Influenza and Other Respiratory Virus–Related Emergency Department Visits Among Young Children
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ABSTRACT
BACKGROUND. Influenza and other winter respiratory viruses cause substantial morbidity among children. Previous estimates of the burden of illness of these viruses have neglected to include the emergency department, where a large number of patients seek acute care for respiratory illnesses. This study provides city- and statewide population estimates of the burden of illness attributable to respiratory viruses for children receiving emergency department–based care for respiratory infections during the winter months.
METHODS. The number of patients 7 years of age presenting to the emergency department of an urban tertiary care pediatric hospital with acute respiratory infections was estimated by using a classifier based on presenting complaints. The rates of specific viral infections in this population were estimated by using the rates of positivity for respiratory syncytial virus, influenza virus, parainfluenza virus, adenovirus, and enterovirus. Local emergency department market share and US Census data enabled determination of the rates of emergency department visits in the Boston, Massachusetts, area and in Massachusetts.
RESULTS. During the 11-year study period, the mean yearly number of patients 7 years of age presenting to the study emergency department during the winter season was 17397. On the basis of the respiratory classifier, the mean number of patients with an acute respiratory infection was 6923, or 398 per 1000 emergency department visits. In the city population, the mean number of emergency department visits for acute respiratory infections was 17906, which is equivalent to 113.9 per 1000 children residing in the city, and in the state population the mean number was 61529, or 94.5 per 1000 children residing in the state. At the state level, 23114 of the visits were for respiratory syncytial virus, 5650 for influenza, 1751 for parainfluenza virus, 2848 for adenovirus, and 798 for enterovirus. For patients 6 to 23 months of age in the state population, there were 19860 emergency department visits for acute respiratory infections, or 168 per 1000 children in this age group, with 6235 visits resulting from respiratory syncytial virus and 2112 resulting from influenza.
CONCLUSION. There is a high incidence of emergency department visits for infectious respiratory illnesses among children. This important component of health care use should be included in estimates of the burden of illness attributable to influenza and other winter respiratory viruses.
Key Words: burden of illness ? influenza ? respiratory syncytial virus ? RSV ? emergency department ? population-based
Abbreviations: ARI—acute respiratory infection ? RSV—respiratory syncytial virus ? PIV—parainfluenza virus ? ED—emergency department ? CHB—Children’s Hospital Boston ? PPV—positive predictive value ? DFA—direct immunofluorescent antibody stain ? CI—confidence interval
Influenza and other viral acute respiratory infections (ARIs) are responsible for substantial morbidity and costly resource use among young children, especially during the winter months.1–5 In the United States, respiratory syncytial virus (RSV) alone infects nearly 100% of children by the age of 3 years and is the principal cause of hospitalization during the first year of life.6 Parainfluenza virus (PIV), another common cause of childhood ARIs, has been estimated to result in >65000 hospitalizations among children every year in the United States, and influenza virus infections are associated with an estimated 25000 hospitalizations among young children annually.5,7 Yearly influenza-infection rates have been estimated to exceed 40% among preschool-aged children and 30% among schoolchildren, who represent the major source of household introduction and community spread of influenza virus.4,8–10 There has been recent evidence of increasing morbidity due to both RSV and influenza infections among patients of all age groups.3,11,12
Estimating the annual disease burden resulting from respiratory viruses is important for the development and assessment of prevention efforts and for resource planning by health care facilities.13–15 Influenza-immunization recommendations were recently extended to include all children 6 to 23 months of age on the basis of findings demonstrating high rates of morbidity among those in this age group.16 Efforts are underway to develop vaccines for RSV and PIV, and a new agent (more potent than palivizumab) is in development for RSV prophylaxis.17–19 To assess the cost-effectiveness of interventions, accurate estimates of the disease burden attributable to specific viruses are paramount.
Several studies have examined rates of hospitalizations and outpatient clinic visits by children resulting from RSV, influenza, and PIV.1,2,7,20,21 However, these studies have not included health care use in the emergency department (ED) setting, where many patients seek acute care for ARIs. EDs represent a vital component in the assessment of disease burden and health care use for ARIs. In this study, we take advantage of a viral test data set as well as unique hospital market-share data to estimate the city- and statewide burden of illness attributable to respiratory viruses for children who receive ED-based care for ARIs during the winter months.
METHODS
Study Design and Participants
Using a population-based study design, we estimated the rate of ED visits for ARIs among children in the Boston, Massachusetts, area and in Massachusetts. The study was conducted in the ED of Children’s Hospital Boston (CHB), a large pediatric teaching hospital. The study population was comprised of patients 7 years of age who were seen in the CHB ED every year between November 1 and April 30 during the 11-year period from 1993–2004. These months were chosen on the basis of the peak activity of winter respiratory viruses.1,2,22 Two overlapping patient groups were selected. The first group included all children 7 years of age who presented to the ED with a complaint related to an ARI. The second group included all children 7 years of age who had viral testing performed as part of their routine clinical care. Registry data from the Massachusetts Division of Healthcare Finance and Policy were used to determine population rates of visits for ARIs at the city and state levels. Statewide ED and 2000 US Census data were used to calculate population-based rates of ED visits for ARIs.
The viral tests collected during routine care were not from a systematically selected population and therefore were validated against the viral test results of prospectively recruited patients with ARIs from whom a nasopharyngeal aspirate was collected. This was done to ensure that the viral distribution among patients receiving routine testing was representative of the distribution among children with a known ARI (on the basis of predetermined criteria). A total of 361 patients with ARIs were enrolled between December 7, 2003, and June 19, 2004, and nasopharyngeal aspirates were obtained. A strong correlation was found between the test results from these specimens and those routinely collected on patients during the same time period, with a Spearman correlation coefficient of 0.863 (P < .001). This indicated that the results from viral tests obtained during routine clinical care are an appropriate representation of the rates of infection with specific viruses among children with ARIs and supported the use of the routine viral data in the analysis. Table 1 summarizes the data sources used in the study.
Estimation of the Incidence of ARIs Using a Respiratory Illness Classifier
Patient visits related to ARIs were identified on the basis of presenting complaints, which are elicited routinely from all patients or parents on presentation to the CHB ED and recorded by triage nurses. This free-text description is subsequently numerically encoded using a constrained list of 181 possible codes. Seventeen of these describe respiratory complaints related to ARIs and were combined to create a respiratory classifier. Using this classifier, we identified all patients 7 years of age presenting to the CHB ED with an ARI every year between November and April during the 11-year study period.
We were careful to validate this respiratory classifier, because not every patient describing a respiratory problem in triage is correctly assigned a respiratory complaint, nor is the assignment of a respiratory complaint always indicative of an ARI. Therefore, a sample of patients 7 years of age presenting to the CHB was prospectively enrolled between December 1, 2003, and April 30, 2004, and used to determine the sensitivity and positive predictive value (PPV) of the respiratory classifier. Patients in the validation group were carefully screened for the presence of an ARI, and their assigned complaint code was examined. An ARI was defined as the presence of at least 2 of the following symptoms: fever, cough, sneezing, sore throat, runny nose, and congestion.
Using the sensitivity and PPV of the respiratory classifier, we calculated a corrected proportion of CHB ED visits for ARIs. This estimation was performed by multiplying the proportion of subjects identified using the respiratory classifier by a correction factor calculated as the ratio of the PPV to the sensitivity. This corrected proportion was multiplied with the mean yearly number of patients treated in the CHB ED to yield an overall mean yearly incidence of CHB ED visits for ARIs for all patients 7 years. Following the same procedure, yearly age-specific rates for patients 0 to 5 months, 6 to 23 months, 2 to 4 years, and 5 to 7 years of age were calculated.
Estimation of Virus-Specific ARI Incidence
Viral tests collected during routine clinical care from patients 7 years of age treated in the CHB ED during the study period were identified. Tests were performed to detect RSV, influenza A and B viruses, PIV types 1 through 3, adenovirus, and enterovirus. Testing consisted of direct immunofluorescent antibody stains (DFAs) and viral culture. DFA assays used pooled antibodies for RSV, influenza virus, PIV, and adenovirus (SimulFluor Respiratory Screen, Light Diagnostics, Chemicon International, Temecula, CA) or single virus-specific antibodies (Imagen influenza virus A and B, DakoCytomation, Carpinteria, CA; Bartels RSV DFA kit, Trinity Biotech, Carlsbad, CA; ViraStat parainfluenza test, ZymeTx, Inc, Oklahoma City, OK; adenovirus antibody fluorescein isothiocyanate reagent, Light Diagnostics, Chemicon International). Viral cultures were performed by using RMK, Hep-2, MRC-5, and Hel cells. Cultures with a cytopathic effect or hemagglutination were stained with immunofluorescent antibodies for identification of RSV, influenza, PIV, or adenovirus. Enterovirus was identified by viral passage and characteristic cytopathic effect. Results for influenza A and B viruses were grouped, as were results for PIV types 1 through 3. If a test was positive for >1 virus, all viruses identified were included in the analysis.
Using these test results, the mean yearly proportion of positive test results for specific viruses was determined. The incidence of CHB ED visits associated with ARIs caused by a specific virus was calculated by multiplying the estimated mean yearly proportion of virus-specific ARIs with the incidence of CHB ED visits for ARIs.
Estimation of Population-Based Rates of ARIs
The proportion of CHB ED visits among Boston and Massachusetts ED visits (market share of the CHB ED in the Boston area and Massachusetts) was determined to estimate the incidence of ED visits for ARIs among Boston and Massachusetts EDs. The Boston area was defined as the area within Interstates 93 and 95, which encircle the city, encompassing the urban area and most of the surrounding suburbs. Registry data were obtained from the Massachusetts Division of Healthcare Finance and Policy on patient volume to the 19 EDs in Boston and 71 EDs in Massachusetts during the time period from July 1, 2002, to June 30, 2003.23 Because the proportion of children seeking treatment at a tertiary care children’s hospital may vary depending on the child’s age, information on ED visits were obtained for all patients 7 years of age in addition to age-specific subgroups. Using these data we determined the overall and age-specific market shares of the CHB ED. The estimated market shares were used to calculate the mean yearly rates of Boston and Massachusetts ED visits attributable to ARIs by dividing the incidence of CHB ED visits for ARIs by the overall and age-specific market share for the Boston area and Massachusetts. Data from the 2000 US Census were used to calculate population-based rates of ED visits per 1000 children at the city and state levels.24
Statistical Analysis
Variances for 95% confidence intervals (CIs) were estimated on the basis of the method and conditional probability rules. The method was used to estimate variances of products or other transformations of the original proportions or means.25 All calculations were performed in S-plus 6.2 (Insightful, Seattle, WA) with user-developed code.
Estimation of the Incidence of ARIs
We assumed that PPV and sensitivity, as well as the yearly proportion of CHB ED visits for ARIs, were constant over the 11-year study period. Using the method, we obtained the variance of the logarithm of the proportion of CHB ED visits for ARIs. To estimate the variance of the incidence of CHB ED visits for ARIs, we assumed that the conditional distribution of the incidence of CHB ED visits for ARIs was binomially distributed, that the estimated proportion of ED visits for ARIs was normally distributed, and that the estimated number of patients treated in the ED was normally distributed and represented the rate from an overdispersed Poisson distribution. Estimation for age-specific rates followed the same procedure.
Estimation of Virus-Specific ARI Incidence
Variances for the incidences were based on a binomial variance, given the estimated virus-specific proportion of ARIs, the conditional incidence of CHB ED visits for ARIs, the estimated proportion of CHB ED visits for ARIs, and the estimated incidence of CHB ED visits per year.
Estimation of Population-Based Rates of ARIs
Variances were estimated assuming that the conditional mean incidences of Boston and Massachusetts ED visits for ARIs were distributed according to a negative binomial.
To estimate rates per 1000 children, we divided the mean incidence of Boston and Massachusetts ED visits for ARIs by the overall and age-specific census population in each of these regions.
RESULTS
Incidence of CHB ED Visits for ARIs
During the 11-year study period, the mean yearly number of children 7 years of age treated in the CHB ED between November 1 and April 30 was 17397 (95% CI: 16 941–17 853). Among these, the mean yearly number presenting with an ARI was 8001 (95% CI: 7872–8130). The sensitivity of the respiratory illness classifier was 94% (95% CI: 90%–98%), and the PPV was 82% (95% CI: 75%–88%). As shown in Table 2, on the basis of these values, the adjusted mean yearly incidence of patients with an ARI was 6923 (95% CI: 6331–7515), which is equivalent to 398 per 1000 ED visits (95% CI: 366–429).
Incidence of CHB ED Visits for Virus-Specific ARIs
During the study period, a total of 4198 tests were performed for RSV, 1579 for influenza, 4181 for PIV, 1426 for adenovirus, and 1311 for enterovirus. The mean yearly rates of positive test results were 37.6% for RSV, 9.2% for influenza, 2.8% for PIV, 4.6% for adenovirus, and 1.3% for enterovirus. On the basis of the incidence of ARI visits, the mean yearly rates of visits to the ED per 1000 visits were 149 for RSV, 37 for influenza, 11 for PIV, 18 for adenovirus, and 5 for enterovirus (Table 2).
Population-Based Rates of ED Visits for ARIs
Among Boston EDs, the proportion of visits to the CHB ED (Boston market share) was 38.7% (95% CI: 38.3–39.0) and among Massachusetts EDs (Massachusetts market share) was 11.2% (95% CI: 11.1–11.4). Table 3 shows the mean yearly incidence of ED visits for all ARIs and for virus-specific ARIs. There were 17906 (95% CI: 16331–19481) visits for ARIs to Boston EDs and 61529 (95% CI: 56052–67006) to Massachusetts EDs. On a population basis, this represents 114 ED visits per 1000 children residing in the Boston area and 94 visits per 1000 children in Massachusetts for ARIs. Infections with RSV and influenza accounted for the largest number of visits, with 36 and 9 visits, respectively, per 1000 children at the state level.
Age-Specific Rates of ED Visits for ARIs
We determined the age-specific rates of positive viral test results and the incidence of ED visits for ARIs among children 0 to 5 months, 6 to 23 months, 2 to 4 years, and 5 to 7 years of age (Tables 4–7).Viral test results for RSV were most frequently positive among children <6 months old and accounted for nearly half of all viral infections identified. In contrast, the rates of positive influenza test results were lowest for this age group and ranged from 10.6% to 12.0% for the other 3 groups. Parainfluenza had similar rates of test positivity for all age groups, ranging from 2.6% to 3.4%. Test results for adenovirus were highest for the 2- to 4-year-old group at 8.2%, whereas enterovirus was most prevalent among the youngest children with a rate of 2.3%.
In the statewide population, the mean yearly rates of ED visits per 1000 children for ARIs were 289 for children aged 0 to 5 months, 168 for children aged 6 to 23 months, 83 for children aged 2 to 4 years, and 40 for children 5 to 7 years. Children 0 to 5 months of age had, by far, the most ED visits for RSV with 144 visits per 1000 children. Influenza resulted in the greatest number of ED visits among children 6 to 23 months of age, with 18 visits per 1000 children, whereas visits for parainfluenza were most prevalent among children 0 to 5 months of age, with 8 visits per 1000 children. ED visits for ARIs resulting from adenovirus occurred at similar frequencies in the younger age groups, with 6 to 8 visits per 1000 children before declining among children 5 to 7 years of age. Enterovirus was most prevalent among children in the youngest age group, with 7 visits per 1000 children.
DISCUSSION
This study is the first to use population-based rates to assess the impact of winter respiratory infections on rates of ED visits by infants and young children. We found ED-visit rates of 113.9 and 94.5 per 1000 children during the winter months, with the highest rates among children 0 to 5 months of age, who had the highest rate of visits for infections with RSV. Compared with other age groups, children in the 6- to 23-month age group had the highest rates of ED visits for influenza-related illnesses, supporting the recent recommendations by the Advisory Committee on Immunization Practices to administer the influenza vaccine to children of this age.
Our findings represent an important contribution to the measurement of the disease burden of respiratory viruses among children. Although several studies have assessed the effect of respiratory viruses on hospitalizations and outpatient visits, none have closely examined the impact on the ED, where many parents seek acute care for their children, especially during evening and weekend hours. ED utilization is a critical component of health care use resulting from respiratory viruses and must be measured to achieve accurate estimates of the disease burden of these viruses. In this study, we used laboratory test results from an ED population over an 11-year time period to estimate rates of visits resulting from infections with RSV, influenza virus, PIV, adenovirus, and enterovirus. A common method is to use codes as a proxy for laboratory-confirmed illness.1,2,21,26 The use of viral test results enabled us to avoid the misclassification that is associated with this method. In addition, we were able to directly examine the effects of several different viruses, thereby avoiding the problem of separating the overlapping effects of multiple viruses on winter respiratory illnesses.
Although retrospective data were used, we verified its accuracy with a prospectively enrolled patient group. First, the use of complaint codes to identify patients with ARIs was validated by screening the prospective patient group for ARIs and examining the accuracy of the complaint code assigned to them. We found the assigned complaint codes to have a high sensitivity and PPV and made adjustments to the number of ARI-related visits identified using our findings. Second, the laboratory test results were verified to ensure that these results were representative of the viral distribution among children with ARIs, which was done by comparing the results from the routinely collected specimens to the results from specimens collected from patients prospectively screened for ARIs. A very close correlation was found between these 2 sets of results, validating our use of the routinely collected specimens to determine rates of infections with specific viruses among patients with ARIs.
Studies in which rates of hospitalizations and outpatient visits by pediatric populations were examined have found a high burden of illness from respiratory viruses, especially among young children.1,2,7,20,21,27 Influenza virus has been studied most extensively, with estimates of annual hospitalization rates for healthy children <5 years of age ranging from 0.9 to 10.4 per 1000.1,2,20,21,26,27 Overall hospitalization rates for children with acute respiratory illnesses were examined in 1 study; it was found that 18 per 1000 children <5 years of age were admitted annually.20
Outpatient visits for influenza illnesses are similarly high in children <5 years of age, who have visit rates of 80 to 150 per 1000 children annually, with the highest rates among children <3 years of age.1,21,28 In our study, ED-visit rates for influenza ranged from 10 to 18 per 1000 children, with the highest rates in children <2 years of age. These findings are consistent with the outpatient estimates and indicate that for approximately every 10 children seen in the outpatient setting, 1 child is evaluated in the ED.
ED-visit rates for influenza illnesses were examined in a study conducted in Canada among children 0 to 14 years of age.29 On the basis of diagnostic codes, the authors found that the ED-visit rate for influenza and pneumonia was 3.9 per 1000 children and for all acute respiratory diseases likely related to influenza was 16.3 per 1000 children. These rates are similar to the visit rate for influenza illness of 8.7 per 1000 among children 7 years of age in this study, although a different age group and definition for influenza illness were used.
Accurate estimates of the disease burden of specific respiratory viruses are needed to direct vaccine-research efforts, identify targets for prevention, and evaluate the cost-effectiveness of immunization policies. Currently, vaccines and antiviral agents are available only for influenza virus, although progress is being made toward developing vaccines for RSV and PIV, as well as improved prophylactic agents for RSV.17–19 In addition, a live-attenuated intranasal influenza vaccine was recently licensed and used for the first time in the United States during the 2003–2004 influenza season. To evaluate the efficacy of these new agents, as well as allocate funding for future research and guide public health policy, accurate age-specific baseline rates of the disease burden of specific viruses are essential. The ED utilization resulting from respiratory infections is a key component in the health care use related to respiratory viruses that, to date, has been neglected. Our findings indicate that there are high rates of ED visits for respiratory infections, and these must be taken into account when evaluating the impact and cost-effectiveness of prevention strategies.
Our study did have some limitations. First, it is a retrospective study. Second, many of the figures are extrapolated from a single ED, and the number and characteristics of patients presenting with respiratory problems at other EDs may be different. The study ED, a tertiary care site that may have a more heavily referral-based population, may not be entirely representative. Also, the market-share data are only available from 2002–2003, and there may have been some shifts in market share over the study period. Finally, we did not include all possible viruses that cause respiratory infections, such as rhinovirus or human metapneumovirus, and there may also be additional, still-undiscovered agents that were not accounted for in this analysis. Therefore, it is possible that some of the subjects had concomitant infections with other agents. ED utilization by children with respiratory infections represents an important component of the health care utilization attributable to viral respiratory infections. The impact of respiratory viruses on this type of health care use must be included in measurements of the disease burden of respiratory viruses and assessments of the efficacy of vaccination policies. Future studies are needed to more closely define the impact of specific viruses and the cost associated with respiratory illness–related ED visits.
ACKNOWLEDGMENTS
This work was supported by grant MO1 RR-02172 from the General Clinical Research Center at Children’s Hospital Boston, contract 290-00-0020 from the Agency for Healthcare Research and Quality; grant R01LM007970-01 from the National Library of Medicine, National Institutes of Health; and National Research Service Awards 5 T32 HD40128-03 and 5 T32 HD40128-04.
We thank Jennifer Woo, BS, Hector Rivera, BS, Sara Ivey, BS, MPH, and Gordon Tam, BS, for assistance in data collection and processing; James West, PhD, for compilation of the registry data from the Massachusetts Division of Healthcare Finance and Policy; David Wypij, PhD, for suggestions on data analysis; Don Goldman for guidance and expertise in infectious diseases; Karen Olson for developing and managing the data sets; and John Brownstein for analytic insights.
FOOTNOTES
The authors have indicated they have no financial relationships relevant to this article to disclose.
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a Division of Emergency Medicine
c Clinical Research Program
e Department of Laboratory Medicine
f Children’s Hospital Informatics Program at the Harvard-MIT Division of Health Sciences and Technology, Children’s Hospital Boston, Boston, Massachusetts
b Department of Pediatrics, Harvard Medical School, Boston, Massachusetts
d Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts(Florence T. Bourgeois, MD)
BACKGROUND. Influenza and other winter respiratory viruses cause substantial morbidity among children. Previous estimates of the burden of illness of these viruses have neglected to include the emergency department, where a large number of patients seek acute care for respiratory illnesses. This study provides city- and statewide population estimates of the burden of illness attributable to respiratory viruses for children receiving emergency department–based care for respiratory infections during the winter months.
METHODS. The number of patients 7 years of age presenting to the emergency department of an urban tertiary care pediatric hospital with acute respiratory infections was estimated by using a classifier based on presenting complaints. The rates of specific viral infections in this population were estimated by using the rates of positivity for respiratory syncytial virus, influenza virus, parainfluenza virus, adenovirus, and enterovirus. Local emergency department market share and US Census data enabled determination of the rates of emergency department visits in the Boston, Massachusetts, area and in Massachusetts.
RESULTS. During the 11-year study period, the mean yearly number of patients 7 years of age presenting to the study emergency department during the winter season was 17397. On the basis of the respiratory classifier, the mean number of patients with an acute respiratory infection was 6923, or 398 per 1000 emergency department visits. In the city population, the mean number of emergency department visits for acute respiratory infections was 17906, which is equivalent to 113.9 per 1000 children residing in the city, and in the state population the mean number was 61529, or 94.5 per 1000 children residing in the state. At the state level, 23114 of the visits were for respiratory syncytial virus, 5650 for influenza, 1751 for parainfluenza virus, 2848 for adenovirus, and 798 for enterovirus. For patients 6 to 23 months of age in the state population, there were 19860 emergency department visits for acute respiratory infections, or 168 per 1000 children in this age group, with 6235 visits resulting from respiratory syncytial virus and 2112 resulting from influenza.
CONCLUSION. There is a high incidence of emergency department visits for infectious respiratory illnesses among children. This important component of health care use should be included in estimates of the burden of illness attributable to influenza and other winter respiratory viruses.
Key Words: burden of illness ? influenza ? respiratory syncytial virus ? RSV ? emergency department ? population-based
Abbreviations: ARI—acute respiratory infection ? RSV—respiratory syncytial virus ? PIV—parainfluenza virus ? ED—emergency department ? CHB—Children’s Hospital Boston ? PPV—positive predictive value ? DFA—direct immunofluorescent antibody stain ? CI—confidence interval
Influenza and other viral acute respiratory infections (ARIs) are responsible for substantial morbidity and costly resource use among young children, especially during the winter months.1–5 In the United States, respiratory syncytial virus (RSV) alone infects nearly 100% of children by the age of 3 years and is the principal cause of hospitalization during the first year of life.6 Parainfluenza virus (PIV), another common cause of childhood ARIs, has been estimated to result in >65000 hospitalizations among children every year in the United States, and influenza virus infections are associated with an estimated 25000 hospitalizations among young children annually.5,7 Yearly influenza-infection rates have been estimated to exceed 40% among preschool-aged children and 30% among schoolchildren, who represent the major source of household introduction and community spread of influenza virus.4,8–10 There has been recent evidence of increasing morbidity due to both RSV and influenza infections among patients of all age groups.3,11,12
Estimating the annual disease burden resulting from respiratory viruses is important for the development and assessment of prevention efforts and for resource planning by health care facilities.13–15 Influenza-immunization recommendations were recently extended to include all children 6 to 23 months of age on the basis of findings demonstrating high rates of morbidity among those in this age group.16 Efforts are underway to develop vaccines for RSV and PIV, and a new agent (more potent than palivizumab) is in development for RSV prophylaxis.17–19 To assess the cost-effectiveness of interventions, accurate estimates of the disease burden attributable to specific viruses are paramount.
Several studies have examined rates of hospitalizations and outpatient clinic visits by children resulting from RSV, influenza, and PIV.1,2,7,20,21 However, these studies have not included health care use in the emergency department (ED) setting, where many patients seek acute care for ARIs. EDs represent a vital component in the assessment of disease burden and health care use for ARIs. In this study, we take advantage of a viral test data set as well as unique hospital market-share data to estimate the city- and statewide burden of illness attributable to respiratory viruses for children who receive ED-based care for ARIs during the winter months.
METHODS
Study Design and Participants
Using a population-based study design, we estimated the rate of ED visits for ARIs among children in the Boston, Massachusetts, area and in Massachusetts. The study was conducted in the ED of Children’s Hospital Boston (CHB), a large pediatric teaching hospital. The study population was comprised of patients 7 years of age who were seen in the CHB ED every year between November 1 and April 30 during the 11-year period from 1993–2004. These months were chosen on the basis of the peak activity of winter respiratory viruses.1,2,22 Two overlapping patient groups were selected. The first group included all children 7 years of age who presented to the ED with a complaint related to an ARI. The second group included all children 7 years of age who had viral testing performed as part of their routine clinical care. Registry data from the Massachusetts Division of Healthcare Finance and Policy were used to determine population rates of visits for ARIs at the city and state levels. Statewide ED and 2000 US Census data were used to calculate population-based rates of ED visits for ARIs.
The viral tests collected during routine care were not from a systematically selected population and therefore were validated against the viral test results of prospectively recruited patients with ARIs from whom a nasopharyngeal aspirate was collected. This was done to ensure that the viral distribution among patients receiving routine testing was representative of the distribution among children with a known ARI (on the basis of predetermined criteria). A total of 361 patients with ARIs were enrolled between December 7, 2003, and June 19, 2004, and nasopharyngeal aspirates were obtained. A strong correlation was found between the test results from these specimens and those routinely collected on patients during the same time period, with a Spearman correlation coefficient of 0.863 (P < .001). This indicated that the results from viral tests obtained during routine clinical care are an appropriate representation of the rates of infection with specific viruses among children with ARIs and supported the use of the routine viral data in the analysis. Table 1 summarizes the data sources used in the study.
Estimation of the Incidence of ARIs Using a Respiratory Illness Classifier
Patient visits related to ARIs were identified on the basis of presenting complaints, which are elicited routinely from all patients or parents on presentation to the CHB ED and recorded by triage nurses. This free-text description is subsequently numerically encoded using a constrained list of 181 possible codes. Seventeen of these describe respiratory complaints related to ARIs and were combined to create a respiratory classifier. Using this classifier, we identified all patients 7 years of age presenting to the CHB ED with an ARI every year between November and April during the 11-year study period.
We were careful to validate this respiratory classifier, because not every patient describing a respiratory problem in triage is correctly assigned a respiratory complaint, nor is the assignment of a respiratory complaint always indicative of an ARI. Therefore, a sample of patients 7 years of age presenting to the CHB was prospectively enrolled between December 1, 2003, and April 30, 2004, and used to determine the sensitivity and positive predictive value (PPV) of the respiratory classifier. Patients in the validation group were carefully screened for the presence of an ARI, and their assigned complaint code was examined. An ARI was defined as the presence of at least 2 of the following symptoms: fever, cough, sneezing, sore throat, runny nose, and congestion.
Using the sensitivity and PPV of the respiratory classifier, we calculated a corrected proportion of CHB ED visits for ARIs. This estimation was performed by multiplying the proportion of subjects identified using the respiratory classifier by a correction factor calculated as the ratio of the PPV to the sensitivity. This corrected proportion was multiplied with the mean yearly number of patients treated in the CHB ED to yield an overall mean yearly incidence of CHB ED visits for ARIs for all patients 7 years. Following the same procedure, yearly age-specific rates for patients 0 to 5 months, 6 to 23 months, 2 to 4 years, and 5 to 7 years of age were calculated.
Estimation of Virus-Specific ARI Incidence
Viral tests collected during routine clinical care from patients 7 years of age treated in the CHB ED during the study period were identified. Tests were performed to detect RSV, influenza A and B viruses, PIV types 1 through 3, adenovirus, and enterovirus. Testing consisted of direct immunofluorescent antibody stains (DFAs) and viral culture. DFA assays used pooled antibodies for RSV, influenza virus, PIV, and adenovirus (SimulFluor Respiratory Screen, Light Diagnostics, Chemicon International, Temecula, CA) or single virus-specific antibodies (Imagen influenza virus A and B, DakoCytomation, Carpinteria, CA; Bartels RSV DFA kit, Trinity Biotech, Carlsbad, CA; ViraStat parainfluenza test, ZymeTx, Inc, Oklahoma City, OK; adenovirus antibody fluorescein isothiocyanate reagent, Light Diagnostics, Chemicon International). Viral cultures were performed by using RMK, Hep-2, MRC-5, and Hel cells. Cultures with a cytopathic effect or hemagglutination were stained with immunofluorescent antibodies for identification of RSV, influenza, PIV, or adenovirus. Enterovirus was identified by viral passage and characteristic cytopathic effect. Results for influenza A and B viruses were grouped, as were results for PIV types 1 through 3. If a test was positive for >1 virus, all viruses identified were included in the analysis.
Using these test results, the mean yearly proportion of positive test results for specific viruses was determined. The incidence of CHB ED visits associated with ARIs caused by a specific virus was calculated by multiplying the estimated mean yearly proportion of virus-specific ARIs with the incidence of CHB ED visits for ARIs.
Estimation of Population-Based Rates of ARIs
The proportion of CHB ED visits among Boston and Massachusetts ED visits (market share of the CHB ED in the Boston area and Massachusetts) was determined to estimate the incidence of ED visits for ARIs among Boston and Massachusetts EDs. The Boston area was defined as the area within Interstates 93 and 95, which encircle the city, encompassing the urban area and most of the surrounding suburbs. Registry data were obtained from the Massachusetts Division of Healthcare Finance and Policy on patient volume to the 19 EDs in Boston and 71 EDs in Massachusetts during the time period from July 1, 2002, to June 30, 2003.23 Because the proportion of children seeking treatment at a tertiary care children’s hospital may vary depending on the child’s age, information on ED visits were obtained for all patients 7 years of age in addition to age-specific subgroups. Using these data we determined the overall and age-specific market shares of the CHB ED. The estimated market shares were used to calculate the mean yearly rates of Boston and Massachusetts ED visits attributable to ARIs by dividing the incidence of CHB ED visits for ARIs by the overall and age-specific market share for the Boston area and Massachusetts. Data from the 2000 US Census were used to calculate population-based rates of ED visits per 1000 children at the city and state levels.24
Statistical Analysis
Variances for 95% confidence intervals (CIs) were estimated on the basis of the method and conditional probability rules. The method was used to estimate variances of products or other transformations of the original proportions or means.25 All calculations were performed in S-plus 6.2 (Insightful, Seattle, WA) with user-developed code.
Estimation of the Incidence of ARIs
We assumed that PPV and sensitivity, as well as the yearly proportion of CHB ED visits for ARIs, were constant over the 11-year study period. Using the method, we obtained the variance of the logarithm of the proportion of CHB ED visits for ARIs. To estimate the variance of the incidence of CHB ED visits for ARIs, we assumed that the conditional distribution of the incidence of CHB ED visits for ARIs was binomially distributed, that the estimated proportion of ED visits for ARIs was normally distributed, and that the estimated number of patients treated in the ED was normally distributed and represented the rate from an overdispersed Poisson distribution. Estimation for age-specific rates followed the same procedure.
Estimation of Virus-Specific ARI Incidence
Variances for the incidences were based on a binomial variance, given the estimated virus-specific proportion of ARIs, the conditional incidence of CHB ED visits for ARIs, the estimated proportion of CHB ED visits for ARIs, and the estimated incidence of CHB ED visits per year.
Estimation of Population-Based Rates of ARIs
Variances were estimated assuming that the conditional mean incidences of Boston and Massachusetts ED visits for ARIs were distributed according to a negative binomial.
To estimate rates per 1000 children, we divided the mean incidence of Boston and Massachusetts ED visits for ARIs by the overall and age-specific census population in each of these regions.
RESULTS
Incidence of CHB ED Visits for ARIs
During the 11-year study period, the mean yearly number of children 7 years of age treated in the CHB ED between November 1 and April 30 was 17397 (95% CI: 16 941–17 853). Among these, the mean yearly number presenting with an ARI was 8001 (95% CI: 7872–8130). The sensitivity of the respiratory illness classifier was 94% (95% CI: 90%–98%), and the PPV was 82% (95% CI: 75%–88%). As shown in Table 2, on the basis of these values, the adjusted mean yearly incidence of patients with an ARI was 6923 (95% CI: 6331–7515), which is equivalent to 398 per 1000 ED visits (95% CI: 366–429).
Incidence of CHB ED Visits for Virus-Specific ARIs
During the study period, a total of 4198 tests were performed for RSV, 1579 for influenza, 4181 for PIV, 1426 for adenovirus, and 1311 for enterovirus. The mean yearly rates of positive test results were 37.6% for RSV, 9.2% for influenza, 2.8% for PIV, 4.6% for adenovirus, and 1.3% for enterovirus. On the basis of the incidence of ARI visits, the mean yearly rates of visits to the ED per 1000 visits were 149 for RSV, 37 for influenza, 11 for PIV, 18 for adenovirus, and 5 for enterovirus (Table 2).
Population-Based Rates of ED Visits for ARIs
Among Boston EDs, the proportion of visits to the CHB ED (Boston market share) was 38.7% (95% CI: 38.3–39.0) and among Massachusetts EDs (Massachusetts market share) was 11.2% (95% CI: 11.1–11.4). Table 3 shows the mean yearly incidence of ED visits for all ARIs and for virus-specific ARIs. There were 17906 (95% CI: 16331–19481) visits for ARIs to Boston EDs and 61529 (95% CI: 56052–67006) to Massachusetts EDs. On a population basis, this represents 114 ED visits per 1000 children residing in the Boston area and 94 visits per 1000 children in Massachusetts for ARIs. Infections with RSV and influenza accounted for the largest number of visits, with 36 and 9 visits, respectively, per 1000 children at the state level.
Age-Specific Rates of ED Visits for ARIs
We determined the age-specific rates of positive viral test results and the incidence of ED visits for ARIs among children 0 to 5 months, 6 to 23 months, 2 to 4 years, and 5 to 7 years of age (Tables 4–7).Viral test results for RSV were most frequently positive among children <6 months old and accounted for nearly half of all viral infections identified. In contrast, the rates of positive influenza test results were lowest for this age group and ranged from 10.6% to 12.0% for the other 3 groups. Parainfluenza had similar rates of test positivity for all age groups, ranging from 2.6% to 3.4%. Test results for adenovirus were highest for the 2- to 4-year-old group at 8.2%, whereas enterovirus was most prevalent among the youngest children with a rate of 2.3%.
In the statewide population, the mean yearly rates of ED visits per 1000 children for ARIs were 289 for children aged 0 to 5 months, 168 for children aged 6 to 23 months, 83 for children aged 2 to 4 years, and 40 for children 5 to 7 years. Children 0 to 5 months of age had, by far, the most ED visits for RSV with 144 visits per 1000 children. Influenza resulted in the greatest number of ED visits among children 6 to 23 months of age, with 18 visits per 1000 children, whereas visits for parainfluenza were most prevalent among children 0 to 5 months of age, with 8 visits per 1000 children. ED visits for ARIs resulting from adenovirus occurred at similar frequencies in the younger age groups, with 6 to 8 visits per 1000 children before declining among children 5 to 7 years of age. Enterovirus was most prevalent among children in the youngest age group, with 7 visits per 1000 children.
DISCUSSION
This study is the first to use population-based rates to assess the impact of winter respiratory infections on rates of ED visits by infants and young children. We found ED-visit rates of 113.9 and 94.5 per 1000 children during the winter months, with the highest rates among children 0 to 5 months of age, who had the highest rate of visits for infections with RSV. Compared with other age groups, children in the 6- to 23-month age group had the highest rates of ED visits for influenza-related illnesses, supporting the recent recommendations by the Advisory Committee on Immunization Practices to administer the influenza vaccine to children of this age.
Our findings represent an important contribution to the measurement of the disease burden of respiratory viruses among children. Although several studies have assessed the effect of respiratory viruses on hospitalizations and outpatient visits, none have closely examined the impact on the ED, where many parents seek acute care for their children, especially during evening and weekend hours. ED utilization is a critical component of health care use resulting from respiratory viruses and must be measured to achieve accurate estimates of the disease burden of these viruses. In this study, we used laboratory test results from an ED population over an 11-year time period to estimate rates of visits resulting from infections with RSV, influenza virus, PIV, adenovirus, and enterovirus. A common method is to use codes as a proxy for laboratory-confirmed illness.1,2,21,26 The use of viral test results enabled us to avoid the misclassification that is associated with this method. In addition, we were able to directly examine the effects of several different viruses, thereby avoiding the problem of separating the overlapping effects of multiple viruses on winter respiratory illnesses.
Although retrospective data were used, we verified its accuracy with a prospectively enrolled patient group. First, the use of complaint codes to identify patients with ARIs was validated by screening the prospective patient group for ARIs and examining the accuracy of the complaint code assigned to them. We found the assigned complaint codes to have a high sensitivity and PPV and made adjustments to the number of ARI-related visits identified using our findings. Second, the laboratory test results were verified to ensure that these results were representative of the viral distribution among children with ARIs, which was done by comparing the results from the routinely collected specimens to the results from specimens collected from patients prospectively screened for ARIs. A very close correlation was found between these 2 sets of results, validating our use of the routinely collected specimens to determine rates of infections with specific viruses among patients with ARIs.
Studies in which rates of hospitalizations and outpatient visits by pediatric populations were examined have found a high burden of illness from respiratory viruses, especially among young children.1,2,7,20,21,27 Influenza virus has been studied most extensively, with estimates of annual hospitalization rates for healthy children <5 years of age ranging from 0.9 to 10.4 per 1000.1,2,20,21,26,27 Overall hospitalization rates for children with acute respiratory illnesses were examined in 1 study; it was found that 18 per 1000 children <5 years of age were admitted annually.20
Outpatient visits for influenza illnesses are similarly high in children <5 years of age, who have visit rates of 80 to 150 per 1000 children annually, with the highest rates among children <3 years of age.1,21,28 In our study, ED-visit rates for influenza ranged from 10 to 18 per 1000 children, with the highest rates in children <2 years of age. These findings are consistent with the outpatient estimates and indicate that for approximately every 10 children seen in the outpatient setting, 1 child is evaluated in the ED.
ED-visit rates for influenza illnesses were examined in a study conducted in Canada among children 0 to 14 years of age.29 On the basis of diagnostic codes, the authors found that the ED-visit rate for influenza and pneumonia was 3.9 per 1000 children and for all acute respiratory diseases likely related to influenza was 16.3 per 1000 children. These rates are similar to the visit rate for influenza illness of 8.7 per 1000 among children 7 years of age in this study, although a different age group and definition for influenza illness were used.
Accurate estimates of the disease burden of specific respiratory viruses are needed to direct vaccine-research efforts, identify targets for prevention, and evaluate the cost-effectiveness of immunization policies. Currently, vaccines and antiviral agents are available only for influenza virus, although progress is being made toward developing vaccines for RSV and PIV, as well as improved prophylactic agents for RSV.17–19 In addition, a live-attenuated intranasal influenza vaccine was recently licensed and used for the first time in the United States during the 2003–2004 influenza season. To evaluate the efficacy of these new agents, as well as allocate funding for future research and guide public health policy, accurate age-specific baseline rates of the disease burden of specific viruses are essential. The ED utilization resulting from respiratory infections is a key component in the health care use related to respiratory viruses that, to date, has been neglected. Our findings indicate that there are high rates of ED visits for respiratory infections, and these must be taken into account when evaluating the impact and cost-effectiveness of prevention strategies.
Our study did have some limitations. First, it is a retrospective study. Second, many of the figures are extrapolated from a single ED, and the number and characteristics of patients presenting with respiratory problems at other EDs may be different. The study ED, a tertiary care site that may have a more heavily referral-based population, may not be entirely representative. Also, the market-share data are only available from 2002–2003, and there may have been some shifts in market share over the study period. Finally, we did not include all possible viruses that cause respiratory infections, such as rhinovirus or human metapneumovirus, and there may also be additional, still-undiscovered agents that were not accounted for in this analysis. Therefore, it is possible that some of the subjects had concomitant infections with other agents. ED utilization by children with respiratory infections represents an important component of the health care utilization attributable to viral respiratory infections. The impact of respiratory viruses on this type of health care use must be included in measurements of the disease burden of respiratory viruses and assessments of the efficacy of vaccination policies. Future studies are needed to more closely define the impact of specific viruses and the cost associated with respiratory illness–related ED visits.
ACKNOWLEDGMENTS
This work was supported by grant MO1 RR-02172 from the General Clinical Research Center at Children’s Hospital Boston, contract 290-00-0020 from the Agency for Healthcare Research and Quality; grant R01LM007970-01 from the National Library of Medicine, National Institutes of Health; and National Research Service Awards 5 T32 HD40128-03 and 5 T32 HD40128-04.
We thank Jennifer Woo, BS, Hector Rivera, BS, Sara Ivey, BS, MPH, and Gordon Tam, BS, for assistance in data collection and processing; James West, PhD, for compilation of the registry data from the Massachusetts Division of Healthcare Finance and Policy; David Wypij, PhD, for suggestions on data analysis; Don Goldman for guidance and expertise in infectious diseases; Karen Olson for developing and managing the data sets; and John Brownstein for analytic insights.
FOOTNOTES
The authors have indicated they have no financial relationships relevant to this article to disclose.
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a Division of Emergency Medicine
c Clinical Research Program
e Department of Laboratory Medicine
f Children’s Hospital Informatics Program at the Harvard-MIT Division of Health Sciences and Technology, Children’s Hospital Boston, Boston, Massachusetts
b Department of Pediatrics, Harvard Medical School, Boston, Massachusetts
d Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts(Florence T. Bourgeois, MD)