Asthma-Related Health Care Resource Use Among Asthmatic Children With and Without Concomitant Allergic Rhinitis
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《小儿科》
Department of General Practice and Primary Care, University of Aberdeen, Foresterhill Health Centre, Westburn Road, Aberdeen, United Kingdom
Merck and Co, Inc, Worldwide Outcomes Research Department, Whitehouse Station, New Jersey
ABSTRACT
Objective. To determine the incremental effect of allergic rhinitis on health care resource use in children with asthma.
Design. Population-based historical cohort study.
Setting. Data in a general practice database in the United Kingdom during 1998 to 2001.
Patients. Children 6 to 15 years old with asthma and with 1 asthma-related visits to a general practitioner (GP) during a 12-month follow-up period.
Main Outcome Measures. Asthma-related hospitalizations, GP visits, and prescription drug costs during the 12-month follow-up period for patients with and without comorbid allergic rhinitis.
Results. Of 9522 children with asthma, 1879 (19.7%) had allergic rhinitis recorded in the GP medical records. Compared with children with asthma alone, children with comorbid allergic rhinitis experienced more GP visits (4.4 vs 3.4) and more of them were hospitalized for asthma (1.4% vs 0.5%) during the 12-month follow-up period. In multivariable regression analyses, comorbid allergic rhinitis was an independent predictor of hospitalization for asthma (odds ratio: 2.34; 95% confidence interval [CI]: 1.41–3.91) and was associated with increases in the number of asthma-related GP visits (mean increase: 0.53; 95% CI: 0.52–0.54) and asthma drug costs (mean increase ￡: 6.7; 95% CI: 6.5–7.0). The association between allergic rhinitis and higher costs of prescriptions for asthma drugs was independent of asthma severity, measured indirectly by the intensity of use of asthma drugs.
Conclusions. Children with comorbid allergic rhinitis incurred greater prescription drug costs and experienced more GP visits and hospitalizations for asthma than did children with asthma alone. A unified treatment strategy for asthma and allergic rhinitis, as recommended by the Allergic Rhinitis and Its Impact on Asthma initiative, might reduce the costs of treating these conditions.
Key Words: asthma allergic rhinitis children medical resource use
Abbreviations: ED, emergency department GP, general practitioner SABA, short-acting -agonist CI, confidence interval
Asthma and allergic rhinitis are both common childhood illnesses that place a substantial burden on health care systems. At least 20% of children are affected by asthma in the United Kingdom,1 which has one of the highest prevalences of childhood asthma worldwide.2 Much of the data relating to the health care burden applies to the United States, where the prevalence of current childhood asthma is 8.7%.3 Each year in the United States, asthma is responsible for 6.5 office or clinic visits, 1.0 emergency department (ED) visit, and 0.30 hospitalizations per 100 children.3 Emergency care (ED visits or hospitalization) for childhood asthma is relatively infrequent but consumes a disproportionate percentage of expenditures: 62% of expenditures on childhood asthma nationwide and from 37% to >50% of health care expenditures for childhood asthma in studies of US managed care data systems.4–6
Childhood allergic rhinitis is also highly prevalent; the worldwide prevalence ranges up to 40% in 13- to 14-year-olds.7 When viewed in isolation, allergic rhinitis is not associated with significant emergency care costs. In the United States, ED visits represent only 1% of the direct medical costs of allergic rhinitis.8,9
Allergic rhinitis and asthma are linked epidemiologically and therapeutically, and it is theorized that both conditions are manifestations of a single inflammatory process in the airways.10,11 In population-based studies conducted in the United States, 50% of children with allergic rhinitis also had asthma,12 and 50% of children with asthma also had allergic rhinitis.13 Some medications, such as corticosteroids and antileukotrienes, are effective against both conditions.10 There is, however, little information about medical resource use by children with both asthma and allergic rhinitis or of the impact of comorbid allergic rhinitis on the use of emergency and other health care services related to asthma. The objective of this study was to determine the direct medical burden of comorbid allergic rhinitis and asthma compared with that of asthma alone.
METHODS
Data Source
The data source for this study was the United Kingdom MediPlus general practice database. This database contains medical records for 2 million patient visits to the offices of a nationally representative sample of >500 general practitioners (GPs). It includes information about the reason for consultation, diagnosis, prescribed treatment, and secondary medical care, linked to encrypted patient identifiers. The database has been widely used in observational research and has been described elsewhere.14
Study Design
This was a retrospective cohort study consisting of 3 time periods: a 3-year diagnostic period, overlapping with a 6-month baseline period and a 12-month follow-up period. Records of a diagnosis of allergic rhinitis or prescriptions indicating allergic rhinitis were sought within the diagnostic period from October 1, 1998, to September 30, 2001. In the baseline period from April 1, 2000, to September 30, 2000, patient demographic data and the use of asthma-related drugs were determined. Study outcomes were determined for the follow-up period between October 1, 2000, and September 30, 2001.
Identification of Asthma and Allergic Rhinitis
Patients were included in the study if they had asthma, were 6 to 15 years old during the diagnostic period, and had >1 asthma-related GP visits during the 12-month follow-up period. A patient was classified as having comorbid allergic rhinitis if an allergic rhinitis diagnosis or >1 prescriptions indicating allergic rhinitis were recorded during the 3-year diagnostic period. An asthma-related GP visit was defined by diagnostic codes indicating asthma, extrinsic asthma-atopy, intrinsic asthma, status asthmaticus, asthma attack not otherwise specified, asthma not otherwise specified, or history of asthma. A diagnosis of allergic rhinitis was defined by codes for hay fever, allergic rhinitis not otherwise specified, or history of hay fever. Allergic rhinitis-related prescriptions were identified by drug codes for systemic antihistamines, nasal corticosteroids without antiinfectives, nasal corticosteroids with anti-infectives, nasal antiallergic agents, and nasal decongestants.
Study Variables
Patient demographics and asthma-related drug use in the baseline period were considered as covariates in the analysis of health care resource use during the follow-up period. Baseline covariates were: patient age, gender, oral corticosteroid use, number of short-acting -agonist (SABA) prescriptions, and dosage of inhaled corticosteroids, classified as low, medium, or high, as defined in the Global Initiative for Asthma guidelines.15 The study outcome variables were: asthma-related hospitalizations including unscheduled emergency admissions (yes/no), number of GP visits, and asthma-related prescription drug costs. Prescription drugs for asthma included quick-relief medications (ie, SABAs), long-term preventive medications (inhaled corticosteroids, antileukotrienes, long-acting -agonists, cromoglycate, and theophylline), and antibiotics. Drug costs were estimated by multiplying the number of prescriptions by the unit cost, obtained from IMS Health (Middlesex, United Kingdom). IMS Health prices for April 2001 (the midpoint of the follow-up period) were used; September 2001 (the last month of follow-up) prices were used for items that were unavailable in April 2001.
Statistical Analysis
The baseline characteristics of children with and without allergic rhinitis were compared in a univariate analysis using the t test for continuous data and the 2 test for categorical data. The Wilcoxon rank-sum test was also used in univariate analyses of asthma-related resource use. A logistic regression analysis was developed with asthma-related hospital admission during the follow-up period as the response variable and comorbid allergic rhinitis, use of oral corticosteroids, dose of inhaled corticosteroids, and number of SABA prescriptions as explanatory variables. Linear regression analyses were performed with comorbid allergic rhinitis as the explanatory variable, baseline patient characteristics as control variables, and the number of asthma-related GP visits and asthma drug costs as response variables. The number of GP visits and asthma-related drug costs were log-transformed to correct for their nonnormal distributions. The bootstrap resampling method was used to estimate confidence intervals (CIs) of the predicted mean difference in the number of GP visits and drug costs. We used tolerance or the variance inflation factor to assess multicollinearity in the multivariable regression analyses. Variables that were not statistically significant at a P value of .05 were dropped from the final model. All statistical analyses were performed using SAS (version 8.2; SAS Institute, Cary, NC).
RESULTS
Baseline Characteristics
The general practice database contained records for 14650 children who had asthma and who were 6 to 15 years old during the diagnostic period. Of these children, 9522 had one or more asthma-related GP visits during the follow-up period and were included in study. Of the 9522 children, 7643 (80.3%) had asthma only, and 1879 (19.7%) had both asthma and allergic rhinitis (Fig 1). As seen in Table 1, the mean age was 10.6 years and boys predominated (58.6%). During the baseline period, children with both asthma and allergic rhinitis were more likely to be prescribed inhaled steroids and on average received more SABA prescriptions when compared with children with asthma alone (Table 1).
Relationship Between Allergic Rhinitis and Asthma Hospitalizations and GP Visits
During the 12-month follow-up period, children with comorbid allergic rhinitis were more likely to be hospitalized for asthma and had 29% more GP visits for asthma, when compared with children with asthma alone (Table 2). In multivariable analyses, comorbid allergic rhinitis was an independent predictor of hospitalization (Table 3) and was associated with increased GP visits (Table 4) for asthma. Greater use of SABAs and use of oral and inhaled corticosteroids during the baseline period were also predictive of hospitalization for asthma (Table 3).
Relationship Between Allergic Rhinitis and Drug Costs
Comorbid allergic rhinitis was an independent predictor of higher costs for medications for asthma during the follow-up period (Table 4). Children with comorbid allergic rhinitis incurred greater costs for all categories of asthma medications than did children with asthma alone (Fig 2). The mean number (95% CI) of SABA prescriptions in the follow-up period for children with and without allergic rhinitis were, respectively, 2.25 (2.12–2.37) and 1.81 (1.76–1.86; P <.0001); corresponding values for oral corticosteroid prescriptions were 0.146 (0.123–0.170) and 0.091 (0.082–0.100, P <.0001). Children with allergic rhinitis incurred higher costs for asthma-related drugs regardless of the severity of asthma, as indicated by the number of SABA prescriptions (Fig 3) or dosage of inhaled corticosteroids (Fig 4) during the baseline period.
DISCUSSION
We have described a historical cohort study of >9000 children treated for asthma by a nationally representative sample of GPs in the United Kingdom. Comorbid allergic rhinitis was associated with increased asthma-related hospitalizations, GP visits, SABA and oral corticosteroid use, and overall asthma-related drug costs.
These results are consistent with those of 2 US studies that investigated the incremental effect of comorbid allergic rhinitis or related illnesses on medical care costs due to asthma. In the first study, which included 1412 children with asthma, total and respiratory-related medical care charges for children with comorbid allergic rhinitis were almost twice those for children with asthma alone.13 The second study included 9797 children with asthma and/or >1 upper-airway diagnoses (allergic rhinitis, sinusitis, or otitis media).16 The costs of outpatient visits for asthma and an upper-airway condition were additive, ie, the costs for those with both asthma and an upper-airway diagnosis were approximately the sum of the costs for asthma alone and an upper-airway diagnosis alone. The effects of comorbid upper-airway disease on hospitalizations, however, were more than additive with those of asthma, ie, the per-patient costs of hospitalizations were more than the sum of those associated with the individual diagnoses in patients with only asthma or only an upper-airway condition.16 A third study set in Germany did not confirm a relationship between increased medical service use and comorbid allergic rhinitis but included a sample of only 276 children.17
Evidence that allergic rhinitis increases the use of asthma-related emergency medical services by children is complemented by evidence that treating upper-airway conditions reduces asthma symptoms11,18 and asthma-related emergency care.18 The latter is suggested by a managed care study that included children with asthma and comorbid rhinitis, sinusitis, or otitis media: treatment directed at the upper airways was associated with an 30% reduction in asthma-related ED visits.18
This study suggests that comorbid rhinitis severe enough to have come to the attention of a primary care physician is associated with adverse asthma outcomes. A number of mechanisms linking rhinitis with asthma severity have been postulated. Rhinitis results in nasal dysfunction and mouth breathing and so may cause a failure of the normal humidification, warming, and filtration functions of the upper airway. The possible significance of this mechanism is illustrated by studies showing that nasal dysfunction may result in acute bronchospasm and increased bronchial hyperresponsiveness.19–21 In addition, it has been postulated that a nasobronchial reflex exists,22 with reflex bronchoconstriction occurring in response to nasal inflammation, which may be attenuated by treatment of the nasal inflammation with antiinflammatory nasal medication.21 The pathologic process occurring in the upper airway in allergic rhinitis is similar in many respects to that occurring in the lower airway in asthma, involving T helper 2 cytokines and an eosinophilic inflammatory process.23 Active inflammation in the upper airway may therefore result in the local or systemic spread of inflammatory cells and mediators, which may have a proinflammatory effect in the lower airway.24,25 There have been a number of reports of improvements in bronchial hyperresponsiveness and in clinical and immunologic asthma severity markers after treatment of comorbid rhinitis with antiinflammatory medication.26–29 Epidemiologic and clinical studies have underlined the basic pathologic links between asthma and rhinitis and led to the concept of "united airways disease," in which both conditions are considered to be manifestations of the same fundamental disease process.30 Longitudinal cohort studies have shown that clinically manifest rhinitis may precede the expression of asthma in atopic individuals.31 The presence of more severe upper-airway disease may thus act as a marker for the development of more severe, lower-airway disease and hence for worsened asthma outcomes.
Studies based on general practice databases are limited by the data they contain.32 First, epidemiologic studies indicate that the prevalence of allergic rhinitis among children with asthma is 50%,13 much greater than the 19.7% observed in this study. The value of 19.7% likely reflects an underestimation of allergic rhinitis in the general practice database, perhaps because the symptoms were not recognized or because the condition was treated with medications available in the United Kingdom without a prescription. Treatment of allergic rhinitis with over-the-counter drugs, which is likely to have been frequent, is not recorded in the general practice database. It is also possible that a record of allergic rhinitis in the general practice database indicated a more severe form of rhinitis, which might be associated with worse asthma outcomes and costs than are milder forms of allergic rhinitis. Second, the correlation between asthma-related emergency care and allergic rhinitis could reflect an association between rhinitis and a more severe form of asthma. We attempted to control for this by using intensity of use of asthma medications as a surrogate measure of severity, but this procedure is limited by confounding between asthma severity and control, ie, the use of asthma medications is associated positively with underlying disease severity and negatively with asthma symptoms manifested by exacerbations and the use of emergency care. Third, the distinction between intermittent and persistent subtypes of allergic rhinitis, which is recommended in guidelines promulgated by the Allergic Rhinitis and Its Impact on Asthma initiative,10 is rarely documented in general practice records. Fourth, identification of allergic rhinitis at any time in the 3-year diagnostic period might have biased asthma-related resource use in the comorbid group upwards. Patients diagnosed with allergic rhinitis in the last study month, for example, were assigned to the comorbid group. Because of evidence of underdiagnosis of allergic rhinitis in general practice, we assumed that resource use before diagnosis of the comorbidity reflected the burden of both conditions. Fifth, a large sample size might artificially inflate the apparent differences between groups by identifying statistically significant differences that are clinically meaningless. Because the results of this study are consistent with other findings using different designs and populations, we are confident that the differences we found are clinically meaningful. Finally, systemic antihistamines, which were included in the list of drugs used to identify patients with concomitant allergic rhinitis, may also have been prescribed for other conditions. We performed a sensitivity analysis to examine this possible source of bias. Excluding systemic antihistamines reduced the prevalence of concomitant allergic rhinitis from 19.7% to 17.2% but did not change the main study outcomes: values for asthma-related GP visits, hospitalizations, and drug costs were still significantly greater at the P < .0001 level among patients with concomitant allergic rhinitis than among those with asthma alone.
CONCLUSIONS
Children with comorbid allergic rhinitis required more asthma-related emergency and nonemergency medical care and asthma drugs than did children with asthma alone. The coexistence of asthma and allergic rhinitis identifies a high-risk group of children that should be targeted for care. A unified treatment strategy applied to these children, as recommended in the Allergic Rhinitis and Its Impact on Asthma guidelines,10 would be expected to reduce the costs of emergency care for childhood asthma.
ACKNOWLEDGMENTS
Funding for this study was provided by Merck and Co, Inc.
We thank Dr Alan Morrison for help in drafting this manuscript.
FOOTNOTES
Accepted Jul 6, 2004.
No conflict of interest declared.
REFERENCES
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International Study of Asthma and Allergies in Childhood (ISAAC) Steering Committee. Worldwide variation in prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and atopic eczema: ISAAC. Lancet. 1998;351 :1225 –1232
Lozano P, Sullivan SD, Smith DH, Weiss KB. The economic burden of asthma in US children: estimates from the National Medical Expenditure Survey. J Allergy Clin Immunol. Nov 1999;104 :957 –963
Stempel DA, Hedblom EC, Durcanin-Robbins JF, Sturm LL. Use of a pharmacy and medical claims database to document cost centers for 1993 annual asthma expenditures. Arch Fam Med. 1996;5 :36 –40
Lozano P, Fishman P, VonKorff M, Hecht J. Health care utilization and cost among children with asthma who were enrolled in a health maintenance organization. Pediatrics. 1997;99 :757 –764
Strachan D, Sibbald B, Weiland S, Ait-Khaled N, Anabwani G, Anderson HR, et al. Worldwide variations in prevalence of symptoms of allergic rhinoconjunctivitis in children: the International Study of Asthma and Allergies in Childhood (ISAAC). Pediatr Allergy Immunol. Nov 1997;8 :161 –176
Malone DC, Lawson KA, Smith DH, Arrighi HM, Battista C. Cost of illness study of allergic rhinitis in the United States. J Allergy Clin Immunol. 1997;99 :22 –27
Law AW, Reed SD, Sundy JS, Schulman KA. Direct costs of allergic rhinitis in the United States: estimates from the 1996 Medical Expenditure Panel Survey. J Allergy Clin Immunol. 2003;111 :296 –300
Bachert C, van Cauwenberge P, Khaltaev N, Bousquet J. Allergic rhinitis and its impact on asthma. In collaboration with the World Health Organization. Executive summary of the workshop report. December 7–10, 1999. Geneva, Switzerland. Allergy. 2002;57 :841 –855
Simons FE. Allergic rhinobronchitis: the asthma-allergic rhinitis link. J Allergy Clin Immunol. 1999;104 :534 –540
Wright AL, Holberg CJ, Martinez FD, Halonen M, Morgan W, Taussig LM. Epidemiology of physician-diagnosed allergic rhinitis in childhood. Pediatrics. 1994;94 :895 –901
Yawn BP, Yunginger JW, Wollan PC, Reed CE, Silverstein MD, Harris AG. Allergic rhinitis in Rochester, Minnesota residents with asthma: frequency and impact on health care charges. J Allergy Clin Immunol. 1999;103 :54 –59
Price DB, Ben-Joseph RH, Zhang Q. Changes in asthma drug therapy costs for patients receiving chronic montelukast therapy in the U.K. Respir Med. Jan 2001;95 :83 –89
Grupp-Phelan J, Lozano P, Fishman P. Health care utilization and cost in children with asthma and selected comorbidities. J Asthma. 2001;38 :363 –373
Schramm B, Ehlken B, Smala A, Quednau K, Berger K, Nowak D. Cost of illness of atopic asthma and seasonal allergic rhinitis in Germany: 1-yr retrospective study. Eur Respir J. 2003;21 :116 –122
Adams RJ, Fuhlbrigge AL, Finkelstein JA, Weiss ST. Intranasal steroids and the risk of emergency department visits for asthma. J Allergy Clin Immunol. 2002;109 :636 –642
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Merck and Co, Inc, Worldwide Outcomes Research Department, Whitehouse Station, New Jersey
ABSTRACT
Objective. To determine the incremental effect of allergic rhinitis on health care resource use in children with asthma.
Design. Population-based historical cohort study.
Setting. Data in a general practice database in the United Kingdom during 1998 to 2001.
Patients. Children 6 to 15 years old with asthma and with 1 asthma-related visits to a general practitioner (GP) during a 12-month follow-up period.
Main Outcome Measures. Asthma-related hospitalizations, GP visits, and prescription drug costs during the 12-month follow-up period for patients with and without comorbid allergic rhinitis.
Results. Of 9522 children with asthma, 1879 (19.7%) had allergic rhinitis recorded in the GP medical records. Compared with children with asthma alone, children with comorbid allergic rhinitis experienced more GP visits (4.4 vs 3.4) and more of them were hospitalized for asthma (1.4% vs 0.5%) during the 12-month follow-up period. In multivariable regression analyses, comorbid allergic rhinitis was an independent predictor of hospitalization for asthma (odds ratio: 2.34; 95% confidence interval [CI]: 1.41–3.91) and was associated with increases in the number of asthma-related GP visits (mean increase: 0.53; 95% CI: 0.52–0.54) and asthma drug costs (mean increase ￡: 6.7; 95% CI: 6.5–7.0). The association between allergic rhinitis and higher costs of prescriptions for asthma drugs was independent of asthma severity, measured indirectly by the intensity of use of asthma drugs.
Conclusions. Children with comorbid allergic rhinitis incurred greater prescription drug costs and experienced more GP visits and hospitalizations for asthma than did children with asthma alone. A unified treatment strategy for asthma and allergic rhinitis, as recommended by the Allergic Rhinitis and Its Impact on Asthma initiative, might reduce the costs of treating these conditions.
Key Words: asthma allergic rhinitis children medical resource use
Abbreviations: ED, emergency department GP, general practitioner SABA, short-acting -agonist CI, confidence interval
Asthma and allergic rhinitis are both common childhood illnesses that place a substantial burden on health care systems. At least 20% of children are affected by asthma in the United Kingdom,1 which has one of the highest prevalences of childhood asthma worldwide.2 Much of the data relating to the health care burden applies to the United States, where the prevalence of current childhood asthma is 8.7%.3 Each year in the United States, asthma is responsible for 6.5 office or clinic visits, 1.0 emergency department (ED) visit, and 0.30 hospitalizations per 100 children.3 Emergency care (ED visits or hospitalization) for childhood asthma is relatively infrequent but consumes a disproportionate percentage of expenditures: 62% of expenditures on childhood asthma nationwide and from 37% to >50% of health care expenditures for childhood asthma in studies of US managed care data systems.4–6
Childhood allergic rhinitis is also highly prevalent; the worldwide prevalence ranges up to 40% in 13- to 14-year-olds.7 When viewed in isolation, allergic rhinitis is not associated with significant emergency care costs. In the United States, ED visits represent only 1% of the direct medical costs of allergic rhinitis.8,9
Allergic rhinitis and asthma are linked epidemiologically and therapeutically, and it is theorized that both conditions are manifestations of a single inflammatory process in the airways.10,11 In population-based studies conducted in the United States, 50% of children with allergic rhinitis also had asthma,12 and 50% of children with asthma also had allergic rhinitis.13 Some medications, such as corticosteroids and antileukotrienes, are effective against both conditions.10 There is, however, little information about medical resource use by children with both asthma and allergic rhinitis or of the impact of comorbid allergic rhinitis on the use of emergency and other health care services related to asthma. The objective of this study was to determine the direct medical burden of comorbid allergic rhinitis and asthma compared with that of asthma alone.
METHODS
Data Source
The data source for this study was the United Kingdom MediPlus general practice database. This database contains medical records for 2 million patient visits to the offices of a nationally representative sample of >500 general practitioners (GPs). It includes information about the reason for consultation, diagnosis, prescribed treatment, and secondary medical care, linked to encrypted patient identifiers. The database has been widely used in observational research and has been described elsewhere.14
Study Design
This was a retrospective cohort study consisting of 3 time periods: a 3-year diagnostic period, overlapping with a 6-month baseline period and a 12-month follow-up period. Records of a diagnosis of allergic rhinitis or prescriptions indicating allergic rhinitis were sought within the diagnostic period from October 1, 1998, to September 30, 2001. In the baseline period from April 1, 2000, to September 30, 2000, patient demographic data and the use of asthma-related drugs were determined. Study outcomes were determined for the follow-up period between October 1, 2000, and September 30, 2001.
Identification of Asthma and Allergic Rhinitis
Patients were included in the study if they had asthma, were 6 to 15 years old during the diagnostic period, and had >1 asthma-related GP visits during the 12-month follow-up period. A patient was classified as having comorbid allergic rhinitis if an allergic rhinitis diagnosis or >1 prescriptions indicating allergic rhinitis were recorded during the 3-year diagnostic period. An asthma-related GP visit was defined by diagnostic codes indicating asthma, extrinsic asthma-atopy, intrinsic asthma, status asthmaticus, asthma attack not otherwise specified, asthma not otherwise specified, or history of asthma. A diagnosis of allergic rhinitis was defined by codes for hay fever, allergic rhinitis not otherwise specified, or history of hay fever. Allergic rhinitis-related prescriptions were identified by drug codes for systemic antihistamines, nasal corticosteroids without antiinfectives, nasal corticosteroids with anti-infectives, nasal antiallergic agents, and nasal decongestants.
Study Variables
Patient demographics and asthma-related drug use in the baseline period were considered as covariates in the analysis of health care resource use during the follow-up period. Baseline covariates were: patient age, gender, oral corticosteroid use, number of short-acting -agonist (SABA) prescriptions, and dosage of inhaled corticosteroids, classified as low, medium, or high, as defined in the Global Initiative for Asthma guidelines.15 The study outcome variables were: asthma-related hospitalizations including unscheduled emergency admissions (yes/no), number of GP visits, and asthma-related prescription drug costs. Prescription drugs for asthma included quick-relief medications (ie, SABAs), long-term preventive medications (inhaled corticosteroids, antileukotrienes, long-acting -agonists, cromoglycate, and theophylline), and antibiotics. Drug costs were estimated by multiplying the number of prescriptions by the unit cost, obtained from IMS Health (Middlesex, United Kingdom). IMS Health prices for April 2001 (the midpoint of the follow-up period) were used; September 2001 (the last month of follow-up) prices were used for items that were unavailable in April 2001.
Statistical Analysis
The baseline characteristics of children with and without allergic rhinitis were compared in a univariate analysis using the t test for continuous data and the 2 test for categorical data. The Wilcoxon rank-sum test was also used in univariate analyses of asthma-related resource use. A logistic regression analysis was developed with asthma-related hospital admission during the follow-up period as the response variable and comorbid allergic rhinitis, use of oral corticosteroids, dose of inhaled corticosteroids, and number of SABA prescriptions as explanatory variables. Linear regression analyses were performed with comorbid allergic rhinitis as the explanatory variable, baseline patient characteristics as control variables, and the number of asthma-related GP visits and asthma drug costs as response variables. The number of GP visits and asthma-related drug costs were log-transformed to correct for their nonnormal distributions. The bootstrap resampling method was used to estimate confidence intervals (CIs) of the predicted mean difference in the number of GP visits and drug costs. We used tolerance or the variance inflation factor to assess multicollinearity in the multivariable regression analyses. Variables that were not statistically significant at a P value of .05 were dropped from the final model. All statistical analyses were performed using SAS (version 8.2; SAS Institute, Cary, NC).
RESULTS
Baseline Characteristics
The general practice database contained records for 14650 children who had asthma and who were 6 to 15 years old during the diagnostic period. Of these children, 9522 had one or more asthma-related GP visits during the follow-up period and were included in study. Of the 9522 children, 7643 (80.3%) had asthma only, and 1879 (19.7%) had both asthma and allergic rhinitis (Fig 1). As seen in Table 1, the mean age was 10.6 years and boys predominated (58.6%). During the baseline period, children with both asthma and allergic rhinitis were more likely to be prescribed inhaled steroids and on average received more SABA prescriptions when compared with children with asthma alone (Table 1).
Relationship Between Allergic Rhinitis and Asthma Hospitalizations and GP Visits
During the 12-month follow-up period, children with comorbid allergic rhinitis were more likely to be hospitalized for asthma and had 29% more GP visits for asthma, when compared with children with asthma alone (Table 2). In multivariable analyses, comorbid allergic rhinitis was an independent predictor of hospitalization (Table 3) and was associated with increased GP visits (Table 4) for asthma. Greater use of SABAs and use of oral and inhaled corticosteroids during the baseline period were also predictive of hospitalization for asthma (Table 3).
Relationship Between Allergic Rhinitis and Drug Costs
Comorbid allergic rhinitis was an independent predictor of higher costs for medications for asthma during the follow-up period (Table 4). Children with comorbid allergic rhinitis incurred greater costs for all categories of asthma medications than did children with asthma alone (Fig 2). The mean number (95% CI) of SABA prescriptions in the follow-up period for children with and without allergic rhinitis were, respectively, 2.25 (2.12–2.37) and 1.81 (1.76–1.86; P <.0001); corresponding values for oral corticosteroid prescriptions were 0.146 (0.123–0.170) and 0.091 (0.082–0.100, P <.0001). Children with allergic rhinitis incurred higher costs for asthma-related drugs regardless of the severity of asthma, as indicated by the number of SABA prescriptions (Fig 3) or dosage of inhaled corticosteroids (Fig 4) during the baseline period.
DISCUSSION
We have described a historical cohort study of >9000 children treated for asthma by a nationally representative sample of GPs in the United Kingdom. Comorbid allergic rhinitis was associated with increased asthma-related hospitalizations, GP visits, SABA and oral corticosteroid use, and overall asthma-related drug costs.
These results are consistent with those of 2 US studies that investigated the incremental effect of comorbid allergic rhinitis or related illnesses on medical care costs due to asthma. In the first study, which included 1412 children with asthma, total and respiratory-related medical care charges for children with comorbid allergic rhinitis were almost twice those for children with asthma alone.13 The second study included 9797 children with asthma and/or >1 upper-airway diagnoses (allergic rhinitis, sinusitis, or otitis media).16 The costs of outpatient visits for asthma and an upper-airway condition were additive, ie, the costs for those with both asthma and an upper-airway diagnosis were approximately the sum of the costs for asthma alone and an upper-airway diagnosis alone. The effects of comorbid upper-airway disease on hospitalizations, however, were more than additive with those of asthma, ie, the per-patient costs of hospitalizations were more than the sum of those associated with the individual diagnoses in patients with only asthma or only an upper-airway condition.16 A third study set in Germany did not confirm a relationship between increased medical service use and comorbid allergic rhinitis but included a sample of only 276 children.17
Evidence that allergic rhinitis increases the use of asthma-related emergency medical services by children is complemented by evidence that treating upper-airway conditions reduces asthma symptoms11,18 and asthma-related emergency care.18 The latter is suggested by a managed care study that included children with asthma and comorbid rhinitis, sinusitis, or otitis media: treatment directed at the upper airways was associated with an 30% reduction in asthma-related ED visits.18
This study suggests that comorbid rhinitis severe enough to have come to the attention of a primary care physician is associated with adverse asthma outcomes. A number of mechanisms linking rhinitis with asthma severity have been postulated. Rhinitis results in nasal dysfunction and mouth breathing and so may cause a failure of the normal humidification, warming, and filtration functions of the upper airway. The possible significance of this mechanism is illustrated by studies showing that nasal dysfunction may result in acute bronchospasm and increased bronchial hyperresponsiveness.19–21 In addition, it has been postulated that a nasobronchial reflex exists,22 with reflex bronchoconstriction occurring in response to nasal inflammation, which may be attenuated by treatment of the nasal inflammation with antiinflammatory nasal medication.21 The pathologic process occurring in the upper airway in allergic rhinitis is similar in many respects to that occurring in the lower airway in asthma, involving T helper 2 cytokines and an eosinophilic inflammatory process.23 Active inflammation in the upper airway may therefore result in the local or systemic spread of inflammatory cells and mediators, which may have a proinflammatory effect in the lower airway.24,25 There have been a number of reports of improvements in bronchial hyperresponsiveness and in clinical and immunologic asthma severity markers after treatment of comorbid rhinitis with antiinflammatory medication.26–29 Epidemiologic and clinical studies have underlined the basic pathologic links between asthma and rhinitis and led to the concept of "united airways disease," in which both conditions are considered to be manifestations of the same fundamental disease process.30 Longitudinal cohort studies have shown that clinically manifest rhinitis may precede the expression of asthma in atopic individuals.31 The presence of more severe upper-airway disease may thus act as a marker for the development of more severe, lower-airway disease and hence for worsened asthma outcomes.
Studies based on general practice databases are limited by the data they contain.32 First, epidemiologic studies indicate that the prevalence of allergic rhinitis among children with asthma is 50%,13 much greater than the 19.7% observed in this study. The value of 19.7% likely reflects an underestimation of allergic rhinitis in the general practice database, perhaps because the symptoms were not recognized or because the condition was treated with medications available in the United Kingdom without a prescription. Treatment of allergic rhinitis with over-the-counter drugs, which is likely to have been frequent, is not recorded in the general practice database. It is also possible that a record of allergic rhinitis in the general practice database indicated a more severe form of rhinitis, which might be associated with worse asthma outcomes and costs than are milder forms of allergic rhinitis. Second, the correlation between asthma-related emergency care and allergic rhinitis could reflect an association between rhinitis and a more severe form of asthma. We attempted to control for this by using intensity of use of asthma medications as a surrogate measure of severity, but this procedure is limited by confounding between asthma severity and control, ie, the use of asthma medications is associated positively with underlying disease severity and negatively with asthma symptoms manifested by exacerbations and the use of emergency care. Third, the distinction between intermittent and persistent subtypes of allergic rhinitis, which is recommended in guidelines promulgated by the Allergic Rhinitis and Its Impact on Asthma initiative,10 is rarely documented in general practice records. Fourth, identification of allergic rhinitis at any time in the 3-year diagnostic period might have biased asthma-related resource use in the comorbid group upwards. Patients diagnosed with allergic rhinitis in the last study month, for example, were assigned to the comorbid group. Because of evidence of underdiagnosis of allergic rhinitis in general practice, we assumed that resource use before diagnosis of the comorbidity reflected the burden of both conditions. Fifth, a large sample size might artificially inflate the apparent differences between groups by identifying statistically significant differences that are clinically meaningless. Because the results of this study are consistent with other findings using different designs and populations, we are confident that the differences we found are clinically meaningful. Finally, systemic antihistamines, which were included in the list of drugs used to identify patients with concomitant allergic rhinitis, may also have been prescribed for other conditions. We performed a sensitivity analysis to examine this possible source of bias. Excluding systemic antihistamines reduced the prevalence of concomitant allergic rhinitis from 19.7% to 17.2% but did not change the main study outcomes: values for asthma-related GP visits, hospitalizations, and drug costs were still significantly greater at the P < .0001 level among patients with concomitant allergic rhinitis than among those with asthma alone.
CONCLUSIONS
Children with comorbid allergic rhinitis required more asthma-related emergency and nonemergency medical care and asthma drugs than did children with asthma alone. The coexistence of asthma and allergic rhinitis identifies a high-risk group of children that should be targeted for care. A unified treatment strategy applied to these children, as recommended in the Allergic Rhinitis and Its Impact on Asthma guidelines,10 would be expected to reduce the costs of emergency care for childhood asthma.
ACKNOWLEDGMENTS
Funding for this study was provided by Merck and Co, Inc.
We thank Dr Alan Morrison for help in drafting this manuscript.
FOOTNOTES
Accepted Jul 6, 2004.
No conflict of interest declared.
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