Influenza virus infection in infancy and early childhood

PAEDIATRIC RESPIRATORY REVIEWS (2003) 4, 99–104 doi: 10.1016/S1526–0542(03)00027-7

MINI-SYMPOSIUM: RESPIRATORY VIRUSES – PART I

Influenza virus infection in infancy and early childhood Flor M. Munoz Molecular Virology and Microbiology, Baylor College of Medicine, Rm 221-D, BCM-280, Houston, TX 77030, USA KEYWORDS influenza; infancy; vaccination; prevention; maternal immunisation

Summary Infants and young children have the highest influenza infection and hospitalisation rates in paediatrics. The immaturity of the infant’s immune system and the absence of prior immunity and exposure to the virus are potential contributors. Although most children that suffer from influenza infection are otherwise healthy, an underlying chronic medical condition further increases the risk for complications. Annual immunisation with influenza vaccine is recommended for any child 6 months of age and older in whom prevention of disease is desirable, particularly for those with underlying medical conditions. Offering influenza vaccine to pregnant women who will deliver during the influenza season can potentially reduce the frequency and severity of influenza disease in infants less than 6 months of age. Family members, including other children and all other close contacts, should also receive influenza vaccine to reduce transmission to children at risk and infants in the first 6 months of life. ß 2003 Elsevier Science Ltd. All rights reserved.

INTRODUCTION The impact of influenza epidemics varies from year to year depending on the virulence of the circulating virus strain, the presence or lack of prior immunity to the epidemic virus in the population and the intensity of exposure to the virus. The direct impact of influenza in young children can be difficult to assess because clinical manifestations of influenza in infants are often atypical and because they are susceptible to infection with many other respiratory viruses with activity coinciding with that of influenza virus, particularly respiratory syncytial virus and parainfluenza viruses. New viral diagnostic methods help better to define the different clinical illnesses associated with influenza virus infection in the very young. Specific anti-viral treatment is currently available for children 1 year of age and older. Prevention through immunisation is the most important intervention to reduce the effects of influenza in infancy.

Correspondence to: F. M. Munoz, Assistant Professor of Pediatrics. Tel.: þ1-713-798-5248; Fax: þ1-713-798-6802; E-mail: [email protected] 1526–0542/03/$ – see front matter

CLINICAL PRESENTATION OF INFLUENZA The clinical presentation of influenza in children varies in different age groups, but in general, influenza is more commonly associated with a febrile illness than other respiratory viruses.1 After an incubation period of 1–4 days, uncomplicated influenza in older children and adults is characterised by a sudden onset of fever that can be accompanied by chills and sweats, myalgia, malaise, headache, non-productive cough, rhinitis and sore throat. In children younger than 5 years, fever, cough and rhinitis are the most common findings. Constitutional symptoms can be absent in very young children, whose only manifestation may be high fever. Fever without localising signs is a diagnosis of concern in infants under 6 months of age and it is a reason for hospitalisation, particularly in neonates. In a recent survey carried out at Texas Children’s Hospital in Houston, Texas, USA, fever was the reason for hospitalisation in 22 of 34 (65%) otherwise healthy infants 0–60 days of age with laboratory-confirmed influenza illness.2 Other manifestations of influenza in infancy include irritability, decreased oral intake, vomiting, diarrhoea, abdominal pain, lethargy, difficulty breathing, dyspnoea and apnoea. These symptoms are non-specific and may ß 2003 Elsevier Science Ltd. All rights reserved.

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be attributed to other causes of serious disease in infants if diagnostic tests to establish a definitive diagnosis of influenza are not available to the clinician. Complications of influenza infection include viral pneumonia, secondary bacterial pneumonia often caused by S. pneumoniae, group A b-haemolytic streptococcus or Staphylococcus aureus, bronchiolitis, laryngotracheobronchitis (croup) and otitis media.3–6 Non-respiratory-tract complications include myositis, myocarditis and central nervous system involvement with encephalitis, febrile seizures and Reye’s syndrome.7–9 Otherwise healthy children under 5 years of age, and particularly those less than 2 years of age, are more likely to develop lower respiratory tract disease (pneumonia, bronchiolitis and croup) and otitis media.5,10– 13 Persistent or recurrent fever and cough indicate the presence of one of these complications. An antecedent influenza infection can predispose children to the development of severe pneumococcal pneumonia. In a recent study, children with severe pneumonia were 12 times more likely to have experienced influenza-like illness and almost four times more likely to have positive influenza convalescent serology than matched controls.4 There is also evidence that influenza may be an important factor in the pathogenesis of acute otitis media6 and that concurrent viral and bacterial middle ear infection significantly worsens the course of acute otitis media.14 Approximately 3–5% of children experience influenza-associated acute otitis media every year.10 Myositis, myocarditis and central nervous system involvement are less common. The association of influenza and febrile seizures or encephalopathy has been described recently in China and Japan,7,8 raising awareness of the potential extent of clinical disease associated with influenza virus. Children with underlying medical conditions, particularly prematurity and cardiopulmonary diseases, experience exacerbations of pulmonary disease and are prone todevelopseriousinfluenzadiseaseanditscomplications.11,15

influenza infection and hospitalisation. Annual attack rates of influenza disease range from 15 to 42% in pre-school and school-age children,10,17 and depending on the year, rates of annual outpatient visits attributable to influenza can vary from 6 to 29%.10,16 Due to its association with febrile illness, otitis media and bacterial pneumonia, influenza leads to a 10–30% increase in the number of anti-microbial courses prescribed to children during the influenza season.11 Otitis media is the most frequent reason for outpatient antibiotic therapy in the USA. High rates of hospitalisation of young children during influenza epidemics have also been demonstrated through the years,16,22–24 although population-based studies have only recently attempted to distinguish the proportion of hospitalisations attributable to influenza virus from those caused by other common respiratory viruses of infancy, in particular respiratory syncytial virus.11,13 Despite the variability in the severity of influenza epidemics, and the different populations and methodology used, taken together, these studies have consistently shown that children younger than 5 years of age, and particularly those under 12 months of age, are at substantially higher risk of hospitalisation for influenza than older children. The risk of influenza-associated hospitalisation in infants in the first year of life is as high as that of elderly adults and higher than the risk for adults 50–64 years of age, groups for whom annual influenza immunisation is recommended. Deaths attributable to influenza are far less common in children than they are in the elderly. The risk of mortality from influenza is highest among adults over 65 years of age, who account for over 90% of deaths attributable to influenza and pneumonia, and estimated mortality rates ranging from 30 to >150 deaths/ 100 000.25,26 In children, the influenza fatality rate has been estimated to be 3.8 per 100 000.27 Infants and children with chronic medical conditions are also at increased risk of influenza-associated mortality.26,28

EPIDEMIOLOGY AND IMPACT OF INFLUENZA IN YOUNG CHILDREN

CHILDREN AT HIGH RISK FOR INFLUENZA MORBIDITY AND MORTALITY

Children play a significant role in the introduction and spread of influenza virus into households and in the community.16 Cases among school-age children usually peak in the early stage of an epidemic and are followed by cases in infants and adults.17 The presence of school-age children in the household is the most important determinant related to the occurrence of influenza infection. There is also evidence that seroconversion to influenza virus in children continues to occur between epidemics, suggesting persistence of viral activity throughout the year.17–19 During an annual winter epidemic, influenza may be the most frequently isolated virus in children requiring medical attention or hospitalisation for acute respiratory tract disease.20,21 Community studies carried out by different investigators from the 1960s to the 1990s have consistently shown that young children have the highest rates of

Children with underlying medical conditions have rates of hospitalisation for influenza-related illnesses two to six times higher than in otherwise healthy children. In studies of epidemics from the 1960s to the early 1990s, the highest rates of hospitalisation in high-risk children were observed in those under 5 years of age15,23,29 and particularly in children under 1 year of age, who have hospitalisation rates two to four times higher than those of healthy children of similar age in the same population.11,28 Interestingly, rates of outpatient visits do not appear to be significantly higher in children with chronic cardiopulmonary conditions including asthma, suggesting that the severity of influenza illness is indeed greater as it is more likely to result in hospitalisation.28 The most common reason for admission in children at risk is lower respiratory tract disease.

INFLUENZA VIRUS INFECTION

The most common underlying conditions in children with influenza complications are asthma and congenital heart disease. The presence of more than one underlying condition per child is common, and the overall case fatality rate in these children is high (2–3/100 000 influenza-related hospitalisations).15 Other conditions that place children at risk for severe influenza include immunodeficiencies, malignancies, cardiopulmonary disease, renal disease, haemoglobinopathies and metabolic disorders, including diabetes.26 Chronic lung disease associated with prematurity is a risk factor for influenza in infants with prolonged hospitalisation after birth. Nosocomial outbreaks of influenza A and B virus infections in neonatal intensive care units have been reported recently.30–32 Nosocomial influenza infection is also a concern for high-risk children, including infants less than 1 year of age.33,34 Although most infants recover, fatalities have occurred due to severe pneumonia. In developing countries, influenza virus is one of the most common viral causes of acute respiratory infections and a predisposing condition to secondary bacterial infections. In this setting, risk factors that increase the incidence and severity of viral lower respiratory tract disease include large family size, lateness in birth order, crowding, low birthweight, malnutrition, vitamin-A deficiency, lack of breast feeding and young age.35

MATERNAL ANTIBODIES AND PROTECTION FROM INFLUENZA Most influenza infections in infants under 1 year of age occur in the second 6 months of life.36 Considering the high infection rates observed in school-age children, infants are at greater risk of infection if they are exposed to the virus by contact with older siblings or other children in out-of-home care environments.36,37 Maternally derived antibodies are likely to provide protection against influenza in the first 6 months after birth. The degree and duration of protection is directly dependent on the immunological history of the mother, i.e. previous exposure to the circulating influenza virus strain or an antigenically similar strain and the amount of specific antibody transferred to the infant at birth. Puck et al.38 followed 26 infants from whom cord sera was available and who had culture-documented influenza infection in the first 4 months of life between 1975 and 1978. They found that there was a direct correlation between the cord serum level of neutralising antibody to influenza A and the age at the time of the first infection in infants, so that the higher the level of antibody, the older the children were when they experienced their first influenza infection. Similarly, infants of mothers with H1-specific serum antibody (considered immune) and infants of mothers without antibodies (considered non-immune) were followed by Reuman et al.39 during the 1979 H1N1 epidemic, who found that mothers who were immune before the epidemic were less frequently infected with influenza, that the levels of antibody in infant cord serum correlated with that

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of the mothers and that the onset of symptomatic influenza infection was delayed in infants of immune mothers. Infected infants of immune mothers also had a shorter duration of symptoms in this study. The transplacental transport of influenza antibodies from mother to infants is a well-documented active process that results in a higher concentration in the fetal side of the circulation.40–42 The duration of passively acquired antibody in infants depends on the initial cord blood concentration, and is probably less than 6 months.43 Similarly, protection of infants against respiratory infections through breast milk is a commonly described epidemiological phenomenon,44,45 although the specific mechanisms of protection continue to be elucidated as multiple protective factors are present in breast milk. Animal studies suggesting protection of pups from an influenza virus challenge by antibodies acquired through breast feeding have been carried out in mice,46 ferrets,47,48 and guinea pigs.49 The presence of high concentrations of secretory IgA in the respiratory tract correlates with protection against influenza.50 Breast-fed infants coat their upper respiratory tract with breast milk secretory IgA during the normal process of breast feeding.44

DIAGNOSIS OF INFLUENZA IN INFANTS The accuracy of clinical diagnosis of influenza may be up to 85% at best for experienced clinicians, although it is lower with decreasing patient age. Laboratory confirmation can be achieved by virus isolation, or detection of viral proteins, viral RNA or antibodies to influenza. Culture-confirmed cases of influenza only account for approximately one-third of all cases because of the limitations of viral-isolation techniques, including the timing of specimen collection in relation to onset of illness, variable viral shedding in different age groups, and adequate specimen collection and processing.51 Viral titres and shedding are higher in infants and the yield of viral cultures is greater, up to 50% in this age group, but declines thereafter. New and rapid tests for detection of influenza virus in clinical samples of nasal secretions are now available. Most detect viral antigens using a monoclonal antibody against a highly conserved viral nucleoprotein, and newer tests are able to differentiate between influenza A and B. Rapid tests tend to have higher detection rates in patients younger than 5 years of age52 and allow the clinician the ability to distinguish influenza from other causes of febrile illnesses in the very young. In recent studies, young patients with positive rapid tests for influenza A were less likely to receive antibiotics when discharged home from the emergency centre than those with a negative test,53 and were also less likely to undergo extensive testing to determine the source of fever.54 Hospitalised children with positive rapid tests for influenza tend to have shorter hospitalisation stays and duration of antibiotic use.53,55 The occurrence of dual bacterial and influenza infection

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Table 1

F. M. MUNOZ

Anti-viral drugs for treatment and prophylaxis of influenza in children. M2 inhibitors

Virus activity Treatment age approved Prophylaxis age approved Adult treatment dose Paediatric treatment dosea

Administration/formulations Adverse effects

Neuraminidase inhibitors

Amantadine

Rimantadine

Oseltamivir

Zanamavir

A 1 year 1 year 100 mg PO BID  5 days 5 mg/kg/day up to 150 mg in 1 or 2 divided dosesb

A 13 years 1 year 100 mg PO BID  5 days 5 mg/kg/day up to 150 mg in 1 or 2 divided dosesb

A and B 7 years Not approved 2 puffs (5 mg each) BID  5 days Children  7 years, same as adults

PO, syrup: 50 mg/5 ml, 100 mg capsule Anxiety, nausea, dizziness, insomnia

PO, syrup: 50 mg/5 ml, 100 mg capsule Anxiety, nausea, dizziness, insomnia

A and B 1 year 13 years 75 mg PO BID  5 days <15 kg: 30 mg BID, 15–23 kg: 45 mg BID, 23–40 kg: 60 mg BID, >40 kg: 75 mg BID PO, suspension and 75 mg capsule Nausea, vomiting

Inhalation, 5 mg/puff inhaler Bronchospasm

BID, twice per day; PO, oral. a Prophylaxis doses are generally one-half of the treatment dose administered once a day. b Children >10 years of age should receive adult dose. Dosage adjustments are necessary for children with renal disease.

is very rare,55,56 and in such cases, children tend to be more symptomatic than those with influenza infection alone. Having a positive rapid test for influenza has not modified the use of antibiotics in hospitalised children, and unfortunately the use of anti-virals has not increased either. The practitioner must exert clinical judgement to determine the extent of the work-up, observation and use of antibiotic therapy in the youngest infants. Molecular testing for influenza virus is investigational, and serologic diagnosis is not practical in most cases.

TREATMENT OF INFLUENZA IN INFANTS There are no anti-virals licensed for the treatment of influenza in infants younger than 1 year of age. Four antiTable 2

virals are licensed in the USA for the treatment of influenza in older children, and three anti-virals are approved for prophylaxis (Table 1). In order to be effective, treatment must be started within 48 h of the onset of symptoms. The most important intervention to protect infants against influenza is prevention through immunisation.

PREVENTION OF INFLUENZA Annual immunisation with influenza vaccine is currently recommended in the USA for children 6 months of age and older with any underlying condition that increases their risk for severe illness and mortality (Table 2).26 In 2002, the Advisory Committee on Immunization Practices (ACIP) released a statement encouraging annual influenza immunisation in children 6–23 months of age who are otherwise

Recommendations for influenza immunisation in paediatrics.

 Children of any age with underlying chronic conditions that increase the risk for severe influenza disease and complications, such as: - asthma and other chronic pulmonary diseases such as bronchopulmonary dysplasia and cystic fibrosis - haemodynamically significant cardiac disease - immunosuppressive disorders or therapy - HIV infection - sickle cell anaemia and other haemoglobinopathies - diseases requiring long-term aspirin therapy - chronic renal dysfunction - chronic metabolic disease, including diabetes mellitus.  Healthy children between 6 and 24 months of age during the influenza season. Immunisation in this age group is encouraged by the American Academy of Pediatrics.  Persons who are in contact with high-risk children and infants 0–24 months of age. This group includes: - all household contacts - home and out-of-home caregivers - healthcare personnel.  Women who will be in their second or third trimester of pregnancy during the influenza season.

INFLUENZA VIRUS INFECTION

healthy, due to their higher risk of hospitalisation and complications from influenza.57,58 There are no licensed influenza vaccines for active immunisation of children under 6 months of age. Therefore, the only means of protection of children younger than 6 months is by immunisation of their household contacts and out-of-home caregivers. In addition, immunisation of women in the third trimester of pregnancy has the potential to result in higher concentrations of influenza antibody in infants at birth and to protect young infants from severe disease. The effects of influenza infection in women who are in the latter part of pregnancy can be devastating due to the alterations in respiratory physiology and changes in the immune system associated with pregnancy.59 Influenza immunisation of women during pregnancy is safe and has the potential to protect both mother and baby.60 Breast feeding is not a contraindication for vaccination. In addition, immunisation of previously healthy young and school-age children has been suggested as a strategy to modify the impact of community-wide influenza epidemics. Although universal immunisation of children is not yet recommended, a few well-conducted studies have shown its potential beneficial effects of reducing influenza disease and mortality in large communities.61–63 The trivalent live attenuated influenza vaccine administered intranasally is a new alternative for immunisation of otherwise healthy children 5 years of age and older.

PRACTICE POINTS  Infants and children less than 2 years of age have the highest risk of hospitalisation for severe influenza and influenza-associated complications in paediatrics.  The clinical presentation of influenza disease may be atypical in infants.  In the USA, vaccination with trivalent inactivated influenza vaccine is highly encouraged for all children 6–23 months of age, and recommended for children 6 months of age and older with underlying cardiopulmonary diseases or other chronic high-risk conditions.  Vaccination with trivalent inactivated influenza vaccine of women in the second or third trimester of gestation is likely to protect both the mother and infants less than 6 months of age against complications of influenza disease.  Vaccination with influenza vaccine to all household members of families with infants less than 6 months of age or other high-risk individuals is also an important prevention strategy.  The new intranasal trivalent live attenuated influenza vaccine is an alternative to the intramuscularly administered trivalent inactivated influenza vaccine for healthy children 5–18 years of age and adults.

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RESEARCH DIRECTIONS  Improved methods for rapid and early diagnosis of influenza infection.  The protective effect of maternal immunisation with influenza vaccine on the frequency and severity of infant disease.  The safety of the intranasal trivalent live attenuated influenza vaccine in children <5 years of age, adults >50 years of age, and persons with underlying chronic diseases.  The herd immunity effect of influenza vaccine when used as a universal immunisation strategy.

REFERENCES 1. Glezen WP, Couch RB. Influenza viruses. In: Evans AS, Kaslow RA (eds). Viral Infections of Humans. Epidemiology and Control, 4th edn. New York: Plenum, 1997; pp. 473–505. 2. Munoz FM, Demmler GJ, Glezen WP. Influenza in children in Houston, Texas. Pediatr Res 2002; 47: 272A. 3. Dowell SF, Kupronis BA, Zell ER, Shay DK. Mortality from pneumonia in children in the United States, 1939 through 1996. N Engl J Med 2000; 342: 1399–1407. 4. O’Brien KL, Walters MI, Sellman J et al. Severe pneumococcal pneumonia in previously healthy children: the role of preceding influenza infection. Clin Infect Dis 2000; 30: 784–789. 5. Peltola V, Heikkinen T, Ruuskanen O. Clinical courses of croup caused by influenza and parainfluenza viruses. Pediatr Infect Dis J 2002; 21: 76–78. 6. Heikkinen T, Thint M, Chonmaitree T. Prevalence of various respiratory viruses in the middle ear during acute otitis media. N Engl J Med 1999; 340: 260–264. 7. Sugaya N. Influenza-associated encephalopathy in Japan. Semin Pediatr Infect Dis 2002; 13: 79–84. 8. Chiu SS, Tse CY, Lau YL, Peiris M. Influenza A infection is an important cause of febrile seizures. Pediatrics 2001; 108: E63. 9. Belay ED, Bresee JS, Holman RC, Khan AS, Shahriari A, Schonberger LB. Reye’s syndrome in the United States from 1981 through 1997. N Engl J Med 1999; 340: 1377–1382. 10. Neuzil KM, Zhu Y, Griffin MR et al. Burden of interpandemic influenza in children younger than 5 years: a 25-year prospective study. J Infect Dis 2002; 185: 147–152. 11. Neuzil KM, Mellen BG, Wright PF, Mitchel EF Jr, Griffin MR. The effect of influenza on hospitalisations, outpatient visits, and courses of antibiotics in children. N Engl J Med 2000; 342: 225–231. 12. Meier CR, Napalkov PN, Wegmuller Y, Jefferson T, Jick H. Population-based study on incidence, risk factors, clinical complications and drug utilisation associated with influenza in the United Kingdom. Eur J Clin Microbiol Infect Dis 2000; 19: 834–842. 13. Izurieta HS, Thompson WW, Kramarz P et al. Influenza and the rates of hospitalisation for respiratory disease among infants and young children. N Engl J Med 2000; 342: 232–239. 14. Chonmaitree T, Owen MJ, Patel JA, Hedgpeth D, Horlick D, Howie VM. Effect of viral respiratory tract infection on outcome of acute otitis media. J Pediatr 1992; 120: 856–862. 15. Glezen WP, Decker M, Perrotta DM. Survey of underlying conditions of persons hospitalized with acute respiratory disease during influenza epidemics in Houston, 1978–1981. Am Rev Respir Dis 1987; 136: 550–555. 16. Glezen WP, Decker M, Joseph SW, Mercready RG Jr. Acute respiratory disease associated with influenza epidemics in Houston, 1981–1983. J Infect Dis 1987; 155: 1119–1126.

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17. Glezen WP, Couch RB. Interpandemic influenza in the Houston area, 1974–76. N Engl J Med 1978; 298: 587–592. 18. Monto AS, Kioumehr F. The Tecumseh study of respiratory illness. IX. Occurrence of influenza in the community, 1966–1971. Am J Epidemiol 1975; 102: 553–563. 19. Hall CE, Cooney MK, Fox JP. The Seattle virus watch. IV. Comparative epidemiologic observations of infections with influenza A and B viruses, 1965–1969, in families with young children. Am J Epidemiol 1973; 98: 365–380. 20. Glezen WP, Paredes A, Taber LH. Influenza in children. Relationship to other respiratory agents. JAMA 1980; 243: 1345–1349. 21. Sugaya N, Mitamura K, Nirasawa M, Takahashi K. The impact of winter epidemics of influenza and respiratory syncytial virus on paediatric admissions to an urban general hospital. J Med Virol 2000; 60: 102–106. 22. Glezen WP. Serious morbidity and mortality associated with influenza epidemics. Epidemiol Rev 1982; 4: 25–44. 23. Mullooly JP, Barker WH. Impact of type A influenza on children: a retrospective study. Am J Public Health 1982; 72: 1008–1016. 24. Monto AS, Napier JA, Metzner HL. The Tecumseh study of respiratory illness. I. Plan of study and observations on syndromes of acute respiratory disease. Am J Epidemiol 1971; 94: 269–279. 25. Simonsen L, Clarke MJ, Schonberger LB, Arden NH, Cox NJ, Fukuda K. Pandemic versus epidemic influenza mortality: a pattern of changing age distribution. J Infect Dis 1998; 178: 53–60. 26. Centers for Disease Control and Prevention. Prevention and Control of Influenza: Recommendations of the Advisory Committee on Immunisation Practices. Report No.: 51(RR03), 2002. 27. Glezen WP, Payne AA, Snyder DN, Downs TD. Mortality and influenza. J Infect Dis 1982; 146: 313–321. 28. Neuzil KM, Wright PF, Mitchel EF Jr, Griffin MR. The burden of influenza illness in children with asthma and other chronic medical conditions. J Pediatr 2000; 137: 856–864. 29. Glezen WP, Greenberg SB, Atmar RL, Piedra PA, Couch RB. Impact of respiratory virus infections on persons with chronic underlying conditions. JAMA 2000; 283: 499–505. 30. Munoz FM, Campbell JR, Atmar RL et al. Influenza A virus outbreak in a neonatal intensive care unit. Pediatr Infect Dis J 1999; 18: 811–815. 31. Cunney RJ, Bialachowski A, Thornley D, Smaill FM, Pennie RA. An outbreak of influenza A in a neonatal intensive care unit. Infect Control Hosp Epidemiol 2000; 21: 449–454. 32. van den Dungen FA, van Furth AM, Fetter WP, Zaaijer HL, van Elburg RM. Fatal case of influenza B virus pneumonia in a preterm neonate. Pediatr Infect Dis J 2001; 20: 82–84. 33. Serwint JR, Miller RM. Why diagnose influenza infections in hospitalized pediatric patients? Pediatr Infect Dis J 1993; 12: 200–204. 34. Serwint JR, Miller RM, Korsch BM. Influenza type A and B infections in hospitalized pediatric patients. Who should be immunized? Am J Dis Child 1991; 145: 623–626. 35. Berman S. Epidemiology of acute respiratory infections in children of developing countries. Rev Infect Dis 1991; 13(supplement 6): S454–S462. 36. Glezen WP, Taber LH, Frank AL, Gruber WC, Piedra PA. Influenza virus infections in infants. Pediatr Infect Dis J 1997; 16: 1065–1068. 37. Long CE, Hall CB, Cunningham CK et al. Influenza surveillance in community-dwelling elderly compared with children. Arch Fam Med 1997; 6: 459–465. 38. Puck JM, Glezen WP, Frank AL, Six HR. Protection of infants from infection with influenza A virus by transplacentally acquired antibody. J Infect Dis 1980; 142: 844–849. 39. Reuman PD, Ayoub EM, Small PA. Effect of passive maternal antibody on influenza illness in children: a prospective study of influenza A in mother–infant pairs. Pediatr Infect Dis J 1987; 6: 398– 403. 40. Griffiths PD, Berney SI, Argent S, Heath RB. Antibody against viruses in maternal and cord sera: specific antibody is concentrated on the fetal side of the circulation. J Hygiene (Lond) 1982; 89: 303–310.

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41. Sumaya CV, Gibbs RS. Immunisation of pregnant women with influenza A/New Jersey/76 virus vaccine: reactogenicity and immunogenicity in mother and infant. J Infect Dis 1979; 140: 141–146. 42. Englund JA, Mbawuike IN, Hammill H, Holleman MC, Baxter BD, Glezen WP. Maternal immunisation with influenza or tetanus toxoid vaccine for passive antibody protection in young infants. J Infect Dis 1993; 168: 647–656. 43. Irving WL, James DK, Stephenson T et al. Influenza virus infection in the second and third trimesters of pregnancy: a clinical and seroepidemiological study. BJOG 2000; 107: 1282–1289. 44. Hanson LA. Breastfeeding provides passive and likely long-lasting active immunity. Ann Allergy Asthma Immunol 1998; 81: 523–533. 45. Watkins CJ, Leeder SR, Corkhill RT. The relationship between breast and bottle feeding and respiratory illness in the first year of life. J Epidemiol Community Health 1979; 33: 180–182. 46. Mbawuike IN, Six HR, Cate TR, Couch RB. Vaccination with inactivated influenza A virus during pregnancy protects neonatal mice against lethal challenge by influenza A viruses representing three subtypes. J Virol 1990; 64: 1370–1374. 47. Sweet C, Jakeman KJ, Smith H. Role of milk-derived IgG in passive maternal protection of neonatal ferrets against influenza. J Gen Virol 1987; 68: 2681–2686. 48. Husseini RH, Sweet C, Overton H, Smith H. Role of maternal immunity in the protection of newborn ferrets against infection with a virulent influenza virus. Immunology 1984; 52: 389–394. 49. Ali HM, Scott R, Toms GL. The effect of foster feeding and bottle feeding expressed breast-milk on the susceptibility of guinea-pig infants to influenza virus. Br J Exp Pathol 1989; 70: 183–191. 50. Renegar KB, Small PA Jr. Immunoglobulin A mediation of murine nasal anti-influenza virus immunity. J Virol 1991; 65: 2146–2148. 51. Demmler GJ. Laboratory diagnosis of influenza: recent advances. Semin Pediatr Infect Dis 2002; 13: 85–89. 52. Rodriguez WJ, Schwartz RH, Thorne MM. Evaluation of diagnostic tests for influenza in a pediatric practice. Pediatr Infect Dis J 2002; 21: 193–196. 53. Noyola DE, Demmler GJ. Effect of rapid diagnosis on management of influenza A infections. Pediatr Infect Dis J 2000; 19: 303–307. 54. Sharma V, Dowd MD, Slaughter AJ, Simon SD. 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. 55. Poehling KA, Griffin MR, Dittus RS et al. Bedside diagnosis of influenzavirus infections in hospitalized children. Pediatrics 2002; 110: 83–88. 56. Munoz FM. The impact of influenza in children. Semin Pediatr Infect Dis 2002; 13: 72–78. 57. Rennels MB, Meissner HC. Technical Report: Reduction of the influenza burden in children. Pediatrics 2002; 110: e80. 58. American Academy of Pediatrics Committee on Infectious Diseases. Reduction of the burden of influenza in children – Policy Statement. Pediatrics 2002; 110: 1246–1252. 59. Neuzil KM, Reed GW, Mitchel EF, Simonsen L, Griffin MR. Impact of influenza on acute cardiopulmonary hospitalizations in pregnant women. Am J Epidemiol 1998; 148: 1094–1102. 60. Gall SA. Influenza and current guidelines for its control. Infect Dis Obstet Gynecol 2001; 9: 193–195. 61. Monto AS, Davenport FM, Napier JA, Francis T Jr. Modification of an outbreak of influenza in Tecumseh, Michigan by vaccination of schoolchildren. J Infect Dis 1970; 122: 16–25. 62. Reichert TA, Sugaya N, Fedson DS, Glezen WP, Simonsen L, Tashiro M. The Japanese experience with vaccinating schoolchildren against influenza. N Engl J Med 2001; 344: 889–896. 63. Piedra PA, Gaglani M, Hershler G, Glezen WP. Safety and Effectiveness of the Trivalent Cold-adapted Influenza Vaccine (CAIV-T) in Children. New York: Elsevier, 2001(Proceedings of the World Congress for Options for the Control of Influenza, Crete, Greece, 2000).