PEDIATRICS Vol. 118 No. 6 December 2006, pp. 2409-2417 (doi:10.1542/peds.2006-1475)
ARTICLE |
Epidemiology, Complications, and Cost of Hospitalization in Children With Laboratory-Confirmed Influenza Infection
a Divisions of Pediatric Infectious Diseases
c Inpatient Medicine
b Department of Pediatrics
g Division of Clinical Epidemiology, Department of Medicine, University of Utah Health Sciences Center, Salt Lake City, Utah
e Department of Pediatrics, University of Colorado Health Science Center, Denver, Colorado
d Institute for Health Care Delivery Research
f Primary Children's Medical Center, Intermountain Health Care, Salt Lake City, Utah
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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BACKGROUND. Influenza causes significant morbidity among children. Previous studies used indirect case ascertainment methods with little cost data. We sought to measure the burden of laboratory-confirmed influenza from hospitalized children.
METHODS. We conducted a retrospective cohort study during 3 viral seasons at Primary Children's Medical Center (Salt Lake City, UT). Children 
18 years of age who were hospitalized with laboratory-confirmed influenza infection were included. Outcomes included hospitalization rates, complications including intensive care unit stays, mechanical ventilation, length of stay, and total hospital costs.
RESULTS. A total of 325 children had hospitalizations attributable to influenza over 3 viral seasons: 28% <6 months of age, 33% between 6 and 23 months of age; and 39% >2 years of age; 37% had high-risk medical conditions. Population-based rates of hospitalization for Salt Lake County residents ranged from 6.3 to 252.7 per 100000 children. The highest rates were in children younger than 6 months, and rates decreased with increasing age. Forty-nine (15%) children had an ICU stay; 27 required mechanical ventilation, and half of these patients were >2 years of age. Total hospital cost for the cohort was $2 million; 55% was accounted for by children >2 years of age. Length of stay and total hospital costs were significantly higher in all children >2 years of age compared with children <6 months of age and were comparable to all children 6 to 23 months of age.
CONCLUSIONS. Proven influenza infection in children results in substantial hospital resource utilization and morbidity. Nationwide, the median hospital costs may total $55 million. Our data support the Advisory Committee on Immunization's recommendations to expand the use of influenza vaccine to children >2 years of age.
Key Words: influenza • children • resource utilization • complications • hospitalization
Abbreviations: ACIP—Advisory Committee on Immunization Practices • PCMC—Primary Children's Medical Center • IHC—Intermountain Health Care • EDW—Enterprise Data Warehouse • LOS—length of stay • DFA—direct fluorescent antibody • RSV—respiratory syncytial virus • ICD-9—International Classification of Diseases, Ninth Revision • IQR—interquartile range
Influenza is responsible for seasonal epidemics of pediatric respiratory illness each year, resulting in substantial morbidity, mortality, and increased health care utilization and costs. Population-based studies in the United States have used indirect methods to calculate the burden and severity of influenza infection in children.1–5 These studies demonstrated increases between 24% to 35% in outpatient health care visits, 18% to 20% in hospital admissions, and 14% to 20% in antibiotic use in children during influenza season. The estimated excess hospitalization rates attributable to influenza virus infection varied by age in healthy children and children with high-risk medical conditions. The highest rates of hospitalization occurred in children younger than 2 years of age and were similar to those among the elderly.6–8 In 2004, the Centers for Disease Control and Prevention's Advisory Committee on Immunization Practices (ACIP) added children 6 to 23 months of age to the groups for whom annual influenza vaccine is recommended, and in 2006, they added children 24 to 59 months of age.5,9,10 The purpose of this study was to describe the epidemiology, complications, and total hospital costs of pediatric hospitalizations resulting from laboratory-confirmed influenza virus infections during 3 influenza seasons and to lend support to the expanded new ACIP influenza vaccine recommendation in children.11
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Setting and Study Population
Approval for this study was obtained from the institutional review board of the University of Utah and Primary Children's Medical Center (PCMC). PCMC is owned and operated by Intermountain Health Care (IHC), a large, vertically integrated not-for-profit health care system in the Intermountain West. PCMC is a 233-bed children's hospital that serves as both the community hospital for Salt Lake County, Utah, and as a tertiary referral center for 5 states in the intermountain west (Utah, Idaho, Wyoming, Nevada, and Montana).
Study Design
We retrospectively examined demographic, clinical, and financial data for all children 18 years of age seen at PCMC with hospitalization attributable to laboratory-confirmed influenza virus A or B infection during 3 viral seasons (July 2001–June 2002, July 2002–June 2003, and July 2003–June 2004) by using the IHC Enterprise Data Warehouse (EDW). In addition to routine administrative and financial information about individual hospitalizations, the EDW contains detailed data about the cost of providing health care derived from the IHC cost-accounting system. Length of stay (LOS), total hospital costs and charges, and ICU admissions were obtained from the EDW. Paper and electronic medical charts of all identified cases of influenza were reviewed; data abstracted included underlying medical conditions, admission diagnosis, complications including radiologic diagnoses of pneumonia, mechanical ventilation, and bacterial tracheitis.
Respiratory Viral Testing
Viral testing by 7-valent direct fluorescent antibody (DFA) staining (Simufluor respiratory screen; Light Diagnostics, Temecula, CA), which detects influenza A and B; parainfluenza 1, 2, and 3; respiratory syncytial virus (RSV); and adenovirus was required by PCMC infection control for all hospitalized patients with respiratory symptoms during the study period. In addition, DFA testing was recommended for all febrile infants <90 days of age. Viral testing for other children was at the discretion of the attending physician. Samples were obtained by saline-assisted nasopharyngeal aspiration. DFA testing was performed 3 to 5 times daily, with a mean turnaround time of 4 hours. For all DFA-negative specimens, viral culture was performed. Sensitivity of DFA testing compared with viral culture was 80% for influenza A and 67% for influenza B, with specificity >90% in our laboratory.12
Selection Criteria
Inpatient Cohort
The selection of patients is outlined in Fig 1. Case patients were those with virologically confirmed influenza whose admission was principally attributable to influenza. Because an individual patient could undergo viral testing multiple times during an encounter, all patient encounters during which at least 1 sample was submitted for viral testing during 1 of the 3 seasons were eligible for the study (13360 individual tests and 12251 individual encounters). Patients were excluded if they did not test positive for influenza during an encounter (12121 individual tests and 11075 encounters). Of the 1176 individual encounters during which influenza virus was detected, 347 (30%) children with moderate-to-severe influenza infection and complications because of concurrent high-risk conditions were hospitalized; the remaining 829 (70%) were discharged from the hospital from the emergency department, an outpatient clinic, or a pediatric observation unit.
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Influenza-Related Illness
An admission was determined to be principally attributable to influenza using the principal discharge International Classification of Diseases, Ninth Revision (ICD-9) diagnoses codes from the hospitalized cohort (independently reviewed by Drs Ampofo, Gesteland, Bender, Pavia, and Srivastava). Children with ICD-9 codes that met consensus for an influenza-related illness were included in the study cohort. Codes not reaching consensus triggered a second review of medical charts (Drs Ampofo and Bender) for adjudication. Because statistical outliers could unduly influence the analyses, all children within each age cohort (<6 months, 6–23 months, and >2 years of age) whose LOS was >2 standard deviations above the mean were also reviewed to determine that the hospitalization was primarily attributable to influenza. Seven children with mixed respiratory viral infection (influenza A and B: 1; influenza A and RSV: 1; influenza A and parainfluenza virus: 1; influenza A and adenovirus: 2; influenza A and parainfluenza virus and RSV: 1; influenza B and parainfluenza virus: 1) were included in the analysis. Patients with nosocomial influenza infections were excluded.
Definition of Study Terms
To determine whether children had high-risk conditions as defined by the ACIP, paper and electronic medical charts were reviewed by using a previously published list of ICD-9 codes defined by O'Brien et al.4 We included the 2005 ACIP recommendations for neurologic disease in children as defined by Keren et al.13 We classified children as having a high-risk condition if any of the ICD-9 codes from this list appeared in the coding summary. Discrepancies between chart review and ICD-9 codes triggered rereview of the entire chart for consensus. Bacterial tracheitis was defined as copious purulent secretions identified in the trachea and upper bronchus with a positive tracheal culture (Staphylococcus aureus and group A Streptococcus) or a positive Gram-stain with necrotic respiratory mucosa in purulent tracheal aspirate.
Costs were derived from the hospital's cost-accounting program, the Standard Cost Master, which is a transaction-based microcosting system. This system identifies and aggregates the variable- and fixed-cost components of patient activities, hospital services, and products according to the date of service.14–18 Total hospital charges are also shown. Hospital costs and charges incurred in years 2002–2004 were standardized to 2001 US dollars by applying a yearly consumer price index for hospital services.19
Study Outcomes
We analyzed the burden of influenza in hospitalized children by age and high-risk medical condition by examining the following outcomes: hospitalization rates, complications including pneumonia (focal infiltrate on a chest radiograph as reported by a PCMC radiologist), ICU stay, mechanical ventilation, death, LOS, and total hospital cost.
Statistical Analysis
Descriptive statistics were used to describe the study cohort. Mean, median, and interquartile ranges (IQRs) for LOS and total hospital costs were determined and compared for each group. Kruskal-Wallis tests were used for the continuous variables LOS and total hospital cost, which had nonnormal distribution among the age groups. Mann-Whitney U tests were used for pairwise comparisons for the age groups. Mantel-Haenszel test for trend was used to compare complication rates by age groups. To estimate population-based incidence rates per 100000 person years for influenza-related hospitalization, we used all children 18 years of age or under who were residents of Salt Lake County, defined by zip code for primary residence at time of admission divided by the age-specific population for the county using US Census data for 2000.20
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Virologic Testing and Seasons
A total of 12251 individual patients had respiratory samples submitted for viral testing; influenza virus was detected in 1176 (9.6%). The percentage of respiratory specimens positive for influenza ranged from 5.7% to 12% during the 3 seasons. The hospitalization rate among those with moderate-to-severe influenza ranged from 20% to 44%. Of 347 hospitalized children with influenza, 22 were excluded because the admission or the majority of the admission was not attributable to influenza (in 19 children, the primary reason for admission was surgical: 18 for elective surgery and 1 case of near drowning; 3 were excluded because LOS was attributable to other medical conditions, ie, cystic fibrosis with failure to thrive, acute osteomyelitis with exacerbation of chorea, and nonaccidental trauma), resulting in our study cohort of 325 children (Fig 1).
Demographics
Characteristics of the 325 hospitalized children are shown in Table 1. A total of 88% had influenza A infection, and 37% had a high-risk condition. The age distribution and cumulative percentage of hospitalized children is shown in Fig 2.
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Population-Based Incidence of Hospitalization
A total of 222 hospitalized children were 18 years of age or younger and residents of Salt Lake County. The average hospitalization rates among Salt Lake County residents are shown in Table 2. Hospitalization rates were highest in children younger than 6 months (253 of 100000) and decreased with increasing age, but remained elevated through age 6.
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Complications
Of the 325 hospitalized children, 52 (16%) had pneumonia, 49 (15%) were in the ICU with a median stay of 4.5 days (IQR: 2.2–7.6 days), and 27 (8%) required mechanical ventilation. Of the patients who were ventilated, 3 (11%) were younger than 6 months, 9 (33%) were 6 to 23 months old, and 15 (56%) were 2 years or older.
When comparing the 3 age groups (<6 months, 6–23 months, and >2 years old), there were significant differences in the proportion of children who developed pneumonia (5.4% vs 19.4% vs 20.3%, respectively; P = .005), who were admitted to the ICU (10% vs 13% vs 20.3%, respectively; P = .03), and who required mechanical ventilation (3.3% vs 8.3% vs 11.7%, respectively; P = .03). Thirty-three percent of patients with respiratory failure had a high-risk condition, and 15% had bacterial tracheitis, all attributable to S aureus infection. Rates of mechanical ventilation did not differ for children 2 years or older whether they were healthy or had a high-risk condition (10% vs 13%; P = not significant).
Influenza-Associated Mortality
Two children (0.6%) died. One was an 8-year-old with trisomy 21 who developed respiratory failure. DFA staining was positive for influenza A, and microbiologic studies were otherwise negative. Hospitalization was complicated by seizures, encephalopathy, and brain death. Autopsy findings included immunohistochemical positive influenza A necrotizing bronchiolitis and alveolitis. Other findings included severe cerebral edema, and tonsillar and uncal herniation with acute anoxic/ischemic changes in the brain. No influenza antigen was found in the brain.
The second death occurred in a previously healthy 20-month-old, who developed nausea, vomiting, diarrhea, dehydration, and lethargy. Acetaminophen and ibuprofen were administered before admission. Hospitalization was complicated by disseminated intravascular coagulation, renal failure, hepatitis, encephalopathy, and brain death. Autopsy findings revealed acute bronchopneumonia and hemorrhage, cerebral edema, tonsillar herniation, and necrosis with conglutination of the molecular layer of the cerebellum. There was diffuse microvesicular steatosis of the liver; however, electron microscopy failed to reveal mitochondrial abnormalities suggestive of Reye syndrome. A comprehensive microbiologic evaluation revealed only premortem nasopharyngeal culture positive for influenza B.
High-Risk Medical Conditions
A total of 120 (37%) hospitalized children had a high-risk medical condition, summarized in Table 1. The most common was pulmonary disease, accounting for 64% of high-risk medical conditions. Twenty-six (22%) had >1 high-risk condition. On the basis of the ACIP and American Academy of Pediatrics Committee on Infectious Diseases influenza vaccine recommendations,9,10 183 (56%) of children with influenza-related hospitalization were in groups for whom influenza vaccination is recommended.
LOS, Hospital Costs, and Charges
LOS, total hospital costs, and charges in hospitalized children with influenza are shown in Table 3. Overall, children 2 years or older stayed significantly longer (median LOS: 2.0; IQR: 1.0–6.0 days vs median LOS: 2.0; IQR: 1.0–3.0 days; P = .004) and had higher total hospital costs (median cost: $3127; IQR: $1764–$8056 vs median cost: $2534, IQR: $1945–$3838; P = .03) when compared with children younger than 6 months old. LOS and hospital costs for children ages 6 to 23 months were not statistically different from children 2 years or older but were also greater than children younger than 6 months old. Over the 3-year period, the total direct cost associated with influenza hospitalization for the entire study cohort was $2 million. Children 2 years or older accounted for 55% of the total hospital cost. We reanalyzed the above data but restricted the upper age group to children 2 to <5 years (as in the 2006 ACIP recommendations) with similar results.
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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In this 3-year study of children hospitalized for laboratory-confirmed influenza, we demonstrated the substantial burden of influenza measured by hospitalization rates, hospital stay, complications, and total hospital cost. In our study, between 20% and 44% of children seen in the emergency department and who tested positive for influenza were hospitalized. The population-based rates of hospitalization for Salt Lake County residents ranged from 6.3 to 252.7 per 100000 children. If the observed hospitalization rates and cost are extrapolated to the US population20 by using the median total hospital cost and IQR, we estimate that influenza may result in almost 20000 hospitalizations per year in children younger than 18 and median total hospital costs of $55 million (IQR: $37 million–$100 million).
In February 2006, the ACIP voted to expand the recommendation for routine annual vaccination to include all children 24 to 59 months of age.9,10 Our data provide compelling evidence for this policy. We estimate that the new guideline would target 80% of children hospitalized for influenza (Fig 2). Children 2 years or older had lower hospitalization rates than younger children but accounted for a higher absolute number of hospitalizations. For children 
2 years of age, the median LOS and hospital costs were comparable to children 6 to 23 months of age. Children 2 years of age had an increased rate of pneumonia, intensive care stay, and mechanical ventilation and accounted for 55% of the total hospital costs. Forty percent of these children would not be covered by risk-based recommendations.
Incidence of Hospitalization
The incidence of hospitalization because of influenza was highest among children younger than 6 months, and rates decreased with increasing age. When compared with other studies of laboratory-confirmed influenza-associated hospitalization in children, our findings are similar in magnitude but somewhat higher than results of a recent pediatric study in Colorado; 1-year hospitalization rates were 183, 66.3, 28.9, and 6.1 per 100000 in children <6 months, 6 to <23 months, 2 to 4 years, and 5 to 17 years, respectively.21 Adjusting the denominator of published studies to match ours, Iwane et al1 reported slightly lower rates of 170, 50, and 20 per 100000 among children <1 year, 1 year, and 2 to 5 years, respectively, Neuzil et al3 reported higher rates of 300 to 400 per 100000 in children <2 years. Most recently, Grijalva et al22 and Poehling et al23 reported rates of 90 and 240 per 100000 in children <5 years of age, respectively.1,6,22,23 Taken together, these estimates are remarkably consistent, when one considers the confidence intervals and the differences in seasons and methods.
High-Risk Medical Conditions
In our study, 120 (37%) of children hospitalized with influenza had at least 1 high-risk condition. Asthma was the underlying condition for almost half, confirming previous studies emphasizing the burden of influenza on asthmatic children.2,4,7,24 Neurologic, cardiovascular, metabolic, and immunosuppressive disorders occurred in 23%, 21%, 7.5%, and 6.7% of hospitalized children with a high-risk condition, respectively. Our findings lend support to the ACIP recommendation for annual influenza vaccination for children with high-risk conditions, including neurologic disease.5,25 Influenza vaccination rates among asthmatics and other children with a high-risk condition range from 7% to 25% in primary care and medical specialty clinics.26–29 A regional cystic fibrosis center report immunization rates as high as 79%.30 Vaccination of all children 6 to 59 months of age may increase the level of coverage for children at high risk compared with risk-based recommendations.
Complications
In our study, the rates of serious complications in children 2 years of age or older, including respiratory failure, were similar to other studies31–34 We found that the frequency of respiratory failure increased significantly with increasing age. There were only 2 deaths (0.6%) in this cohort, consistent with previous reports on mortality associated with pediatric influenza.35
Hospital Burden of Influenza
There is a paucity of data on total hospital cost and charges associated with influenza hospitalization. During the study period, influenza-associated hospital costs totaled $1990260. The national impact for pediatric hospitalizations attributable to RSV has been estimated at $300 million dollars annually, whereas hospitalizations attributable to parainfluenza infection are estimated to cost $190 million.24,35–38 Extrapolating from our data to the US population, direct costs alone of hospitalizations for influenza in children younger than 18 years of age would total in excess of $55 million.
As in other studies, we observed the highest rates of hospitalization in children younger than 6 months of age. However, the youngest children had the shortest hospitalization, lowest hospital cost, and fewest complications.
Methodologic Considerations in Estimation of Influenza Burden
Important estimates of the burden of influenza have been made using indirect case ascertainment of pediatric influenza hospitalizations by using periods when influenza predominates.2,4,7 In our study for 2 of 3 seasons, influenza overlapped completely with RSV, and in the 2003–2004 season, there was partial overlap. Using published methods would have resulted in substantial overestimation of the true burden of influenza during these years.39 Indeed, the rates reported in studies using indirect methods2,7,39 have generally been higher than in our study and in other studies of laboratory-confirmed influenza.39 However, our study may underestimate the true rate because of selection bias and exclusion criteria.
Strengths and Limitations
A strength our study is that it includes laboratory-proven influenza infection over 3 consecutive seasons. This reduces confounding because of RSV, human metapneumovirus, and other respiratory viruses, and the role of seasonal variation. We could determine item-based cost for each patient, which is a closer estimate of true cost than hospital charges. The population is not limited to Medicaid participants or enrollees in a managed care organization and may be more representative of the broad range of children.
This study has a number of limitations. We do not have accurate data on individual immunization history for the majority of children in our study. However, recent reviews of influenza vaccination among US children, despite the ACIP strong recommendations, suggest low rates of vaccination even among high-risk groups.23,40–42 We believe influenza vaccination rates in Utah were also low, similar to rates reported in other US centers. Younger children were more likely to be tested for influenza because testing was recommended for febrile infants younger than 90 days; therefore, these infants may be over-represented. In addition, because of the requirement for laboratory confirmation of influenza, we may have underestimated the incidence and burden of influenza in older children. However, because viral testing was required for all hospitalized children with respiratory symptoms, we believe ascertainment is reasonably complete. Because only 85% to 90% of pediatric admissions among children in Salt Lake County occur at PCMC, we likely underestimated the true incidence of hospitalization. Referral bias may lead to under-representation of children with milder disease. Not all hospital costs may be attributable solely to influenza, but our analysis was limited to patients with influenza-related hospitalization, and outliers were excluded. Our study does not include indirect medical and nonmedical costs, such as parental work absences, which may overshadow the direct cost of pediatric influenza.43
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CONCLUSIONS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Proven influenza infection in children results in substantial hospital admissions, serious morbidity, extended hospital stays and high costs. Nationwide, these costs may total more than $55 million annually. Forty-six percent of hospitalizations were among children who were not targeted for influenza vaccine until the recently expanded recommendations. These data provide strong support for the expanded use of influenza vaccine in children.
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ACKNOWLEDGMENTS |
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Dr Byington was supported, in part, by National Institute of Child Health and Human Development grant 1 K24 HD047249-01A1. Dr Gesteland was supported, in part, by the PCMC Foundation. Dr Srivastava was supported, in part, by Agency for Healthcare Research and Quality grant P20 HS11826 and by the Children's Health Research Center, University of Utah, and PCMC Foundation.
We thank Brent James, MD, MStat, for thoughtful review of an earlier draft of this manuscript and Alice Dowling, Kris Gerber, Kent Korgenski, Bill Raines, and John Holmen for their help in obtaining data from the EDW.
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FOOTNOTES |
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Accepted Aug 9, 2006.
Address correspondence Krow Ampofo, MB, BS, Division of Pediatric Infectious Disease and Geographic Medicine, University of Utah Health Sciences Center, 30 North 1900 E, Room 2A100, Salt Lake City, UT 84132. E-mail: krow.ampofo{at}hsc.utah.edu
The authors have indicated they have no financial relationship relevant to this article to disclose.
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- Meltzer ML, Neuzil KM, Griffin MR, Fukuda K. An economic analysis of annual influenza vaccination of children. Vaccine. 2005;231004 –1014:
PEDIATRICS (ISSN 1098-4275). ©2006 by the American Academy of Pediatrics
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