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Antibiotic consumption in children prior to diagnosis of asthma Marra, Fawziah; Marra, Carlo A; Richardson, Kathryn; Lynd, Larry D; FitzGerald, Mark J May 31, 2011

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RESEARCH ARTICLE Open AccessAntibiotic consumption in children prior todiagnosis of asthmaFawziah Marra1*†, Carlo A Marra2*†, Kathryn Richardson3, Larry D Lynd4 and Mark J FitzGerald5ABSTRACTBackground: 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 asthmarelative to those without asthma.Methods: Using population-based data, 128,872 children were identified with at least 6 years of follow-up. Theadjusted rate-ratio (RR) of antibiotics dispensed to asthmatic as compared to non-asthmatic children wasdetermined.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 antibioticconsumption 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 thefirst 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 tomisdiagnosis and over treatment with antibiotics.BackgroundStudies performed in varying populations over the last30 years have indicated that the prevalence of asthmahas significantly increased [1,2]. Asthma rates are parti-cularly high in children with one in eight school chil-dren being affected [3]. Asthma is difficult to diagnose -particularly in children as frequently their only symptomis coughing which may be mistaken for an upperrespiratory tract infection in addition to the fact thatthey cannot participate in many of the standard diagnos-tic tests. The North American guidelines [4,5] for pedia-tric asthma management outline a stepwise approach toasthma management with the aim being to initiate con-trol of asthma with regular anti-inflammatory therapyand monitor the level of control by use of rescue medi-cation as well as symptoms, and in older children withassessment of airflow obstruction [6,7]. As such, patientsshould start treatment that is consistent with the initialseverity of their asthma and then step down when con-trol has been achieved. The availability of guidelinesdoes not necessarily mean a high uptake by clinicians.Several studies have evaluated the use of asthma medi-cations in adults and children and have shown that 40to 60% of prescribing does not reflect the recommenda-tions in guidelines [8-10].In contrast to the use of asthma medications, antibio-tics are over utilized in children and often prescribedfor viral infections [11-15]. Our recent studies have eval-uated the use of antibiotics in Canadian children and weshowed that although overall antibiotic use had declinedover a decade, their use in a Canadian populationexceeds that of European children [11]. In addition, theuse of antibiotics in children under 4 years of age, was* Correspondence: fawziah.marra@bccdc.ca; carlo.marra@ubc.ca† Contributed equally1Professor, Faculty of Pharmaceutical Sciences, University of British Columbia;Director, Pharmacy and Vaccine Services, British Columbia Centre for DiseaseControl, Vancouver, B.C., Canada2Associate Professor and Director, Collaboration for Outcomes Research andEvaluation, Faculty of Pharmaceutical Sciences, University of British Columbia;Scientist, Centre for Health Evaluation and Outcome Sciences, ProvidenceHealth Research Institute, Vancouver, B.C. CanadaFull list of author information is available at the end of the articleMarra et al. BMC Pulmonary Medicine 2011, 11:32http://www.biomedcentral.com/1471-2466/11/32© 2011 Marra et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative CommonsAttribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction inany medium, provided the original work is properly cited.double that of children between 10-14 years of age - andwas primarily associated with upper respiratory tractinfections, acute otitis media and bronchitis [12].We know that antibiotics are not routinely used in thetreatment of asthma - the asthma treatment guidelinesclearly state that although symptoms associated withpoor asthma control often overlap with symptoms asso-ciated with respiratory tract infections, clinicians shouldtake care in differentiating between the two conditions.We conducted this study to determine the patterns ofantibiotic consumption in children with asthma. Specifi-cally, we wanted to determine if antibiotic consumptionwas greater in children who developed asthma com-pared to those who did not and to examine the rate ofantibiotic consumption prior to the diagnosis of asthma.MethodsStudy PopulationThe longitudinal study cohort consisted of all live birthsin British Columbia (BC), Canada, from January 1997through December 2003. Follow-up information wasavailable from all data files up to December 2005.Data SourcesWe used population-based, linked administrative healthdata that contained information on all physician services(known as MSP), hospital admissions, vital status infor-mation, socioeconomic status (SES) (determinedthrough postal code and census classifications such asmedian neighbourhood income and split by quintilestherefore those in neighborhoods reporting the greatest20% of incomes in the population will be in the 5thquintile) and outpatient dispensing episodes of prescrip-tion drugs (PharmaNet) to assess potential antibioticexposures, potential confounders, and outcomes. Lin-kages among the various data files were achievedthrough the use of a personal health number unique toevery BC resident; all traceable personal identifiers wereremoved to protect patient confidentiality. Ethicsapproval was obtained from the University of BritishColumbia Behavioral Research Ethics Board.Information on dispensed asthma drugs and antibioticsbetween 1997 and 2005 was extracted based on the 2009Anatomical Therapeutic Chemical Classification System(ATC) codes [16]. Asthma medications (ATC codesR03A-D) consisted of short-acting b-agonists, inhaledcorticosteroids, ipratropium, or leukotriene receptorantagonists and ketotifen (ATC code R06AX17). Antibio-tics (ATC code J01) were classified as penicillins, cepha-losporins, macrolides, sulfonamide, or other classes.Physician visits in the database were classified accord-ing to the 3-digit diagnostic code (International Classifi-cation of Diseases, Ninth Revision (ICD-9)) associatedwith that visit and the type of physician (e.g. generalpractitioner versus specialist). These visits were alsoextracted in the year prior to asthma diagnosis. In addi-tion, any visits to an allergist, respirologist, or immunol-ogist visit were obtained. Similar codes were used toclassify hospitalizations.Asthma Definition and Index DateThe definition of asthma employed in our study waseither: (1) a hospital discharge for asthma (ICD9 493);or (2) two medical fee-for-service claims coded ICD9493 within a moving 12-month period; or (3) two pre-scriptions for a known asthma medication within a mov-ing 12-month period. The index date was defined as thedate of the first episode by which the diagnosis ofasthma was established. Previous research comparingvarious database asthma definitions to a gold standardof an allergist’s diagnosis of childhood asthma foundthat this definition of asthma had a positive predictivevalue of 92%, which was higher than other definitionsrequiring fewer visits and prescriptions [17,18].Statistical AnalysisAntibiotic rates in asthmatics versus controlsRates of antibiotic dispensing in asthmatics and non-asthmatics by age 6 were examined in those with atleast 6 years of follow-up from birth (n = 128,872). Wedefined five groups according to their asthma diagnosisin this period: ‘no asthma by age 6’ or asthma definitionreached at age 2, 3, 4, and 5 years. Asthmatics reachingthe index date within their first two years of life (n =22,736) were excluded since the diagnosis of asthma isdifficult and confounded by other illnesses and the rateof antibiotic dispensing was high and variable in this agerange. Annual antibiotic dispensing rates until age 6years were calculated in these five cohorts. As previouswork has shown changes in antibiotic prescribing ratesin this population over time [12], we adjusted for calen-dar year in all analyses. Rate ratios for antibiotic dispen-sing in the four asthma groups compared to the ‘noasthma by age 6’ reference group were also plotted.Antibiotic rates near the asthma index dateWe examined incident asthma cases identified prospec-tively from age two years until the earliest of: 31stDecember 2005, death, or departure from BC (n =18,864). For children not registered in the MSP on 31stDecember 2005, the date of departure from BC wasdefined as the latest occurrence of: MSP coverage, MSPvisits, hospital separations, or PharmaNet records. Thisallowed follow-up up to capture asthma diagnosed to amaximum age of 8 years. The monthly rates of antibio-tic and asthma medication dispensing were plotted byage at asthma index date in those followed for 6 monthsprior to and also for 6 months post the asthma indexdate (n = 17,297).Marra et al. BMC Pulmonary Medicine 2011, 11:32http://www.biomedcentral.com/1471-2466/11/32Page 2 of 10Poisson regression analysis was used to estimate rateratios (RR) and their 95% confidence intervals (CI) forthe rate of antibiotic dispensing in the six months priorto the index date adjusting for the various potential con-founders. As the number of antibiotics dispensed perchild was overdispersed, the deviance chi-square wasused to adjust the standard errors. Potential confoun-ders adjusted for included gender, birth weight, andcongenital anomalies. Time varying covariates includedcalendar year, seasonality, child age, and in the preced-ing year: quintiles of socioeconomic status (SES), fre-quency of physician visits, and allergist/respirologist/immunologist visit.To calculate the RR and 95% CI for the antibiotic pre-scribing rate in the month before the index date comparedto the 5 months before that, Poisson models were usedwith general estimating equations to obtain robust stan-dard errors accounting for the correlation between thetwo rates being estimated for each child [19]. Interactionsbetween the RR and all of the confounders were tested ina Poisson model and results were presented for confoun-ders that independently significantly altered this RR.To examine indications for antibiotics prescribing inthe six months prior to the index date, the infectiousdiagnosis (according to ICD9 codes) were reported forthe most temporal MSP billing code within 5 days pre-ceding the dispensing episode. Proportions of the indica-tions for antibiotic prescribing in the month prior to theindex date and the 5 months prior to that were com-pared via chi-square tests.ResultsAntibiotic rates in asthmatics versus controlsFor those 106,136 children with at least 6 years of fol-low-up (excluding asthmatics reaching their index datein the first 2 years of life), 96,496 (91%) did not meetthe definition of asthma by age 6 years and the remain-ing met the definition at age 2 (2.6%), 3 (2.4%), 4 (2.1%)and 5 (1.9%). The asthmatics first met the criteria fordiagnosis in 57% of cases via a medical claim, 53% byprescription, and 5% by hospital discharge. 12% met thecriteria for asthma diagnosis by medical claim and pre-scription simultaneously. The rates of antibiotic pre-scribing by year of age and by age at the asthma indexdate (adjusted for calendar year - presented for year2000) were characterized for these children (Table 1).The rate was elevated in the asthmatics compared tothe non-asthmatics and this ratio peaked during theyear of asthma diagnosis with a RR of around 2.30-2.36(Table 1).Antibiotic rates near the asthma index dateA total of 18,864 children first met our definition ofasthma between their 2nd birthday and 31 December2005. Antibiotics were dispensed to 9,841 (52%) of thesechildren in the 6 months leading up to their asthmaindex date. They were dispensed 17,245 courses of anti-biotics during this period and 4,293 (25%) of these anti-biotics were dispensed in the month before the indexdate. The three most frequently antibiotics/type of anti-biotics dispensed were amoxicillin (45%), macrolides(29%) and cephalosporins (14%). Antibiotic dispensingincreased prior to the asthma index date and rapidlydecreased in the 6 months afterwards (Figure 1). Veryfew asthma medications were dispensed prior to theasthma index date, a large rate dispensed on the asthmaindex date (61% of asthmatics dispensed asthma medica-tions on the index date), and then a level similar to thatof antibiotic dispensing afterwards (around 200 per 100PY) (Figure 2).Exposure to antibiotics in the first year of life wasassociated with increased antibiotic dispensing in the 6months 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 dis-pensing. Asthma diagnosed in spring and summer wasassociated with a greater rate of antibiotics being dis-pensed in the previous 6 months than asthma diagnosedin the winter or fall. A decreasing rate of antibiotics dis-pensing was observed across increasing SES quintileswith the highest SES quintile being associated with 0.91(95% CI, 0.86-0.96) fold fewer antibiotics being dis-pensed. Also an increasing rate of dispensing wasobserved across increasing frequencies of physician visitsin the last year, so those visiting a physician ≥ 12 timesin the previous year were dispensed antibiotics 7.79(95% CI, 7.13-8.51) times more frequently relative tothose visiting a physician <12 times.The rate of antibiotic dispensing one month prior tothe index date was elevated (RR 1.66, 95% CI 1.60-1.71)compared to the immediate 5 months before this (Table3). Gender, season, SES, visit to a specialist, and fre-quency of physician visits in the year prior to diagnosisall independently modified this RR. Specifically, in thesubgroup analysis, the rate of antibiotic dispensing ingirls and boys was significantly higher in the one monthprior to the index date as compared to the 5 monthsprior (RR 1.77, 95% 1.68-1.87 and 1.58; 95% CI 1.51 -1.65, respectively). Similarly, those who had not visited aspecialist in the year prior had a higher ratio (RR 1.67,95% 1.61-1.73) relative to those that had. The RR wasgreater in the fall and winter than spring and summer,although all seasons were associated with a significantlygreater rate of antibiotic dispensing one month prior tothe index rate than in the previous 5 months. The ratioswere also higher for those with fewer physician visits inMarra et al. BMC Pulmonary Medicine 2011, 11:32http://www.biomedcentral.com/1471-2466/11/32Page 3 of 10the 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 dispensingin the one month prior to the index date compared tothe 5 months prior.Upper and lower respiratory tract infections (RTIs),otitis media and bronchitis were the most frequent diag-noses preceding the antibiotic dispensations in the 6months prior to the index date (Table 4). Lower RTIand bronchitis were more frequently associated withantibiotic dispensing in the one month before the indexdate compared to the 5 months before. Upper RTI,acute otitis media, lower urinary tract infection, andskin/soft tissue infection were less frequently associatedwith antibiotic dispensing in the one month before theindex date compared to the 5 months before that.DiscussionThis is the first study to clearly show a pattern ofincreased consumption of antibiotics in children in theperiod immediately before the diagnosis of asthma.Those children who were eventually diagnosed withasthma had a higher rate of antibiotic use than thosewho were never diagnosed with asthma during thefollow up period of the study. However, the rate of anti-biotic use was at the highest in the year that asthmawas diagnosed. Specifically, in the one month periodleading up to their first asthma-related episode, childrenwith asthma were almost 1.7 times more likely toreceive an antibiotic prescription than in the fivemonths prior. In addition, these children were morelikely to receive a diagnosis of a lower respiratory tractinfection or bronchitis rather than asthma in this timeperiod. This finding, coupled with the fact that thosechildren that were ultimately diagnosed with asthmahad a higher baseline rate of antibiotic consumption,highlights the need for clinicians to diagnosis asthma inchildren promptly and not to inappropriately prescribeantibiotics, especially in those with respiratorysymptoms.Antibiotics are an important component of treatingbacterial infections in both adults and children. Buttheir overuse has important public health consequencesas it leads to drug resistance [20-24]. Several studieshave showed that antibiotic use in Canadian children isnot only higher than their European counterparts butthat penicillins are more likely to be prescribed in Eur-ope compared to macrolides in Canadian children[11,12]. Furthermore, clinicians should also keep inTable 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 dateAge 2 (n = 2,791) Age 3 (n = 2,572) Age 4 (n = 2,238) Age 5 (n = 2,039)Age,yearsRate of ABX per 100PYRate of ABXper 100 PYRR (95%CI)*Rate of ABXper 100 PYRR (95%CI)*Rate of ABXper 100 PYRR (95%CI)*Rate of ABXper 100 PYRR (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)Beforeage 691.5 162.5 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 yearAbbreviations: ABX - antibiotics; PY - person years; RR - rate ratioMarra et al. BMC Pulmonary Medicine 2011, 11:32http://www.biomedcentral.com/1471-2466/11/32Page 4 of 10mind that young children who present with symptomsof shortness of breath and wheezing may have an infec-tion but for the most part it is viral rather than bacter-ial, negating the need for antibiotics [25]. As such,much of the antibiotic use documented in this studymay have been avoidable. Given the high probability ofcough and shortness of breath in young children beingdue to a viral infection or possibly non-infectious cause(e.g., asthma), a “watch and wait” approach [26-28] isadvocated for upper respiratory tract infections and fre-quently for otitis media. Asthma guidelines have beenshown to be effective in controlling antibiotic prescrib-ing in this regard but are often challenging to imple-ment [29].It is well known that the diagnosis of asthma in chil-dren less than 5 years of age is difficult and related tothe fact that episodic wheezing and shortness of breathare also present in children who do not have asthma[30]. In addition, there is a challenge to objectively mea-suring airflow obstruction in this age group especially inprimary care where access to spirometry in all agegroups is not readily available. Thus, guidelines suggestthe following as having a high positive predictive valueof asthma in children - frequent (more then once amonth) episodes of wheeze, activity induced cough orwheeze, nocturnal cough when the child does not havea viral infection, absence of seasonal variation in wheezeand persistence of respiratory symptoms after the age of3 years. In young children, the diagnosis of asthma isbased on a clinician’s judgment, symptomatic improve-ment after a trial of therapy with inhaled corticosteroidsand use of a short acting beta-agonist for symptomrelief. In our study, we partially circumvented the pro-blem by excluding all asthma diagnoses in the first twoyears of life. In addition, the patterns of antibiotic usewere the same for older children (5 years old andgreater) as younger children (< 5 yrs) increasing theconfidence of our results in younger children.Several of our observations require further thought.The strongest associations occurred in children fromlower socioeconomic status. Our data do not allow for adefinitive statement regarding this phenomenon. How-ever, since higher socioeconomic status is associatedwith higher education, it is possible that parents ofhigher socioeconomic status were more inquisitive ofthe child’s care leading to the consideration of alternatediagnoses other than infection. Also, we found thatfemales were more likely to have a higher number of0100200300400500-6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6Time from index date (months)Incidence of ABX (per 100PY)Figure 1 Monthly rate of antibiotic medication dispensing per 100 person-years by months before and months after asthma indexdate 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 postasthma index dateMarra et al. BMC Pulmonary Medicine 2011, 11:32http://www.biomedcentral.com/1471-2466/11/32Page 5 of 10prescriptions for antibiotics prior to the diagnosis ofasthma. Given that asthma is more common in prepu-bescent boys than in girls, this result seems counterin-tuitive. However, given this difference in incidencephysicians may be even more reluctant to considerasthma as a diagnosis for girls in this age group andtherefore are more likely to prescribe more antibiotics.Another finding of note included that exposure to anti-biotics in the first year of life was associated withincreased antibiotic dispensing in the 6 months prior tothe index date. Despite the fact that the frequency ofphysician visits were adjusted for in the analysis, it ispossible that this finding might be due to residual con-founding due to treatment seeking behavior. Finally, wefound that asthma diagnosed in spring and summer wasassociated with a greater rate of antibiotics being dis-pensed in the previous 6 months than asthma diagnosedin the winter or fall. A possible explanation for this find-ing is that, due to the presence of allergens in the springand summer, clinicians might experience patients withmore severe respiratory infections and can easily ruleout seasonal influenza as the cause. As such, more anti-biotics are prescribed during these seasons. All of thesefindings merit further examination in well-conductedprospective studies.Our study is not without limitations. Due to the nat-ure 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 mul-tivariable models. However, these variables are unlikelyto impact the main analysis which showed an increasedrate of antibiotic prescription just before the diagnosisof asthma.There are many ways to define asthma diagnosis inadministrative data [31-33]. We employed a methodthat was developed and validated by researchers inCanada although on a slightly older group of asthmatics[18]. However, it is possible that, by using this method,we have misclassified some children as asthmaticswhose symptoms subsequently resolve. In addition, theconverse is also possible with some asthmatic childrenbeing classified as non-asthmatic. It’s likely there is phy-sician and possibly parental reluctance, to considerasthma as a diagnosis given the potential implicationssuch a label brings. For example, Their et al showedthat physicians were very likely to prescribe inhaled cor-ticosteroids for children with asthma but only a smallminority of patients had their prescription filled [34]. Assuch, these patients might be misclassified in an admin-istrative database study.0200400600800100012001400-6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6Time since index date (months)Incidence of asthma medications   (per 100PY)Figure 2 Monthly rate of asthma medication dispensing per 100 person-years by months before and months after asthma index dateand 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 postasthma index dateMarra et al. BMC Pulmonary Medicine 2011, 11:32http://www.biomedcentral.com/1471-2466/11/32Page 6 of 10Table 2 Multivariable rate ratios of antibiotic dispensing in six months prior to the index dateConfounder n % Rate of ABX per 100 PY (6 months prior to diagnosis) RR 95% CI pAge at asthma diagnosis2 6,254 33.2 209.9 1.00 <.00013 4,810 25.5 185.5 1.03 0.98 - 1.074 3,316 17.6 164.4 1.00 0.95 - 1.055 2,338 12.4 171.9 1.10 1.04 - 1.176 1,272 6.7 153.9 1.03 0.96 - 1.127-8 874 4.6 117.4 0.89 0.81 - 0.99Year of asthma diagnosis1999 475 2.5 226.9 1.00 <.00012000 1,484 7.9 207.8 0.98 0.88 - 1.092001 2,165 11.5 206.0 1.03 0.93 - 1.142002 2,924 15.5 178.0 0.95 0.86 - 1.062003 3,494 18.5 180.4 0.97 0.88 - 1.072004 4,351 23.1 174.2 0.98 0.89 - 1.082005 3,971 21.1 171.3 1.05 0.95 - 1.16Season of asthma diagnosisWinter 5,085 27.0 179.9 1.00 <.0001Spring 5,140 27.2 217.8 1.24 1.19 - 1.30Summer 3,142 16.7 194.9 1.13 1.07 - 1.18Fall 5,156 27.3 150.6 0.85 0.81 - 0.89Antibiotic exposure in first yearNo 8,542 45.3 145.6 1.00 <.0001Yes 10,322 54.7 213.8 1.26 1.22 - 1.30GenderFemale 7,762 41.2 181.0 1.00 0.38Male 11,102 58.9 184.3 0.99 0.95 - 1.02Allergist/respirologist/immunologist visit (in last year)No 18,487 98.0 182.7 1.00 0.008Yes 377 2.0 196.7 0.85 0.75 - 0.96Congenital anomalies (in first year)No 16,943 89.8 182.0 1.00 0.006Yes 1,921 10.2 190.9 0.93 0.88 - 0.98SES in the year before diagnosis (quintiles of whole population)*First quintile 4,357 23.1 201.6 1.00 0.004Second quintile 4,074 21.6 189.8 0.98 0.94 - 1.03Third quintile 3,744 19.9 185.4 0.98 0.93 - 1.03Fourth quintile 3,290 17.4 170.0 0.95 0.90 - 1.00Fifth quintile 2,744 14.6 157.9 0.91 0.86 - 0.96Unknown 655 3.5 171.3 1.05 0.96 - 1.15Physician visits in last year0-2 2,838 15.0 44.3 1.00 <.00013-4 3,147 16.7 92.5 2.07 1.87 - 2.295-9 4,626 24.5 147.3 3.31 3.02 - 3.6210-12 4,308 22.8 220.7 4.91 4.49 - 5.37>12 3,945 20.9 355.3 7.79 7.13 - 8.51Birth weight (kg) 0.92< 1.5 177 0.9 185.3 1.001.5 - 2.5 923 4.9 195.2 1.01 0.85 - 1.212.5 - 3.5 9,593 50.9 185.6 1.01 0.86 - 1.193.5 - 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 - 1.23Unknown 22 0.1 127.3 0.93 0.52 - 1.66Abbreviations: 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.Marra et al. BMC Pulmonary Medicine 2011, 11:32http://www.biomedcentral.com/1471-2466/11/32Page 7 of 10We acknowledge that the diagnosis of asthma is diffi-cult in those less than 5 years of age but believe that theconsistency of our results between the younger (<5years) and older (> or = to 5 years) is a validation ofour definition. Although we document an associationbetween antibiotic use and the diagnosis of asthma, ourstudy does not address the issue of whether asthma iscaused by antibiotics or is an associated finding.Table 3 Rate ratios of the frequency of antibiotic dispensing in month before the index date compared to 5 monthsbefore in significant subgroupsRate of ABX per Rate of ABX per Rate of ABX in month before diagnosis vs 5 months before100 PY (month 100 PY (1-6 monthsSubgroup n % before diagnosis) before diagnosis) RR 95% CI pOverall 18,864 100.0 273.1 164.9 1.66 1.60 - 1.71 <.0001GenderFemale 7,762 41.2 284.5 160.4 1.77 1.68 - 1.87 <.0001Male 11,102 58.9 265.1 168.1 1.58 1.51 - 1.65 <.0001Season of asthma diagnosisWinter 5,085 27.0 336.3 155.1 2.17 2.04 - 2.30 <.0001Spring 5,140 27.2 290.9 202.9 1.43 1.35 - 1.53 <.0001Summer 3,142 16.7 210.8 191.7 1.10 1.00 - 1.21 0.04Fall 5,156 27.3 249.0 131.2 1.90 1.77 - 2.04 <.0001Allergist/respirologist/immunologist visit (in last year)No 18,487 98.0 274.1 164.4 1.67 1.61 - 1.73 <.0001Yes 377 2.0 213.2 193.4 1.10 0.80 - 1.51 0.54Physician visits in last year (quintiles)0-2 2,838 15.0 81.6 36.8 2.22 1.86 - 2.64 <.00013-4 3,147 16.7 155.2 80.0 1.94 1.73 - 2.18 <.00015-9 4,626 24.5 228.3 131.2 1.74 1.61 - 1.88 <.000110-12 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 <.0001SES 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 <.0001Second quintile 4,074 21.6 185.6 114.8 1.62 1.51 - 1.62 <.0001Third quintile 3,744 19.9 195.9 109.1 1.80 1.66 - 1.80 <.0001Fourth quintile 3,290 17.4 165.1 103.0 1.60 1.47 - 1.60 <.0001Fifth quintile 2,744 14.6 146.4 97.1 1.51 1.36 - 1.51 <.0001Abbreviations: 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.Table 4 Most common diagnoses related to antibiotics dispensed in the 6 months prior to the index date (N = 17,245antibiotic prescriptions)One month before 1-6 months before Six months beforeDiagnosis (ICD9 code) Number of antibioticprescriptions% Number of antibioticprescriptions% Number of antibioticprescriptions%Upper respiratory tract infection(034, 461-465)993 23.1 3062 23.6 4055 23.1Bronchitis (466, 490-491)* 785 18.3 1658 12.8 2443 13.9Acute otitis media (381-382)* 544 12.7 2140 16.5 2684 15.3Lower respiratory tract infection(481-486)*211 4.9 386 3.0 597 3.4Skin/soft tissue infection (035, 680-686)*39 0.9 205 1.6 244 1.4Lower urinary tract infection (595,597, 599)*25 0.6 206 1.6 231 1.3Asthma (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 beforethat.Marra et al. BMC Pulmonary Medicine 2011, 11:32http://www.biomedcentral.com/1471-2466/11/32Page 8 of 10Clarifying the answer to this question would be difficultto prove conclusively without a clinical trial whichwould obviously be prohibited by ethical issues. How-ever, the pattern of use of antibiotics and the immediatereduction in their use post-asthma diagnosis suggeststhat antibiotics were being used for asthmatic wheeze.This assumption is strengthened by considered the rea-sons for antibiotic prescription leading up to the asthmadiagnosis (bronchitis and upper respiratory infections).ConclusionsOur study shows an increased use of antibiotics in chil-dren ultimately diagnosed with asthma compared tochildren without this diagnosis and use of antibiotics ishighest just before the diagnosis of asthma. This sug-gests that clinicians are initially slow to respond to apattern of cough as being due to asthma but rather labelit as an acute infection. In the setting where antibioticsare often prescribed, a wait and see approach and earlierconsideration of the possibility of asthma would lead toa faster resolution of symptoms and the establishmentof a correct diagnosis. Less use of antibiotics would alsofacilitate a lower risk for the development of bacterialresistance as well as the avoidance of antibiotic relatedmorbidity linked to adverse events. We therefore pro-pose that the prescription of more than two courses ofantibiotics for respiratory symptoms in a child over a sixmonth period should be sufficient to warrant considera-tion of an asthma diagnosis.FundingFunding for this study was provided by the BC LungAssociation, British Columbia, Canada. Dr. Carlo Marrais a Canada Research Chair in Pharmaceutical Outcomesand a Michael Smith for Health Research (MSFHR)Scholar. Dr. Larry Lynd is a CIHR New Investigator anda MSFHR Research Scholar. Dr. Mark FitzGerald is aMSFHR Distinguished Scholar and a CIHR/BC LungAssociation Investigator Award.Author details1Professor, Faculty of Pharmaceutical Sciences, University of British Columbia;Director, Pharmacy and Vaccine Services, British Columbia Centre for DiseaseControl, Vancouver, B.C., Canada. 2Associate Professor and Director,Collaboration for Outcomes Research and Evaluation, Faculty ofPharmaceutical Sciences, University of British Columbia; Scientist, Centre forHealth Evaluation and Outcome Sciences, Providence Health ResearchInstitute, Vancouver, B.C. Canada. 3Medical Statistician, Department of PublicHealth and Primary Care, University of Cambridge, Cambridge, UK. 4AssistantProfessor and Associate Director, Collaboration for Outcomes Research andEvaluation, Faculty of Pharmaceutical Sciences, University of British Columbia;Scientist, Centre for Health Evaluation and Outcome Sciences, ProvidenceHealth Research Institute, Vancouver, B.C. Canada. 5Professor and Head,Division of Respiratory Medicine, Centre for Lung Health, Faculty ofMedicine, University of British Columbia; Scientist, Centre for ClinicalEpidemiology and Evaluation Vancouver Coastal Health Research Institute,Vancouver, B.C., Canada.Authors’ contributionsFM was involved in the design of the study, submission of ethics,interpretation of the data, and created the first draft of the manuscript. CMdesigned the study, interpreted the data and created the first draft of themanuscript. KR, is a statistician who was analyzed the data and helped withdata interpretation. LL and MF conceived the study and were involved indata interpretation. All authors read and approved the final manuscript.Competing interestsThe author declares that they have no competing interests.Received: 8 November 2010 Accepted: 31 May 2011Published: 31 May 2011References1. Masoli M, Fabian D, Holt S, Beasley R: The global burden of asthma:executive summary of the GINA Dissemination Committee report. Allergy2004, 59:469-478.2. Measuring Childhood Asthma Prevalence Before and After the 1997Redesign of the National Health Interview Survey–United States. InMMWR. Volume 49. Centers for Disease Control and Prevention;2000:(40):908-911[http://www.cdc.gov/mmwr/preview/mmwrhtml/mm4940a2.htm].3. Health 4 Kids. Health Canada 2009 [http://www.hc-sc.gc.ca/english/for_you/health4kids/body/asthma.htm].4. Global strategy for asthma management and prevention. Global Initiativefor Asthma (GINA) 2008 [http://www.ginasthma.org].5. Guidelines for the diagnosis and management of asthma (EPR-3).National Heart Lung and Blood Institute (NHLBI) 2007 [http://www.nhlbi.nih.gov/guidelines/asthma/index.htm].6. British Thoracic Society/Scottish Intercollegiate Guidelines Network: Britishguideline on the management of asthma. 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Spiro DM, Tay KY, Arnold DH, Dziura JD, Baker MD, Shapiro ED: Wait-and-see prescription for the treatment of acute otitis media: A randomizedcontrolled trial. JAMA 2006, 296:1235-41.28. Little P, Gould C, Williamson I, Moore M, Warner G, Dunleavey J: Pragmaticrandomized controlled trial of two prescribing strategies for childhoodacute otitis media. BMJ 2001, 322:336-42.29. FitzGerald JM, Quon B: The impact of asthma guidelines. The Lancet 2010,376:751-753.30. Global strategy for diagnosis and management of asthma in childrenless than 5 years of age. Global Initiative for Asthma (GINA) 2009 [http://www.ginasthma.org].31. Blais L, Beauchesne MF, Lévesque S: Socioeconomic status andmedication prescription patterns in pediatric asthma in Canada. JAdolesc Health 2006, 38:607.e9-16.32. Wu AC, Li L, Miroshnik I, Glauber J, Gay C, Lieu TA: Outcomes afterperiodic use of inhaled corticosteroids in children. J Asthma 2009,46:517-22.33. Dombkowski KJ, Wasilevich EA, Lyon-Callo SK: Pediatric asthmasurveillance using Medicaid claims. Public Health Rep 2005, 120:515-24.34. Thier SL, Yu-Isenberg KS, Leas BF, Cantrell CR, DeBussey S, Goldfarb NI,Nash DB: In chronic disease, nationwide data show poor adherence bypatients to medications and by physicians to guidelines. Manag Care2008, 17:48-52.Pre-publication historyThe pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2466/11/32/prepubdoi:10.1186/1471-2466-11-32Cite this article as: Marra et al.: Antibiotic consumption in children priorto diagnosis of asthma. BMC Pulmonary Medicine 2011 11:32.Submit your next manuscript to BioMed Centraland take full advantage of: • Convenient online submission• Thorough peer review• No space constraints or color figure charges• Immediate publication on acceptance• Inclusion in PubMed, CAS, Scopus and Google Scholar• Research which is freely available for redistributionSubmit your manuscript at www.biomedcentral.com/submitMarra et al. BMC Pulmonary Medicine 2011, 11:32http://www.biomedcentral.com/1471-2466/11/32Page 10 of 10


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