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Clinical Investigations

Respiration 2012;84:416–422

DOI: 10.1159/000340038

Overweight is Associated with AirflowObstruction and Poor Disease Control but Notwith Exhaled Nitric Oxide Change in anAsthmatic Population

Roberta Pisia Marina Aielloa Panagiota Tzania Emilio Marangioa

Dario Olivieria Giovanna Pisib Alfredo Chettaa

a Clinical & Experimental Medicine Department, Respiratory Disease Unit, and b Paediatrics Department,Cystic Fibrosis Unit, University Hospital of Parma, Parma, Italy

independently of gender, atopy, smoking habit, and inhaled

steroid therapy. No difference was observed in FeNO values

between overweight and normal weight patients (27.78 2.3

vs. 27.98 2.2 ppb).Conclusions: Our results show that, in an

asthmatic population, overweight is associated with airflow

obstruction and poor disease control but not with FeNO

change. The findings of the present study support the view

that other factors besides airway inflammation alone may

explain the relationship between asthma and an elevated

BMI. Copyright © 2012 S. Karger AG, Basel

Introduction

In Western countries, asthma and obesity are chronicand prevalent conditions [1]. Epidemiologic investiga-tions have shown an association between obesity or anelevated body mass index (BMI) and prevalent and inci-dent asthma [1]. However, the role of obesity in asthmacontrol and severity remains unclear. As compared withnormal weight patients, severe asthma was found to bemore prevalent in obese patients [2], and obesity has beenrecognized as a risk factor for poor disease control [3]. On

Key Words

Overweight Airflow obstruction Disease control FeNO

Asthma

Abstract

Background: The role of an elevated body mass index (BMI)

in asthma remains controversial. Objectives: To investigate

the relationship between overweight (BMI 1 25 and ̂30),

lung function, disease control, and airway inflammation in

an asthmatic population. Methods: We consecutively stud-

ied 348 patients (age 438 16 years; 211 females). In all pa-

tients, BMI, spirometry, the Asthma Control Test (ACT), and

fractional exhaled nitric oxide (FeNO; ppb) were measured.

Results: One hundred forty-five patients were overweight

and, as compared to those with normal BMI, had lower val-ues of FVC, FEV1 , and FEV1 /FVC and of FEF25–75 even when

normalized for FVC (p ! 0.05 for each comparison). The ratio

between the number of patients with well-controlled asth-

ma (ACT 6 20) and that of patients with poorly controlled

asthma (ACT ! 20) was significantly lower in overweight pa-

tients (1.07 vs. 1.84; 2 = 6.030, p ! 0.01). In overweight pa-

tients, the odds ratio of uncontrolled asthma expressed by

logistic regression analysis was 1.632 (95% CI = 1.043–2.553),

Received: February 2, 2012

Accepted after revision: June 7, 2012

Published online: September 11, 2012

Prof. Alfredo ChettaSSD Funzionalità Polmonare, Padiglione Rasori, Azienda Ospedaliero-UniversitariaViale Rasori 10IT–43125 Parma (Italy)Tel. +39 0 521 703475, E-Mail chetta @ unipr.it

© 2012 S. Karger AG, Basel0025–7931/12/0845–0416$38.00/0

Accessible online at:www.karger.com/res

http://dx.doi.org/10.1159%2F000340038

http://dx.doi.org/10.1159%2F000340038

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Overweight, Airflow Obstruction,

Disease Control, and FeNO in Asthma

Respiration 2012;84:416–422 417

the other hand, elevated BMI was associated with worseasthma control and quality of life but not with asthmaseverity [4]. Furthermore, among adults presenting to theemergency department with acute asthma, asthma exac-erbations in obese and nonobese adults were similar [5].Lastly, using four validated asthma control question-

naires, Clerisme-Beaty et al. [6] failed to find an associa-tion between obesity and asthma control in an urbanpopulation with asthma.

It is also worth noting that the value of airway inf lam-mation in asthmatic patients with elevated BMI remainsto be fully clarif ied [7]. Measurement of the fractional ex-haled nitric oxide (FeNO), a reliable noninvasive markerof airway inflammation [8–11] which has become a clin-ical routine [12–14] in asthmatic patients, has providedconflicting results in patients with asthma when catego-rized by BMI. As compared with normal weight patients,obese asthmatic patients showed lower [15, 16] or similar

[17, 18] FeNO values. Discrepancies in reports on the asthma-obesity rela-

tionship may be partly due to the fact that obesity may beassociated with lung volume changes and comorbidity,such as gastroesophageal reflux disease, which in obesepatients may mimic asthma and may determine inaccu-racy both in diagnosis and in severity grading of asthma.Notably, up to now, no study has been specifically ad-dressed to investigate the relation between asthma andoverweight, a condition in which the effects on lung me-chanics as well as comorbidity are likely to be less re-markable than in morbidly obese patients.

The aim of the present study was to ascertain whetheror not, in a large cohort of asthmatic patients recruited inan Italian tertiary care asthma clinic, overweight patientsdiffer from normal weight patients both in terms of clin-ical and functional features and in terms of airway in-flammation, assessed by FeNO measurement.

Methods

SubjectsPatients (14 years of age and older) with asthma diagnosis ac-

cording to the international guidelines [19] were eligible to takepart in the study and were prospectively recruited over an18-month period, from April 2010 to September 2011, from ourAsthma Outpatient Clinic. In each patient, BMI, duration of dis-ease, smoking habit, and asthma therapy were recorded.

BMI was defined as the weight in kilograms divided by thesquare of the height in meters. In each subject it was calculatedfrom patients’ self-reported height and weight. The internationalstandard definition of obesity was used [20]. Patients were classi-fied as underweight (BMI ! 18.5), normal (18.5 ^ BMI ^ 25),

overweight (25 ! BMI ^ 30), or obese (BMI 1 30). The patientsprovided information on their duration of disease, smoking hab-it, and current medication use by completing a questionnaire.

Atopy was assessed by skin prick tests with a battery of 10 com-mon inhalant allergens. All patients underwent FeNO measure-ment, completed the Asthma Control Test (ACT), and underwentspirometry as part of their visit.

The study was approved by the local ethics committee and allpatients gave their informed consent.

FeNO MeasurementWe ensured that the patients were not affected by any acute

respiratory infection and had followed the pretest instructions,i.e. no nitrate-rich foods or beverages, including alcoholic ones,no tobacco smoking, and no exercise within 1 h preceding the test,as these factors can affect the test results. Moreover, all patientsunderwent FeNO measurement before the lung function test.Only patients able to perform at least two acceptable FeNO mea-surements were included in the analysis. FeNO was measured ac-cording to American Thoracic Society/European Respiration So-ciety (ATS/ERS) guidelines [21] using an FeNO stationary chemi-luminescence analyzer (NIOX; Aerocrine AB, Solna, Sweden).

All FeNO measurements were performed at the same time ofday (8 2 h) to allow a possible circadian rhythm effect. Patientswere seated in the upright position without a nose clip and wereasked to inhale nitric oxide-free air through a filter connected tothe device deeply to total lung capacity and then to exhale for 10sat a constant pressure guided by a visual cue to stabilize the flowrate. All tests were performed at an exhalation pressure of 10–20cm H2 O to maintain a fixed flow rate of 50 ml/s. Measurementswere repeated after a brief rest period until two acceptable values(8 2.5 ppb for measurements ! 50 ppb and 8 5% for measure-ments 6 50 ppb) were obtained (maximum six attempts). Themean of two adequate values for each subject was recorded foranalysis. The system calibration was performed every 14 days.

Asthma Control AssessmentAsthma control was assessed using the Italian version of the

ACT [22]. Patients subjectively evaluated the degree of impair-ment caused by their disease during the preceding 4 weeks by re-sponding to five questions using a five-point scale. The ACT isreliable, valid, and responsive to changes in asthma control overtime [22, 23]. The sum of the scores of the five questions gave thetotal ACT score (range 0–25). A cut-off score of 19 or less identi-fies patients with poorly controlled asthma.

Lung Function TestingLung function was measured by a flow-sensing spirometer

connected to a computer for data analysis (CPFS/D Spirometer;MedGraphics, St. Paul, Minn., USA) which met the ATS stan-dards. The forced vital capacity (FVC), forced expiratory volumein the first second (FEV1 ), FEV1 /FVC ratio, and forced expiratoryflow rate over the middle 50% of the FVC (FEF25–75 ) were record-ed. FVC, FEV1 and FEF25–75 are expressed as absolute values andas percents of predicted values [24], FEV1 /FVC is expressed as apercent.

Statistical AnalysisThe distribution of variables was assessed by means of a Kol-

mogorov-Smirnov goodness-of-fit test. Variables are expressed as

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Pisi /Chetta

Respiration 2012;84:416–422418

means 8 SD unless otherwise specified. Because of their non-Gaussian distribution, FeNO values were log-transformed beforeanalysis and are expressed as geometric means with the corre-sponding standard error (SEGM). An unpaired t test, a Mann-Whitney test, Pearson’s 2 test, and ANOVA for repeated mea-sures were used for comparisons when appropriate. To examinerelationships between measures, Pearson’s correlation coefficient

(r) and Spearman’s rank order correlation coefficient (rs ) wereused when appropriate. Logistic regression analysis was per-formed to test the association between the presence of overweight(dependent variable) and gender, smoking habit, atopy, poorlycontrolled asthma, and inhaled steroid treatment as independent variables. Odds ratios are presented with 95% confidence inter- vals. p^ 0.05 was considered statistically significant.

Results

Of the 422 patients who agreed to participate in the

study, 14 had a BMI ! 18.5 (3.3%), 203 had a BMI 6 18.5and ̂25 (44.6%), and 205 had a BMI 1 25 (48.6%). Of the205 patients with elevated BMI, 145 were overweight(34.3%) and 60 were obese (14.2%). Underweight andobese patients were excluded from the study, leaving 348patients suitable for the final analysis (table 1).

The overweight patients were significantly older thanthe patients with normal BMI (p ! 0.001). The majorityof patients were atopic (75%) with no difference between

the two subgroups of patients (table 1). Patients with nor-mal BMI did not differ from patients with increased BMIin terms of gender distribution, disease duration, andsmoking habit (table 1). In the two subgroups of patients,the ratio between the number of patients treated with in-haled steroids and that of untreated patients tended to besignificantly higher in overweight patients as comparedto normal weight patients (104/41 vs. 130/73; 2 = 2.268,p = 0.082) (table 1). In all patients, spirometry rangedfrom a severe obstructive ventilatory defect to a normal

value (FEV1 /FVC range: 45–98 % and FEV1 range: 43–137%) (table 1).

The spirometry values were significantly lower inoverweight patients as compared to the correspondingones in normal weight patients (table 1). Notably,FEF25–75 values, even when corrected for FVC, were sig-nificantly lower in overweight patients (table 1). Addi-

tionally, in all patients an inverse significant correlationwas found between BMI and FEV1 (r = –0.154; p = 0.004),FEV1 /FVC (r = –0.233; p ! 0.001), and FEF25–75 (r =–0.152; p ! 0.005).

The ACT score was significantly different betweenoverweight and normal weight patients (table 1). In thetwo subgroups of patients, the ratio between the numberof patients with well-controlled asthma (ACT 1 20) andthat of patients with poorly controlled asthma (ACT

Table 1. Patients’ characteristics by BMI category

Overall(n = 408)

18.5 ≤ BMI ≤ 25(n = 203)

25 < BMI ≤ 30(n = 145)

p value*

Age, years 43816 37815 48816 <0.001Gender (M/F) 0.65 0.65 0.65 0.537Atopy (yes/no) 3.00 3.41 2.54 0.143Disease duration, years 11812 11812 11811 0.347Smoking habit (yes/no) 0.18 0.19 0.17 0. 432Steroids (yes/no) 2.05 1.78 2.53 0.082FVC, % predicted 105816 107815 103818 0.045FVC, liters 3.9381.14 4.1681.09 3.6181.12 <0.001FEV1, % predicted 94817 97815 91819 0.001FEV1, liters 2.9880.94 3.2180.89 2.6680.90 <0.001FEV1/FVC, % 7589 7789 7389 <0.001FEF25–75, % predicted 76829 80827 71830 0.005FEF25–75, % liters/s 2.5781.27 2.8781.25 2.1581.17 <0.001FEF25–75, /FVC 0.6480.26 0.6880.26 0.5980.25 0.001ACT (0–25) 20 (17–23) 21 (18–24) 20 (16–23) 0.012FeNO, ppb 27.8 (2.3) 27.9 (2.2) 27.7 (2.3) 0.927

Values are expressed as means8 SD, ratios, medians (25–75% percentile) or geometric means (SEGM).* Patients with BMI ≥18.5 and ≤25 vs. patients with BMI >25 and ≤30.

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Respiration 2012;84:416–422 419

̂ 19) was significantly lower in overweight patients ascompared to patients with normal BMI (1.07 vs. 1.84; 2 = 6.030, p = 0.01) (fig. 1). In the whole study popula-tion, the ratio between the number of well-controlled andpoorly controlled patients was 1.46. Moreover, in all pa-tients ACT score values were inversely related to BMI val-ues (rs = –0.170; p ! 0.001). Logistic regression analysisshowed that overweight was significantly associated withpoorly controlled asthma, but not with gender, smoking

habit, atopy, or inhaled steroids (table 2). No difference was observed in FeNO values betweenoverweight and normal weight patients (table 1), evenwhen patients were further grouped according to BMIand inhaled steroid treatment. The geometric mean val-ues (SEGM) of FeNO of overweight treated, overweightuntreated, normal weight treated, and normal weight un-treated patients were 27.4 (2.3) ppb, 28.5 (2.2) ppb, 27.6(2.3) ppb, and 28.6 (2.2) ppb, respectively (p = 0.783).

Discussion

The main finding of the present study is that over-weight patients with asthma had worse spirometry anddisease control as compared with normal weight patients,regardless of gender, smoking habit, and atopy. The per-

cent of patients who were receiving inhaled steroids tend-ed to be higher among overweight patients than normalweight patients. Importantly, no significant difference inairway inflammation, assessed by FeNO measurement,was found between the two groups of patients. Lastly, ashas been reported in the Italian general population [25],we found that an increased BMI becomes more commonwith increasing age. Incidentally, our results indicate ahigh rate of obesity among adult asthmatics referred toan Italian tertiary care asthma clinic.

Physiologically, an elevated BMI may affect lung vol-umes, with no direct effect on airway caliber [26]. Spiro-

metric variables, such as FVC and FEV1 , tend to decreasewith increasing BMI with no change or increase in FEV1 /FVC [26]. Expiratory flows decrease with increasingweight in proportion to the lung volume, and in obesepatients specific airway resistance, calculated by adjust-ing for the lung volume at which the measurement weremade, is in the normal range [26]. Whether or not asthmaand elevated BMI may interact on lung function has beenlittle investigated so far. In a large group of subjects withnormal values for airway function but a wide range ofBMI, including subjects with a working diagnosis of asth-ma, Jones et al. [27] showed a significant linear relation-ship between BMI and lung volumes with no change inFEV1 /FVC. The study did not provide any separate anal-ysis for asthmatic and nonasthmatic subjects. In a largecohort of young adults aged 28–30 years, King et al. [28]found that after adjusting data for smoking and asthma,an elevated BMI was associated with reduced lung vol-ume, which was in turn linked with airway narrowing asassessed by airway conductance. Interestingly, this studyshowed that the reduction in airway caliber was onlypartly related to the reduction in lung volume, suggestingother nonvolume-related mechanisms.

In this study, we found that f low-volume curve param-eters, such as FVC, FEV1 , and FEF25–75 , were significant-ly lower in overweight asthmatic patients than in normalweight patients. Interestingly, when compared to normalweight patients, the reductions in FVC and in FEV1 werenot affected to the same extent in overweight patients,since in these patients the FEV1 /FVC ratio was signifi-cantly lower. In addition, even when corrected for FVC,the FEF25–75 values were significantly lower in overweight

Table 2. Odds ratios (95% CI) by logistic regression analysis offemale gender, smoking habit, atopy, inhaled steroid therapy, andpoorly controlled disease for overweight patients with asthma

OR (95% CI) p value

Female gender 0.903 (0.577–1.412) 0.653Smoking habit 0.934 (0.508–1.718) 0.827Atopy 0.735 (0.446–1.211) 0.227Inhaled steroids 1.292 (0.803–2.081) 0.291Poorly controlled asthma 1.632 (1.043–2.553) 0.032

0

P a t i e n t s ( % )

Femalegender

Smokinghabit

Atopy Inhaledsteroids

Poorlycontrolled

asthma

NW OW NW OW NW OW NW OW NW OW

20

40

60

80

*100

Fig. 1. Percent of asthmatic patients, categorized by BMI, with fe-male gender, smoking habit, atopy, inhaled steroid therapy, andpoorly controlled asthma. NW = Normal weight; OW = over-weight. * p = 0.012 by 2 .

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patients. Taken together these findings indicate thatoverweight patients, as compared to normal weight pa-tients, had a higher degree of both proximal and periph-eral airflow obstruction, which was greater than expect-ed on the basis of the reduction in lung volume.

The increased airflow obstruction, which we found in

overweight patients, cannot refer to an increase in airwayinflammation since FeNO values did not differ betweenthe two groups of patients. Interestingly, asthmatic pa-tients with elevated BMI as compared to normal weightpatients do not appear to have increased airway cellularinflammation [29]. It also seems likely that the elevatedBMI does not contribute to asthma through convention-al Th type 2-mediated inflammatory pathways [29]. Dix-on et al. [30] recently showed that, in obese patients withasthma, bariatric surgery does not reduce airway eosino-philia even though symptoms and airway hyperrespon-siveness improve. In obese patients, it has been hypoth-

esized that airway structures could be remodelled by ex-posure to pro-inflammatory adipokines or damaged bythe continual opening and closing of small airwaysthroughout the breathing cycle [29] and it cannot be ex-cluded that even in overweight asthmatic patients thesemechanisms may play a role.

Even when our patients were grouped consideringboth BMI and inhaled steroid treatment, we did not findany difference in FeNO values between overweight andnormal weight patients. Previous studies on FeNO mea-surement in asthmatic patients categorized by BMI haveprovided conflicting results, with patients with increasedBMI showing lower [15, 16] or similar [17, 18] values ascompared to controls. It is also worth noting that in largesamples of the general population neither weight [31] norbody fat [32] was significantly associated with FeNO val-ues, whereas in smaller studies including obese patientswith comorbidities [33, 34] an increase in FeNO valueswas associated with obesity. Discrepancies are likely todepend on the heterogeneity of the enrolled patients (e.g.severe obesity, a large range of BMI, comorbidities).

In the present study, overweight patients had worsedisease control and tended to take more inhaled steroids

as compared to normal weight patients. Patients with el-evated BMI may experience wheezing and breathlessnessdue to their excess weight [35] and, consequently, mayfalsely attribute weight-related respiratory symptoms toasthma, causing increased medication use [36]. However,this explanation could be only partly taken into accountfor our results since overweight patients had a greater de-gree of airflow obstruction, to which the asthmatic symp-toms could be attributed. In this context, it is conceivable

that in overweight patients even increased inhaled steroidtherapy, as compared to normal weight patients, was notenough to achieve disease control. It is important to notethat an increase in BMI was associated with an increasein the delay/avoidance of health care [37]. In other words,in overweight patients behavioral factors could condition

self-management both in terms of asthma control and interms of diet and physical activity. Previous studies provided discordant results on the re-

lationship between asthma and elevated BMI, showingpoor [3, 4] or similar [6] asthma control in obese patientsin comparison to normal weight patients. Notably, stud-ies showing poor control [3, 4] recruited patients in out-patient clinics, whereas the study showing no difference[6] recruited patients in community-based outpatientprimary care practices. Moreover, there are some differ-ences between these studies and ours. These studies [3, 4,6] were mainly addressed to obese patients and did not

provide any information on the airway inflammation ofthe patients. Notably, only in one study [4] were the pa-tients assessed by spirometry, which showed a reductionof FVC values in obese patients when compared to nor-mal weight patients.

As compared to the Italian general population [25], inour cohort of patients we found a higher rate of obese pa-tients. Our data are consistent with the results of a previ-ous Canadian report [4] and suggest that in industrial-ized countries obesity may be more common amongadult tertiary care asthmatics than in the general popula-tion. This finding could be due to the fact that asthmaticpatients followed at a tertiary care hospital may be morelikely to have comorbidity than patients followed by pri-mary care physicians.

We acknowledge that this study has some limitations.Firstly, we defined normal weight and overweight only interms of BMI and we cannot exclude that other measuresof excess body weight, such as the waist-hip ratio or waistcircumference, might better clarify the impact of increas-ing body fat on asthma. However, which is the best riskfactor among adiposity measures is still debatable [38].Additionally, we calculated the BMI using self-reported

height and weight. It has been reported that, despite thehigh correlation between measured and self-reporteddata, the prevalence of overweight calculated from mea-sured values is higher than that calculated from self-re-ported values among older adults [39]. When calculatedbased on a self-reported height, the BMI was one unitlower than when calculated from a measured height forpersons older than 70 years [39]. As most of our patientswere young adults (median age 41 years, 30–54 years 25–

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75% percentile), we are confident in our estimates of BMI.Finally, in this study we did not record the comorbiditiesof our patients, such as gastroesophageal reflux disease,which could be a confounding factor in asthmatic pa-tients with elevated BMI. However, it is conceivable thatoverweight is a condition in which the comorbidities

might play a less remarkable role than in morbidly obesepatients. In conclusion, although we cannot infer any cause-ef-

fect relationship between adiposity and clinical and func-tional features of asthma from our data, the present studyshows that preobese asthmatic patients are at an increased

risk of airf low obstruction and poor disease control. Thisstudy also supports the view that factors other than air-way inflammation alone may explain the relationship be-tween an elevated BMI and asthma and further under-lines the relevance which behavioral factors may have inthe management of asthma.

Financial Disclosure and Conflicts of Interest

The authors have no conflict of interest.

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