Original Studies
Burden of Seasonal Influenza in Children With Neurodevelopmental Conditions Catherine Burton, MD,* Wendy Vaudry, MD,* Dorothy Moore, MD,† Julie A. Bettinger, PhD, MPH,‡ Dat Tran, MD, MSc,§ Scott A. Halperin, MD,¶ and David W. Scheifele, MD,‡ for the IMPACT investigators Background: Studies have identified certain neurologic and neurodevelopmental conditions (NNC) as risk factors for severe influenza infection. The Canadian National Advisory Committee on Immunization does not currently recognize children with NNC as having a high risk of complicated influenza infection unless their condition compromises handling of respiratory secretions. We describe the burden of influenza in hospitalized children with NNC, focusing on those without potential airway compromise. Methods: Using multi-year surveillance data obtained by the Canadian Immunization Monitoring Program, Active (IMPACT), we examined presenting signs and symptoms, risk factors and outcomes of children hospitalized with seasonal influenza at 12 Canadian pediatric referral centers. Comparisons were made between children with various NNC and other medical conditions, with and without influenza vaccine indications. The analysis is descriptive with selected comparisons made among groups for important indicators of disease severity. Results: We identified 1991 children hospitalized with influenza over 5 seasons: 293 had NNC, 115 of whom did not have airway compromise or another vaccine indication. The latter group presented with seizures more frequently than those with NNC and a vaccine indication (41.7% vs. 26.4%; P = 0.006) and required intensive care unit admission (20.9% vs. 11.8%; P = 0.02) and mechanical ventilation (14.8% vs. 4.5%; P < 0.001) more often than children without NNC but with a vaccine indication. Conclusions: The burden of influenza infection in children with NNC, even those whose conditions do not obviously compromise respiratory function, is significant. All children with NNC should be recognized as having a high risk of complicated influenza infection and be targeted to receive influenza immunization. Key Words: influenza, children, nervous system diseases, developmental disabilities, seizures (Pediatr Infect Dis J 2014;33:710–714)
Accepted for publication December 11, 2013. From the *Division of Infectious Diseases, Department of Pediatrics, Stollery Children’s Hospital, University of Alberta, Edmonton, Alberta; †Division of Infectious Diseases, Department of Pediatrics, Montreal Children’s Hospital, McGill University, Montreal, Québec; ‡Vaccine Evaluation Center, BC Children’s Hospital, University of British Columbia, Vancouver, British Columbia; §Division of Infectious Diseases, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario; and ¶Canadian Center for Vaccinology, IWK Health Center, Dalhousie University, Halifax, Nova Scotia, Canada. The Canadian Immunization Monitoring Program, Active (IMPACT) is managed by the Canadian Paediatric Society, which receives ongoing funding from the PHAC’s Centre for Immunization and Respiratory Infectious Diseases for IMPACT influenza surveillance. Canadian Paediatric Society and the PHAC had no role in data collection and analysis or decision to publish. PHAC was involved in the review and approval of the study design and manuscript. The authors have no conflicts of interest to disclose. Address for correspondence: Wendy Vaudry, MD, Department of Pediatrics, University of Alberta: 3-588D Edmonton Clinic Health Academy, 11405 87 Ave. NW, Edmonton, Alberta, Canada, T6G 1C9. E-mail: [email protected]. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (www.pidj.com). Copyright © 2014 by Lippincott Williams & Wilkins ISSN: 0891-3668/14/3307-0710 DOI: 10.1097/INF.0000000000000272
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nfluenza infection is common among children and is associated with significant morbidity. The influenza vaccine is the most effective method for preventing influenza infection and its complications. Several studies examining comorbidities of children hospitalized with influenza infection have identified neurologic conditions as risk factors for respiratory failure, prolonged hospital stay and neurologic complications.1–4 The most recent Canadian National Advisory Committee on Immunization (NACI) 2013–2014 statement on influenza vaccination recommends targeting groups at high risk of severe influenza infection including all children aged 6–59 months and children with defined high risk medical conditions.5 However, children with neurologic and neurodevelopmental conditions (NNC) are not currently specified as at high risk unless their condition compromises the handling of respiratory secretions and increases the risk of aspiration and pneumonia. Since 2004, the Canadian Immunization Monitoring Program, Active (IMPACT) surveillance network has conducted active surveillance for laboratory-confirmed influenza admissions among children 0–16 years of age. IMPACT comprises 12 centers, which draw referrals from every province and territory, representing over 90% of the pediatric tertiary care beds in Canada. We describe influenza in children with NNC hospitalized at IMPACT centers in Canada from 2004–2005 through 2008–2009 influenza seasons, focusing on those without potential airway compromise, to determine if they are also at high risk of severe or complicated influenza infection and might benefit from targeted influenza vaccination.
MATERIALS AND METHODS IMPACT hospitals routinely test children admitted with respiratory symptoms for viral infection. Children ≤ 16 years of age admitted to an IMPACT center between September 11, 2004, and March 31, 2009, with laboratory-confirmed influenza infection were identified prospectively through virology laboratory reports and/or admission records. Acceptable laboratory evidence of influenza infection included positive viral culture, immunofluorescence assay or nucleic acid molecular test. Once patients were identified, trained nurse monitors reviewed hospital records to determine the reason for admission. Only children admitted because of influenza or a complication of influenza were included. Nosocomial cases and those with influenza A (H1N1)pdm09 virus were excluded. The cut-off date of March 31, 2009, was chosen to avoid including patients with influenza A (H1N1)pdm09 virus. Infection with the Influenza A (H1N1)pdm09 virus may have a different clinical course and different risk factors for severe infection as previously described.6 Therefore, this study focused on children with seasonal influenza only. Demographic data, underlying medical conditions, clinical manifestations, treatment, course in hospital and outcome data were collected from the hospital record by study monitors using a standard case report form. Influenza vaccination status was verified by the child’s vaccine provider or immunization record. Consistent with current NACI guidelines, children ≤ 9 years were considered fully vaccinated if they had received 2 doses of influenza vaccine for their first influenza season or 1 dose for a second season with the last dose
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received > 14 days before admission. Children > 9 years of age were considered fully vaccinated if they had received 1 dose during the current flu season >14 days before admission.5 Cases were assigned to 1 of 5 groups based on underlying medical conditions: children with NNC whose NNC and/or other underlying conditions were recognized vaccine indications (NCV); children with NNC whose neurologic or any other underlying conditions were not recognized vaccine indications (NC); children without NNC with other underlying conditions that were recognized vaccine indications (OCV); children without NNC with other underlying conditions that were not recognized vaccine indications and healthy children (Healthy). Conditions considered being vaccine indications refer to medical conditions identified as high risk in the NACI statement for the influenza season at the time of case identification.7–11 Determination of vaccine indication was based only on underlying medical conditions; age of the child was not considered in the group assignment. Two physician investigators (C.B. and W.V.) independently reviewed cases identified as NNC to ensure accurate classification. NNC cases were sorted further into the following categories: seizures (all types), febrile seizures, cerebral palsy, developmental delay, hydrocephalus, myopathy/neuropathy or hypotonia and other NNC. The latter included traumatic or anoxic brain injury, various syndromes, brain malformations and other rare neurologic conditions. Discrepancies were independently reviewed by a third physician investigator (D.M.). Categories were not mutually exclusive; children could have >1 underlying NNC. The primary focus of the analysis was to provide a standardized description of each group of children admitted with influenza, including proportions and percent. To highlight influenza illness severity in the group of interest, NC, we examined the burden of influenza according to the specific category of NNC. We also compared the NC group to the groups of children with vaccine indications (OCV and NCV) to identify statistically significant differences in indicators of severe or complicated influenza infection (including median duration of hospital stay and intensive care unit (ICU) stay, ICU admission, need for mechanical ventilation and presentation with seizures) among the groups. Continuous variables that were not normally distributed were expressed using median and 25th and 75th percentiles, and selected comparisons were analyzed using the Kruskal-Wallis 1-way analysis of variance by ranks and the Wilcoxon signed-rank test. Discrete variables were analyzed with χ2 or Fisher exact test and reported as odds ratios with 95% confidence intervals [OR (95% CI)]. Statistical significance was considered as P < 0.05. Data were analyzed using SAS v9.2 (SAS Institute, Cary, NC). Adjustments were not made for multiple comparisons. IMPACT is administered by the Canadian Paediatric Society, with funding from the Public Health Agency of Canada (PHAC). All centers had Research Ethics Board or equivalent approval for the surveillance.
RESULTS In total, 1991 children were admitted to IMPACT centers with influenza over the 5 influenza seasons from 2004–2005 through 2008–2009. Baseline characteristics of these children are shown in Table, Supplemental Digital Content 1, http://links. lww.com/INF/B812. NNC were present in 293 children (14.7%) and were second only to chronic lung disease (17.7%, n = 352) as the most commonly identified underlying health condition among cases. Among the children with NNC, 178 (60.8%) had a vaccine indication (NCV) while 115 (39.2%) did not (NC). Among the 115 children with NC, only 17 (14.7%) had another underlying nonneurologic or neurodevelopmental condition. © 2014 Lippincott Williams & Wilkins
Children with NNC at High Risk of Influenza
Respiratory distress was the most common presenting symptom overall (41.3%, n = 822) and in each group except in those with NC, in whom seizure was the most common presentation (41.7%, n = 48). Pneumonia was most frequently present in children with NCV (31.5%, n = 56) and was least frequent in those with NC (14.8%, n = 17). Overall (9.9%, n = 198) children presented with seizures, many of whom (72.7%, n = 144) were between 6 months and 4 years of age (Table, Supplemental Digital Content 2, http:// links.lww.com/INF/B813). Among admitted children in this age group, over 50% of those with NC and almost 15% of healthy children presented with seizures. Children with NC presented with seizures significantly more often than all other groups, including those with NCV [OR: 2.00 (1.21–3.29), P = 0.006]. The hospital stay, treatment, complications and outcomes of children admitted with influenza are summarized in Table 1. Children with NC had a shorter hospital stay than children with NCV (P < 0.001) and OCV (P = 0.03). Children with NC required ICU admission and mechanical ventilation significantly more often than children with OCV [OR: 1.96 (1.18–3.27), P = 0.02 and OR: 3.70 (1.95–7.01), P < 0.001, respectively]. There was no significant difference in rates of ICU admission or mechanical ventilation between the NC and NCV groups. The NCV group had a longer median length of ICU stay than the NC group (P < 0.001). There was no significant difference in median duration of ICU stay between the NC and OCV groups. Vaccination status and use of antivirals and antibiotics are summarized in Table 1. Of the 1991 children, 803 (40.3%) had an indication for influenza vaccination based on presence of a high risk health condition. At admission, 8.8% (n = 176) of all children and 16.8% (n = 135) of those with any underlying condition warranting immunization were documented to be fully immunized against influenza. Vaccination history was unknown in 441 cases (22.1%) and the remainder was either partially immunized or unimmunized. Influenza vaccination coverage was highest in children with NCV (25.3%, n = 45, fully immunized), but was 5.2% (n = 6) in the NC group. Antiviral drugs were used significantly more often in the NCV and OCV groups (12.4%, n = 22, and 12.3%, n = 77) than in children with NC [3.5%, n = 4; OR: 3.91 (1.31–11.67), P = 0.009, OR: 3.90 (1.40–10.87), P = 0.005, respectively]. Antibiotic use was common in all groups (70.5%, n=1403 overall). There were no significant differences among the groups in the identification of invasive bacterial infection. Table 2 provides information about the specific NNC among the 115 children with NC along with the frequency of seizures, length of stay and need for pediatric intensive care unit (PICU) admission per subgroup. More than 1 NNC was present in 38 children. There were 14 influenza-related deaths during the study years. Eight (57.1%) of the children who died had an underlying NNC. Seven had vaccine indications including: severe cerebral palsy; Leigh’s disease associated with seizures; hypoxic ischemic encephalopathy associated with seizures; severe anoxic brain injury requiring permanent tracheostomy and severe seizure disorder requiring institutionalization. Some of these children also had chronic lung disease secondary to recurrent aspiration. There was 1 death in a child with a history of encephalopathy and no other underlying health conditions (NC). The other 6 influenza-related deaths were in previously healthy children. Only 2 of the 14 children had been fully immunized against influenza at the time of admission.
DISCUSSION Neurologic and neuromuscular diseases have been identified as risk factors for respiratory failure, prolonged hospital stay www.pidj.com | 711
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TABLE 1. Vaccination Status and Course in Hospital for Children Admitted With Influenza by Underlying Condition Without NNC With Other Underlying Conditions (n = 821)
With NNC (n = 293) NCV (n = 178) Influenza vaccination status Fully vaccinated, N (%) Unknown vaccination status, N (%) Treatment Antiviral therapy, N (%) Antibiotic therapy, N (%) Complications Bacterial infection,* N (%) Myocarditis/cardiomyopathy, N (%) Meningitis, N (%) Encephalitis, N (%) Hepatitis, N (%) Outcome Median length of hospital stay in days (25–75%) PICU admission, N (%) Mechanical ventilation, N (%) Median length of PICU stay in days (25–75%) Mortality, N (%)
NC (n = 115)
OCV (n = 625)
OC (n = 196)
Healthy Children (n = 877)
45 (25.3) 54 (30.3)
6 (5.2) 31 (27.0)
90 (14.4) 132 (21.1)
8 (4.1) 47 (24.0)
27 (3.1) 177 (20.2)
22 (12.4) 139 (78.1)
4 (3.5) 78 (67.8)
77 (12.3) 491 (78.6)
9 (4.6) 127 (64.8)
17 (1.9) 568 (64.8)
12 (6.7) 0 (0) 0 (0) 2 (1.1) 1 (0.6)
8 (7.0) 0 (0) 0 (0) 2 (1.7) 2 (1.7)
38 (6.1) 0 (0) 0 (0) 4 (0.6) 6 (1.0)
19 (9.7) 1 (0.5) 1 (0.5) 3 (1.5) 3 (1.5)
63 (7.2) 4 (0.5) 4 (0.5) 20 (2.3) 5 (0.6)
4.0 (2.0–7.0) 74 (11.8) 28 (4.5) 2.0 (1.0–5.0) 0 (0)
3.0 (2.0–7.0) 31 (15.8) 17 (8.7) 4.0 (2.0–8.0) 1 (0.5)
2.0 (1.0–4.0) 83 (9.5) 55 (6.3) 2.0 (1.0–5.0) 5 (0.6)
6.0 (3.0–11.0) 49 (27.5) 36 (20.2) 5.0 (2.0–10.0) 7 (3.9)
3.0 (2.0–6.0) 24 (20.9) 17 (14.8) 2.0 (1.0–3.5) 1 (0.9)
*Defined as a positive bacterial culture from normally sterile site or clinical presentation compatible with invasive bacterial infection without positive culture (osteomyelitis, septic arthritis, cellulitis, empyema and mastoiditis). Urinary tract infections are excluded. OC, children without NNC with other underlying conditions that were not recognized vaccine indications.
TABLE 2. Presentation with Seizures, Length of Stay and Need for PICU Admission by Underlying Neurologic and Neurodevelopmental Condition in Children Without Vaccine Indication (NC; n = 115) Underlying NNC
NC
Presented With Seizures
Required ICU Admission
Median Duration of Hospital Stay in Days (25–75%)
Isolated febrile seizures Isolated seizure disorders* Seizures and another NNC† Isolated CP Isolated developmental delay All other NNC‡ Total
17 17 16 3 26 36 115
16/17 (94.1%) 9/17 (52.9%) 6/16 (37.5%) 0/3 (0) 9/26 (34.6%) 8/36 (22.2%) 48/115 (41.7%)
4/17 (23.5%) 3/17 (17.6) 2/16 (12.5%) 0/3 (0) 8/26 (30.7%) 7/36 (19.4%) 24/115 (20.9%)
3.0 (1.0–4.0) 2.0 (1.0–5.0) 4.5 (3.0–6.5) 6.0 (2.0–10.0) 4.5 (3.0–7.0) 2.5 (2.0–4.0) 3 (2.0–6.0)
*But not febrile seizures. †Seizure disorder + any additional NNC. ‡Hydrocephalus, neuropathy, hypotonia and other NNC. CP, cerebral palsy.
and influenza-related neurologic complications in children.1–4 NNC were the second most commonly identified underlying medical conditions in children admitted with influenza infection between 2004 and 2009 at IMPACT centers. Our study is novel in that we characterize the burden of influenza in children with NNC whose conditions do not warrant influenza vaccination based on current Canadian guidelines. This was the largest group of children admitted with influenza having chronic conditions that are not targeted for immunization. Moreover, this NC group was significantly more likely to present with seizures than those with NNC targeted for immunization. The NC children also required ICU admission and mechanical ventilation more frequently than children without NNC who have other high risk conditions for which influenza vaccination is recommended (OCV). Influenza is an important cause of seizures in previously healthy children and in those with a history of seizures.3,12–14 In this study, over 70% of children presenting with seizures were between the ages of 6 months and 4 years, supporting previous work identifying this age group as being at high risk of influenza-related neurologic complications.3 The particularly high frequency of seizures
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in children of this age, both NC and healthy, further highlights the importance of targeting this age group for influenza immunization. In this study, pneumonia was most often the presenting complication of influenza in children with NCV, the group that includes children whose NNC potentially compromise the handling of respiratory secretions or respiratory function, supporting the rationale for targeted immunization of this group. This finding may also reflect a lower threshold to admit children with known respiratory compromise during a respiratory illness. Other studies, particularly with influenza A (H1N1)pdm09 virus infection, have found that underlying neurologic conditions conferred increased risks of pneumonia.15,16 Interestingly, in this study, the NC group were least likely to present with pneumonia and were most likely to present with seizures, highlighting the differences among children with NNC. While many children had multiple underlying NNC, the burden of severe influenza in children with a history of febrile seizures, other isolated seizure disorders or isolated developmental delay was notable. Between 17% and 30% of the children in these groups required intensive care for management of seizures or other complications. © 2014 Lippincott Williams & Wilkins
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Influenza-related deaths are uncommon in children in Canada; however, 8 of the 14 children who died from influenza infection during this study had underlying NNC. This mirrors findings from the US Centers for Disease Control and Prevention pediatric mortality surveillance system which showed that neurologic conditions were the most frequently reported underlying medical condition among children with seasonal influenza-associated mortality.17,18 Neurologic conditions were also the most frequently reported underlying medical conditions among children with influenza A (H1N1) pdm09 virus-associated mortality in the United States.15 Influenza vaccination coverage was low overall but was highest in the NCV group, followed by the OCV group, perhaps reflecting attempts to follow influenza immunization recommendations. The large amount of missing data on immunization in this study reflects poor tracking of influenza vaccination in many jurisdictions. Use of antivirals was also higher in children with underlying conditions with vaccine indications and was very low in the NC group. Although the US Centers for Disease Control Guidelines have targeted all children with underlying neurologic conditions for immunization and antiviral treatment since 2005, a recent survey has documented that vaccination coverage levels for these children is no higher than for healthy children and a majority of physicians are not aware of their increased risk.19 The most recent Canadian guidelines for influenza immunization and use of anti-influenza drugs only identify children with neurologic conditions as at high risk if their condition compromises handling of respiratory secretions.5,20 Given the increased burden of influenza demonstrated in this study among children with NNC that do not obviously compromise respiratory function, identifying all children with NNC as being at high risk for influenza-related complications in guidelines for vaccination and antiviral use may be of benefit. Even with universal influenza immunization recommendations, it is still important to identify specific high risk groups so that they can be targeted for priority in immunization campaigns. We assigned patients to 5 groups based solely on underlying medical conditions, without taking patient age into account, recognizing that some children with NNC or other medical conditions would have had vaccine indication based on age. At the time this data was collected, Canadian NACI guidelines recognized children aged 6–23 months as being at high risk, and current NACI and American Centers for Disease Control guidelines recognize children aged 6–59 months as at high risk for influenza-related complications. While age-based recommendations are important, identifying children with high risk underlying conditions is still crucial in targeted immunization compliance strategies regardless of patient age. Our study had limitations. Participating IMPACT centers had routine hospital policies of testing admitted children with respiratory symptoms for influenza but there may have been some variability in this practice. Some children presenting with non-respiratory manifestations of influenza may not have been tested so may have been missed. There may have been ascertainment bias towards identifying NNC in patients presenting with seizures or other neurologic manifestations as healthcare professionals might be more thorough in eliciting a full neurodevelopmental history in these patients. Children with underlying medical conditions, including NNC, may have been more likely to present to a tertiary care center, where they regularly receive outpatient care, than previously healthy children. Conditions that compromise respiratory function were not considered vaccine-indicated conditions until the 2005–2006 season; hence, there may have been cases during the 2004–2005 season misclassified as not warranting immunization. As our study included only hospitalized children, it is possible that children with conditions warranting vaccine were in fact protected by immunization in the community and less likely to be admitted to hospital that may have resulted in children with isolated NNC being overrepresented in the hospitalized study sample. The large © 2014 Lippincott Williams & Wilkins
Children with NNC at High Risk of Influenza
amount of missing data on immunizations limits the interpretation of immunization coverage for children in this study.
CONCLUSIONS The burden of influenza is significant in children with neurodevelopmental conditions not obviously compromising the handling of respiratory secretions. These children should be considered to be at high risk of complicated influenza infection, recommended to receive influenza immunization and considered for antiviral therapy.
ACKNOWLEDGMENTS IMPACT is a national surveillance initiative conducted by the IMPACT network of pediatric investigators. We gratefully acknowledge the expert assistance provided by the Monitor Liaison (Heather Samson), the IMPACT nurse monitors and staff of the data center (Kim Marty, Wenli Zhang, Shu Yu Fan, Engy Grove and Debbe Heayn). Investigators and centers participating in this IMPACT project from 2004 to 2009 included: R. Morris, MD, Janeway Children’s Health and Rehabilitation Centre, St. John’s, NL; S. Halperin, MD, IWK Health Center, Halifax, NS; P. Déry, MD, Centre Mere-Enfant de Quebec, CHUL, Quebec City, PQ; D. Moore, MD, The Montreal Children’s Hospital, Montreal, PQ; M. Lebel, MD, CHU Ste-Justine, Montreal, PQ; N. Le Saux, MD, Children’s Hospital of Eastern Ontario, Ottawa, ON; D. Tran, MD and L. Ford-Jones, MD, The Hospital for Sick Children, Toronto, ON; J. Embree, MD and B. Law, MD, Winnipeg Children’s Hospital, Winnipeg, MB; B. Tan, MD, Royal University Hospital, Saskatoon, SK; T. Jadavji, MD, Alberta Children’s Hospital, Calgary, AB; W. Vaudry, MD, Stollery Children’s Hospital, Edmonton, AB; D. Scheifele, MD, J. Bettinger, PhD and L. Sauvé, MD, BC Children’s Hospital, Vancouver, BC. REFERENCES 1. Ampofo K, Gesteland PH, Bender J, et al. Epidemiology, complications, and cost of hospitalization in children with laboratory-confirmed influenza infection. Pediatrics. 2006;118:2409–2417. 2. Coffin SE, Zaoutis TE, Rosenquist AB, et al. Incidence, complications, and risk factors for prolonged stay in children hospitalized with communityacquired influenza. Pediatrics. 2007;119:740–748. 3. Newland JG, Laurich VM, Rosenquist AW, et al. Neurologic complications in children hospitalized with influenza: characteristics, incidence, and risk factors. J Pediatr. 2007;150:306–310. 4. Keren R, Zaoutis TE, Bridges CB, et al. Neurological and neuromuscular disease as a risk factor for respiratory failure in children hospitalized with influenza infection. JAMA. 2005;294:2188–2194. 5. National Advisory Committee on Immunization (NACI). Statement on seasonal influenza vaccine for 2013–2014. An Advisory Committee Statement (ACS). Can Commun Dis Rep. 2013;39(ACS-4):1–37. 6. Tran D, Vaudry W, Moore DL, et al.; IMPACT investigators. Comparison of children hospitalized with seasonal versus pandemic influenza A, 20042009. Pediatrics. 2012;130:397–406. 7. National Advisory Committee on Immunization (NACI). Statement on influenza vaccination for the 2008–2009 season. An Advisory Committee Statement (ACS). Can Commun Dis Rep. 2008;34(ACS-3):1–46. 8. National Advisory Committee on Immunization (NACI). Statement on influenza vaccination for the 2004–2005 season. An Advisory Committee Statement (ACS). Can Commun Dis Rep. 2004;30(ACS-3):1–32. 9. National Advisory Committee on Immunization (NACI). Statement on influenza vaccination for the 2005–2006 season. An Advisory Committee Statement (ACS). Can Commun Dis Rep. 2005;31(ACS-6):1–32 10. National Advisory Committee on Immunization (NACI). Statement on influenza vaccination for the 2006–2007 season. An Advisory Committee Statement (ACS). Can Commun Dis Rep. 2006;32(ACS-7):1–28 11. National Advisory Committee on Immunization (NACI). Statement on influenza vaccination for the 2007–2008 season. An Advisory Committee Statement (ACS). Can Commun Dis Rep. 2007;33(ACS-7):1–38
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12. Kwong KL, Lam SY, Que TL, et al. Influenza A and febrile seizures in childhood. Pediatr Neurol. 2006;35:395–399. 13. Chiu SS, Tse CY, Lau YL, et al. Influenza A infection is an important cause of febrile seizures. Pediatrics. 2001;108:E63. 14. Glaser CA, Winter K, DuBray K, et al. A population-based study of neurologic manifestations of severe influenza A(H1N1)pdm09 in California. Clin Infect Dis. 2012;55:514–520. 15. Blanton L, Peacock G, Cox C, et al. Neurologic disorders among pediatric deaths associated with the 2009 pandemic influenza. Pediatrics. 2012;130:390–396. 16. Cox CM, Blanton L, Dhara R, et al. 2009 pandemic influenza A (H1N1) deaths among children-United States 2009–2010. Clin Infect Dis 2011: 52(suppl 1):S69–S74.
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17. Bhat N, Wright JG, Broder KR, et al.; Influenza Special Investigations Team. Influenza-associated deaths among children in the United States, 2003–2004. N Engl J Med. 2005;353:2559–2567. 18. Centers for Disease Control and Prevention. Prevention and control of influenza with vaccines. recommendations of the Advisory Committee on Immunization Practices (ACIP), 2010. MMWR Morb Mortal Wkly Rep 2010;59(RR-8):1–62. 19. Smith MJ, McFalls D, Hendricks J, et al. Influenza vaccination practices of physicians and caregivers of children with neurologic and neurodevelopmental conditions—United States, 2011–12 Influenza Season. MMWR 2013; 62:744–746. 20. Aoki F, Allen U, Stiver G, et al. The use of antiviral drugs for influenza: A foundation document for practitioners. Can J Infect Dis. 2013;24:supSC.
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Burden of Seasonal Influenza in Children With Neurodevelopmental Conditions Catherine Burton, MD,* Wendy Vaudry, MD,* Dorothy Moore, MD,† Julie A. Bettinger, PhD, MPH,‡ Dat Tran, MD, MSc,§ Scott A. Halperin, MD,¶ and David W. Scheifele, MD,‡ for the IMPACT investigators Background: Studies have identified certain neurologic and neurodevelopmental conditions (NNC) as risk factors for severe influenza infection. The Canadian National Advisory Committee on Immunization does not currently recognize children with NNC as having a high risk of complicated influenza infection unless their condition compromises handling of respiratory secretions. We describe the burden of influenza in hospitalized children with NNC, focusing on those without potential airway compromise. Methods: Using multi-year surveillance data obtained by the Canadian Immunization Monitoring Program, Active (IMPACT), we examined presenting signs and symptoms, risk factors and outcomes of children hospitalized with seasonal influenza at 12 Canadian pediatric referral centers. Comparisons were made between children with various NNC and other medical conditions, with and without influenza vaccine indications. The analysis is descriptive with selected comparisons made among groups for important indicators of disease severity. Results: We identified 1991 children hospitalized with influenza over 5 seasons: 293 had NNC, 115 of whom did not have airway compromise or another vaccine indication. The latter group presented with seizures more frequently than those with NNC and a vaccine indication (41.7% vs. 26.4%; P = 0.006) and required intensive care unit admission (20.9% vs. 11.8%; P = 0.02) and mechanical ventilation (14.8% vs. 4.5%; P < 0.001) more often than children without NNC but with a vaccine indication. Conclusions: The burden of influenza infection in children with NNC, even those whose conditions do not obviously compromise respiratory function, is significant. All children with NNC should be recognized as having a high risk of complicated influenza infection and be targeted to receive influenza immunization. Key Words: influenza, children, nervous system diseases, developmental disabilities, seizures (Pediatr Infect Dis J 2014;33:710–714)
Accepted for publication December 11, 2013. From the *Division of Infectious Diseases, Department of Pediatrics, Stollery Children’s Hospital, University of Alberta, Edmonton, Alberta; †Division of Infectious Diseases, Department of Pediatrics, Montreal Children’s Hospital, McGill University, Montreal, Québec; ‡Vaccine Evaluation Center, BC Children’s Hospital, University of British Columbia, Vancouver, British Columbia; §Division of Infectious Diseases, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario; and ¶Canadian Center for Vaccinology, IWK Health Center, Dalhousie University, Halifax, Nova Scotia, Canada. The Canadian Immunization Monitoring Program, Active (IMPACT) is managed by the Canadian Paediatric Society, which receives ongoing funding from the PHAC’s Centre for Immunization and Respiratory Infectious Diseases for IMPACT influenza surveillance. Canadian Paediatric Society and the PHAC had no role in data collection and analysis or decision to publish. PHAC was involved in the review and approval of the study design and manuscript. The authors have no conflicts of interest to disclose. Address for correspondence: Wendy Vaudry, MD, Department of Pediatrics, University of Alberta: 3-588D Edmonton Clinic Health Academy, 11405 87 Ave. NW, Edmonton, Alberta, Canada, T6G 1C9. E-mail: [email protected]. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (www.pidj.com). Copyright © 2014 by Lippincott Williams & Wilkins ISSN: 0891-3668/14/3307-0710 DOI: 10.1097/INF.0000000000000272
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nfluenza infection is common among children and is associated with significant morbidity. The influenza vaccine is the most effective method for preventing influenza infection and its complications. Several studies examining comorbidities of children hospitalized with influenza infection have identified neurologic conditions as risk factors for respiratory failure, prolonged hospital stay and neurologic complications.1–4 The most recent Canadian National Advisory Committee on Immunization (NACI) 2013–2014 statement on influenza vaccination recommends targeting groups at high risk of severe influenza infection including all children aged 6–59 months and children with defined high risk medical conditions.5 However, children with neurologic and neurodevelopmental conditions (NNC) are not currently specified as at high risk unless their condition compromises the handling of respiratory secretions and increases the risk of aspiration and pneumonia. Since 2004, the Canadian Immunization Monitoring Program, Active (IMPACT) surveillance network has conducted active surveillance for laboratory-confirmed influenza admissions among children 0–16 years of age. IMPACT comprises 12 centers, which draw referrals from every province and territory, representing over 90% of the pediatric tertiary care beds in Canada. We describe influenza in children with NNC hospitalized at IMPACT centers in Canada from 2004–2005 through 2008–2009 influenza seasons, focusing on those without potential airway compromise, to determine if they are also at high risk of severe or complicated influenza infection and might benefit from targeted influenza vaccination.
MATERIALS AND METHODS IMPACT hospitals routinely test children admitted with respiratory symptoms for viral infection. Children ≤ 16 years of age admitted to an IMPACT center between September 11, 2004, and March 31, 2009, with laboratory-confirmed influenza infection were identified prospectively through virology laboratory reports and/or admission records. Acceptable laboratory evidence of influenza infection included positive viral culture, immunofluorescence assay or nucleic acid molecular test. Once patients were identified, trained nurse monitors reviewed hospital records to determine the reason for admission. Only children admitted because of influenza or a complication of influenza were included. Nosocomial cases and those with influenza A (H1N1)pdm09 virus were excluded. The cut-off date of March 31, 2009, was chosen to avoid including patients with influenza A (H1N1)pdm09 virus. Infection with the Influenza A (H1N1)pdm09 virus may have a different clinical course and different risk factors for severe infection as previously described.6 Therefore, this study focused on children with seasonal influenza only. Demographic data, underlying medical conditions, clinical manifestations, treatment, course in hospital and outcome data were collected from the hospital record by study monitors using a standard case report form. Influenza vaccination status was verified by the child’s vaccine provider or immunization record. Consistent with current NACI guidelines, children ≤ 9 years were considered fully vaccinated if they had received 2 doses of influenza vaccine for their first influenza season or 1 dose for a second season with the last dose
The Pediatric Infectious Disease Journal • Volume 33, Number 7, July 2014
The Pediatric Infectious Disease Journal • Volume 33, Number 7, July 2014
received > 14 days before admission. Children > 9 years of age were considered fully vaccinated if they had received 1 dose during the current flu season >14 days before admission.5 Cases were assigned to 1 of 5 groups based on underlying medical conditions: children with NNC whose NNC and/or other underlying conditions were recognized vaccine indications (NCV); children with NNC whose neurologic or any other underlying conditions were not recognized vaccine indications (NC); children without NNC with other underlying conditions that were recognized vaccine indications (OCV); children without NNC with other underlying conditions that were not recognized vaccine indications and healthy children (Healthy). Conditions considered being vaccine indications refer to medical conditions identified as high risk in the NACI statement for the influenza season at the time of case identification.7–11 Determination of vaccine indication was based only on underlying medical conditions; age of the child was not considered in the group assignment. Two physician investigators (C.B. and W.V.) independently reviewed cases identified as NNC to ensure accurate classification. NNC cases were sorted further into the following categories: seizures (all types), febrile seizures, cerebral palsy, developmental delay, hydrocephalus, myopathy/neuropathy or hypotonia and other NNC. The latter included traumatic or anoxic brain injury, various syndromes, brain malformations and other rare neurologic conditions. Discrepancies were independently reviewed by a third physician investigator (D.M.). Categories were not mutually exclusive; children could have >1 underlying NNC. The primary focus of the analysis was to provide a standardized description of each group of children admitted with influenza, including proportions and percent. To highlight influenza illness severity in the group of interest, NC, we examined the burden of influenza according to the specific category of NNC. We also compared the NC group to the groups of children with vaccine indications (OCV and NCV) to identify statistically significant differences in indicators of severe or complicated influenza infection (including median duration of hospital stay and intensive care unit (ICU) stay, ICU admission, need for mechanical ventilation and presentation with seizures) among the groups. Continuous variables that were not normally distributed were expressed using median and 25th and 75th percentiles, and selected comparisons were analyzed using the Kruskal-Wallis 1-way analysis of variance by ranks and the Wilcoxon signed-rank test. Discrete variables were analyzed with χ2 or Fisher exact test and reported as odds ratios with 95% confidence intervals [OR (95% CI)]. Statistical significance was considered as P < 0.05. Data were analyzed using SAS v9.2 (SAS Institute, Cary, NC). Adjustments were not made for multiple comparisons. IMPACT is administered by the Canadian Paediatric Society, with funding from the Public Health Agency of Canada (PHAC). All centers had Research Ethics Board or equivalent approval for the surveillance.
RESULTS In total, 1991 children were admitted to IMPACT centers with influenza over the 5 influenza seasons from 2004–2005 through 2008–2009. Baseline characteristics of these children are shown in Table, Supplemental Digital Content 1, http://links. lww.com/INF/B812. NNC were present in 293 children (14.7%) and were second only to chronic lung disease (17.7%, n = 352) as the most commonly identified underlying health condition among cases. Among the children with NNC, 178 (60.8%) had a vaccine indication (NCV) while 115 (39.2%) did not (NC). Among the 115 children with NC, only 17 (14.7%) had another underlying nonneurologic or neurodevelopmental condition. © 2014 Lippincott Williams & Wilkins
Children with NNC at High Risk of Influenza
Respiratory distress was the most common presenting symptom overall (41.3%, n = 822) and in each group except in those with NC, in whom seizure was the most common presentation (41.7%, n = 48). Pneumonia was most frequently present in children with NCV (31.5%, n = 56) and was least frequent in those with NC (14.8%, n = 17). Overall (9.9%, n = 198) children presented with seizures, many of whom (72.7%, n = 144) were between 6 months and 4 years of age (Table, Supplemental Digital Content 2, http:// links.lww.com/INF/B813). Among admitted children in this age group, over 50% of those with NC and almost 15% of healthy children presented with seizures. Children with NC presented with seizures significantly more often than all other groups, including those with NCV [OR: 2.00 (1.21–3.29), P = 0.006]. The hospital stay, treatment, complications and outcomes of children admitted with influenza are summarized in Table 1. Children with NC had a shorter hospital stay than children with NCV (P < 0.001) and OCV (P = 0.03). Children with NC required ICU admission and mechanical ventilation significantly more often than children with OCV [OR: 1.96 (1.18–3.27), P = 0.02 and OR: 3.70 (1.95–7.01), P < 0.001, respectively]. There was no significant difference in rates of ICU admission or mechanical ventilation between the NC and NCV groups. The NCV group had a longer median length of ICU stay than the NC group (P < 0.001). There was no significant difference in median duration of ICU stay between the NC and OCV groups. Vaccination status and use of antivirals and antibiotics are summarized in Table 1. Of the 1991 children, 803 (40.3%) had an indication for influenza vaccination based on presence of a high risk health condition. At admission, 8.8% (n = 176) of all children and 16.8% (n = 135) of those with any underlying condition warranting immunization were documented to be fully immunized against influenza. Vaccination history was unknown in 441 cases (22.1%) and the remainder was either partially immunized or unimmunized. Influenza vaccination coverage was highest in children with NCV (25.3%, n = 45, fully immunized), but was 5.2% (n = 6) in the NC group. Antiviral drugs were used significantly more often in the NCV and OCV groups (12.4%, n = 22, and 12.3%, n = 77) than in children with NC [3.5%, n = 4; OR: 3.91 (1.31–11.67), P = 0.009, OR: 3.90 (1.40–10.87), P = 0.005, respectively]. Antibiotic use was common in all groups (70.5%, n=1403 overall). There were no significant differences among the groups in the identification of invasive bacterial infection. Table 2 provides information about the specific NNC among the 115 children with NC along with the frequency of seizures, length of stay and need for pediatric intensive care unit (PICU) admission per subgroup. More than 1 NNC was present in 38 children. There were 14 influenza-related deaths during the study years. Eight (57.1%) of the children who died had an underlying NNC. Seven had vaccine indications including: severe cerebral palsy; Leigh’s disease associated with seizures; hypoxic ischemic encephalopathy associated with seizures; severe anoxic brain injury requiring permanent tracheostomy and severe seizure disorder requiring institutionalization. Some of these children also had chronic lung disease secondary to recurrent aspiration. There was 1 death in a child with a history of encephalopathy and no other underlying health conditions (NC). The other 6 influenza-related deaths were in previously healthy children. Only 2 of the 14 children had been fully immunized against influenza at the time of admission.
DISCUSSION Neurologic and neuromuscular diseases have been identified as risk factors for respiratory failure, prolonged hospital stay www.pidj.com | 711
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TABLE 1. Vaccination Status and Course in Hospital for Children Admitted With Influenza by Underlying Condition Without NNC With Other Underlying Conditions (n = 821)
With NNC (n = 293) NCV (n = 178) Influenza vaccination status Fully vaccinated, N (%) Unknown vaccination status, N (%) Treatment Antiviral therapy, N (%) Antibiotic therapy, N (%) Complications Bacterial infection,* N (%) Myocarditis/cardiomyopathy, N (%) Meningitis, N (%) Encephalitis, N (%) Hepatitis, N (%) Outcome Median length of hospital stay in days (25–75%) PICU admission, N (%) Mechanical ventilation, N (%) Median length of PICU stay in days (25–75%) Mortality, N (%)
NC (n = 115)
OCV (n = 625)
OC (n = 196)
Healthy Children (n = 877)
45 (25.3) 54 (30.3)
6 (5.2) 31 (27.0)
90 (14.4) 132 (21.1)
8 (4.1) 47 (24.0)
27 (3.1) 177 (20.2)
22 (12.4) 139 (78.1)
4 (3.5) 78 (67.8)
77 (12.3) 491 (78.6)
9 (4.6) 127 (64.8)
17 (1.9) 568 (64.8)
12 (6.7) 0 (0) 0 (0) 2 (1.1) 1 (0.6)
8 (7.0) 0 (0) 0 (0) 2 (1.7) 2 (1.7)
38 (6.1) 0 (0) 0 (0) 4 (0.6) 6 (1.0)
19 (9.7) 1 (0.5) 1 (0.5) 3 (1.5) 3 (1.5)
63 (7.2) 4 (0.5) 4 (0.5) 20 (2.3) 5 (0.6)
4.0 (2.0–7.0) 74 (11.8) 28 (4.5) 2.0 (1.0–5.0) 0 (0)
3.0 (2.0–7.0) 31 (15.8) 17 (8.7) 4.0 (2.0–8.0) 1 (0.5)
2.0 (1.0–4.0) 83 (9.5) 55 (6.3) 2.0 (1.0–5.0) 5 (0.6)
6.0 (3.0–11.0) 49 (27.5) 36 (20.2) 5.0 (2.0–10.0) 7 (3.9)
3.0 (2.0–6.0) 24 (20.9) 17 (14.8) 2.0 (1.0–3.5) 1 (0.9)
*Defined as a positive bacterial culture from normally sterile site or clinical presentation compatible with invasive bacterial infection without positive culture (osteomyelitis, septic arthritis, cellulitis, empyema and mastoiditis). Urinary tract infections are excluded. OC, children without NNC with other underlying conditions that were not recognized vaccine indications.
TABLE 2. Presentation with Seizures, Length of Stay and Need for PICU Admission by Underlying Neurologic and Neurodevelopmental Condition in Children Without Vaccine Indication (NC; n = 115) Underlying NNC
NC
Presented With Seizures
Required ICU Admission
Median Duration of Hospital Stay in Days (25–75%)
Isolated febrile seizures Isolated seizure disorders* Seizures and another NNC† Isolated CP Isolated developmental delay All other NNC‡ Total
17 17 16 3 26 36 115
16/17 (94.1%) 9/17 (52.9%) 6/16 (37.5%) 0/3 (0) 9/26 (34.6%) 8/36 (22.2%) 48/115 (41.7%)
4/17 (23.5%) 3/17 (17.6) 2/16 (12.5%) 0/3 (0) 8/26 (30.7%) 7/36 (19.4%) 24/115 (20.9%)
3.0 (1.0–4.0) 2.0 (1.0–5.0) 4.5 (3.0–6.5) 6.0 (2.0–10.0) 4.5 (3.0–7.0) 2.5 (2.0–4.0) 3 (2.0–6.0)
*But not febrile seizures. †Seizure disorder + any additional NNC. ‡Hydrocephalus, neuropathy, hypotonia and other NNC. CP, cerebral palsy.
and influenza-related neurologic complications in children.1–4 NNC were the second most commonly identified underlying medical conditions in children admitted with influenza infection between 2004 and 2009 at IMPACT centers. Our study is novel in that we characterize the burden of influenza in children with NNC whose conditions do not warrant influenza vaccination based on current Canadian guidelines. This was the largest group of children admitted with influenza having chronic conditions that are not targeted for immunization. Moreover, this NC group was significantly more likely to present with seizures than those with NNC targeted for immunization. The NC children also required ICU admission and mechanical ventilation more frequently than children without NNC who have other high risk conditions for which influenza vaccination is recommended (OCV). Influenza is an important cause of seizures in previously healthy children and in those with a history of seizures.3,12–14 In this study, over 70% of children presenting with seizures were between the ages of 6 months and 4 years, supporting previous work identifying this age group as being at high risk of influenza-related neurologic complications.3 The particularly high frequency of seizures
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in children of this age, both NC and healthy, further highlights the importance of targeting this age group for influenza immunization. In this study, pneumonia was most often the presenting complication of influenza in children with NCV, the group that includes children whose NNC potentially compromise the handling of respiratory secretions or respiratory function, supporting the rationale for targeted immunization of this group. This finding may also reflect a lower threshold to admit children with known respiratory compromise during a respiratory illness. Other studies, particularly with influenza A (H1N1)pdm09 virus infection, have found that underlying neurologic conditions conferred increased risks of pneumonia.15,16 Interestingly, in this study, the NC group were least likely to present with pneumonia and were most likely to present with seizures, highlighting the differences among children with NNC. While many children had multiple underlying NNC, the burden of severe influenza in children with a history of febrile seizures, other isolated seizure disorders or isolated developmental delay was notable. Between 17% and 30% of the children in these groups required intensive care for management of seizures or other complications. © 2014 Lippincott Williams & Wilkins
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Influenza-related deaths are uncommon in children in Canada; however, 8 of the 14 children who died from influenza infection during this study had underlying NNC. This mirrors findings from the US Centers for Disease Control and Prevention pediatric mortality surveillance system which showed that neurologic conditions were the most frequently reported underlying medical condition among children with seasonal influenza-associated mortality.17,18 Neurologic conditions were also the most frequently reported underlying medical conditions among children with influenza A (H1N1) pdm09 virus-associated mortality in the United States.15 Influenza vaccination coverage was low overall but was highest in the NCV group, followed by the OCV group, perhaps reflecting attempts to follow influenza immunization recommendations. The large amount of missing data on immunization in this study reflects poor tracking of influenza vaccination in many jurisdictions. Use of antivirals was also higher in children with underlying conditions with vaccine indications and was very low in the NC group. Although the US Centers for Disease Control Guidelines have targeted all children with underlying neurologic conditions for immunization and antiviral treatment since 2005, a recent survey has documented that vaccination coverage levels for these children is no higher than for healthy children and a majority of physicians are not aware of their increased risk.19 The most recent Canadian guidelines for influenza immunization and use of anti-influenza drugs only identify children with neurologic conditions as at high risk if their condition compromises handling of respiratory secretions.5,20 Given the increased burden of influenza demonstrated in this study among children with NNC that do not obviously compromise respiratory function, identifying all children with NNC as being at high risk for influenza-related complications in guidelines for vaccination and antiviral use may be of benefit. Even with universal influenza immunization recommendations, it is still important to identify specific high risk groups so that they can be targeted for priority in immunization campaigns. We assigned patients to 5 groups based solely on underlying medical conditions, without taking patient age into account, recognizing that some children with NNC or other medical conditions would have had vaccine indication based on age. At the time this data was collected, Canadian NACI guidelines recognized children aged 6–23 months as being at high risk, and current NACI and American Centers for Disease Control guidelines recognize children aged 6–59 months as at high risk for influenza-related complications. While age-based recommendations are important, identifying children with high risk underlying conditions is still crucial in targeted immunization compliance strategies regardless of patient age. Our study had limitations. Participating IMPACT centers had routine hospital policies of testing admitted children with respiratory symptoms for influenza but there may have been some variability in this practice. Some children presenting with non-respiratory manifestations of influenza may not have been tested so may have been missed. There may have been ascertainment bias towards identifying NNC in patients presenting with seizures or other neurologic manifestations as healthcare professionals might be more thorough in eliciting a full neurodevelopmental history in these patients. Children with underlying medical conditions, including NNC, may have been more likely to present to a tertiary care center, where they regularly receive outpatient care, than previously healthy children. Conditions that compromise respiratory function were not considered vaccine-indicated conditions until the 2005–2006 season; hence, there may have been cases during the 2004–2005 season misclassified as not warranting immunization. As our study included only hospitalized children, it is possible that children with conditions warranting vaccine were in fact protected by immunization in the community and less likely to be admitted to hospital that may have resulted in children with isolated NNC being overrepresented in the hospitalized study sample. The large © 2014 Lippincott Williams & Wilkins
Children with NNC at High Risk of Influenza
amount of missing data on immunizations limits the interpretation of immunization coverage for children in this study.
CONCLUSIONS The burden of influenza is significant in children with neurodevelopmental conditions not obviously compromising the handling of respiratory secretions. These children should be considered to be at high risk of complicated influenza infection, recommended to receive influenza immunization and considered for antiviral therapy.
ACKNOWLEDGMENTS IMPACT is a national surveillance initiative conducted by the IMPACT network of pediatric investigators. We gratefully acknowledge the expert assistance provided by the Monitor Liaison (Heather Samson), the IMPACT nurse monitors and staff of the data center (Kim Marty, Wenli Zhang, Shu Yu Fan, Engy Grove and Debbe Heayn). Investigators and centers participating in this IMPACT project from 2004 to 2009 included: R. Morris, MD, Janeway Children’s Health and Rehabilitation Centre, St. John’s, NL; S. Halperin, MD, IWK Health Center, Halifax, NS; P. Déry, MD, Centre Mere-Enfant de Quebec, CHUL, Quebec City, PQ; D. Moore, MD, The Montreal Children’s Hospital, Montreal, PQ; M. Lebel, MD, CHU Ste-Justine, Montreal, PQ; N. Le Saux, MD, Children’s Hospital of Eastern Ontario, Ottawa, ON; D. Tran, MD and L. Ford-Jones, MD, The Hospital for Sick Children, Toronto, ON; J. Embree, MD and B. Law, MD, Winnipeg Children’s Hospital, Winnipeg, MB; B. Tan, MD, Royal University Hospital, Saskatoon, SK; T. Jadavji, MD, Alberta Children’s Hospital, Calgary, AB; W. Vaudry, MD, Stollery Children’s Hospital, Edmonton, AB; D. Scheifele, MD, J. Bettinger, PhD and L. Sauvé, MD, BC Children’s Hospital, Vancouver, BC. REFERENCES 1. Ampofo K, Gesteland PH, Bender J, et al. Epidemiology, complications, and cost of hospitalization in children with laboratory-confirmed influenza infection. Pediatrics. 2006;118:2409–2417. 2. Coffin SE, Zaoutis TE, Rosenquist AB, et al. Incidence, complications, and risk factors for prolonged stay in children hospitalized with communityacquired influenza. Pediatrics. 2007;119:740–748. 3. Newland JG, Laurich VM, Rosenquist AW, et al. Neurologic complications in children hospitalized with influenza: characteristics, incidence, and risk factors. J Pediatr. 2007;150:306–310. 4. Keren R, Zaoutis TE, Bridges CB, et al. Neurological and neuromuscular disease as a risk factor for respiratory failure in children hospitalized with influenza infection. JAMA. 2005;294:2188–2194. 5. National Advisory Committee on Immunization (NACI). Statement on seasonal influenza vaccine for 2013–2014. An Advisory Committee Statement (ACS). Can Commun Dis Rep. 2013;39(ACS-4):1–37. 6. Tran D, Vaudry W, Moore DL, et al.; IMPACT investigators. Comparison of children hospitalized with seasonal versus pandemic influenza A, 20042009. Pediatrics. 2012;130:397–406. 7. National Advisory Committee on Immunization (NACI). Statement on influenza vaccination for the 2008–2009 season. An Advisory Committee Statement (ACS). Can Commun Dis Rep. 2008;34(ACS-3):1–46. 8. National Advisory Committee on Immunization (NACI). Statement on influenza vaccination for the 2004–2005 season. An Advisory Committee Statement (ACS). Can Commun Dis Rep. 2004;30(ACS-3):1–32. 9. National Advisory Committee on Immunization (NACI). Statement on influenza vaccination for the 2005–2006 season. An Advisory Committee Statement (ACS). Can Commun Dis Rep. 2005;31(ACS-6):1–32 10. National Advisory Committee on Immunization (NACI). Statement on influenza vaccination for the 2006–2007 season. An Advisory Committee Statement (ACS). Can Commun Dis Rep. 2006;32(ACS-7):1–28 11. National Advisory Committee on Immunization (NACI). Statement on influenza vaccination for the 2007–2008 season. An Advisory Committee Statement (ACS). Can Commun Dis Rep. 2007;33(ACS-7):1–38
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12. Kwong KL, Lam SY, Que TL, et al. Influenza A and febrile seizures in childhood. Pediatr Neurol. 2006;35:395–399. 13. Chiu SS, Tse CY, Lau YL, et al. Influenza A infection is an important cause of febrile seizures. Pediatrics. 2001;108:E63. 14. Glaser CA, Winter K, DuBray K, et al. A population-based study of neurologic manifestations of severe influenza A(H1N1)pdm09 in California. Clin Infect Dis. 2012;55:514–520. 15. Blanton L, Peacock G, Cox C, et al. Neurologic disorders among pediatric deaths associated with the 2009 pandemic influenza. Pediatrics. 2012;130:390–396. 16. Cox CM, Blanton L, Dhara R, et al. 2009 pandemic influenza A (H1N1) deaths among children-United States 2009–2010. Clin Infect Dis 2011: 52(suppl 1):S69–S74.
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17. Bhat N, Wright JG, Broder KR, et al.; Influenza Special Investigations Team. Influenza-associated deaths among children in the United States, 2003–2004. N Engl J Med. 2005;353:2559–2567. 18. Centers for Disease Control and Prevention. Prevention and control of influenza with vaccines. recommendations of the Advisory Committee on Immunization Practices (ACIP), 2010. MMWR Morb Mortal Wkly Rep 2010;59(RR-8):1–62. 19. Smith MJ, McFalls D, Hendricks J, et al. Influenza vaccination practices of physicians and caregivers of children with neurologic and neurodevelopmental conditions—United States, 2011–12 Influenza Season. MMWR 2013; 62:744–746. 20. Aoki F, Allen U, Stiver G, et al. The use of antiviral drugs for influenza: A foundation document for practitioners. Can J Infect Dis. 2013;24:supSC.
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