BACKGROUND:

Influenza-associated pediatric deaths became a notifiable condition in the United States in 2004.

METHODS:

We analyzed deaths in children aged <18 years with laboratory-confirmed influenza virus infection reported to the Centers for Disease Control and Prevention during the 2010–2011 to 2015–2016 influenza seasons. Data were collected with a standard case report form that included demographics, medical conditions, and clinical diagnoses.

RESULTS:

Overall, 675 deaths were reported. The median age was 6 years (interquartile range: 2–12). The average annual incidence was 0.15 per 100 000 children (95% confidence interval: 0.14–0.16) and was highest among children aged <6 months (incidence: 0.66; 95% confidence interval: 0.53–0.82), followed by children aged 6–23 months (incidence: 0.33; 95% confidence interval: 0.27–0.39). Only 31% (n = 149 of 477) of children aged ≥6 months had received any influenza vaccination. Overall, 65% (n = 410 of 628) of children died within 7 days after symptom onset. Half of the children (n = 327 of 654) had no preexisting medical conditions. Compared with children with preexisting medical conditions, children with none were younger (median: 5 vs 8 years old), less vaccinated (27% vs 36%), more likely to die before hospital admission (77% vs 48%), and had a shorter illness duration (4 vs 7 days; P < .05 for all).

CONCLUSIONS:

Each year, influenza-associated pediatric deaths are reported. Young children have the highest death rates, especially infants aged <6 months. Increasing vaccination among children, pregnant women, and caregivers of infants may reduce influenza-associated pediatric deaths.

What’s Known on This Subject:

In 2004, influenza-associated pediatric mortality became a notifiable condition, and deaths are reported annually. Young children and children with preexisting conditions, particularly neurologic disorders, are overrepresented among influenza-associated pediatric deaths. Influenza vaccination for all children ≥6 months old is recommended.

What This Study Adds:

From 2010 to 2016, young children continued to be at the greatest risk for influenza-associated pediatric deaths. Children without preexisting medical conditions accounted for half of all deaths. Vaccination coverage was low among influenza-associated pediatric deaths.

In 2004, after a particularly severe influenza season with 153 reported pediatric deaths, influenza-associated pediatric deaths became a nationally notifiable disease, and the Influenza-Associated Pediatric Mortality Surveillance System was implemented in the United States.1,2 Since 2004, surveillance data have been used to describe the burden and risk factors associated with both seasonal and pandemic influenza-associated pediatric deaths.3,8 Previous results that were summarized from this surveillance system have contributed to evidence used by the Advisory Committee on Immunization Practices for influenza vaccination recommendations for children.9,10 In this report, we update previous reports and describe influenza-associated pediatric deaths for the 6 seasons after the 2009 (H1N1)pdm09 pandemic, from the 2010–2011 season to the 2015–2016 season.

We analyzed data from the Influenza-Associated Pediatric Mortality Surveillance System for 6 influenza seasons, 2010–2011 to 2015–2016. For this analysis, an influenza season was defined as October 1 through September 30 of the following year. This system has been described in detail previously.3,6,8 Briefly, an influenza-associated pediatric death is defined as a death resulting from a clinically compatible illness in a US resident aged <18 years with laboratory-confirmed influenza virus infection, with no period of complete recovery between the illness and death. State and territorial health departments report deaths to the Centers for Disease Control and Prevention using a standard case report form and transmit the information through a secure, Web-based interface. The form is used to collect information on demographics, dates of illness onset and death, hospital admissions, complications, location of death, preexisting medical conditions, influenza virus testing and results, and influenza vaccination status. In addition, states report whether bacterial testing was performed on specimens from sterile sites after illness onset or from postmortem tissue (if the specimen was collected within 24 hours after death) and results.

We compared the relative proportion of influenza A and B viruses detected among pediatric deaths with the proportions detected in persons aged ≤24 years as reported by the US Influenza Virologic Surveillance System. The Influenza Virologic Surveillance System collects data from ∼100 public health and 300 clinical laboratories in the United States through either the US World Health Organization Collaborating Laboratories System or the National Respiratory and Enteric Virus Surveillance System.11 Each week, these laboratories report to the Centers for Disease Control and Prevention the total number of respiratory specimens tested, the number that are positive for influenza viruses by virus type, and the (when available) influenza A virus subtypes and influenza B virus lineage. In addition, the World Health Organization collaborating laboratories report on the age or age group (0–4 years, 5–24 years, 25–64 years, and ≥65 years) of the person tested.12 

Children aged ≥6 months at the date of illness onset were considered eligible for vaccination. Children aged 6 months to 8 years were considered fully vaccinated if they were reported to have received the recommended doses of the influenza vaccine ≥14 days before illness onset in that season13,18; they were considered partially vaccinated if they were reported to have received 1 dose of the vaccine ≥14 days before illness onset but no vaccination in the immediate-previous season or if they received 2 doses in the current season but the interval between the 2 doses was <28 days or the interval between the second dose and illness onset was <14 days. Data on maternal vaccination were not collected. Children with ≥1 of the following conditions before illness onset were considered to have a preexisting medical condition: asthma and/or reactive airway disease, cancer, cardiac and congenital heart diseases, cerebral palsy, chronic pulmonary diseases, cystic fibrosis, chromosomal diseases, moderate to severe developmental delay, diabetes mellitus, endocrine disorders, febrile seizures, immunosuppressive conditions, metabolic diseases, mitochondrial disorder, neurologic or neurodevelopmental disorders, neuromuscular disorder, premature at birth, pregnancy, renal diseases, or seizure disorder.

A Wilcoxon rank test was used to compare medians, and a χ2 test was used to compare proportions among different groups. A Cochran-Armitage trend test was used for trend analysis. Population estimates from the US Census Bureau (2011–2015) were used to calculate minimum mortality rates.19 Population estimates for 2016 were not available at the time of this analysis, so the population estimates of 2015 were used for 2016 population calculation. Although the true burden was likely underestimated, the mortality rates allowed us to compare the burden across different groups. Exact 95% confidence intervals were calculated with Poisson distribution. All P values were 2 sided, and P values <.05 were considered statistically significant. Data were analyzed with SAS 9.3 (SAS Institute, Inc, Cary, NC).

From October 2010 to September 2016, 675 influenza-associated pediatric deaths were reported by 49 states and Puerto Rico. The median age was 6 years (interquartile range [IQR]: 2–12 years). The average annual mortality rate was 0.15 deaths per 100 000 children (Table 1). Children aged <6 months had the highest mortality rate (0.66 deaths per 100 000 children). Compared with children aged 13 to 17 years, infants aged <6 months were >6 times as likely to have an influenza-associated death, and children aged 6 to 23 months were >3 times as likely to have an influenza-associated death. During the 6 seasons examined, annual mortality rates were consistently the highest in children <6 months and children 6 to 23 months. Native Hawaiian and/or Pacific Islander and American Indian and/or Alaskan native children had higher mortality rates than children who were white, African American, or Asian American.

TABLE 1

Demographic Characteristics Among Influenza-Associated Pediatric Deaths in the United States, 2010–2016

CharacteristicNo. Children (%)Average Annual Incidence of Deaths per 100 000 Children (95% CI)
All agesa 675 (100) 0.15 (0.14–0.16) 
 <6 mo 78 (12) 0.66 (0.53–0.82) 
 6–23 mo 116 (17) 0.33 (0.27–0.39) 
 24–59 mo 103 (15) 0.14 (0.12–0.17) 
 5–8 y 131 (19) 0.13 (0.11–0.16) 
 9–12 y 117 (17) 0.12 (0.10–0.14) 
 13–17 y 130 (19) 0.10 (0.09–0.12) 
Raceb   
 White 435 (72) 0.13 (0.12–0.15) 
 African American 111 (18) 0.17 (0.14–0.20) 
 Asian American 29 (5) 0.13 (0.09–0.19) 
 Native Hawaiian and/or Pacific Islander 8 (1) 0.64 (0.32–1.30) 
 American Indian and/or Alaskan native 20 (3) 0.29 (0.18–0.44) 
Ethnicityc   
 Non-Hispanic, non-Latino 436 (76) 0.13 (0.12–0.14) 
 Hispanic or Latino 141 (24) 0.13 (0.11–0.14) 
Sex   
 Male 351 (52) 0.16 (0.14–0.17) 
 Female 324 (48) 0.15 (0.13–0.17) 
Geographic census regiond   
 South 263 (39) 0.16 (0.14–0.18) 
 West 173 (26) 0.16 (0.14–0.19) 
 Northeast 97 (14) 0.14 (0.11–0.17) 
 Midwest 140 (21) 0.15 (0.12–0.17) 
CharacteristicNo. Children (%)Average Annual Incidence of Deaths per 100 000 Children (95% CI)
All agesa 675 (100) 0.15 (0.14–0.16) 
 <6 mo 78 (12) 0.66 (0.53–0.82) 
 6–23 mo 116 (17) 0.33 (0.27–0.39) 
 24–59 mo 103 (15) 0.14 (0.12–0.17) 
 5–8 y 131 (19) 0.13 (0.11–0.16) 
 9–12 y 117 (17) 0.12 (0.10–0.14) 
 13–17 y 130 (19) 0.10 (0.09–0.12) 
Raceb   
 White 435 (72) 0.13 (0.12–0.15) 
 African American 111 (18) 0.17 (0.14–0.20) 
 Asian American 29 (5) 0.13 (0.09–0.19) 
 Native Hawaiian and/or Pacific Islander 8 (1) 0.64 (0.32–1.30) 
 American Indian and/or Alaskan native 20 (3) 0.29 (0.18–0.44) 
Ethnicityc   
 Non-Hispanic, non-Latino 436 (76) 0.13 (0.12–0.14) 
 Hispanic or Latino 141 (24) 0.13 (0.11–0.14) 
Sex   
 Male 351 (52) 0.16 (0.14–0.17) 
 Female 324 (48) 0.15 (0.13–0.17) 
Geographic census regiond   
 South 263 (39) 0.16 (0.14–0.18) 
 West 173 (26) 0.16 (0.14–0.19) 
 Northeast 97 (14) 0.14 (0.11–0.17) 
 Midwest 140 (21) 0.15 (0.12–0.17) 

The overall national incidence rate, incidence rates by sex, and incidence rates by census regions are adjusted by age group. CI, confidence interval.

a

Age at date of death.

b

Races of 72 children are unknown

c

Ethnicity of 98 children is unknown.

d

Two cases from Puerto Rico were excluded from the calculation because of their geographic census region.

The annual average number of influenza-associated pediatric deaths from 2010 to 2016 was 113; the 2012–2013 season had the highest number of pediatric deaths reported (n = 171), and the 2011–2012 season had the lowest number (n = 37; Fig 1).12 Overall, 65% (n = 436 of 675) of pediatric deaths coincided with an influenza A virus infection, 33% (n = 225 of 675) of case patients had an influenza B virus infection reported, <1% (n = 5 of 675) had A and B viruses coinfections, and 1% (n = 9 of 675) were not typed. This relative proportion of A and B viruses for each season was similar to that seen among all persons aged ≤24 years in the virologic surveillance (except for the 2012–2013 season, during which influenza A viruses [48%] were detected less frequently than B viruses [52%] among pediatric deaths). In virologic surveillance, influenza A viruses were predominant (>65%) during all 6 seasons. The actual proportion of influenza B viruses detected in pediatric deaths was higher than the proportion of influenza B viruses detected in children of a similar age (≤24 years old) from virologic surveillance for each of the 6 seasons. This finding remained when we limited the analysis to children aged <5 years in both surveillance systems (data not shown). Overall, among the 4 age groups of children who died (<6 months, 6 to 23 months, 24 to 59 months, and 5–17 years), young children had a higher proportion of influenza A viruses detected than older children; 83% (n = 63 of 76) of children aged <6 months had influenza A viruses detected compared with 58% (n = 216 of 371) of children aged 5 to 17 years (test for trend P < .01).

FIGURE 1

Comparison of influenza A and B viruses detected among influenza-associated pediatric deaths and persons aged ≤24 years by the Influenza Virologic Surveillance System in the United States (2010–2016). The number of specimens that were able to be typed as either influenza A or B infection among pediatric deaths were as follows: 2010–2011 season, 123 of 123; 2011–2012 season, 36 of 37; 2012–2013 season, 168 of 171; 2013–2014 season, 107 of 111; 2014–2015 season, 145 of 148; and 2015–2016 season, 82 of 85. P values for the difference in the proportions of influenza B viruses between the 2 systems were as follows: 2010–2011 season, P < .01; 2011–2012 season, P = .06; 2012–2013 season, P < .01; 2013–2014 season, P = .38; 2014–2015 season, P = .01; 2015–2016 season, P < .01; and from 2010 to 2016, P < .01. Data were downloaded from FluView.20 

FIGURE 1

Comparison of influenza A and B viruses detected among influenza-associated pediatric deaths and persons aged ≤24 years by the Influenza Virologic Surveillance System in the United States (2010–2016). The number of specimens that were able to be typed as either influenza A or B infection among pediatric deaths were as follows: 2010–2011 season, 123 of 123; 2011–2012 season, 36 of 37; 2012–2013 season, 168 of 171; 2013–2014 season, 107 of 111; 2014–2015 season, 145 of 148; and 2015–2016 season, 82 of 85. P values for the difference in the proportions of influenza B viruses between the 2 systems were as follows: 2010–2011 season, P < .01; 2011–2012 season, P = .06; 2012–2013 season, P < .01; 2013–2014 season, P = .38; 2014–2015 season, P = .01; 2015–2016 season, P < .01; and from 2010 to 2016, P < .01. Data were downloaded from FluView.20 

Half of the children who died had ≥1 preexisting medical condition before illness onset (Table 2). Neurologic disorders (27%) were the most commonly reported conditions, followed by asthma and/or reactive airway disease, cardiac or congenital heart disease, and chronic pulmonary diseases. Of the 477 children who were eligible for vaccination and for whom vaccination information was available, 31% had evidence of any influenza vaccination, and 22% had evidence of full vaccination. Two of the children who were partially vaccinated were <7 months of age and therefore did not have time for full vaccination before death. The median time from symptom onset to death was 5 days (IQR: 2–11 days). The majority of children (65%) died within 7 days of illness onset, and 13% died within 1 day of illness onset. Thirty-eight percent (n = 255 of 665) of the children died in the community or emergency department (ED) before hospital admission.

TABLE 2

Characteristics of Influenza-Associated Pediatric Deaths in the United States, 2010–2016

CharacteristicsValue, n/N (%)
Preexisting medical conditions  
 ≥1 preexisting medical conditionsa 327/654 (50) 
  Neurologic disordersb 178/654 (27) 
  Asthma, reactive airway disease 78/654 (12) 
  Cardiac and congenital heart diseases 76/654 (12) 
  Pulmonary diseasesc 65/654 (10) 
  Endocrine diseasesd 37/654 (6) 
  Premature at birth 33/654 (5) 
  Immunosuppressive conditionse 30/654 (5) 
  Renal diseases 15/654 (2) 
  Other conditionsf 10/654 (2) 
 No information reported 23/677 (3) 
 Information reported 654/677 (97) 
Influenza vaccination status  
 Ineligible for vaccination 81/675 (12) 
 Eligible but no information reported 117/594 (20) 
 Eligible and with information reported 477/594 (80) 
 No vaccination 328/477 (69) 
 Any vaccination 149/477 (31) 
 Full vaccination 105/477 (22) 
Days from symptom onset to death  
 ≤1 83/628 (13) 
 2–7 327/628 (52) 
 >7 218/628 (35) 
 No information reported 47/675 (7) 
 Information reported 628/675 (93) 
Location of death  
 Community 116/665 (17) 
 ED 139/665 (21) 
 Inpatient ward or ICU 410/665 (62) 
 No information reported 10/675 (1) 
 Information reported 665/675 (99) 
Bacterial coinfections from normally sterile sites  
 ≥1 bacterial coinfectionsa 156/362 (43) 
  β-hemolytic Streptococcus 69/362 (19) 
  S aureusg 63/362 (17) 
  Streptococcus pneumoniae 30/362 (8) 
  Pseudomonas aeruginosa 11/362 (3) 
  Escherichia coli 8/362 (2) 
  Other Gram-negative bacteriah 25/362 (7) 
 No information reported 313/675 (46) 
 Information reported 362/675 (54) 
Clinical complications during acute illness phase  
 ≥1 clinical complicationsa 451/601 (75) 
  Pneumonia 245/601 (41) 
  Sepsis or shock 185/601 (31) 
  ARDS 175/601 (29) 
  Seizures 79/601 (13) 
  Encephalopathy or encephalitis 56/601 (9) 
  Cardiomyopathy, myocarditis 45/601 (7) 
  Hemorrhagic pneumonia, pneumonitis 31/601 (5) 
  Other complications 176/601 (29) 
 No information reported 74/675 (11) 
 Information reported 601/675 (89) 
Mechanical ventilation  
 No information reported 41/675 (6) 
 Information reported 634/675 (94) 
 With mechanical ventilation treatment 354/634 (56) 
CharacteristicsValue, n/N (%)
Preexisting medical conditions  
 ≥1 preexisting medical conditionsa 327/654 (50) 
  Neurologic disordersb 178/654 (27) 
  Asthma, reactive airway disease 78/654 (12) 
  Cardiac and congenital heart diseases 76/654 (12) 
  Pulmonary diseasesc 65/654 (10) 
  Endocrine diseasesd 37/654 (6) 
  Premature at birth 33/654 (5) 
  Immunosuppressive conditionse 30/654 (5) 
  Renal diseases 15/654 (2) 
  Other conditionsf 10/654 (2) 
 No information reported 23/677 (3) 
 Information reported 654/677 (97) 
Influenza vaccination status  
 Ineligible for vaccination 81/675 (12) 
 Eligible but no information reported 117/594 (20) 
 Eligible and with information reported 477/594 (80) 
 No vaccination 328/477 (69) 
 Any vaccination 149/477 (31) 
 Full vaccination 105/477 (22) 
Days from symptom onset to death  
 ≤1 83/628 (13) 
 2–7 327/628 (52) 
 >7 218/628 (35) 
 No information reported 47/675 (7) 
 Information reported 628/675 (93) 
Location of death  
 Community 116/665 (17) 
 ED 139/665 (21) 
 Inpatient ward or ICU 410/665 (62) 
 No information reported 10/675 (1) 
 Information reported 665/675 (99) 
Bacterial coinfections from normally sterile sites  
 ≥1 bacterial coinfectionsa 156/362 (43) 
  β-hemolytic Streptococcus 69/362 (19) 
  S aureusg 63/362 (17) 
  Streptococcus pneumoniae 30/362 (8) 
  Pseudomonas aeruginosa 11/362 (3) 
  Escherichia coli 8/362 (2) 
  Other Gram-negative bacteriah 25/362 (7) 
 No information reported 313/675 (46) 
 Information reported 362/675 (54) 
Clinical complications during acute illness phase  
 ≥1 clinical complicationsa 451/601 (75) 
  Pneumonia 245/601 (41) 
  Sepsis or shock 185/601 (31) 
  ARDS 175/601 (29) 
  Seizures 79/601 (13) 
  Encephalopathy or encephalitis 56/601 (9) 
  Cardiomyopathy, myocarditis 45/601 (7) 
  Hemorrhagic pneumonia, pneumonitis 31/601 (5) 
  Other complications 176/601 (29) 
 No information reported 74/675 (11) 
 Information reported 601/675 (89) 
Mechanical ventilation  
 No information reported 41/675 (6) 
 Information reported 634/675 (94) 
 With mechanical ventilation treatment 354/634 (56) 
a

The categories shown are not mutually exclusive because some children had ≥1 preexisting medical condition, infection, or complication.

b

Neurologic disorders included moderate to severe developmental delay (n = 141), chromosomal diseases (n = 81), seizure disorder (n = 93), neurodevelopmental disorder (n = 83), cerebral palsy (n = 50), neuromuscular disorder (n = 12), and mitochondrial disorder (n = 8).

c

Pulmonary diseases included chronic pulmonary disease (n = 62) and cystic fibrosis (n = 3).

d

Endocrine diseases included endocrine disorder (n = 27) and diabetes mellitus (n = 10).

e

Immunosuppressive conditions included cancer (n = 17) and immunosuppressive conditions (n = 14).

f

Other conditions included febrile seizures (n = 4), pregnancy (n = 2), and other nondefined diseases (n = 4).

g

Sixty-four percent (n = 30 of 47) of S aureus isolates were methicillin resistant, 34% (n = 16 of 47) were methicillin sensitive, and 2% (n = 1 of 47) were erythromycin, penicillin, and ampicillin resistant. The drug-resistant status of 16 isolates is unknown.

h

Other Gram-negative bacteria included Citrobacter freundii complex (n = 3), Enterobacter cloacae (n = 3), Burkholderia spp (n = 1), Stenotrophomonas maltophilia (n = 2), Klebsiella pneumoniae (n = 3), Haemophilus influenzae non–type B (n = 5), Haemophilus spp (n = 1), Moraxella catarrhalis (n = 2), Morganella morganii (n = 1), Serratia marcescens (n = 1), S maltophilia (n = 1), Neisseria lactamica (n = 1), and Veillonella species (n = 1).

Specimens from normally sterile sites were collected from 362 children for bacterial testing, among these, blood or blood combined with other samples (85%) were the most frequently reported. Overall, 43% had bacteria detected. Of those, β-hemolytic Streptococcus (19%) and Staphylococcus aureus (17%) were the most commonly reported bacterial coinfections (Table 2). The majority (66%; n = 31 of 47) of S aureus isolates that had sensitivity testing performed on them were antibiotic resistant. We found no difference in the proportion of bacterial coinfections that were detected among children who died within 5 days of illness onset compared with children who died later in their illnesses (P = .39). In 13% (n = 62 of 488) of influenza-associated pediatric deaths, coinfection with another virus was reported, with respiratory syncytial virus (40%) being the most frequently identified.

Overall, clinical complications before death were reported for 75% of the children (Table 2). The most frequently reported complications were pneumonia (41%), sepsis or shock (31%), and acute respiratory distress syndrome (ARDS) (29%). We did not detect a higher proportion of invasive bacterial infections among patients with pneumonia complications compared with nonpneumonia patients (43% [n = 73 of 167] vs 40% [n = 53 of 133]; P = .50). In addition to the syndromes that are typically recognized as complications, 22 (4%) and 17 (3%) deaths had bronchiolitis and croup reported, respectively. Antiviral treatment was reported in 53% (n = 321 of 611) of pediatric deaths; as expected, most antiviral use (n = 282; 88%) was among children who were admitted to the hospital. Antibiotic treatment was reported in 51% (n = 310 of 611) of pediatric deaths, and most antibiotic use (n = 266; 86%) was among children who were admitted to the hospital.

Children who died with and without preexisting medical conditions differed by age, vaccination status, bacterial coinfections, clinical complications, illness duration, antiviral treatment, and location of death (Table 3). Preexisting medical conditions were more common among older children, and the proportion of children who died with preexisting medical conditions increased with age; of children <6 months old, 29% had preexisting medical conditions, but 60% of children aged 9 to 17 years had preexisting medical conditions (P for trend <.01). Children without preexisting medical conditions were less likely to be vaccinated, have clinical complications, receive antiviral treatment, and to be admitted to a hospital, but they were more likely to have bacterial coinfections or die more quickly than children with preexisting medical conditions. Among the children who died before hospital admission, the median number of days from illness onset to death was the same for children with or without preexisting medical conditions (Fig 2). Among children who were admitted to the hospital before death, the time between illness onset and death among those with preexisting medical conditions was longer compared with those without preexisting medical conditions. However, the time from illness onset to admission was the same for these 2 groups (median: 2 days; P = .10).

TABLE 3

Selected Characteristics Among Influenza-Associated Pediatric Deaths by Presence of Preexisting Medical Conditions in the United States, 2010–2016 (N = 654)

CharacteristicChildren Without Preexisting Medical Conditions (N = 327)Children With Preexisting Medical Conditions (N = 327)P
Agea, y, median (IQR) 5 (1–10) 8 (3–13) <.01 
Vaccination status    
 Any 60/225 (27) 88/244 (36) .01 
 Full 37/225 (17) 67/244 (27) — 
Invasive bacterial coinfections 91/172 (53) 64/185 (35) <.01 
Clinical complications 214/291 (74) 254/299 (85) <.01 
 Pneumonia 102/291 (35) 138/299 (46) <.01 
 ARDS 69/291 (24) 104/299 (35) <.01 
 Hemorrhagic pneumonia, pneumonitis 21/291 (7) 10/299 (3) .035 
Days from onset to death, median (IQR) 4 (2–7) 7 (3–15) <.01 
 ≤1 51/307 (17) 29/305 (10) <.01 
 2–7 184/307 (60) 134/305 (44) — 
 >7 72/307 (23) 142/305 (47) — 
Location of death    
 Community 81/323 (25) 29/324 (9) <.01 
 ED 86/323 (27) 45/324 (14) — 
 Inpatient ward or ICU 156/323 (48) 250/324 (77) — 
Antiviral treatment 127/304 (42) 192/296 (65) <.01 
Mechanical ventilation 148/323 (46) 206/311 (66) <.01 
CharacteristicChildren Without Preexisting Medical Conditions (N = 327)Children With Preexisting Medical Conditions (N = 327)P
Agea, y, median (IQR) 5 (1–10) 8 (3–13) <.01 
Vaccination status    
 Any 60/225 (27) 88/244 (36) .01 
 Full 37/225 (17) 67/244 (27) — 
Invasive bacterial coinfections 91/172 (53) 64/185 (35) <.01 
Clinical complications 214/291 (74) 254/299 (85) <.01 
 Pneumonia 102/291 (35) 138/299 (46) <.01 
 ARDS 69/291 (24) 104/299 (35) <.01 
 Hemorrhagic pneumonia, pneumonitis 21/291 (7) 10/299 (3) .035 
Days from onset to death, median (IQR) 4 (2–7) 7 (3–15) <.01 
 ≤1 51/307 (17) 29/305 (10) <.01 
 2–7 184/307 (60) 134/305 (44) — 
 >7 72/307 (23) 142/305 (47) — 
Location of death    
 Community 81/323 (25) 29/324 (9) <.01 
 ED 86/323 (27) 45/324 (14) — 
 Inpatient ward or ICU 156/323 (48) 250/324 (77) — 
Antiviral treatment 127/304 (42) 192/296 (65) <.01 
Mechanical ventilation 148/323 (46) 206/311 (66) <.01 

Unless otherwise specified, data are presented as n/N (%). —, not applicable.

a

At date of death.

FIGURE 2

Days from illness onset to death for children with influenza-associated pediatric death by presence of preexisting medical conditions and location of death in the United States (2010–2016; N = 647). Days are presented as a median and IQR.

FIGURE 2

Days from illness onset to death for children with influenza-associated pediatric death by presence of preexisting medical conditions and location of death in the United States (2010–2016; N = 647). Days are presented as a median and IQR.

During influenza seasons 2010–2011 to 2015–2016, an average of 113 influenza-associated pediatric deaths were reported each year. This number is likely an underestimate, with the true number perhaps being as much as twofold higher.21 Half of the reported deaths were among children with preexisting medical conditions, with neurologic disorders being the most commonly reported. Children aged <6 months were >4 times as likely and children aged 6 to 23 months were >2 times as likely to die compared with children aged 2 to 17 years. Young children <2 years of age were less likely to have preexisting medical conditions compared with older children who died. Reported influenza vaccination coverage levels among pediatric deaths for all age groups were below the nationally reported level of 59% during the 2015–2016 influenza season.22 Our results reinforce the need to continue efforts to improve vaccination coverage among all children aged ≥6 months as well as pregnant women and household members who care for infants aged <6 months to meet the Healthy People 2020 goal of 70%.23 

Young children are at an increased risk for severe influenza infections. In addition to high rates of influenza-associated deaths, young children also had the highest rates of influenza-associated pediatric hospitalization from 2003 to 2009 and pediatric hospitalizations because of lower respiratory tract infections from 2007 to 2011.24,27 Also, most young children who were hospitalized had no preexisting medical conditions.25,26,28,29 For children aged ≥6 months, influenza vaccination has been estimated to reduce the risk of pediatric deaths by half among children with preexisting medical conditions and by nearly two-thirds among children without preexisting medical conditions from 2010 to 2014.30 Vaccination in pregnant woman has been demonstrated to reduce laboratory-confirmed influenza among infants in the first 4 to 6 months of life.31,33 

Children with certain preexisting medical conditions are at an increased risk for influenza complications,34 including hospitalization or death.35,36 Among influenza-associated pediatric deaths, neurologic disorders were the most commonly reported conditions, as previously described.1,7,8 These conditions are rare in the general population but are overrepresented among pediatric deaths and children who are hospitalized with influenza.37,39 Vaccine coverage was low for these high-risk children, and ongoing educational efforts are needed.

The time from illness onset to death was short for most children in our data set. The majority of children died within 7 days after illness onset, and 13% died within 1 day; this percentage was even higher among children without preexisting medical conditions. Also, ∼40% of the children died in the community or ED before hospital admission. The reasons for such a rapid demise remain unknown, but we cannot rule out that the overall shorter illness duration in previously healthy children may be related to differences in health care–seeking behavior or the timing of health care interventions after illness onset.

During the 6 seasons studied, the proportion of influenza B viruses relative to A viruses detected among pediatric deaths was higher than among children of a similar age in the US Influenza Virologic Surveillance System. This has been documented previously.1,3,6,8 Thus, both influenza A and B viruses are associated with pediatric deaths, but the relative proportion of B virus infections might be slightly higher among deaths than in general surveillance. Additional studies are underway in an effort to describe this observation more completely. Some researchers suggest slower age-dependent accumulation in the innate immune response to influenza B relative to influenza A illnesses, although the exact immune system changes are unknown.40,41 

The children who died experienced a range of complications with pneumonia, sepsis, or shock, and ARDS was reported most commonly, which is similar to what’s been revealed in previous reports.1,8 Pneumonia and ARDS were also frequently reported in hospitalized pediatric patients.42,44 Consistent with previous reports, Streptococcus and S aureus were the most commonly identified bacterial coinfections in addition to influenza virus infection.1,5,8 More bacterial coinfections were identified in children without preexisting medical conditions than in those with preexisting conditions, which is consistent with other reports.8,37 Information on the receipt of other pediatric vaccines was not collected. However, these results highlight the importance of the receipt of vaccination against other vaccine-preventable diseases among young children and ongoing research to prevent respiratory diseases that currently have no vaccines.

Overall, more than half of the pediatric patients who died were reported to have received antiviral or antibiotic treatment; we do not have information on the timing of treatment relative to death. Antiviral treatment is recommended for all persons with severe illnesses that are suspected to be associated with influenza, such as hospitalized illness, and for illnesses among persons with high-risk conditions.45 

Our findings are subject to several limitations. First, there is a potential underestimation of mortality numbers and rates because influenza testing was not always performed or was performed later in the illness, when the virus could not be detected anymore. The testing practices may also vary by age and the presence of preexisting medical conditions. In addition to underestimating mortality, these variations in testing practices might also affect the representation of certain children in our data. Second, the misclassification of preexisting medical conditions and vaccination status may have occurred because of the challenges of diagnosing underlying conditions in young children and missing data. Third, we compared the proportion of influenza virus types among pediatric deaths to surveillance data from a larger age group (persons aged ≤24 years) because of the format of surveillance data. Finally, we are unable to assess the effect of antiviral or antibacterial treatment on deaths with the information collected.

Influenza-associated pediatric deaths are reported each year in the United States. Influenza-associated pediatric mortality was highest among young children aged <2 years. Although many pediatric deaths occurred in children with preexisting medical conditions, half of the deaths were in previously healthy children. This report reinforces the need to improve influenza vaccination coverage to meet the Healthy People 2020 goals. Also, prompt antiviral treatment should be initiated when young children and children with high-risk conditions are suspected to have influenza and when children are hospitalized with suspected influenza.

     
  • ARDS

    acute respiratory distress syndrome

  •  
  • ED

    emergency department

  •  
  • IQR

    interquartile range

Ms Shang performed the statistical analysis, interpreted the data, and drafted and revised the manuscript; Mrs Blanton acquired and interpreted the data and revised the manuscript; Ms Brammer acquired data, supervised data collection, interpreted the data, and revised the manuscript; Drs Olsen and Fry conceptualized and designed the study, interpreted the data, and revised the manuscript; and all authors approved the final manuscript as submitted.

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.

FUNDING: No external funding.

COMPANION PAPER: A companion to this article can be found online at www.pediatrics.org/cgi/doi/10.1542/peds.2017-4313.

1
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
(
24
):
2559
2567
[PubMed]
2
Roush
SW
,
Murphy
TV
;
Vaccine-Preventable Disease Table Working Group
.
Historical comparisons of morbidity and mortality for vaccine-preventable diseases in the United States.
JAMA
.
2007
;
298
(
18
):
2155
2163
[PubMed]
3
Finelli
L
,
Fiore
A
,
Dhara
R
, et al
.
Influenza-associated pediatric mortality in the United States: increase of Staphylococcus aureus coinfection.
Pediatrics
.
2008
;
122
(
4
):
805
811
[PubMed]
4
Centers for Disease Control and Prevention
.
Surveillance for pediatric deaths associated with 2009 pandemic influenza A (H1N1) virus infection - United States, April-August 2009.
MMWR Morb Mortal Wkly Rep
.
2009
;
58
(
34
):
941
947
[PubMed]
5
Cox
CM
,
Blanton
L
,
Dhara
R
,
Brammer
L
,
Finelli
L
.
2009 Pandemic influenza A (H1N1) deaths among children—United States, 2009-2010.
Clin Infect Dis
.
2011
;
52
(
suppl 1
):
S69
S74
[PubMed]
6
Peebles
PJ
,
Dhara
R
,
Brammer
L
,
Fry
AM
,
Finelli
L
.
Influenza-associated mortality among children - United States: 2007-2008.
Influenza Other Respir Viruses
.
2011
;
5
(
1
):
25
31
[PubMed]
7
Blanton
L
,
Peacock
G
,
Cox
C
,
Jhung
M
,
Finelli
L
,
Moore
C
.
Neurologic disorders among pediatric deaths associated with the 2009 pandemic influenza.
Pediatrics
.
2012
;
130
(
3
):
390
396
[PubMed]
8
Wong
KK
,
Jain
S
,
Blanton
L
, et al
.
Influenza-associated pediatric deaths in the United States, 2004-2012.
Pediatrics
.
2013
;
132
(
5
):
796
804
[PubMed]
9
Harper
SA
,
Fukuda
K
,
Uyeki
TM
,
Cox
NJ
,
Bridges
CB
;
Advisory Committee on Immunization Practices (ACIP), Centers for Disease Control and Prevention (CDC)
.
Prevention and control of influenza. Recommendations of the Advisory Committee on Immunization Practices (ACIP).
MMWR Recomm Rep
.
2005
;
54
(
RR-8
):
1
40
10
Smith
NM
,
Bresee
JS
,
Shay
DK
,
Uyeki
TM
,
Cox
NJ
,
Strikas
RA
.
Prevention and Control of Influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP) [published correction appears in MMWR Recomm Rep. 2006;55(29):800].
MMWR Recomm Rep
.
2006
;
55
(
RR–10
):
1
42
11
Centers for Disease Control and Prevention
. Overview of influenza surveillance in the United States. Available at: https://www.cdc.gov/flu/weekly/overview.htm. Accessed May 31, 2017
12
Centers for Disease Control and Prevention
. Influenza weekly update. Available at: https://www.cdc.gov/flu/weekly. Accessed May 31, 2017
13
Fiore
AE
,
Uyeki
TM
,
Broder
K
, et al;
Centers for Disease Control and Prevention
.
Prevention and control of influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2010 [published corrections appear in MMWR Recomm Rep. 2010;59(31):993; 2010;59(35):1147].
MMWR Recomm Rep
.
2010
;
59
(
RR–8
):
1
62
[PubMed]
14
Centers for Disease Control and Prevention
.
Prevention and control of influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2011.
MMWR Morb Mortal Wkly Rep
.
2011
;
60
(
33
):
1128
1132
[PubMed]
15
Centers for Disease Control and Prevention
.
Prevention and control of influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP)–United States, 2012-13 influenza season.
MMWR Morb Mortal Wkly Rep
.
2012
;
61
(
32
):
613
618
[PubMed]
16
Grohskopf
LA
,
Shay
DK
,
Shimabukuro
TT
;
Centers for Disease Control and Prevention (CDC)
.
Prevention and control of seasonal influenza with vaccines. Recommendations of the Advisory Committee on Immunization Practices--United States, 2013-2014.
MMWR Recomm Rep
.
2013
;
62
(
RR-07
):
1
43
17
Grohskopf
LA
,
Olsen
SJ
,
Sokolow
LZ
, et al;
Centers for Disease Control and Prevention
.
Prevention and control of seasonal influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP) – United States, 2014-15 influenza season.
MMWR Morb Mortal Wkly Rep
.
2014
;
63
(
32
):
691
697
[PubMed]
18
Grohskopf
LA
,
Sokolow
LZ
,
Olsen
SJ
,
Bresee
JS
,
Broder
KR
,
Karron
RA
.
Prevention and control of influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices, United States, 2015-16 influenza season.
MMWR Morb Mortal Wkly Rep
.
2015
;
64
(
30
):
818
825
[PubMed]
19
US Census Bureau
. Annual Estimates of the Resident Population by Single Year of Age and Sex for the United States, States, and Puerto Rico Commonwealth: April 1, 2010 to July 1, 2016 Available at: http://factfinder.census.gov/faces/tableservices/jsf/pages/productview.xhtml?src=bkmk. Accessed August 24, 2016
20
Centers for Disease Control and Prevention
. FluView: Age group distribution of influenza positive specimens reported by public health laboratories, national summary, 2015-16 influenza season. Available at: http://gis.cdc.gov/grasp/fluview/flu_by_age_virus.html. Accessed October 17, 2016
21
Wong
KK
,
Cheng
P
,
Foppa
I
,
Jain
S
,
Fry
AM
,
Finelli
L
.
Estimated paediatric mortality associated with influenza virus infections, United States, 2003-2010.
Epidemiol Infect
.
2015
;
143
(
3
):
640
647
[PubMed]
22
Centers for Disease Control and Prevention
. Flu vaccination coverage, United States, 2015–16 influenza season. Available at: https://www.cdc.gov/flu/fluvaxview/coverage-1516estimates.htm. Accessed May 31, 2017
23
Healthy People 2020
. Increase the percentage of children aged 6 months through 17 years who are vaccinated annually against seasonal influenza. Available at: https://www.healthypeople.gov/2020/topics-objectives/topic/Immunization-and-Infectious-Diseases/objectives#4659. Accessed May 31, 2017
24
Ampofo
K
,
Gesteland
PH
,
Bender
J
, et al
.
Epidemiology, complications, and cost of hospitalization in children with laboratory-confirmed influenza infection.
Pediatrics
.
2006
;
118
(
6
):
2409
2417
[PubMed]
25
Dawood
FS
,
Fiore
A
,
Kamimoto
L
, et al;
Emerging Infections Program Network
.
Burden of seasonal influenza hospitalization in children, United States, 2003 to 2008.
J Pediatr
.
2010
;
157
(
5
):
808
814
[PubMed]
26
Poehling
KA
,
Edwards
KM
,
Griffin
MR
, et al
.
The burden of influenza in young children, 2004-2009.
Pediatrics
.
2013
;
131
(
2
):
207
216
[PubMed]
27
Greenbaum
AH
,
Chen
J
,
Reed
C
, et al
.
Hospitalizations for severe lower respiratory tract infections.
Pediatrics
.
2014
;
134
(
3
):
546
554
[PubMed]
28
Quach
C
,
Piché-Walker
L
,
Platt
R
,
Moore
D
.
Risk factors associated with severe influenza infections in childhood: implication for vaccine strategy.
Pediatrics
.
2003
;
112
(
3, pt 1
). Available at: www.pediatrics.org/cgi/content/full/112/3/e197
[PubMed]
29
Chaves
SS
,
Perez
A
,
Farley
MM
, et al;
Influenza Hospitalization Surveillance Network
.
The burden of influenza hospitalizations in infants from 2003 to 2012, United States.
Pediatr Infect Dis J
.
2014
;
33
(
9
):
912
919
[PubMed]
30
Flannery
B
,
Reynolds
SB
,
Blanton
L
, et al
.
Influenza vaccine effectiveness against pediatric deaths: 2010-2014.
Pediatrics
.
2017
;
139
(
5
):
e20164244
[PubMed]
31
Madhi
SA
,
Cutland
CL
,
Kuwanda
L
, et al;
Maternal Flu Trial Team
.
Influenza vaccination of pregnant women and protection of their infants.
N Engl J Med
.
2014
;
371
(
10
):
918
931
[PubMed]
32
Tapia
MD
,
Sow
SO
,
Tamboura
B
, et al
.
Maternal immunisation with trivalent inactivated influenza vaccine for prevention of influenza in infants in Mali: a prospective, active-controlled, observer-blind, randomised phase 4 trial.
Lancet Infect Dis
.
2016
;
16
(
9
):
1026
1035
[PubMed]
33
Steinhoff
MC
,
Katz
J
,
Englund
JA
, et al
.
Year-round influenza immunisation during pregnancy in Nepal: a phase 4, randomised, placebo-controlled trial.
Lancet Infect Dis
.
2017
;
17
(
9
):
981
989
[PubMed]
34
Bramley
AM
,
Bresee
J
,
Finelli
L
.
Pediatric influenza.
Pediatr Nurs
.
2009
;
35
(
6
):
335
345
[PubMed]
35
Principi
N
,
Esposito
S
.
Severe influenza in children: incidence and risk factors.
Expert Rev Anti Infect Ther
.
2016
;
14
(
10
):
961
968
[PubMed]
36
Izurieta
HS
,
Thompson
WW
,
Kramarz
P
, et al
.
Influenza and the rates of hospitalization for respiratory disease among infants and young children.
N Engl J Med
.
2000
;
342
(
4
):
232
239
[PubMed]
37
Randolph
AG
,
Vaughn
F
,
Sullivan
R
, et al;
Pediatric Acute Lung Injury and Sepsis Investigator’s Network
;
National Heart, Lung, and Blood Institute ARDS Clinical Trials Network
.
Critically ill children during the 2009-2010 influenza pandemic in the United States.
Pediatrics
.
2011
;
128
(
6
). Available at: www.pediatrics.org/cgi/content/full/128/6/e1450
[PubMed]
38
Mistry
RD
,
Fischer
JB
,
Prasad
PA
,
Coffin
SE
,
Alpern
ER
.
Severe complications in influenza-like illnesses.
Pediatrics
.
2014
;
134
(
3
). Available at: www.pediatrics.org/cgi/content/full/134/3/e684
[PubMed]
39
Havers
F
,
Fry
AM
,
Chen
J
, et al
.
Hospitalizations attributable to respiratory infections among children with neurologic disorders.
J Pediatr
.
2016
;
170
:
135
141.e1–e5
40
Chen
R
,
Holmes
EC
.
The evolutionary dynamics of human influenza B virus.
J Mol Evol
.
2008
;
66
(
6
):
655
663
[PubMed]
41
van de Sandt
CE
,
Bodewes
R
,
Rimmelzwaan
GF
,
de Vries
RD
.
Influenza B viruses: not to be discounted.
Future Microbiol
.
2015
;
10
(
9
):
1447
1465
[PubMed]
42
Coffin
SE
,
Zaoutis
TE
,
Rosenquist
AB
, et al
.
Incidence, complications, and risk factors for prolonged stay in children hospitalized with community-acquired influenza.
Pediatrics
.
2007
;
119
(
4
):
740
748
[PubMed]
43
Tran
D
,
Vaudry
W
,
Moore
DL
, et al;
IMPACT investigators
.
Comparison of children hospitalized with seasonal versus pandemic influenza A, 2004-2009.
Pediatrics
.
2012
;
130
(
3
):
397
406
[PubMed]
44
Leung
CH
,
Tseng
HK
,
Wang
WS
,
Chiang
HT
,
Wu
AY
,
Liu
CP
.
Clinical characteristics of children and adults hospitalized for influenza virus infection.
J Microbiol Immunol Infect
.
2014
;
47
(
6
):
518
525
45
Centers for Disease Control and Prevention
. Seasonal influenza treatment. Available at: https://www.cdc.gov/flu/antivirals/whatyoushould.htm. Accessed December 11, 2017

Competing Interests

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.