson D, Herlocher M, et al. Zanamivir in the prevention of influenza among healthy adults: A randomized controlled trial. JAMA 1999;282:31-35.

38. Hayden FG, Atmar RL, Schilling M, et al. Use of the selective oral neuraminidase inhibitor oseltamivir to prevent influenza. N Engl J Med 1999;341:1336-1343.

39. Oxford J, Jackson H, Ward P. Short term prophylaxis with oseltamivir effectively prevents spread of influenza A and B. Whitechapel, London: Retroscreen Ltd.

40. Silagy C, Watts R. Zanamivir, a new targeted therapy in the treatment of influenza: A patient perspective assessed by questionnaire. Clin Drug Invest 2000;19:111-121.

41. Joseph AM, Neal D. Managing cold and flu: A protocol for the nurse and pharmacist. Federal Practitioner 1999;Nov:23-51.

42. Sugaya N, Nerome K, Ishida M, et al. Impact of influenza virus infection as a cause of pediatric hospitalization. J Infect Dis 1992; 165:373-375.


CME Objectives

The CME objectives for Pediatric Influenza Update are to help physicians:

1) recognize the historical and clinical symptoms associated with influenza infection;

2) integrate appropriate laboratory diagnostic testing for suspected influenza into clinical practice; and

3) understand and implement into practice utilization of antiviral therapies.

CME Instructions

Physicians participate in this continuing medical education program by reading the article, using the provided references for further research, and studying the questions at the end of the article. Participants should select what they believe to be the correct answers, then refer to the list of correct answers to test their knowledge.

To clarify confusion surrounding any questions answered incorrectly, please consult the source material. After completing this activity, you must complete the enclosed evaluation form and return it in the reply envelope provided to receive a certificate of completion. When your evaluation is received, a certificate will be mailed to you.

Physician CME Questions

1. Gastrointestinal symptoms of vomiting and diarrhea occur in how many children with influenza?

A. Approximately 24%
B. More than 50%
C. More than 75%
D. Almost all

2. The findings of a Texas study with a 50% immunization rate for schoolchildren demonstrated:

A. immunization of schoolchildren was shown to be cost effective when considering indirect costs of illness.
B. immunization made no difference.
C. immunization prevented community epidemics.
D. immunization dramatically reduced excess mortality in the elderly.
E. A, C, and D only are correct.

3. Which of the following statements about the presentation of influenza in children is correct?

A. The infection only presents as classic bronchiolitis.
B. Differentiation from parainfluenza or respiratory syncytial virus (RSV) infections may be accomplished without culture or immunoassay.
C. Febrile seizures may occur in association with an influenza illness.

4. Severe presentations and complications associated with influenza include encephalitis, Guillain-Barré type polyradiculopathy, and myositis.

A. True
B. False

5. Which of the following may be a complication of influenza?

A. Bacterial co-infection
B. Otitis media
C. Pneumonia
D. All of the above

6. Effective treatment of primary viral infections can reduce otitis media occurrence and antibiotic usage.

A. True
B. False

Answer Key: 1. A; 2. E; 3. C; 4. A; 5. D; 6. A