2009 Pandemic Influenza A (H1N1) Deaths among Children United States,

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1 SUPPLEMENT ARTICLE 2009 Pandemic A (H1N1) Deaths among Children United States, Chad M. Cox, 1 Lenee Blanton, 2 Rosaline Dhara, 2 Lynnette Brammer, 2 and Lyn Finelli 2 1 Epidemic Intelligence Service, Office of Workforce and Career Development assigned to Division, and 2 Division, Centers for Disease Control and Prevention, Atlanta, Georgia The 2009 pandemic influenza A (H1N1) () virus emerged in the United States in April 2009 (1) and has since caused significant morbidity and mortality worldwide (2 6). We compared pandemic influenza A (H1N1) () associated deaths occurring from 15 April 2009 through 23 January 2010 with seasonal influenza associated deaths occurring from 1 October 2007 through 14 April 2009, a period during which data collected were most comparable. Among 317 children who died of -associated illness, 301 (95%) had a reported medical history. Of those 301, 205 (68%) had a medical condition associated with an increased risk of severe illness from influenza. Children who died of -associated illness had a higher median age (9.4 vs 6.2 years; P,.01) and longer time from onset of symptoms to death (7 vs 5 days, P,.01) compared with children who died of seasonal influenza associated illness. The majority of pediatric deaths from were in older children with high-risk medical conditions. Vaccination continues to be critical for all children, especially those at increased risk of influenza-related complications. The 2009 pandemic influenza A (pandemic influenza A [H1N1][]) virus emerged in the United States in April 2009 [1] and has since caused significant morbidity and mortality worldwide [2 6]. Few studies reporting on -associated mortality in children have been published to date [7 9]. In the United States, laboratoryconfirmed influenza-associated pediatric deaths have been monitored since the season, and in 2004, influenza-related pediatric deaths were made a nationally notifiable condition. Since , an average of 82 pediatric deaths (range, deaths) associated with seasonal influenza have been reported annually (Figure 1). Population-based studies have suggested that individuals with certain chronic illnesses (including The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. Correspondence: Dr Chad M. Cox,1600 Clifton Rd, MS-A32,Atlanta, GA (cyv5@cdc.gov). Clinical Infectious Diseases 2011;52(S1):S69 S74 Published by Oxford University Press on behalf of the Infectious Diseases Society of America /2011/52S1-0001$37.00 DOI: /cid/ciq011 pulmonary, cardiovascular, renal, hepatic, neurological, hematological, or metabolic disorders) are at an increased risk for morbidity and mortality associated with seasonal influenza infection [10 12]. More recent studies involving children have shown an association between these chronic medical conditions and an increased risk of influenza-related complications [13 15]. In July 2005, the Advisory Committee on Immunization Practices (ACIP) added a new high-risk category for seasonal influenza vaccination that includes any condition (e.g., cognitive dysfunction, spinal cord injuries, seizure disorders, or other neuromuscular disorders) that can compromise respiratory function or the handling of respiratory secretions or that can increase the risk of aspiration [16]. Multiple studies, both prior to and following the inclusion of these neurological disorders as an ACIP high-risk category, have shown a significant risk of morbidity and mortality in this group [15,17 20]. When the virus emerged, risks posed to children with neurological disorders and other ACIP-defined high-risk medical conditions were assumed to be similar to those associated with seasonal influenza infection, but no data were initially available 2009 H1N1 Deaths among Children d CID 2011:52 (Suppl 1) d S69

2 Figure 1. to support this assumption. In addition, the potential for other non-acip-defined medical conditions, such as obesity, to increase risk were raised, further underscoring the need to collect pediatric mortality data to inform policy decisions. METHODS Reported -associated Pediatric Deaths, United States. To assess for differences in demographic characteristics, underlying medical conditions, and bacterial coinfections, deaths related to were compared with seasonal influenza deaths for the and seasons. A case was defined as the death of a US resident aged,18 years from 15 April 2009 through 23 January 2010 with laboratory-confirmed virus infection. Respiratory specimens were tested for at local, hospital, state, or Centers for Disease Control and Prevention (CDC) laboratories. Diagnostic testing modalities included reverse transcription polymerase chain reaction and fluorescent antibody testing. In some instances, laboratory testing identified influenza A virus infections, however, additional subtyping of the virus, including, was not performed. During the period of this study, national surveillance data indicated that accounted for 99% of all circulating strains. As a result, those cases with laboratory-confirmed influenza A virus infection of undetermined subtype were classified as probable. influenza cases were defined as death of a US resident aged,18 years from 1 October 2007 through 14 April 2009 with an influenza-virus type A or B infection. A positive laboratory test for seasonal influenza may have been determined by rapid influenza diagnostic test, viral isolation, enzyme immunoassay, fluorescent antibody staining, immunohistochemical staining of tissue samples, or reverse transcription polymerase chain reaction. The state or local health departments completed a standardized reporting form for each influenza-associated pediatric death and transmitted the information to CDC via a Web-based interface hosted on CDC s Secure Data Network. Data collected included patient demographics, influenza laboratory test results, culture confirmation of bacterial pathogens from invasive sites, date and location of death, complications during the acute illness, and influenza vaccination history. In addition, the form includes a section to report ACIP-defined high-risk medical conditions as well as a notes section for reporting additional medical diagnoses not categorized as high-risk conditions. Data from the notes section were categorized into the following categories: gastrointestinal (GI) disorder, obesity, prematurity, scoliosis, and sleep apnea. Neurological disorders were classified into 3 groups: neurodevelopmental disorder, seizure disorder, and neuromuscular disorder. Neurodevelopmental disorders include cerebral palsy, moderate to severe developmental delay, congenital neurological disorders, and other chronic nervous system disorders. Neuromuscular disorders include muscular dystrophy, spinal muscular atrophy, and mitochondrial disorders. Classification for neurological disorders was accomplished with the help of a developmental pediatrician and clinical geneticist. Results of bacterial cultures of blood, cerebrospinal fluid, or pleural fluid samples were included if collected up until the day of death. Information regarding bacterial coinfections from postmortem lung biopsy was not directly elicited; however, this information was reported in the notes section or in another part of the form for some cases and was included as a bacterial coinfection if reported. For our analysis, bacterial coinfections from postmortem lung biopsies were included only if the specimen was collected on the day of death. Staphylococcus epidermidis was considered to be a pathogen only when isolated from a specimen from a neonate aged,28 days or an immunosuppressed child. Culture results not reporting speciation (e.g., gram-positive cocci) were not included in the analysis. Cultures growing.2 bacteria were presumed to be contaminants and were not included in the analysis. Data were analyzed using SAS Enterprise Guide (SAS Institute). The v 2 square and Fisher s exact tests were used to evaluate differences between proportions. A Wilcoxon-Mann- Whitney test was used to evaluate differences between medians. All comparisons were 2-sided, and a P-value <.05 was considered to be significant. RESULTS From 15 April 2009 through 23 January 2010, 272 pediatric deaths associated with laboratory-confirmed were reported to CDC. An additional 45 cases, classified as probable, were reported during the same time period (Figure 1). Of the 317 total pediatric deaths, 51% were male, and the S70 d CID 2011:52 (Suppl 1) d Cox et al.

3 median age at death was 9.4 years (Table 1). Two hundred twenty-nine (72%) of the children were >5 years of age at time of death. The median time from onset of symptoms to death was 7 days (range, days). Of those with a reported location of death, 74% died in the intensive care unit or inpatient ward, and 26% died in the emergency department or outside the hospital. From 1 October 2007 through 14 April 2009, 155 pediatric deaths associated with seasonal influenza were reported to CDC. Of the 155 children, 52% were male, and the median age at death was 6.2 years. Eighty-six (55%) of the children were >5 years of age at time of death. The median time from onset of symptoms to death was 5 days (range, 0 64 days). Of those with a reported location of death, 64% died in the intensive care unit or inpatient ward, and 36% died in the emergency department or outside the hospital. When compared with children who died of seasonal influenza-associated illness, children who died of - associated illness were older (P,.01), and a higher proportion were 5 17 years of age (P,.01). Children who died of - Table 1. Demographic Characteristics of the Study Population Characteristic (n 5 317) (n 5 155) a P-value Male, n (%) 161 (51) Race/Ethnicity, n (%).76 White 135 (43) Hispanic 83 (26) Black 53 (17) Asian 13 (4) 6 (4) American Indian 7 (2) 2 (1) Pacific Islander 2 (1) 2 (1) Unknown 24 (8) 7 (5) Age Group, n (%), mo 21 (7) 19 (12) 6 23 mo 35 (11) 24 (15) mo 32 (10) 26 (17) 5 17 yr 229 (72) 86 (55) Age, median years 9.4 (0 17) 6.2 (0 17),.01 (range) Time from onset to 7 (0 141) 5 (0 64),.01 death, median days (range) Location of Death, n (%) b Intensive care unit 198 (70) 90 (60).02 Inpatient ward 11 (4) 7 (4).80 Emergency department 72 (26) 54 (36).03 or outside of hospital Cardiac arrest outside the hospital 67/270 (25) 43/139 (31).19 a Includes seasonal influenza cases from 1 October 2007 to 14 April b Data on location of death was not available for 36 influenza deaths and 4 seasonal influenza deaths. associated illness had a significantly longer period from onset of symptoms to death (P,.01) and were less likely to die in the emergency department or outside the hospital (P 5.03), although no difference in the proportion of patients with cardiac arrest outside the hospital was seen. There was no statistically significant difference when comparing the race and ethnicity between the 2 groups. Information on preexisting conditions was reported for 301 (95%) of the children who died of -associated illness (Table 2). Of these, 205 (68%) had an ACIP-defined high-risk Table 2. Advisory Committee on Immunization Practices (ACIP) Defined High-Risk Medical Conditions a Among Children with -Associated Mortality b n c n n % n % P-value ACIP-defined high-risk medical condition Yes <.01 No Unknown Deaths with ACIP-defined high-risk condition, n 5 205, n 5 67 Neurological disorders d Neurodevelopmental disorder e Seizure disorder Neuromuscular disorder f Pulmonary disease g (excluding asthma) Asthma Cystic fibrosis Cardiac disease Renal disease Sickle Cell Diabetes Febrile seizure Metabolic disorder h Immunosuppressive condition NOTE. a Medical conditions included in this table are not mutually exclusive. b Includes 45 cases classified as probable influenza. c Includes seasonal influenza cases from 1 October 2007 to 14 April d Includes neurodevelopmental disorders, seizures disorders, and neuromuscular disorders. Categories are not mutually exclusive. e Includes cerebral palsy, moderate/severe developmental delay, congenital neurologic disorders, and other chronic nervous system disorders. f Includes muscular dystrophy, spinal muscular atrophy, and mitochondrial disorders. g The most commonly reported chronic pulmonary diseases were bronchopulmonary dysplasia and restrictive lung disease. h Excludes cases with concurrent diagnosis of mitochondrial disorder H1N1 Deaths among Children d CID 2011:52 (Suppl 1) d S71

4 medical condition. Of those with an ACIP-defined high-risk medical condition, the most commonly reported were neurodevelopmental disorder (60%), seizure disorder (33%), chronic non-asthma pulmonary disease (29%), asthma (24%), and cardiac disease (20%). Of the 69 patients reporting a non-acipdefined medical condition (Table 3), the most frequently reported were GI disorder (49%), prematurity (23%), scoliosis (20%), and obesity (17%). Information on preexisting conditions was reported for 146 (94%) of children who died of seasonal influenza-associated illness during the 2 preceding influenza seasons. Of these, 67 (46%) had an ACIP-defined high-risk medical condition. For those with an ACIP-defined high-risk condition, the most frequently reported were neurodevelopmental disorder (45%), asthma (30%), cardiac disease (30%), and seizure disorder (25%). Of the 13 cases reporting a non-acip-defined medical condition, the most frequently reported were GI disorder (54%) and prematurity (46%). When compared with deaths from seasonal influenza, pediatric deaths associated with were more common in those with an ACIP-defined high-risk medical condition. A significant difference was found between the two groups when comparing Table 3. Non-ACIP Defined Medical Conditions a Among Children with -Associated Mortality b n c n n % n % P-value Reported non-acip-defined medical condition d Yes ,.01 No Gastrointestinal disorder (including gastroesophageal reflux disease) Deaths with reported non-acip medical condition e, n 5 69, n Obesity Prematurity Scoliosis Sleep apnea NOTE. a Case report forms include a notes section for reporting additional medical diagnoses not categorized as an ACIP high-risk condition. Categories were created using the most common reported diagnoses. b Includes 45 cases classified as probable influenza. c Includes seasonal influenza cases from 1 October 2007 to 14 April d Includes only medical conditions classified into one of the 5 most common categories listed below. Any other reported conditions were not included in the totals. e Categories are not mutually exclusive. the proportion of deaths with any neurological disorder (P5.05), neurodevelopmental disorder (P5.02) and chronic non-asthma pulmonary disease (P5.02). Data on complications were reported for 289 (91%) of the pediatric deaths associated with. Reported complications included pneumonia (55%), acute respiratory distress syndrome (35%), sepsis (19%), shock (16%), and encephalopathy/encephalitis (5%). Data on complications were reported for 137 (88%) of the pediatric deaths associated with seasonal influenza, including pneumonia (42%), acute respiratory distress syndrome (34%), sepsis (23%), and shock (22%). Immunization status with the monovalent 2009 H1N1 vaccine was provided for 161 (51%) of children with infection. One child was reported as fully vaccinated, 2 children were vaccinated,14 days before illness onset, and 1 child was vaccinated 1 day after illness onset. Nineteen children were ineligible (aged,6 months) for vaccination, and the remaining 138 were not vaccinated. influenza vaccination status was reported for 195 (62%) of pediatric deaths of whom 21 (11%) were ineligible. Of the remaining 174 children, 31 (18%) were reported to be fully vaccinated. Of the 122 children >6 months of age with an ACIP-defined high-risk medical condition and known seasonal vaccination status, 24 (20%) were reported as fully vaccinated. After further excluding those who died prior to widespread vaccine availability, 16 of 83 children (17%) were fully vaccinated for seasonal influenza. Of the 317 pediatric deaths associated with, 156 children (49%) had a specimen collected from a sterile site or from postmortem lung biopsy. Of these, 46 (28%) had evidence of bacterial coinfection (Table 4). Staphylococcus aureus was the most common bacterial pathogen identified. Of the 18 S. aureus coinfections identified, 11 were methicillin-resistant S. aureus (MRSA), 5 were methicillin-sensitive S. aureus (MSSA), and the antimicrobial sensitivity for the remaining 2 was not performed. Multiple Streptococcus species were identified from sterile sites and postmortem lung biopsies. Twelve children had coinfection with S. pneumonia, 4 with S. pyogenes, and 5 with other Streptococcus species. Coinfection with gram-negative bacterium was reported for 6 individuals. Of the 155 seasonal influenza deaths, 84 children (54%) had a specimen collected from a sterile site or from postmortem lung biopsy on the day of death. Of these, 32 (38%) had evidence of a bacterial coinfection. Staphylococcus aureus was the most common coinfection. Of 24 S. aureus coinfections identified, 16 were MRSA, 7 were MSSA, and the sensitivity for the remaining isolate was not performed. When compared with pediatric seasonal influenza deaths for the preceding 2 years, pediatric deaths associated with infection were less likely to have a MRSA coinfection(p,.01). No other statistically significant differences between proportions of bacterial coinfections among the 2 groups were found. S72 d CID 2011:52 (Suppl 1) d Cox et al.

5 Table 4. Bacterial Coinfections Among Children with - Associated Mortality DISCUSSION (n5317) (n5155) a n % n % P-value Number of patients tested with known results Staphylococcus aureus Methicillin-resistant ,.01 S. aureus Methicillin-sensitive S. aureus Sensitivity unknown Streptococcus Species S. pneumonia S. pyogenes Other b Other gram-positive 2 c 1 2 d 2 organisms Gram-negative organisms 6 e 4 3 f Total bacterial organisms identified Cases with.51 bacterial coinfection a Includes seasonal influenza cases from 1 October 2007 to 14 April b Includes Streptococcus agalactiae (3), constellatus (1), and intermedius (1). c Includes Peptostreptococcus and Staphylococcus epidermis. d Enterococcus species (2). e Includes Pseudomonas aeruginosa, Escherichia coli, Enterobacter cloacae, Neisseria meningitidis, Klebsiella pneumoniae, andalcaligenes species. f Includes Klebsiella pneumoniae, Citrobacter freundii,andserratia marcescens. This report describes the first 317 cases of influenza associated pediatric mortality within the United States since the commencement of the pandemic in April 2009 and compares these cases with pediatric seasonal influenza associated deaths from the previous 2 influenza seasons. The 2009 H1N1 pandemic affected all age groups but had a particularly adverse impact on children. During the previous 5 influenza seasons, 82 pediatric deaths (range ) were reported on average within the United States, whereas the number of deaths secondary to are nearly 4 times that number. Our results highlight significant differences between children who died with a -associated illness and those children with seasonal influenza associated mortality. Children with -associated mortality tended to be older, were more likely to have an underlying ACIP-defined high-risk medical condition, had a longer time from onset of symptoms to death, and were less likely to die in the emergency department or outside of the hospital. The difference in age between the 2 groups was especially prominent among children >5 years of age. In contrast, previous influenza seasons have shown much higher proportions of deaths in those,5 years of age and more specifically in infants,6 months of age [15, 18]. In contrast to previous influenza seasons, pediatric deaths related to were less likely to have a bacterial coinfection with MRSA. Many also had bacterial coinfections with Streptococcus pneumonia, as has been found in other studies [21 22]. Information on pneumococcal vaccination was not available for pediatric deaths, but because of the relatively high proportion of cases with coinfection, subsequent investigation is merited. Consistent with previous studies of pediatric seasonal influenza morbidity and mortality [17 20], a large proportion of pediatric deaths were in children with neurological disorders. The underlying reason for the vulnerability of these patients remains unclear but is likely due in part to compromised respiratory function and decreased ability to handle secretions. Children with underlying chronic lung disease, asthma and cardiovascular disease are also at an increased risk of influenza-associated mortality. Of medical conditions not classified as ACIP high risk, GI disorders, scoliosis, and prematurity were most frequently listed. All of these conditions commonly accompany a diagnosis of cerebral palsy, which a large proportion of those children also had. Of those reporting a non-acip-defined medical condition among deaths, 17% were reported to be obese. None of the seasonal influenza deaths from the previous 2 seasons reported a diagnosis of obesity. The difference between these groups was not statistically significant, and any direct comparison merits caution. No specific category for obesity exists on the case report form, necessitating its inclusion in the notes section in order to be included in the results. In addition, no information from which to calculate body mass index was collected. Early in the course of the pandemic, obesity was suggested as a risk factor for influenza complications. Therefore, it is possible that this information may have been included selectively by state and local health departments for the cases and not for previous seasonal influenza cases. The majority of the children (73%) in this study died prior to November 2009, when the monovalent 2009 H1N1 vaccine became widely available. Therefore, only a few were reported to have received any 2009 H1N1 monovalent vaccine. influenza vaccines became widely available in September 2009, prior to the majority of pediatric deaths. Our finding that only 17% of -associated deaths with an ACIP-defined highrisk medical condition had received the seasonal influenza vaccine underscores the importance of continued efforts to improve vaccination coverage in all children, especially those at increased risk of influenza-related complications. Our findings are subject to several limitations. First, because of an overall low baseline level of influenza testing among 2009 H1N1 Deaths among Children d CID 2011:52 (Suppl 1) d S73

6 children and underreporting of diagnosed cases, our reported numbers of both - and seasonal influenza associated pediatric deaths are likely underestimates. Second, heightened attention to reporting of pediatric deaths during the pandemic may have improved the completeness of reporting ACIP-defined high-risk medical conditions. To decrease potential bias when comparing proportions between pandemic and seasonal deaths, we used the total number of deaths with any reported ACIPdefined high-risk medical condition as our denominator. Third, we included the most frequently reported medical conditions from the notes section of the reporting form to categorize medical diagnoses other than ACIP-defined conditions included in the reporting form checklist. There could have been selective inclusion of more detailed information on deaths associated with compared to seasonal influenza, although no significant differences were noted between the 2 groups. Last, we elected to include only the previous 2 influenza seasons for comparison due to the uniformity of data collected. The 2 preceding influenza seasons gave a fair representation of pediatric mortality data (one season showed higher levels of H3 virus circulation, while the other was predominated by H1 viruses); however, inclusion of preceding years may have provided increased accuracy. This report describes the first 317 reported pediatric deaths in the United States associated with the influenza virus. The majority of pediatric deaths from were in children >5 years of age and those with an underlying ACIP-defined high-risk medical condition. Vaccination remains the primary tool of influenza prevention. vaccination is recommended for all children >6 months who have not yet received it or are not fully vaccinated. Our results strongly emphasize the importance of influenza vaccination for children with ACIPdefined high-risk medical conditions, especially those children with neurological disorders, chronic pulmonary disease, asthma, and cardiac disease. Acknowledgments We thank Dr Georgina Peacock, developmental pediatrician, and Dr Cynthia Moore, clinical geneticist, from CDC s National Center on Birth Defects and Developmental Disabilities for their assistance in classifying children with underlying developmental disorders. Supplement sponsorship. Published as part of a supplement entitled The 2009 H1N1 Pandemic: Field and Epidemiologic Investigations, sponsored by the Centers for Disease Control and Prevention. Potential conflicts of interest. no conflicts. References 1. Dawood FS, Jain S, Finelli L, et al. Emergence of a novel swine-origin influenza A (H1N1) virus in humans. N Engl J Med 2009; 360: Vaillant L, La Ruche G, Tarantola A, Barboza P. 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