J ALLERGY CLIN IMMUNOL

VOLUME 127, NUMBER 4

LETTERS TO THE EDITOR 1071

from this approach. To provide further support for this conclusion,a double-blind, placebo-controlled study is currently underway toestablish the role of immunotherapy in this type of rhinitis.

We thank Ian Johnstone for help with the final English-language version of

this article.

Carmen Rond�on, MD, PhDa

Natalia Blanca-L�opez, MD, PhDb

Ana Aranda, BSc

Roc�ıo Herrera, BSNc

Jos�e Luis Rodriguez-Bada, BSc

Gabriela Canto, MD, PhDb

Cristobalina Mayorga, PhDc

Mar�ıa Jos�e Torres, MD, PhDa

Paloma Campo, MDa

Miguel Blanca, MD, PhDa

From aAllergy Service, Carlos Haya Hospital, Malaga, Spain; bAllergy Service, Infanta

Leonor Hospital, Madrid, Spain; and cResearch Laboratory, Carlos Haya Hospital-

Fundacion IMABIS, Malaga, Spain. E-mail: carmenrs61@gmail.com.

Supported by the FIS-Thematic Networks and Co-operative Research Centres: RIRAAF

(RD07/0064).

Disclosure of potential conflict of interest: The authors have declared that they have no

conflict of interest.

REFERENCES

1. Huggins KG, Brostoff J. Local production of specific IgE antibodies in allergic-

rhinitis patients with negative skin tests. Lancet 1975;2:148-50.

2. Powe DG, Jagger C, Kleinjan A, Carney AS, Jenkins D, Jones NS. ‘‘Entopy’’:

localized mucosal allergic disease in the absence of systemic responses for atopy.

Clin Exp Allergy 2003;33:1374-9.

3. Rond�on C, Romero JJ, L�opez S, Ant�unez C, Mart�ın-Casa~nez E, Torres MJ, et al.

Local IgE production and positive nasal provocation test in patients with persistent

nonallergic rhinitis. J Allergy Clin Immunol 2007;119:899-905.

4. Rond�on C, Do~na I, L�opez S, Campo P, Romero JJ, Torres MJ, et al. Seasonal id-

iopathic rhinitis with local inflammatory response and specific IgE in absence of

systemic response. Allergy 2008;63:1352-8.

5. Wedb€ackA, EnbomH, ErikssonNE,Mov�erare R,Malcus I. Seasonal non-allergic rhi-

nitis (SNAR)—a new disease entity? A clinical and immunological comparison be-

tween SNAR, seasonal allergic rhinitis and persistent non-allergic rhinitis. Rhinology

2005;43:86-92.

6. Carney AS, Powe DG, Huskisson RS, Jones NS. Atypical nasal challenges in

patients with idiopathic rhinitis: more evidence for the existence of allergy in

the absence of atopy? Clin Exp Allergy 2002;32:1436-40.

7. Ulanova M, Tarkowski A, Hahn-Zoric M, Hanson LA. The common vaccine adju-

vant aluminum hydroxide up-regulates accessory properties of human monocytes

via an interleukin-4-dependent mechanism. Infect Immun 2001;69:1151-9.

8. Rond�on C, Do~na I, Torres MJ, Campo P, Blanca M. Evolution of patients with

nonallergic rhinitis supports conversion to allergic rhinitis. J Allergy Clin Immunol

2009;123:1098-102.

9. Creticos PS, Reed CE, Norman PS, Khoury J, Adkinson NF Jr, Buncher CR, et al.

Ragweed immunotherapy in adult asthma. N Engl J Med 1996;334:501-6.

10. Till SJ, Francis JN, Nouri-Aria K, Durham SR. Mechanisms of immunotherapy.

J Allergy Clin Immunol 2004;113:1025-35.

Available online January 31, 2011.doi:10.1016/j.jaci.2010.12.013

Celiac disease confers a 1.6-fold increased riskof asthma: A nationwide population-basedcohort study

To the Editor:Celiac disease (CD) is a chronic immune-mediated disease that

occurs in about 1% to 2% of individuals in Western Europe.Although the classic form of CD involves gastrointestinal symp-toms, it has become increasingly recognized that extragastrointes-tinal symptoms and complications occur.1 Asthma is a respiratory

disorder characterized by airflow obstruction and inflammationwith a prevalence of 6% to 8% in Swedish children and adults.2

Most earlier research has indicated a positive relationship betweenCD and asthma or airflow obstruction, but relative risk estimateshave varied widely from 1.0 to 7.26, and studies have generallysuffered from small numbers.3 Through the personal identity num-ber,4 wematched nationwide data on small intestinal biopsies withthe Swedish National Patient Register (containing both inpatientcare and hospital outpatient care) to examine the risk of asthmain patients with CD. Through linkageswith theMedical Birth Reg-ister and the Prescribed Drug Register, we also had access to infor-mation on education, cesarean section, bodymass index, smoking,and asthma medication in a subcohort.The exposure of this cohort study was CD according to small

intestinal biopsy (defined as villous atrophy, histopathology stageMarsh 3; see this article’s Table E1 in the Online Repository atwww.jacionline.org). We originally collected data on 351,403 bi-opsy reports representing 287,586 unique individuals. Biopsiestook place from 1969 to 2008. Details on biopsy data collectionhave been published elsewhere.1,5 In all, this study was based on28,281 individuals with CD and 140,295 general population refer-ence individualsmatched for sex, age, and calendar period of studyentry. We defined asthma according to relevant International Clas-sification of Disease (ICD) codes in the Swedish National PatientRegister (see this article’s Table E2 in the Online Repository atwww.jacionline.org). Cox regression estimated hazard ratios(HRs) for subsequent asthma (excluding patients with a diagnosisof asthma before study entry), whereas we used conditional logis-tic regression to examine the risk of previous asthma in CD. Thestudywas approved by the Regional Ethical ReviewBoard of Kar-olinska Institutet.The median age at first asthma diagnosis was 15 years in

patients with CD and 16 years in reference individuals, with amedian duration from study entry (and diagnosis of CD) toasthma of 6 years in both cohorts. During follow-up, 1118individuals with CD and 3379 reference individuals had asubsequent diagnosis of asthma. Detailed results are given inthis article’s Table E3 in the Online Repository at www.jacionline.org.

The risk of asthma was increased in CD (HR, 1.61; 95% CI,1.50-1.72; Table I), with a risk increase remaining 5 years after CDdiagnosis. This risk estimate did not change after adjusting for thecovariates type 1 diabetes and education. Risk estimates did notdiffer by sex or calendar period (Table I). When we requiredindividuals to have had an asthmadiagnosis on at least 2 occasions,the HR was 1.77 (95% CI, 1.62-1.94). Adjusting for smoking,body mass index, and cesarean section, CD was still positively as-sociated with asthma. Restricting our outcome to a diagnosis ofasthma (1) with a record of asthma medication, (2) with at least1 more atopic disorder (allergic rhinitis, allergic conjunctivitis,or eczema), and (3) where study participants had no previous diag-nosis of sarcoidosis, tuberculosis, or pneumonia did not change theHRs. Individuals with CD were also at a 1.7-fold increased risk ofallergic conjunctivitis, allergic rhinitis, and eczema.There was also a positive association between CD and asthma

before the CD diagnosis in the entire study population (odds ratio,1.44; 95% CI, 1.34-1.56).This is the first large population-based study of asthma in

patients with biopsy-verified CD. We found a small but statisti-cally significant increased risk of asthma in CD both before andafter diagnosis. We used biopsy data to ascertain CD. This may

TABLE I. CD and risk of asthma and other atopic disorders

Subgroup

Observed

events, n

Expected

events, n HR; 95% CI P value

Absolute risk/

100,000 PYAR

Excess risk/

100,000 PYAR

Attributable

percentage

Asthma

All 1118 696 1.61; 1.50-1.72 <.001 390 147 38

Year <1 172 86 2.01; 1.69-2.39 <.001 617 310 50

Year 1-4.99 332 236 1.41; 1.25-1.59 <.001 335 97 29

Year 51 614 375 1.64; 1.49-1.79 <.001 384 149 39

Sex

Male 438 261 1.68; 1.51-1.87 <.001 410 166 40

Female 680 435 1.56; 1.43-1.70 <.001 378 136 36

Age

<20 y 711 429 1.66; 1.52-1.80 <.001 560 222 40

20-39 y 118 65 1.80; 1.47-2.22 <.001 222 99 45

40-59 y 177 108 1.64; 1.39-1.94 <.001 263 103 39

601 y 112 96 1.17; 0.95-1.44 .148 285 41 14

Calendar period

1989 and before 194 124 1.56; 1.33-1.84 <.001 243 88 36

1990-1999 586 347 1.69; 1.54-1.85 <.001 407 166 41

2000 and after 338 224 1.51; 1.34-1.70 <.001 538 181 34

Other atopic disease

Allergic conjunctivitis 228 132 1.72; 1.48-2.00 <.001 77 32 42

Allergic rhinitis 816 475 1.72; 1.59-1.86 <.001 277 116 42

Eczema 532 302 1.76; 1.60-1.94 <.001 180 78 43

PYAR, Person-years at risk.

Reference is general population comparison cohort.

J ALLERGY CLIN IMMUNOL

APRIL 2011

1072 LETTERS TO THE EDITOR

explain why we found lower risk estimates for asthma than manyother studies using inpatient data on CD.3 Biopsy data with vil-lous atrophy has a high sensitivity for diagnosed CD as well asa high specificity.In CD, gluten occurring in wheat, barley, and rye is deamidated

by transglutaminase 2 and then presented in the form of peptidesto T cells by antigen-presenting cells in the gut. Activated CD41

T cells produce mainly TH1 cytokines, including IFN-g, whereasasthma has a TH2-type cytokine profile. Regulatory T (Treg) cells,both so-called ‘‘natural’’ forkhead box protein 31 Treg cells andinduced, IL-10 producing Treg cells, have been implicated inthe control of TH2 as well as TH1 responses. However, there isevidence that the Treg-cell function is deficient in patients withallergic and asthmatic disease.6

The positive association between CD and asthma may be aresult of malnutrition, because some 60% to 70% of patients withCD have low levels of 25-(OH) vitamin D,7 often several yearsafter diagnosis.8 Vitamin D affects immune cells, in particularTreg cells, through direct effects of calcitriol on effector T cells,such as inhibition of proliferation and IL-2 production, or througha Treg-cell–promoting effect of calcitriol on T cells, either di-rectly or indirectly via dendritic cells.9 Therefore, vitamin D de-ficiency as seen in CD could lead to a reduced suppressivecapacity of Treg cells, and the resulting inability to controlT-cell responses could contribute to the development of asthma.Alternative explanations for the positive association betweenCD and asthma include shared genetics and high antioxidantlevels. Of note, shared risk factors are consistent with our findingsthat there was a positive association between CD and asthma, alsobefore CD diagnosis.This study has several limitations. We had no data on spirom-

etry, IgE levels, or nitric oxide levels in patients with asthma. Inaddition, we had no information on dietary adherence in patientswith CD and thus cannot rule out that a gluten-free diet reduces

the excess risk of asthma in patients with CD who comply withthis dietary recommendation.In conclusion, this study found a positive association between

CD and asthma. We propose that this association may be a resultof vitamin D deficiency and subsequently insufficient Treg-cellcapacity, or shared risk factors.

Jonas F. Ludvigsson, PhDa,b

Kari Hemminki, PhDc,d

Jan Wahlstr€om, PhDe

Catarina Almqvist, PhDf,g

From athe Department of Pediatrics, €Orebro University Hospital, €Orebro; bthe Clinical

Epidemiology Unit, Department of Medicine, Karolinska University Hospital and

Karolinska Institutet, Stockholm; cthe Division of Molecular Genetic Epidemiology,

German Cancer Research Center, Heidelberg, Germany; dthe Center for Primary

Health Care Research, Lund University, Malm€o; and ethe Department of Medicine

(Solna), Respiratory Medicine Unit, fthe Department of Medical Epidemiology and

Biostatistics, and gthe Department of Women’s and Children’s Health and Astrid

Lindgren Children’s Hospital, Karolinska Institutet, Stockholm, Sweden. E-mail:

jonasludvigsson@yahoo.com.

J.F.L. was supported by a grant from the €Orebro University Hospital while writing this

report.

This project was supported by grants from the Swedish Society of Medicine, the Swed-

ish Research Council–Medicine (522-2A09-195), the Sven Jerring Foundation, the€Orebro Society of Medicine, the Karolinska Institutet, the Clas Groschinsky Founda-

tion, the Juhlin Foundation, the Majblomman Foundation, the Uppsala-€Orebro Re-

gional Research Council, the Swedish Celiac Society, and the Swedish Council for

Working Life and Social Research and grants from the Swedish Research Council

(SIMSAM grant no. 80748301).

This project (2006/633-31/4) was approved by the Regional Ethical Review Board in

Stockholm, Sweden, on June 14, 2006.

Disclosure of potential conflict of interest: The authors have declared that they have no

conflict of interest.

REFERENCES

1. Ludvigsson JF, Montgomery SM, Ekbom A, Brandt L, Granath F. Small-intes-

tinal histopathology and mortality risk in celiac disease. JAMA 2009;302:

1171-8.

FIG 1. Airflow limitation (A, measured as FEV1/FVC%predicted) and air-

trapping (B, measured as plethysmographic RV/TLC%predicted) in boys

and girls with severe and nonsevere asthma classifications, at

medication-hold baseline (BSLN) and PstBD. Significant differences:

***vs baseline; **vs respective nonsevere subgroup; *vs respective fe-

male, severe asthma subgroup. Boxes indicate medians and interquartile

ranges for each subgroup.

J ALLERGY CLIN IMMUNOL

VOLUME 127, NUMBER 4

LETTERS TO THE EDITOR 1073

2. Asher MI, Montefort S, Bjorksten B, Lai CK, Strachan DP, Weiland SK, et al.

Worldwide time trends in the prevalence of symptoms of asthma, allergic rhinocon-

junctivitis, and eczema in childhood: ISAAC Phases One and Three repeat multi-

country cross-sectional surveys. Lancet 2006;368:733-43.

3. Kero J, Gissler M, Hemminki E, Isolauri E. Could TH1 and TH2 diseases coexist?

Evaluation of asthma incidence in children with coeliac disease, type 1 diabetes, or

rheumatoid arthritis: a register study. J Allergy Clin Immunol 2001;108:781-3.

4. Ludvigsson JF, Otterblad-Olausson P, Pettersson BU, Ekbom A. The Swedish per-

sonal identity number: possibilities and pitfalls in healthcare and medical research.

Eur J Epidemiol 2009;24:659-67.

5. Ludvigsson JF, Brandt L, Montgomery SM, Granath F, Ekbom A. Validation study

of villous atrophy and small intestinal inflammation in Swedish biopsy registers.

BMC Gastroenterol 2009;9:19.

6. Robinson DS. Regulatory T cells and asthma. Clin Exp Allergy 2009;39:

1314-23.

7. Kemppainen T, Kroger H, Janatuinen E, Arnala I, Kosma VM, Pikkarainen P,

et al. Osteoporosis in adult patients with celiac disease. Bone 1999;24:

249-55.

8. Hallert C, Grant C, Grehn S, Granno C, Hulten S, Midhagen G, et al. Evidence of

poor vitamin status in coeliac patients on a gluten-free diet for 10 years. Aliment

Pharmacol Ther 2002;16:1333-9.

9. Dimeloe S, Nanzer A, Ryanna K, Hawrylowicz C. Regulatory T cells, inflammation

and the allergic response-the role of glucocorticoids and vitamin D. J Steroid Bio-

chem Mol Biol 2010;120:86-95.

Available online February 11, 2011.doi:10.1016/j.jaci.2010.12.1076

Sex dependence of airflow limitation and airtrapping in children with severe asthma

To the Editor:The National Heart, Lung, and Blood Institute’s Severe

Asthma Research Program (SARP) database is compiled from10 centers with studies involving subjects with severe asthma,1 in-cluding the pediatric cohort at Emory University. A SARP studyof airway physiology in adults with severe asthma found that,compared with patients with nonsevere asthma, the severe groupexhibited marked air-trapping relative to the level of airflow lim-itation, and greater persistence of airflow limitation after maximalbronchodilation (PstBD).2 Male sex and age were independentpredictors of PstBD airflow limitation.2 Previous studies indicatethat the duration of asthma may be an important determinant ofthe severe asthma phenotype seen in adults,3,4 although deteriora-tion of PstBD spirometry may occur at a younger age, especiallyin boys.5 In an earlier publication describing the first 75 childrenevaluated in SARP, we reported that children with severe asthmahad significantly greater air-trapping and airflow limitation duringbronchodilator hold, and more airflow limitation PstBD, indicat-ing that at least some of the <18-year-olds had patterns of airwayphysiology similar to adults with severe asthma.6 However, thatreport was based on relatively few children with severe asthma,and subsequently the SARP characterization procedures havebeen modified to provide a more detailed analysis of airway phys-iology. We therefore hypothesized that the impairment in lungfunction we have seen in adults with severe asthmamight be iden-tified in children and related to duration of asthma, age, and sex.The Emory SARP cohort currently includes data from 77

children with severe asthma and 71 children with nonsevereasthma ages 6 to 17 years. Characterization of airway physiologyincluded baseline spirometry and plethysmographic lung vol-umes after a bronchodilator withhold, and again after maximalbronchodilation with up to 8 puffs of albuterol. Data wereanalyzed by using repeated-measures and single-measure 2-wayANOVA models. The residual lung volume after maximal

expiration/total lung capacity ratio as a percentage of thepredicted value (RV/TLC%predicted) was log-transformed.Post hoc pairwise comparisons of interactive effects were per-formed with the Fisher least significant difference test. Inclusiverepeated-measures ANOVA containing categorical variables forsex and asthma severity group revealed significant (P < .007)group-by-sex interactions for both airflow limitation and air trap-ping, necessitating separation of the repeated-measures analysesby subgroups—that is, severity group effects within each sexand sex effects within each severity group. Fig 1 summarizesthe pre/postbronchodilator data for each subgroup.Subjects in the nonsevere asthma group had modest airflow

limitation at baseline, with only 19% having an FEV1/forced vitalcapacity (FVC) ratio below the lower limit of normal (<89% pre-dicted for boys and<90% predicted for girls7), and no differencesbetween sexes (P > .4; Fig 1, A). The severe asthma groupexhibited greater airflow limitation than the nonsevere group(P < .0001), with 54% of the girls and 73% of the boys havingthe FEV1/FVC ratio as a percentage of the predicted value(FEV1/FVC%predicted) below normal, and the boys significantlymore obstructed than the girls (P 5 .017). Airflow limitationimproved after maximal bronchodilation in both severity

MAIN FINDINGS: SUMMARYDuring follow-up, 1118 individuals with CD and 3379

reference individuals developed asthma. Hence, patients withCD were at increased risk of subsequent asthma (HR, 1.61; 95%CI, 1.50-1.72). The absolute risk of asthma in patients with CDwas 390 per 100,000 person-years with an excess risk of 147 per100,000.Risk estimates for asthma did not change with adjustment for

type 1 diabetes or education or in a subset of participants withadjustment for smoking, body mass index, or cesarean section.Nor did risk estimates change when we restricted our outcome tothose with both a diagnosis of asthma and a record of asthmamedication, or asthma plus at least 1 more atopic disorder(allergic rhinitis, conjunctivitis, or eczema).In this study, a previous asthma diagnosis increased the risk

of having a later CD diagnosis (odds ratio, 1.44; 95% CI,1.34-1.56).

SUBANALYSESThe following 2 subanalyses were not based on the complete

dataset:

d CD-asthma taking smoking and body mass index into ac-count: women with CD, n 5 2485; reference women, n5 11,937.

d CD-asthma, taking cesarean section into account: we haddata on delivery mode in 12,228 patients with CD (bothmales and females) and 59,304 reference individuals.

ATC CODES IN THE SWEDISH PRESCRIBED DRUG

REGISTERWe examined the risk of having a diagnosis of asthma and a

record of medication for asthma according to relevant AnatomicTherapeutic Chemical classification system (ATC) codes. Wethen used the following ATC codes:

d Inhaled b2-agonist: RO3ACd Inhaled corticosteroids including those with long-actingb2-agonists: R03BA and R03AK

d Leukotriene receptor antagonists: R03DC

The Swedish Prescribed Drug Register contains all prescribeddrugs dispensed to Swedish residents at pharmacies in Sweden

since July 1, 2005, and has an almost 99% coverage excludingdrugs in ambulatory care.

ICD CODESThe following International Classification of Disease (ICD)

codes were used in this study:

d Asthma: ICD-7, 241; ICD-8 and ICD-9, 493; ICD-10, J45and J46.

d Sarcoidosis: ICD-7, 138.0; ICD-8, 135; ICD-9, 135; ICD-10, D86.

d Tuberculosis: ICD-7, 001-019; ICD-8, 010-018; ICD-9,010-019; ICD-10, A15-19.

d Pneumonia–not specified: ICD-7, 490, 491.10, and 491.19;ICD-8, 486; ICD-9, 486; ICD-10, J15.

d Pneumonia caused by pneumococci: ICD-8, 481; ICD-9,481; ICD-10, J13.

d Allergic conjunctivitis: ICD-7, 370; ICD-8, 372; ICD-9,372; ICD-10, H10.1.

d Allergic rhinitis: ICD-7, 240; ICD-8, 507; ICD-9, 477;ICD-10, J30.

d Eczema: ICD-7, 701; ICD-8, 691; ICD-9, 691; ICD-10,L20.

d Diabetes: Earlier versions of the Swedish ICD (7-9) did notdistinguish between type 1 and type 2 diabetes. In thisstudy, type 1 diabetes was defined as a relevant ICD-8-10code (ICD-8, 250; ICD-9, 250; ICD-10, E10-14) recordedbefore the age of 30 years.

AGE AS TIME-SCALE IN THE COX REGRESSIONTo examine whether temporal biases skewed our data, we

performed an additional analysis in which we used age instead ofyears since biopsy/study entry as the time scale in our Coxregression. This did not influence our risk estimates, and with thatmodel, the HR for asthma in patients with CD was 1.61 (95% CI,1.51-1.72).

REFERENCE

E1. Corazza GR, Villanacci V, Zambelli C, Milione M, Luinetti O, Vindigni C, et al.

Comparison of the interobserver reproducibility with different histologic criteria

used in celiac disease. Clin Gastroenterol Hepatol 2007;5:838-43.

J ALLERGY CLIN IMMUNOL

APRIL 2011

1073.e1 LETTERS TO THE EDITOR

TABLE E1. Comparison of small intestinal histopathology classifications

Classification used in this project Villous atrophy

Marsh classification Type IIIa Type IIIb Type IIIc

Marsh description Flat destructive

Corazza et alE1 Grade B1 Grade B2

SnoMed codes M58,

D6218,

M58005

M58,

D6218,

M58006

M58,

D6218,

M58007

KVAST/Alexander classification III

Partial VA

IV

Subtotal VA

IV

Total VA

Characteristics

Villous atrophy 1 11 11IEL 1 1 1Crypt hyperplasia 1 11 11

J ALLERGY CLIN IMMUNOL

VOLUME 127, NUMBER 4

LETTERS TO THE EDITOR 1073.e2

TABLE E2. Characteristics of study participants

Characteristics Matched controls CD

Total, n 140,295 28,281

Age at study entry (y), median (range) 31 (0-95) 31 (0-95)

Attained age (y), median (range) 41 (1-105) 41 (1-100)

Age 0-19 y, n (%) 56,643 (40.4) 11,334 (40.1)

Age 20-39 y, n (%) 25,841 (18.4) 5,199 (18.4)

Age 40-59 y, n (%) 31,671 (22.6) 6,375 (22.5)

Age >_60 y, n (%) 26,140 (18.6) 5,373 (19.0)

Entry year, median (range) 1997 (1969-2008) 1997 (1969-2008)

Follow-up,* (y), median (range) 9 (0-40) 9 (0-38)

Follow-up,* (y), mean 6 SD 10.4 6 6.4 10.1 6 6.4

Females, n (%) 87,314 (62.2) 17,560 (62.1)

Males, n (%) 52,981 (37.8) 10,721 (37.9)

Calendar year

1989 and before, n (%) 20,148 (14.4) 4,066 (14.4)

1990-1999, n (%) 58,664 (41.8) 11,808 (41.8)

2000 and after, n (%) 61,483 (43.8) 12,407 (43.9)

Type 1 diabetes, n (%) 524 (0.4) 884 (3.1)

*Follow-up time until diagnosis of asthma, death from other cause, emigration, or December 31, 2008. In reference individuals, follow-up could also end through small-intestinal

biopsy.

J ALLERGY CLIN IMMUNOL

APRIL 2011

1073.e3 LETTERS TO THE EDITOR

TABLE E3. Additional results

Subanalyses: CD and risk of later asthma HR; 95% CI

Adjustment for

Type 1 diabetes 1.61; 1.50-1.72

Education 1.62; 1.52-1.74

Smoking and body mass index 1.65, 1.18-2.29

Cesarean section 1.64; 1.50-1.78

Exclusions

Excluding the first year of follow-up 1.55; 1.44-1.67

Excluding individuals with a diagnosis of sarcoidosis, tuberculosis, or pneumonia 1.60; 1.49-1.72

Additional requirements for the diagnosis of asthma

Diagnosis of asthma with a record of asthma medication 1.55; 1.43-1.67

Diagnosis of asthma and at least 1 more atopic disorder (allergic rhinitis, allergic conjunctivitis, or eczema) 1.78; 1.58-2.00

J ALLERGY CLIN IMMUNOL

VOLUME 127, NUMBER 4

LETTERS TO THE EDITOR 1073.e4