Antibiotic consumption in children prior to diagnosis of asthma

  • Fawziah Marra1Email author,

    Affiliated with

    • Carlo A Marra2Email author,

      Affiliated with

      • Kathryn Richardson3,

        Affiliated with

        • Larry D Lynd4 and

          Affiliated with

          • Mark J FitzGerald5

            Affiliated with

            BMC Pulmonary Medicine201111:32

            DOI: 10.1186/1471-2466-11-32

            Received: 8 November 2010

            Accepted: 31 May 2011

            Published: 31 May 2011

            ABSTRACT

            Background

            Asthma is difficult to diagnose in children and at times misdiagnosis of an infection can occur. However, little is known about the magnitude and patterns of antibiotic consumption in children with asthma relative to those without asthma.

            Methods

            Using population-based data, 128,872 children were identified with at least 6 years of follow-up. The adjusted rate-ratio (RR) of antibiotics dispensed to asthmatic as compared to non-asthmatic children was determined.

            Results

            At age six, the RR of antibiotic consumption for asthmatics compared to non-asthmatics varied between, 1.66 to 2.32, depending on the year of asthma diagnosis. Of the 18,864 children with asthma at ages 2-8, 52% (n = 9,841) had antibiotics dispensed in the 6 months prior to their index date of asthma diagnosis. The RR of antibiotic consumption in the 1 month prior to asthma diagnosis compared to 5 months prior was 1.66 (95% CI 1.60-1.71). The RR was lower in males compared to females (1.58 vs 1.77), and lower in those who received antibiotics in the first year of life relative to those that did not (1.60 vs. 1.76).

            Conclusions

            There is higher antibiotic consumption in children with asthma compared to those without asthma. The pattern of antibiotic use suggests that diagnosis guidelines are difficult to follow in young children leading to misdiagnosis and over treatment with antibiotics.

            Background

            Studies performed in varying populations over the last 30 years have indicated that the prevalence of asthma has significantly increased [1, 2]. Asthma rates are particularly high in children with one in eight school children being affected [3]. Asthma is difficult to diagnose - particularly in children as frequently their only symptom is coughing which may be mistaken for an upper respiratory tract infection in addition to the fact that they cannot participate in many of the standard diagnostic tests. The North American guidelines [4, 5] for pediatric asthma management outline a stepwise approach to asthma management with the aim being to initiate control of asthma with regular anti-inflammatory therapy and monitor the level of control by use of rescue medication as well as symptoms, and in older children with assessment of airflow obstruction [6, 7]. As such, patients should start treatment that is consistent with the initial severity of their asthma and then step down when control has been achieved. The availability of guidelines does not necessarily mean a high uptake by clinicians. Several studies have evaluated the use of asthma medications in adults and children and have shown that 40 to 60% of prescribing does not reflect the recommendations in guidelines [810].

            In contrast to the use of asthma medications, antibiotics are over utilized in children and often prescribed for viral infections [1115]. Our recent studies have evaluated the use of antibiotics in Canadian children and we showed that although overall antibiotic use had declined over a decade, their use in a Canadian population exceeds that of European children [11]. In addition, the use of antibiotics in children under 4 years of age, was double that of children between 10-14 years of age - and was primarily associated with upper respiratory tract infections, acute otitis media and bronchitis [12].

            We know that antibiotics are not routinely used in the treatment of asthma - the asthma treatment guidelines clearly state that although symptoms associated with poor asthma control often overlap with symptoms associated with respiratory tract infections, clinicians should take care in differentiating between the two conditions. We conducted this study to determine the patterns of antibiotic consumption in children with asthma. Specifically, we wanted to determine if antibiotic consumption was greater in children who developed asthma compared to those who did not and to examine the rate of antibiotic consumption prior to the diagnosis of asthma.

            Methods

            Study Population

            The longitudinal study cohort consisted of all live births in British Columbia (BC), Canada, from January 1997 through December 2003. Follow-up information was available from all data files up to December 2005.

            Data Sources

            We used population-based, linked administrative health data that contained information on all physician services (known as MSP), hospital admissions, vital status information, socioeconomic status (SES) (determined through postal code and census classifications such as median neighbourhood income and split by quintiles therefore those in neighborhoods reporting the greatest 20% of incomes in the population will be in the 5th quintile) and outpatient dispensing episodes of prescription drugs (PharmaNet) to assess potential antibiotic exposures, potential confounders, and outcomes. Linkages among the various data files were achieved through the use of a personal health number unique to every BC resident; all traceable personal identifiers were removed to protect patient confidentiality. Ethics approval was obtained from the University of British Columbia Behavioral Research Ethics Board.

            Information on dispensed asthma drugs and antibiotics between 1997 and 2005 was extracted based on the 2009 Anatomical Therapeutic Chemical Classification System (ATC) codes [16]. Asthma medications (ATC codes R03A-D) consisted of short-acting β-agonists, inhaled corticosteroids, ipratropium, or leukotriene receptor antagonists and ketotifen (ATC code R06AX17). Antibiotics (ATC code J01) were classified as penicillins, cephalosporins, macrolides, sulfonamide, or other classes.

            Physician visits in the database were classified according to the 3-digit diagnostic code (International Classification of Diseases, Ninth Revision (ICD-9)) associated with that visit and the type of physician (e.g. general practitioner versus specialist). These visits were also extracted in the year prior to asthma diagnosis. In addition, any visits to an allergist, respirologist, or immunologist visit were obtained. Similar codes were used to classify hospitalizations.

            Asthma Definition and Index Date

            The definition of asthma employed in our study was either: (1) a hospital discharge for asthma (ICD9 493); or (2) two medical fee-for-service claims coded ICD9 493 within a moving 12-month period; or (3) two prescriptions for a known asthma medication within a moving 12-month period. The index date was defined as the date of the first episode by which the diagnosis of asthma was established. Previous research comparing various database asthma definitions to a gold standard of an allergist's diagnosis of childhood asthma found that this definition of asthma had a positive predictive value of 92%, which was higher than other definitions requiring fewer visits and prescriptions [17, 18].

            Statistical Analysis

            Antibiotic rates in asthmatics versus controls

            Rates of antibiotic dispensing in asthmatics and non-asthmatics by age 6 were examined in those with at least 6 years of follow-up from birth (n = 128,872). We defined five groups according to their asthma diagnosis in this period: 'no asthma by age 6' or asthma definition reached at age 2, 3, 4, and 5 years. Asthmatics reaching the index date within their first two years of life (n = 22,736) were excluded since the diagnosis of asthma is difficult and confounded by other illnesses and the rate of antibiotic dispensing was high and variable in this age range. Annual antibiotic dispensing rates until age 6 years were calculated in these five cohorts. As previous work has shown changes in antibiotic prescribing rates in this population over time [12], we adjusted for calendar year in all analyses. Rate ratios for antibiotic dispensing in the four asthma groups compared to the 'no asthma by age 6' reference group were also plotted.

            Antibiotic rates near the asthma index date

            We examined incident asthma cases identified prospectively from age two years until the earliest of: 31st December 2005, death, or departure from BC (n = 18,864). For children not registered in the MSP on 31st December 2005, the date of departure from BC was defined as the latest occurrence of: MSP coverage, MSP visits, hospital separations, or PharmaNet records. This allowed follow-up up to capture asthma diagnosed to a maximum age of 8 years. The monthly rates of antibiotic and asthma medication dispensing were plotted by age at asthma index date in those followed for 6 months prior to and also for 6 months post the asthma index date (n = 17,297).

            Poisson regression analysis was used to estimate rate ratios (RR) and their 95% confidence intervals (CI) for the rate of antibiotic dispensing in the six months prior to the index date adjusting for the various potential confounders. As the number of antibiotics dispensed per child was overdispersed, the deviance chi-square was used to adjust the standard errors. Potential confounders adjusted for included gender, birth weight, and congenital anomalies. Time varying covariates included calendar year, seasonality, child age, and in the preceding year: quintiles of socioeconomic status (SES), frequency of physician visits, and allergist/respirologist/immunologist visit.

            To calculate the RR and 95% CI for the antibiotic prescribing rate in the month before the index date compared to the 5 months before that, Poisson models were used with general estimating equations to obtain robust standard errors accounting for the correlation between the two rates being estimated for each child [19]. Interactions between the RR and all of the confounders were tested in a Poisson model and results were presented for confounders that independently significantly altered this RR.

            To examine indications for antibiotics prescribing in the six months prior to the index date, the infectious diagnosis (according to ICD9 codes) were reported for the most temporal MSP billing code within 5 days preceding the dispensing episode. Proportions of the indications for antibiotic prescribing in the month prior to the index date and the 5 months prior to that were compared via chi-square tests.

            Results

            Antibiotic rates in asthmatics versus controls

            For those 106,136 children with at least 6 years of follow-up (excluding asthmatics reaching their index date in the first 2 years of life), 96,496 (91%) did not meet the definition of asthma by age 6 years and the remaining met the definition at age 2 (2.6%), 3 (2.4%), 4 (2.1%) and 5 (1.9%). The asthmatics first met the criteria for diagnosis in 57% of cases via a medical claim, 53% by prescription, and 5% by hospital discharge. 12% met the criteria for asthma diagnosis by medical claim and prescription simultaneously. The rates of antibiotic prescribing by year of age and by age at the asthma index date (adjusted for calendar year - presented for year 2000) were characterized for these children (Table 1). The rate was elevated in the asthmatics compared to the non-asthmatics and this ratio peaked during the year of asthma diagnosis with a RR of around 2.30-2.36 (Table 1).
            Table 1

            Rates of antibiotics dispensed per year of age, by age of asthma diagnosis and rate ratios compared to non-asthmatics by age 6 (rates standardized for year 2000)

             

            No asthma by age 6 (n = 96,496)

            Age at asthma index date

              

            Age 2 (n = 2,791)

            Age 3 (n = 2,572)

            Age 4 (n = 2,238)

            Age 5 (n = 2,039)

            Age, years

            Rate of ABX per 100 PY

            Rate of ABX per 100 PY

            RR (95% CI)*

            Rate of ABX per 100 PY

            RR (95% CI)*

            Rate of ABX per 100 PY

            RR (95% CI)*

            Rate of ABX per 100 PY

            RR (95% CI)*

            0

            84.6

            123.9

            1.47 (1.40-1.53)

            118.5

            1.40 (1.34-1.47)

            110.8

            1.31 (1.25-1.38)

            108.3

            1.28 (1.22-1.35)

            1

            118.8

            190.1

            1.60 (1.54-1.66)

            173.4

            1.46 (1.40-1.52)

            165.0

            1.39 (1.33-1.45)

            156.4

            1.32 (1.26-1.46)

            2

            90.1

            213.0

            2.36 (2.28-2.45)

            149.0

            1.65 (1.58-1.73)

            140.2

            1.56 (1.48-1.63)

            124.9

            1.39 (1.32-1.46)

            3

            89.0

            170.0

            1.91 (1.84-1.99)

            207.5

            2.33 (2.24-2.42)

            156.8

            1.76 (1.68-1.84)

            136.9

            1.54 (1.46-1.62)

            4

            85.7

            148.1

            1.73 (1.65-1.80)

            162.1

            1.89 (1.81-1.97)

            197.0

            2.30 (2.20-2.40)

            141.9

            1.66 (1.57-1.74)

            5

            85.8

            143.3

            1.67 (1.60-1.75)

            147.2

            1.72 (1.64-1.79)

            164.0

            1.91 (1.83-2.00)

            198.1

            2.31 (2.21-2.41)

            Before age 6

            91.5

            162.5

            1.77 (1.75-1.80)

            156.7

            1.72 (1.69-1.74)

            152.2

            1.66 (1.63-1.69)

            141.0

            1.55 (1.51-1.58)

            * compared to rate of ABX in those without asthma by age 6 and adjusted for calendar year

            Abbreviations: ABX - antibiotics; PY - person years; RR - rate ratio

            Antibiotic rates near the asthma index date

            A total of 18,864 children first met our definition of asthma between their 2nd birthday and 31 December 2005. Antibiotics were dispensed to 9,841 (52%) of these children in the 6 months leading up to their asthma index date. They were dispensed 17,245 courses of antibiotics during this period and 4,293 (25%) of these antibiotics were dispensed in the month before the index date. The three most frequently antibiotics/type of antibiotics dispensed were amoxicillin (45%), macrolides (29%) and cephalosporins (14%). Antibiotic dispensing increased prior to the asthma index date and rapidly decreased in the 6 months afterwards (Figure 1). Very few asthma medications were dispensed prior to the asthma index date, a large rate dispensed on the asthma index date (61% of asthmatics dispensed asthma medications on the index date), and then a level similar to that of antibiotic dispensing afterwards (around 200 per 100 PY) (Figure 2).
            http://static-content.springer.com/image/art%3A10.1186%2F1471-2466-11-32/MediaObjects/12890_2010_262_Fig1_HTML.jpg
            Figure 1

            Monthly rate of antibiotic medication dispensing per 100 person-years by months before and months after asthma index date and by age at asthma index date* (Age (years) at asthma index date: blue diamonds = 3, pink squares = 4, yellow triangles = 5, turquoise crosses = 6, purple stars = 7, brown circles = 8-9). * N = 17,297 with 6 months follow-up before and 6-months follow-up post asthma index date

            http://static-content.springer.com/image/art%3A10.1186%2F1471-2466-11-32/MediaObjects/12890_2010_262_Fig2_HTML.jpg
            Figure 2

            Monthly rate of asthma medication dispensing per 100 person-years by months before and months after asthma index date and by age at asthma index date* (Age (years) at asthma index date: blue diamonds = 3, pink squares = 4, yellow triangles = 5, turquoise crosses = 6, purple stars = 7, brown circles = 8-9). * N = 17,297 with 6 months follow-up before and 6-months follow-up post asthma index date

            Exposure to antibiotics in the first year of life was associated with increased antibiotic dispensing in the 6 months prior to the index date (RR 1.26, 95% CI 1.22-1.30) in the multivariable model (Table 2). In addition, visiting a specialist in the previous year (RR 0.85, 95% CI 0.75-0.96) and congenital anomalies (RR 0.93, 95% CI 0.88-0.98) were associated with lower antibiotic dispensing. Asthma diagnosed in spring and summer was associated with a greater rate of antibiotics being dispensed in the previous 6 months than asthma diagnosed in the winter or fall. A decreasing rate of antibiotics dispensing was observed across increasing SES quintiles with the highest SES quintile being associated with 0.91 (95% CI, 0.86-0.96) fold fewer antibiotics being dispensed. Also an increasing rate of dispensing was observed across increasing frequencies of physician visits in the last year, so those visiting a physician ≥ 12 times in the previous year were dispensed antibiotics 7.79 (95% CI, 7.13-8.51) times more frequently relative to those visiting a physician <12 times.
            Table 2

            Multivariable rate ratios of antibiotic dispensing in six months prior to the index date

            Confounder

            n

            %

            Rate of ABX per 100 PY (6 months prior to diagnosis)

            RR

            95% CI

            p

            Age at asthma diagnosis

                  

               2

            6,254

            33.2

            209.9

            1.00

             

            <.0001

               3

            4,810

            25.5

            185.5

            1.03

            0.98 - 1.07

             

               4

            3,316

            17.6

            164.4

            1.00

            0.95 - 1.05

             

               5

            2,338

            12.4

            171.9

            1.10

            1.04 - 1.17

             

               6

            1,272

            6.7

            153.9

            1.03

            0.96 - 1.12

             

               7-8

            874

            4.6

            117.4

            0.89

            0.81 - 0.99

             

            Year of asthma diagnosis

                  

               1999

            475

            2.5

            226.9

            1.00

             

            <.0001

               2000

            1,484

            7.9

            207.8

            0.98

            0.88 - 1.09

             

               2001

            2,165

            11.5

            206.0

            1.03

            0.93 - 1.14

             

               2002

            2,924

            15.5

            178.0

            0.95

            0.86 - 1.06

             

               2003

            3,494

            18.5

            180.4

            0.97

            0.88 - 1.07

             

               2004

            4,351

            23.1

            174.2

            0.98

            0.89 - 1.08

             

               2005

            3,971

            21.1

            171.3

            1.05

            0.95 - 1.16

             

            Season of asthma diagnosis

                  

               Winter

            5,085

            27.0

            179.9

            1.00

             

            <.0001

               Spring

            5,140

            27.2

            217.8

            1.24

            1.19 - 1.30

             

               Summer

            3,142

            16.7

            194.9

            1.13

            1.07 - 1.18

             

               Fall

            5,156

            27.3

            150.6

            0.85

            0.81 - 0.89

             

            Antibiotic exposure in first year

                 

               No

            8,542

            45.3

            145.6

            1.00

             

            <.0001

               Yes

            10,322

            54.7

            213.8

            1.26

            1.22 - 1.30

             

               Gender

                  

               Female

            7,762

            41.2

            181.0

            1.00

             

            0.38

               Male

            11,102

            58.9

            184.3

            0.99

            0.95 - 1.02

             

            Allergist/respirologist/immunologist visit (in last year)

               

               No

            18,487

            98.0

            182.7

            1.00

             

            0.008

               Yes

            377

            2.0

            196.7

            0.85

            0.75 - 0.96

             

            Congenital anomalies (in first year)

                 

               No

            16,943

            89.8

            182.0

            1.00

             

            0.006

               Yes

            1,921

            10.2

            190.9

            0.93

            0.88 - 0.98

             

            SES in the year before diagnosis (quintiles of whole population)*

               

               First quintile

            4,357

            23.1

            201.6

            1.00

             

            0.004

               Second quintile

            4,074

            21.6

            189.8

            0.98

            0.94 - 1.03

             

               Third quintile

            3,744

            19.9

            185.4

            0.98

            0.93 - 1.03

             

               Fourth quintile

            3,290

            17.4

            170.0

            0.95

            0.90 - 1.00

             

               Fifth quintile

            2,744

            14.6

            157.9

            0.91

            0.86 - 0.96

             

               Unknown

            655

            3.5

            171.3

            1.05

            0.96 - 1.15

             

            Physician visits in last year

                  

               0-2

            2,838

            15.0

            44.3

            1.00

             

            <.0001

               3-4

            3,147

            16.7

            92.5

            2.07

            1.87 - 2.29

             

               5-9

            4,626

            24.5

            147.3

            3.31

            3.02 - 3.62

             

               10-12

            4,308

            22.8

            220.7

            4.91

            4.49 - 5.37

             

               >12

            3,945

            20.9

            355.3

            7.79

            7.13 - 8.51

             

            Birth weight (kg)

                 

            0.92

               < 1.5

            177

            0.9

            185.3

            1.00

              

               1.5 - 2.5

            923

            4.9

            195.2

            1.01

            0.85 - 1.21

             

               2.5 - 3.5

            9,593

            50.9

            185.6

            1.01

            0.86 - 1.19

             

               3.5 - 4.5

            7,748

            41.1

            179.0

            1.03

            0.87 - 1.22

             

               > 4.5

            401

            2.1

            169.6

            1.01

            0.83 - 1.23

             

               Unknown

            22

            0.1

            127.3

            0.93

            0.52 - 1.66

             

            Abbreviations: ABX - antibiotics; PY - person years; RR - rate ratio

            * Socioeconomic status by neighbourhood income quintiles - the fifth is the highest income quintile and the first is the lowest income quintile.

            The rate of antibiotic dispensing one month prior to the index date was elevated (RR 1.66, 95% CI 1.60-1.71) compared to the immediate 5 months before this (Table 3). Gender, season, SES, visit to a specialist, and frequency of physician visits in the year prior to diagnosis all independently modified this RR. Specifically, in the subgroup analysis, the rate of antibiotic dispensing in girls and boys was significantly higher in the one month prior to the index date as compared to the 5 months prior (RR 1.77, 95% 1.68-1.87 and 1.58; 95% CI 1.51 - 1.65, respectively). Similarly, those who had not visited a specialist in the year prior had a higher ratio (RR 1.67, 95% 1.61-1.73) relative to those that had. The RR was greater in the fall and winter than spring and summer, although all seasons were associated with a significantly greater rate of antibiotic dispensing one month prior to the index rate than in the previous 5 months. The ratios were also higher for those with fewer physician visits in the prior year and those with a lower SES. For example, those with ≤2 physician visits (RR 2.22, 95% CI 1.86-2.64) and those in the lowest SES quintile (RR 1.70, 95% CI 1.59-1.82) had a higher rate of antibiotic dispensing in the one month prior to the index date compared to the 5 months prior.
            Table 3

            Rate ratios of the frequency of antibiotic dispensing in month before the index date compared to 5 months before in significant subgroups

               

            Rate of ABX per

            Rate of ABX per

            Rate of ABX in month before diagnosis vs 5 months before

               

            100 PY (month

            100 PY (1-6 months

               

            Subgroup

            n

            %

            before diagnosis)

            before diagnosis)

            RR

            95% CI

            p

            Overall

            18,864

            100.0

            273.1

            164.9

            1.66

            1.60 - 1.71

            <.0001

            Gender

                   

               Female

            7,762

            41.2

            284.5

            160.4

            1.77

            1.68 - 1.87

            <.0001

               Male

            11,102

            58.9

            265.1

            168.1

            1.58

            1.51 - 1.65

            <.0001

            Season of asthma diagnosis

                  

               Winter

            5,085

            27.0

            336.3

            155.1

            2.17

            2.04 - 2.30

            <.0001

               Spring

            5,140

            27.2

            290.9

            202.9

            1.43

            1.35 - 1.53

            <.0001

               Summer

            3,142

            16.7

            210.8

            191.7

            1.10

            1.00 - 1.21

            0.04

               Fall

            5,156

            27.3

            249.0

            131.2

            1.90

            1.77 - 2.04

            <.0001

            Allergist/respirologist/immunologist visit (in last year)

                

               No

            18,487

            98.0

            274.1

            164.4

            1.67

            1.61 - 1.73

            <.0001

               Yes

            377

            2.0

            213.2

            193.4

            1.10

            0.80 - 1.51

            0.54

            Physician visits in last year (quintiles)

                 

               0-2

            2,838

            15.0

            81.6

            36.8

            2.22

            1.86 - 2.64

            <.0001

               3-4

            3,147

            16.7

            155.2

            80.0

            1.94

            1.73 - 2.18

            <.0001

               5-9

            4,626

            24.5

            228.3

            131.2

            1.74

            1.61 - 1.88

            <.0001

               10-12

            4,308

            22.8

            336.2

            197.6

            1.70

            1.59 - 1.82

            <.0001

               >12

            3,945

            20.9

            488.5

            328.6

            1.49

            1.41 - 1.57

            <.0001

            SES in the year before diagnosis (quintiles of whole population)

               

               First quintile

            4,357

            23.1

            204.5

            120.4

            1.70

            1.59 - 1.70

            <.0001

               Second quintile

            4,074

            21.6

            185.6

            114.8

            1.62

            1.51 - 1.62

            <.0001

               Third quintile

            3,744

            19.9

            195.9

            109.1

            1.80

            1.66 - 1.80

            <.0001

               Fourth quintile

            3,290

            17.4

            165.1

            103.0

            1.60

            1.47 - 1.60

            <.0001

               Fifth quintile

            2,744

            14.6

            146.4

            97.1

            1.51

            1.36 - 1.51

            <.0001

            Abbreviations: ABX - antibiotics; PY - person years; RR - rate ratio

            * Socioeconomic status by neighborhood income quintiles - the fifth is the highest income quintile and the first is the lowest income quintile.

            Upper and lower respiratory tract infections (RTIs), otitis media and bronchitis were the most frequent diagnoses preceding the antibiotic dispensations in the 6 months prior to the index date (Table 4). Lower RTI and bronchitis were more frequently associated with antibiotic dispensing in the one month before the index date compared to the 5 months before. Upper RTI, acute otitis media, lower urinary tract infection, and skin/soft tissue infection were less frequently associated with antibiotic dispensing in the one month before the index date compared to the 5 months before that.
            Table 4

            Most common diagnoses related to antibiotics dispensed in the 6 months prior to the index date (N = 17,245 antibiotic prescriptions)

             

            One month before

            1-6 months before

            Six months before

            Diagnosis (ICD9 code)

            Number of antibiotic prescriptions

            %

            Number of antibiotic prescriptions

            %

            Number of antibiotic prescriptions

            %

            Upper respiratory tract infection (034, 461-465)

            993

            23.1

            3062

            23.6

            4055

            23.1

            Bronchitis (466, 490-491)*

            785

            18.3

            1658

            12.8

            2443

            13.9

            Acute otitis media (381-382)*

            544

            12.7

            2140

            16.5

            2684

            15.3

            Lower respiratory tract infection (481-486)*

            211

            4.9

            386

            3.0

            597

            3.4

            Skin/soft tissue infection (035, 680-686)*

            39

            0.9

            205

            1.6

            244

            1.4

            Lower urinary tract infection (595, 597, 599)*

            25

            0.6

            206

            1.6

            231

            1.3

            Asthma (493)

            9

            0.2

            20

            0.2

            29

            0.2

            * p < 0.01 for chi-square test for difference in proportion of antibiotics dispensed due to that diagnosis in the previous month compared to 5 months before that.

            Discussion

            This is the first study to clearly show a pattern of increased consumption of antibiotics in children in the period immediately before the diagnosis of asthma. Those children who were eventually diagnosed with asthma had a higher rate of antibiotic use than those who were never diagnosed with asthma during the follow up period of the study. However, the rate of antibiotic use was at the highest in the year that asthma was diagnosed. Specifically, in the one month period leading up to their first asthma-related episode, children with asthma were almost 1.7 times more likely to receive an antibiotic prescription than in the five months prior. In addition, these children were more likely to receive a diagnosis of a lower respiratory tract infection or bronchitis rather than asthma in this time period. This finding, coupled with the fact that those children that were ultimately diagnosed with asthma had a higher baseline rate of antibiotic consumption, highlights the need for clinicians to diagnosis asthma in children promptly and not to inappropriately prescribe antibiotics, especially in those with respiratory symptoms.

            Antibiotics are an important component of treating bacterial infections in both adults and children. But their overuse has important public health consequences as it leads to drug resistance [2024]. Several studies have showed that antibiotic use in Canadian children is not only higher than their European counterparts but that penicillins are more likely to be prescribed in Europe compared to macrolides in Canadian children [11, 12]. Furthermore, clinicians should also keep in mind that young children who present with symptoms of shortness of breath and wheezing may have an infection but for the most part it is viral rather than bacterial, negating the need for antibiotics [25]. As such, much of the antibiotic use documented in this study may have been avoidable. Given the high probability of cough and shortness of breath in young children being due to a viral infection or possibly non-infectious cause (e.g., asthma), a "watch and wait" approach [2628] is advocated for upper respiratory tract infections and frequently for otitis media. Asthma guidelines have been shown to be effective in controlling antibiotic prescribing in this regard but are often challenging to implement [29].

            It is well known that the diagnosis of asthma in children less than 5 years of age is difficult and related to the fact that episodic wheezing and shortness of breath are also present in children who do not have asthma [30]. In addition, there is a challenge to objectively measuring airflow obstruction in this age group especially in primary care where access to spirometry in all age groups is not readily available. Thus, guidelines suggest the following as having a high positive predictive value of asthma in children - frequent (more then once a month) episodes of wheeze, activity induced cough or wheeze, nocturnal cough when the child does not have a viral infection, absence of seasonal variation in wheeze and persistence of respiratory symptoms after the age of 3 years. In young children, the diagnosis of asthma is based on a clinician's judgment, symptomatic improvement after a trial of therapy with inhaled corticosteroids and use of a short acting beta-agonist for symptom relief. In our study, we partially circumvented the problem by excluding all asthma diagnoses in the first two years of life. In addition, the patterns of antibiotic use were the same for older children (5 years old and greater) as younger children (< 5 yrs) increasing the confidence of our results in younger children.

            Several of our observations require further thought. The strongest associations occurred in children from lower socioeconomic status. Our data do not allow for a definitive statement regarding this phenomenon. However, since higher socioeconomic status is associated with higher education, it is possible that parents of higher socioeconomic status were more inquisitive of the child's care leading to the consideration of alternate diagnoses other than infection. Also, we found that females were more likely to have a higher number of prescriptions for antibiotics prior to the diagnosis of asthma. Given that asthma is more common in prepubescent boys than in girls, this result seems counterintuitive. However, given this difference in incidence physicians may be even more reluctant to consider asthma as a diagnosis for girls in this age group and therefore are more likely to prescribe more antibiotics. Another finding of note included that exposure to antibiotics in the first year of life was associated with increased antibiotic dispensing in the 6 months prior to the index date. Despite the fact that the frequency of physician visits were adjusted for in the analysis, it is possible that this finding might be due to residual confounding due to treatment seeking behavior. Finally, we found that asthma diagnosed in spring and summer was associated with a greater rate of antibiotics being dispensed in the previous 6 months than asthma diagnosed in the winter or fall. A possible explanation for this finding is that, due to the presence of allergens in the spring and summer, clinicians might experience patients with more severe respiratory infections and can easily rule out seasonal influenza as the cause. As such, more antibiotics are prescribed during these seasons. All of these findings merit further examination in well-conducted prospective studies.

            Our study is not without limitations. Due to the nature of the data, many important potential confounders (such as birth order, family history of allergic disease, maternal smoking) could not be adjusted for in the multivariable models. However, these variables are unlikely to impact the main analysis which showed an increased rate of antibiotic prescription just before the diagnosis of asthma.

            There are many ways to define asthma diagnosis in administrative data [3133]. We employed a method that was developed and validated by researchers in Canada although on a slightly older group of asthmatics [18]. However, it is possible that, by using this method, we have misclassified some children as asthmatics whose symptoms subsequently resolve. In addition, the converse is also possible with some asthmatic children being classified as non-asthmatic. It's likely there is physician and possibly parental reluctance, to consider asthma as a diagnosis given the potential implications such a label brings. For example, Their et al showed that physicians were very likely to prescribe inhaled corticosteroids for children with asthma but only a small minority of patients had their prescription filled [34]. As such, these patients might be misclassified in an administrative database study.

            We acknowledge that the diagnosis of asthma is difficult in those less than 5 years of age but believe that the consistency of our results between the younger (< 5years) and older (> or = to 5 years) is a validation of our definition. Although we document an association between antibiotic use and the diagnosis of asthma, our study does not address the issue of whether asthma is caused by antibiotics or is an associated finding. Clarifying the answer to this question would be difficult to prove conclusively without a clinical trial which would obviously be prohibited by ethical issues. However, the pattern of use of antibiotics and the immediate reduction in their use post-asthma diagnosis suggests that antibiotics were being used for asthmatic wheeze. This assumption is strengthened by considered the reasons for antibiotic prescription leading up to the asthma diagnosis (bronchitis and upper respiratory infections).

            Conclusions

            Our study shows an increased use of antibiotics in children ultimately diagnosed with asthma compared to children without this diagnosis and use of antibiotics is highest just before the diagnosis of asthma. This suggests that clinicians are initially slow to respond to a pattern of cough as being due to asthma but rather label it as an acute infection. In the setting where antibiotics are often prescribed, a wait and see approach and earlier consideration of the possibility of asthma would lead to a faster resolution of symptoms and the establishment of a correct diagnosis. Less use of antibiotics would also facilitate a lower risk for the development of bacterial resistance as well as the avoidance of antibiotic related morbidity linked to adverse events. We therefore propose that the prescription of more than two courses of antibiotics for respiratory symptoms in a child over a six month period should be sufficient to warrant consideration of an asthma diagnosis.

            Funding

            Funding for this study was provided by the BC Lung Association, British Columbia, Canada. Dr. Carlo Marra is a Canada Research Chair in Pharmaceutical Outcomes and a Michael Smith for Health Research (MSFHR) Scholar. Dr. Larry Lynd is a CIHR New Investigator and a MSFHR Research Scholar. Dr. Mark FitzGerald is a MSFHR Distinguished Scholar and a CIHR/BC Lung Association Investigator Award.

            Declarations

            Authors’ Affiliations

            (1)
            Professor, Faculty of Pharmaceutical Sciences, University of British Columbia; Director, Pharmacy and Vaccine Services, British Columbia Centre for Disease Control
            (2)
            Associate Professor and Director, Collaboration for Outcomes Research and Evaluation, Faculty of Pharmaceutical Sciences, University of British Columbia; Scientist, Centre for Health Evaluation and Outcome Sciences, Providence Health Research Institute
            (3)
            Medical Statistician, Department of Public Health and Primary Care, University of Cambridge
            (4)
            Assistant Professor and Associate Director, Collaboration for Outcomes Research and Evaluation, Faculty of Pharmaceutical Sciences, University of British Columbia; Scientist, Centre for Health Evaluation and Outcome Sciences, Providence Health Research Institute
            (5)
            Professor and Head, Division of Respiratory Medicine, Centre for Lung Health, Faculty of Medicine, University of British Columbia; Scientist, Centre for Clinical Epidemiology and Evaluation Vancouver Coastal Health Research Institute

            References

            1. Masoli M, Fabian D, Holt S, Beasley R: The global burden of asthma: executive summary of the GINA Dissemination Committee report. Allergy 2004, 59:469–478.PubMedView Article
            2. Measuring Childhood Asthma Prevalence Before and After the 1997 Redesign of the National Health Interview Survey--United States [http://​www.​cdc.​gov/​mmwr/​preview/​mmwrhtml/​mm4940a2.​htm] MMWR Centers for Disease Control and Prevention; 2000,49(40):908–911.
            3. Health 4 Kids [http://​www.​hc-sc.​gc.​ca/​english/​for_​you/​health4kids/​body/​asthma.​htm] Health Canada 2009.
            4. Global strategy for asthma management and prevention [http://​www.​ginasthma.​org] Global Initiative for Asthma (GINA) 2008.
            5. Guidelines for the diagnosis and management of asthma (EPR-3) [http://​www.​nhlbi.​nih.​gov/​guidelines/​asthma/​index.​htm] National Heart Lung and Blood Institute (NHLBI) 2007.
            6. British Thoracic Society/Scottish Intercollegiate Guidelines Network: British guideline on the management of asthma. Thorax 2003,58((suppl 1)i):1–94.
            7. van der Molen T, Østrem A, Stallberg B, Østergaard MS, Singh RB: International Primary Care Respiratory Group (IPCRG) Guidelines: management of asthma. Prim Care Respir J 2006, 15:35–47.PubMedView Article
            8. Roghmann M, Sexton M: Adherence to asthma guidelines in general practices. J Asthma 1999, 36:381–7.PubMedView Article
            9. Cohen S, Taitz J, Jaffe A: Paediatric prescribing of asthma drugs in the UK: are we sticking to the guideline? Arch Dis Child 2007, 92:847–849.PubMedView Article
            10. Goodman D, Lorzano P, Stukel T, Chang Ch, Hecht J: Has asthma medication use in children become more frequent, more appropriate, or both? Pediatrics 1999, 104:187–94.PubMedView Article
            11. Marra F, Monnet DL, Patrick DM, Chong M, Brandt CT, Winters M, Kaltoft MS, Tyrrell GJ, Lovgren M, Bowie WR: A comparison of antibiotic use in children between Canada and Denmark. Ann Pharmacother 2007, 41:659–66.PubMedView Article
            12. Marra F, Patrick DM, Chong M, Bowie WR: Antibiotic use among children in British Columbia, Canada. J Antimicrob Chemother 2006, 58:830–9.PubMedView Article
            13. Kozyrskyj AL, Carrie AG, Mazowita GB, Lix LM, Klassen TP, Law BJ: Decrease in antibiotic use among children in the 1990s: not all antibiotics, not all children. CMAJ 2004, 171:133–8.PubMedView Article
            14. Hamm RM, Hicks RJ, Bemben DA: Antibiotics and respiratory infections: are patients more satisfied when expectations are met? J Fam Pract 1996, 43:56–62.PubMed
            15. Schwartz RH, Freij BJ, Ziai M, Sheridan MJ: Antimicrobial prescribing for acute purulent rhinitis in children: a survey of pediatricians and family practitioners. Pediatr Infect Dis 1997, 16:185–90.View Article
            16. WHO Collaborating Centre for Drug Statistics Methodology: ATC Index with DDDs 2010. Oslo: WHO Collaborating Centre; 2009. (depending on the year you have been using)
            17. Marra F, Marra CA, Richardson K, Lynd LD, Kozyrskyj A, Patrick DM, Bowie WR, Fitzgerald JM: Antibiotic use in children is associated with increased risk of asthma. Pediatrics 2009, 123:1003–10.PubMedView Article
            18. Kozyrskyj AL, Mustard CA, Becker AB: Identifying children with persistent asthma from health care administrative records. Can Respir J 2004,11(2):141–5.PubMed
            19. Diggle P, Liang K, Zeger S: Analysis of Longitudinal Data. London: Oxford University Press; 1994.
            20. Riedel S, Beekmann SE, Heilmann KP, Richter SS, Garcia-de-Lomas J, Ferech M, Goosens H, Doern GV: Antimicrobial use in Europe and antimicrobial resistance in Streptococcus pneumoniae. Eur J Clin Microbiol Infect Dis 2007, 26:485–490.PubMedView Article
            21. Bronzwaer SL, Cars O, Buchholz U, Mölstad S, Goettsch W, Veldhuijzen IK, Kool JL, Sprenger MJ, Degener JE: European Antimicrobial Resistance Surveillance System. A European study on the relationship of antimicrobial use and antimicrobial resistance. Emerging Infectious Diseases 2002, 8:278–282.PubMedView Article
            22. Steinman MA, Landefeld CS, Gonzales R: Predictors of broad-spectrum antibiotic prescribing for acute respiratory tract infections in adult primary care. JAMA 2003,289(6):719–25.PubMedView Article
            23. Gonzales R, Steiner JF, Sande MA: Antibiotic prescribing for adults with colds, upper respiratory tract infections, and bronchitis by ambulatory care physicians. JAMA 1997, 278:901–4.PubMedView Article
            24. Aspinall SL, Good CB, Metlay JP, Mor MK, Fine MJ: Antibiotic prescribing for presumed nonbacterial acute respiratory tract infections. Am J Emerg Med 2009, 27:544–51.PubMedView Article
            25. >National Institute for Health and Clinical Excellence: Prescribing of antibiotics for self-limiting respiratory tract infections in adults and children in primary care. [http://​www.​nice.​org.​uk/​Guidance/​CG69] Clinical guidance CG69 2008.
            26. Little P: Delayed prescribing of antibiotics for upper respiratory tract infection. BMJ 2005, 331:301–2.PubMedView Article
            27. Spiro DM, Tay KY, Arnold DH, Dziura JD, Baker MD, Shapiro ED: Wait-and-see prescription for the treatment of acute otitis media: A randomized controlled trial. JAMA 2006, 296:1235–41.PubMedView Article
            28. Little P, Gould C, Williamson I, Moore M, Warner G, Dunleavey J: Pragmatic randomized controlled trial of two prescribing strategies for childhood acute otitis media. BMJ 2001, 322:336–42.PubMedView Article
            29. FitzGerald JM, Quon B: The impact of asthma guidelines. The Lancet 2010, 376:751–753.View Article
            30. Global strategy for diagnosis and management of asthma in children less than 5 years of age [http://​www.​ginasthma.​org] Global Initiative for Asthma (GINA) 2009.
            31. Blais L, Beauchesne MF, Lévesque S: Socioeconomic status and medication prescription patterns in pediatric asthma in Canada. J Adolesc Health 2006, 38:607.e9–16.View Article
            32. Wu AC, Li L, Miroshnik I, Glauber J, Gay C, Lieu TA: Outcomes after periodic use of inhaled corticosteroids in children. J Asthma 2009, 46:517–22.PubMedView Article
            33. Dombkowski KJ, Wasilevich EA, Lyon-Callo SK: Pediatric asthma surveillance using Medicaid claims. Public Health Rep 2005, 120:515–24.PubMed
            34. Thier SL, Yu-Isenberg KS, Leas BF, Cantrell CR, DeBussey S, Goldfarb NI, Nash DB: In chronic disease, nationwide data show poor adherence by patients to medications and by physicians to guidelines. Manag Care 2008, 17:48–52.PubMed
            35. Pre-publication history

              1. The pre-publication history for this paper can be accessed here:http://​www.​biomedcentral.​com/​1471-2466/​11/​32/​prepub

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