Published online October 1, 2008
PEDIATRICS Vol. 122 No. 4 October 2008, pp. 805-811 (doi:10.1542/peds.2008-1336)
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ARTICLE

Influenza-Associated Pediatric Mortality in the United States: Increase of Staphylococcus aureus Coinfection

Lyn Finelli, DrPHa, Anthony Fiore, MDa, Rosaline Dhara, MPHa, Lynnette Brammer, MPHa, David K. Shay, MDa, Laurie Kamimoto, MDa, Alicia Fry, MDa, Jeffrey Hageman, MPHb, Rachel Gorwitz, MDb, Joseph Bresee, MDa and Timothy Uyeki, MDa

a Influenza Division, National Center for Immunization and Respiratory Diseases
b Division of Healthcare Quality Promotion, National Center for Preparedness, Detection, and Control of Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
OBJECTIVE. Pediatric influenza-associated death became a nationally notifiable condition in the United States during 2004. We describe influenza-associated pediatric mortality from 2004 to 2007, including an increase of Staphylococcus aureus coinfections.

METHODS. Influenza-associated pediatric death is defined as a death of a child who is younger than 18 years and has laboratory-confirmed influenza. State and local health departments report to the Centers for Disease Control and Prevention demographic, clinical, and laboratory data on influenza-associated pediatric deaths.

RESULTS. During the 2004–2007 influenza seasons, 166 influenza-associated pediatric deaths were reported (n = 47, 46, and 73, respectively). Median age of the children was 5 years. Children often progressed rapidly to death; 45% died within 72 hours of onset, including 43% who died at home or in an emergency department. Of 90 children who were recommended for influenza vaccination, only 5 (6%) were fully vaccinated. Reports of bacterial coinfection increased substantially from 2004–2005 to 2006–2007 (6%, 15%, and 34%, respectively). S aureus was isolated from a sterile site or endotracheal tube culture in 1 case in 2004–2005, 3 cases in 2005–2006, and 22 cases in 2006–2007; 64% were methicillin-resistant S aureus. Children with S aureus coinfection were significantly older and more likely to have pneumonia and acute respiratory distress syndrome than those who were not coinfected.

CONCLUSIONS. Influenza-associated pediatric mortality is rare, but the proportion of S aureus coinfection identified increased fivefold over the past 3 seasons. Research is needed to identify risk factors for influenza coinfection with invasive bacteria and to determine the impact of influenza vaccination and antiviral agents in preventing pediatric mortality.

Key Words: influenza • influenza vaccine • mortality rates • Staphylococcus aureus

Abbreviations: CDC—Centers for Disease Control and Prevention • ACIP—Advisory Committee on Immunization Practices • MRSA—methicillin-resistant Staphylococcus aureus

In the United States, seasonal influenza epidemics result in an estimated average of 226000 hospitalizations and 36000 deaths each year.1,2 Influenza virus infection can cause severe morbidity and mortality in all ages, but the highest rates of severe complications from influenza are observed among children who are younger than 2 years, adults who are older than 65 years, and those with chronic medical conditions.1–5

Although influenza virus infection alone can lead to death, most influenza-related deaths are the result of either exacerbation of underlying medical conditions or invasive coinfection with another infectious pathogen.1,2 Severe, sometimes fatal, bacterial pneumonia after influenza has been observed in many studies and is thought to have been a major cause of increased mortality during influenza pandemics.6–8 More than 90% of estimated influenza-attributable deaths occur among people who are ≥65 years of age in the United States.2 Data are limited on mortality associated with influenza in children. One study that modeled death certificate and influenza surveillance data estimated that a range of 28 to 92 influenza-associated deaths occurred per year in children who were younger than 5 years in the United States between 1990 and 1999.2

Influenza-associated pediatric mortality is a nationally notifiable condition in the United States. National surveillance for influenza-associated pediatric mortality was implemented in October 2004, which followed a severe influenza season when 153 pediatric influenza-associated deaths were reported.9 During early 2007, the Centers for Disease Control and Prevention (CDC) noted an increase in the number of reports of influenza-associated pediatric deaths associated with Staphylococcus aureus coinfection compared with previous seasons. In this report, we describe influenza-associated pediatric mortality from 2004 to 2007 and the increase in reports of S aureus coinfection during the 2006–2007 season.


   METHODS
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 METHODS
RESULTS
 DISCUSSION
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An influenza-associated pediatric death is defined as death in a child who is younger than 18 years and has a clinically compatible illness and laboratory-confirmed influenza. Confirmation of influenza virus infection may occur before or after death and requires a positive finding for influenza A or B on at least 1 of the following laboratory methods: a rapid influenza virus diagnostic test or enzyme immunoassay, viral isolation in tissue cell culture, fluorescent antibody staining, reverse transcription polymerase chain reaction, or immunohistochemical staining of tissue samples. Most specimens were tested for influenza at hospital, local, or state health department laboratories, and some influenza A viruses were subtyped.

For influenza surveillance purposes, an influenza season is defined as October 1 to September 30 of the subsequent year. State and local health departments report cases of influenza-associated pediatric mortality to the CDC by using a standardized case report form that includes demographic information, date and location of death, laboratory test results, health history, influenza vaccination status, medical care received related to the illness, and bacterial or fungal coinfection from sterile sites. The case report form contained a comment field where information could be noted on cultures from nonsterile sites and other relevant clinical information. Children with chronic medical conditions recognized by the Advisory Committee on Immunization Practices (ACIP) as an indication for influenza vaccination were considered to have an ACIP-defined high-risk condition.10* For the 2004–2005 influenza season, annual influenza vaccination was recommended for all children who were 6 to 23 months of age; beginning with the 2006–2007 season, all children who were aged 6 to 59 months were recommended for influenza vaccination. ACIP recommends that children who are younger than 9 years receive 2 doses of influenza vaccine in the first season they are vaccinated. A child was considered to be fully vaccinated when documentation was available to verify that he or she had received influenza vaccine in the appropriate number of doses at least 14 days before the onset of illness. Children were categorized as fully vaccinated when they had documentation that they had received influenza vaccine in the appropriate number of doses at least 14 days before the onset of illness. In addition, children who were younger than 9 years were classified as fully vaccinated by the aforementioned definition, fully vaccinated by history when they had a current influenza vaccination documented at least 14 days before the onset of illness and had vaccination in the previous year by history but no documentation, partially vaccinated when they had a current influenza vaccination at least 14 days before the onset of illness and no previous vaccination, and partially vaccinated with missing information when they had a current influenza vaccination at least 14 days before the onset of illness and missing information on previous vaccination.

Data were entered into Microsoft Access 2002 (Redmond, WA) and analyzed in SPSS 15 (SPSS, Inc, Chicago, IL). A {chi}2 test was used to evaluate statistically significant differences between proportions for ≥2 groups. Yates correction for continuity was used to prevent overestimation of statistical significance for cell size data when indicated. All comparisons were 2-sided, and P < .05 was considered significant.


   RESULTS
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DISCUSSION
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A total of 166 influenza-associated pediatric deaths were reported from October 1, 2004, to September 30, 2007, by 41 reporting jurisdictions (39 state and 2 local health departments). The numbers of deaths were approximately equal during the first 2 seasons of surveillance and increased in the third season (n = 47, 46, and 73, respectively; Table 1). Slightly more than half of the decedents were male, and most were white, black, or Hispanic. The median age in years varied by season and was highest (7 years) in the 2006–2007 season. The median number of days between onset of influenza to death ranged from 3 to 4 days, and 75% of deaths occurred within 7 days (Fig 1). Forty-four percent of children died at home or in the emergency department. Over 3 seasons, 74 (45%) children had an ACIP-defined high-risk condition (26, 22, and 26 children, respectively, in these seasons). The proportion of children with an underlying chronic high-risk condition declined from 55% in the 2004–2005 influenza season to 35% in 2006–2007. The most common high-risk conditions reported were asthma (n = 23), seizure disorder (n = 16), and neuromuscular disorder including cerebral palsy (n = 15). Some children had >1 high-risk condition.


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  		TABLE 1 Characteristics of Influenza-Associated Pediatric Deaths: United States, 2004–2007

 

Figure 1
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  		FIGURE 1 Number of days from influenza onset until influenza-associated death: United States, 2004–2007.

 
Few children with an indication for influenza vaccination had received vaccination during the season in which they died. Of 90 children with an age-related or ACIP-defined high-risk condition recommended for vaccination, 18 (20%) were at least partially vaccinated ≥14 days before illness onset per season, respectively; Table 1). One child who was partially vaccinated did not have either an age-related or ACIP-defined high-risk condition recommended for vaccination. Data on complications of influenza were available for 73 children; the most common complications were pneumonia (n = 59), invasive bacterial coinfection (n = 36), acute respiratory distress syndrome (n = 30), seizures (n = 23), encephalopathy (n = 18), and shock (n = 16). Information on antiviral treatment was not available. Both influenza A and B virus infections were associated with pediatric deaths. No predominant influenza virus type was identified among the decedents, and the distribution of influenza virus types was not different among cases in the 3 seasons (Table 2).


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  		TABLE 2 Influenza Type and Bacterial Coinfections Among Children With Influenza-Associated Death: United States 2004–2007

 
Bacterial coinfection increased substantially over the 3 influenza seasons (6%, 15%, and 35%, respectively). S aureus was the most commonly identified bacterial pathogen and accounted for a large proportion of the increase in bacterial coinfection in 2006–2007 compared with the previous 2 seasons (Table 2). S aureus was isolated from a sterile site in 1 (2%) child in 2004–2005, 2 (4%) children in 2005–2006, and 18 (25%) children in 2006–2007 (Table 2). S aureus was isolated from an endotracheal tube culture in 1 (2%) child in 2005–2006 and in 4 (6%) children in 2006–2007. Overall, S aureus was isolated from a sterile site or endotracheal tube culture in 1 child in 2004–2005, 3 children in 2005–2006, and 22 children in 2006–2007 (Table 2). Of all 26 S aureus infections identified, 15 (60%) were methicillin-resistant S aureus (MRSA), 6 were methicillin-susceptible S aureus (MSSA), and 5 had S aureus with susceptibility unknown (Table 3). Information on the date of the bacterial culture was not collected, and whether S aureus coinfection was community-associated or hospital-associated could not be determined.


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  		TABLE 3 Organisms Isolated From Sterile Sites Among Children With Influenza and Bacterial Coinfection: United States, 2004–2007

 
Characteristics of children with and without S aureus-influenza coinfection were evaluated for the 2006–2007 influenza season (Table 4). Children with coinfection were significantly older and more likely to have radiologically confirmed pneumonia or acute respiratory distress syndrome. The proportion of children with an ACIP-defined high-risk condition or who had received influenza vaccination (Table 4) was similar regardless of the presence of S aureus coinfection.


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  		TABLE 4 Characteristics of Children With Influenza-Associated Death According to Presence of S aureus Coinfection: United States, 2006–2007

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
This report describes 166 cases of laboratory-confirmed, influenza-associated deaths that occurred during the 2004–2005, 2005–2006, and 2006–2007 influenza seasons and were reported to the CDC. Several characteristics of children who died from influenza-associated complications are notable. Influenza was often rapidly fatal with almost half of children dying within 72 hours of the onset of symptoms and 75% dying within 7 days; almost half died at home or in the emergency department. The number of bacterial coinfections increased substantially in 2006–2007 with most infections caused by S aureus, primarily MRSA. Finally, many deaths occurred among children without a condition or age that would make them recommended to receive vaccination. Even so, of deaths among children with an indication for influenza vaccination, only 21% had been vaccinated during the season in which they died. This increase in pediatric death and in bacterial coinfection occurred in the context of relatively mild influenza seasons in 2005–2006 and 2006–2007.

Rapid progression to death among many of the children in this study is consistent with pediatric deaths caused by influenza reported in the 2003–2004 influenza season, in which almost half of the influenza-associated deaths occurred outside the hospital setting or in the emergency department.9 In both studies, the majority of deaths occurred in previously healthy children without an underlying medical condition, and few of those children with an indication for influenza vaccination were vaccinated.9 The children in our study experienced a wide range of complications similar to those previously associated with severe influenza, including pneumonia, bacterial coinfection, acute respiratory distress syndrome, seizures, encephalopathy, and shock.11,12 The mechanisms of these influenza-associated deaths are unknown, but some could include an abnormal host inflammatory response to influenza virus infection. Influenza and influenza-like illness have also been associated with S aureus toxic shock syndrome13; however, clinical criteria for S aureus toxic shock syndrome were not collected in our study to determine the presence of toxic shock syndrome.

There are several hypothesized mechanisms by which influenza virus infections increase the risk for subsequent bacterial coinfection. Influenza virus damages the epithelial cell layer of the tracheobronchial tree, thereby enhancing staphylococcal adherence.14,15 Increased adherence might be mediated by the neuraminidase activity of the influenza virus, which increases bacterial adherence two- to fourfold in in vitro models that used human alveolar cells.15 Influenza virus suppresses the respiratory burst response and phagocytic function of neutrophils and macrophages, which might facilitate the development of a secondary bacterial infection.15–18

The proportion of children with bacterial coinfection increased more than fivefold between the 2004–2005 and 2006–2007 influenza seasons, with nearly all of the increase attributable to S aureus coinfections. Bhat et al9 found that 24 of 102 children who had data available and died from influenza-associated complications during the 2003–2004 influenza season had evidence of bacterial coinfection, including 6 patients who had coinfection with MRSA and 5 with methicillin-susceptible S aureus or S aureus with unknown sensitivity. Influenza-associated S aureus pneumonia and sepsis among previously healthy children and adults has been reported for the past century.7,8 Influenza-associated S aureus pneumonia with antecedent staphylococcal soft tissue infection was described during the 1957 pandemic.19 Overwhelming sepsis caused by S aureus has been reported in infants20 and older children,21 and several studies have shown that a recent history of staphylococcal soft tissue infection in the case patient or a family member often precedes the invasive infection, and family clusters of invasive staphylococcal infection have been described.20,22–25

Approximately 30% to 40% of children are colonized with S aureus; colonization prevalence is highest among children who are 6 to 11 years of age.26–28 Whereas frequencies of S aureus nasal carriage have not increased significantly, MRSA nasal carriage has increased. In 2001, data from a nationally representative carriage survey indicated that 0.8% of the US population was colonized by MRSA26; 2003–2004 data from the same study indicated that 1.5% of the US population were colonized.29 In 2001, data from a large pediatric primary care practice in Tennessee demonstrated colonization rates of 0.8%.30 In 2005, a repeat survey in the same Tennessee pediatric primary care practice found that MRSA nasal carriage exceeded 9%.30 Nasal carriage with MRSA has been reported to be as high as 22% among new admissions to a pediatric hospital; 92% of children with MRSA were not known previously to be MRSA carriers, although some children had risk factors for MRSA colonization.28,31–33 In addition to antimicrobial resistance, there is recent evidence that many of these MRSA isolates are the USA300 strain,20,33 which has been associated with the Panton-Valentine leukicidin toxin, an important virulence factor linked with necrotizing pneumonia and necrotic skin lesions.34 As MRSA nasal carriage increases, there is a potential for increasing coinfection with MRSA and influenza virus, resulting in severe morbidity and mortality in children.

Influenza vaccination remains the major prevention strategy for influenza and its associated complications. Currently, all children who are aged 6 to 59 months and those with certain chronic underlying conditions should receive annual influenza vaccination; however, only 21% of the cases recommended for annual vaccination had received influenza vaccine. Notably, 46% of the cases did not meet current criteria for targeted influenza vaccination, but vaccination might have been indicated for some children as household contacts of people at high risk for influenza complications. Influenza vaccination coverage levels among children at high risk for influenza complications remain very low. Only ~21% of children aged 6 to 23 months were fully vaccinated against influenza during the 2005–2006 influenza season,35 and immunization registry data indicate that coverage for the 2006–2007 season was similar.36 This suggests that substantial efforts must be made to increase influenza vaccination coverage among target groups. Influenza vaccination can reduce complications of influenza, such as acute otitis media and pneumonia, in young children and adults.37–39 By reducing the risk for influenza, invasive bacterial infections that are facilitated by disruptions in host defenses during influenza virus infection could also presumably be reduced.

Several studies have demonstrated the effectiveness of influenza antiviral treatment to prevent secondary complications. Early treatment with the neuraminidase inhibitor oseltamivir reduced the development of otitis media in children by 44%40 and reduced the development of various secondary bacterial complications (sinusitis, bronchitis, or pneumonia) that required antibiotics in previously healthy adults.41 The mechanism by which neuraminidase inhibitors reduce secondary bacterial complications is unknown but might be associated with inactivation of viral neuraminidase and elimination of its ability to facilitate bacterial adherence.15,42,43 On the basis of preclinical studies, it has been proposed that even delayed treatment with neuraminidase inhibitors could prevent influenza-associated bacterial complications, although the course of influenza virus infection may not be altered.15,42 A recent study of the effectiveness of oseltamivir treatment of hospitalized adult patients demonstrated a reduction in influenza complications and mortality even when treatment was initiated after 2 days of illness onset.44

Our findings are subject to several potential limitations that could result in an underestimation of influenza deaths in children and bacterial coinfections. Influenza-associated pediatric mortality case reports varied in completeness and were less complete for children who had not been hospitalized. Influenza-associated pediatric deaths are likely underreported, because influenza-associated pediatric mortality became a nationally notifiable condition only in 2004. State-level reporting requirements have been implemented incrementally over the past 3 years, with 42 states requiring reporting currently; however, incremental increases in reporting would affect the total number of reports submitted but should not affect the proportion of cases with bacterial coinfection. Low levels of influenza testing in children might also contribute to underreporting. Despite the availability and utility of influenza tests, influenza testing is not currently routinely incorporated in the diagnostic workup of most children who are seen in primary care or emergency department settings with influenza-like illness.45 Furthermore, physicians may not order influenza diagnostic testing in severe cases, and clinical data are limited for patients who die at home or in an emergency department. Of those who die outside the hospital, not all cases are referred for postmortem examination. Even when referred for postmortem examination, not all cases have routine influenza or staphylococcal diagnostic testing on autopsy tissue specimens.46 We did not systematically collect information on bacterial isolates from nonsterile sites (eg, endotracheal tube), and this information if collected might have captured additional cases of bacterial pneumonia among children with fatal influenza virus infection; therefore, we may have underascertained the proportion of cases with bacterial coinfections, including S aureus. Also, our findings are an underestimation of severe MRSA and influenza because we did not include severe nonfatal cases.

Influenza-associated pediatric mortality is rare, but the proportion of cases in which S aureus was identified has increased fivefold over the past 3 influenza seasons. Increasing rates of MRSA nasal carriage may increase the potential for coinfection with MRSA and influenza virus, resulting in severe morbidity and mortality in children. Influenza vaccination remains the primary prevention strategy for influenza. Although vaccination efforts should be focused on children at highest risk for severe disease and complications, any child who wants (or whose parents want) to reduce his or her risk of influenza infection should be vaccinated. Furthermore, children who are household contacts of people who are at high risk for influenza complications should be vaccinated. In February 2008, the ACIP recommended annual influenza vaccination for all children from 6 months to 18 years of age with incremental implementation over the next 2 years.47


   CONCLUSIONS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
Children who are at risk for influenza complications or healthy children with moderate to severe respiratory illness should be tested for influenza and, when infected, treated with oseltamivir or zanamivir.48 Physicians should consider treating children with suspected S aureus pneumonia during influenza season with vancomycin or other antibiotic to treat MRSA when they reside in areas where MRSA is prevalent24 or have risk factors for MRSA infection (eg, underlying conditions, history of MRSA colonization or infection). Additional studies are needed to evaluate risk factors for coinfection with influenza and bacterial pathogens, to assess increasing influenza vaccination in children, and to determine the role of influenza vaccination and antiviral agents in preventing severe morbidity and mortality that are caused by influenza among children.


   FOOTNOTES
 
Accepted Jul 1, 2008.

Address correspondence to Lyn Finelli, DrPH, Centers for Disease Control and Prevention, Influenza Division, 1600 Clifton Rd, NE, MS A-32, Atlanta, GA 30333. E-mail: lfinelli{at}cdc.gov

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


What's Known on This Subject

Influenza-associated S aureus pneumonia was described as a cause of mortality and severe illness during the 1918 and 1957 influenza pandemics, but high rates of influenza–S aureus coinfection–related mortality have not been seen before in children in seasonal influenza epidemics.

 

What This Study Adds

Reports of influenza-related death complicated by bacterial coinfection increased substantially from 2004–2005 to 2006–2007, and S aureus was isolated from 2% of cases in 2004–2005, 6% of cases in 2005–2006, and 30% of cases in 2006–2007; 64% were MRSA.

 

* Children with ACIP-defined high-risk conditions include those who are receiving long-term aspirin therapy or have chronic pulmonary (including asthma), cardiovascular (except hypertension), renal, hepatic, hematologic, or metabolic disorders (including diabetes mellitus); immunosuppression; or any condition (eg, cognitive dysfunction, spinal cord injuries, seizure disorders, other neuromuscular disorders) that can compromise respiratory function or the handling of respiratory secretions or that can increase the risk for aspiration. Back


   REFERENCES
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