OBESITY & ASTHMAOBESITY & ASTHMAA Specific A Specific

Phenotype?Phenotype?

Andrea Lessard, BSc; Helene Andrea Lessard, BSc; Helene Turcotte, MSc; Yum Cormier, MD; Turcotte, MSc; Yum Cormier, MD;

and Louis-Philippe Boulet, MD, FCCPand Louis-Philippe Boulet, MD, FCCP

Source: CHEST – Official Publication of the Source: CHEST – Official Publication of the American College of Chest Physician Vol.134, American College of Chest Physician Vol.134, No.2, p317-323, 2008No.2, p317-323, 2008

BACKGROUNDBACKGROUND

Obesity is associated with an Obesity is associated with an increased prevalence of asthma, increased prevalence of asthma, especially in women, and appears to be especially in women, and appears to be more severe in obese. more severe in obese.

This study aimed to determine if This study aimed to determine if obese subjects have a specific asthma obese subjects have a specific asthma phenotypephenotype

OBJECTIVESOBJECTIVESTo examine obese & non-obese subjects To examine obese & non-obese subjects with a confirmed diagnosis of asthma with a confirmed diagnosis of asthma based on bronchodilator response or based on bronchodilator response or airway responsiveness measurements & airway responsiveness measurements & compare the ff:compare the ff:

1.1. The level of asthma control.The level of asthma control.2.2. Pulmonary function & airway Pulmonary function & airway

responsiveness to methacholine.responsiveness to methacholine.3.3. Perception of asthma symptoms.Perception of asthma symptoms.4.4. Airway & systemic inflammation.Airway & systemic inflammation.

Keywords:Keywords:

Asthma Asthma

Obesity Obesity

Phenotype Phenotype

Asthma controlAsthma control

BMIBMI

MethacholineMethacholine

FRCFRC

RVRV

FEVFEV

TLCTLC

ERVERV

Sputum inductionSputum induction

Inflammatory Inflammatory markersmarkers

METHODOLOGYMETHODOLOGY

Subjects & Design:Subjects & Design:

→ → obese & non-obese subjects from Laval obese & non-obese subjects from Laval Hosp. outpatient clinics & advertisementHosp. outpatient clinics & advertisement..

→ → diagnosed with asthma based on diagnosed with asthma based on airway response to metacholine airway response to metacholine <16mg/ml.<16mg/ml.

→ → obese (BMI≥30kg/mobese (BMI≥30kg/m22))

→ → non-obese (BMI<25kg/mnon-obese (BMI<25kg/m22))

Exclusion!Exclusion!

No informed consentNo informed consent

PregnantPregnant

Comorbid illnessComorbid illness

Double blindDouble blind

•MeasurementsMeasurements

11stst visit – visit – ht., wt., hip circumference, ht., wt., hip circumference, spirometry w/ bronchodilator response, spirometry w/ bronchodilator response, sputum induction, venous blood samplessputum induction, venous blood samples

PEPE

ACQ (Asthma Control Questionnaire)ACQ (Asthma Control Questionnaire)

- design to evaluate asthma control by - design to evaluate asthma control by asking the subjects to recall symptoms & asking the subjects to recall symptoms & ββ2-agonist use in the last wk & their FEV1.2-agonist use in the last wk & their FEV1.

- 7-point scale- 7-point scale

Skin-prick Test:Skin-prick Test:

24 common aeroallergens24 common aeroallergens

(+) atopy = wheal dm (+) atopy = wheal dm ≥3mm after 15min.≥3mm after 15min.

Bronchodilator measurements Bronchodilator measurements = 15 min. = 15 min. after the administration 200after the administration 200μμg of inhaled g of inhaled salbutamol.salbutamol.

Induced-sputum SamplesInduced-sputum Samples = analyzed for = analyzed for IgE, eosinophil, CRP & fibrinogen.IgE, eosinophil, CRP & fibrinogen.

22ndnd visit visit

- lung volumes using body - lung volumes using body plethysmographyplethysmography

- Methacholine inhalation testing w/ - Methacholine inhalation testing w/ perception of respiratory symptoms.perception of respiratory symptoms.

•Statistical MethodsStatistical Methods

Sample sizeSample size – derived from a pilot project – derived from a pilot project on a small group of obese vs non-obese on a small group of obese vs non-obese subjects & on previous studies published. subjects & on previous studies published.

The study was designed to have 80% The study was designed to have 80% power to detect a significant relationship power to detect a significant relationship between BMI and Asthma Control Score between BMI and Asthma Control Score (ACQ) w/ a type I error of 5%.(ACQ) w/ a type I error of 5%.

Categorical variables were expressed Categorical variables were expressed using Fisher Exact test.using Fisher Exact test.

p value <0.05 using a two-tailed test was p value <0.05 using a two-tailed test was taken as significant for all statistical tests.taken as significant for all statistical tests.

Data analysis was performed using Data analysis was performed using statistical software (statistical software (SAS v9.1.3 and StatView SAS v9.1.3 and StatView

v5.0.1; SAS Inst.;Cary, NCv5.0.1; SAS Inst.;Cary, NC))

ANALYSIS OF RESULTS ANALYSIS OF RESULTS Out of 96 subjects, 88 were eligible in the Out of 96 subjects, 88 were eligible in the study.study.

3 obese and 3 non-obese subjects had 3 obese and 3 non-obese subjects had PCPC2020 ≥ 16mg/mL were excluded.≥ 16mg/mL were excluded.

1 participant was unable to to perform the 1 participant was unable to to perform the methacholine challenge, and another methacholine challenge, and another failed to attend the 2failed to attend the 2ndnd visit. visit.

Table 1 – Demographic & Medical CharacteristicsTable 1 – Demographic & Medical CharacteristicsNON-OBESENON-OBESE

VARIABLESVARIABLES SABAs SABAs (n=22)(n=22) SABAs + ICSSABAs + ICS (n=22) (n=22)

AgeAge 32.5 32.5 ± 10.0± 10.0 43.7 43.7 ± 13.3± 13.3

Female genderFemale gender 15 (68)15 (68) 22 (100)22 (100)

Asthma duration, yrAsthma duration, yr 18.6 18.6 ± 13.8± 13.8 17.5 17.5 ± 12.1± 12.1

Subj. w/ HPNSubj. w/ HPN 00 2 (9)2 (9)

Subj. w/ DM 2Subj. w/ DM 2 00 00

Subj. w/ GERDSubj. w/ GERD 00 1 (4.5)1 (4.5)

Ex. smokersEx. smokers 7 (31.2)7 (31.2) 11 (50)11 (50)

BMIBMI 23.3 23.3 ±1.8±1.8 22.8 22.8 ± 2.4± 2.4

σσ waist-hip ratio waist-hip ratio 0.78 0.78 ± 0.07± 0.07 0.78 0.78 ± 0.06± 0.06

σσ waist circ. waist circ. 79.0 ± 7.279.0 ± 7.2 77.7 ± 8.977.7 ± 8.9

Subj. w/ atopySubj. w/ atopy 22 (100)22 (100) 17 (77.3)17 (77.3)

OBESEOBESE

VARIABLESVARIABLES SABAsSABAs (n=22) (n=22) SABAs + ICSSABAs + ICS (n=22) (n=22)

AgeAge 36.5 36.5 ± 13.0± 13.0 44.1 44.1 ± 13.5± 13.5

Female genderFemale gender 15 (68)15 (68) 22 (100)22 (100)

Asthma duration, yrAsthma duration, yr 16.7 16.7 ± 8.7± 8.7 24.7 24.7 ± 13.6± 13.6

Subj. w/ HPNSubj. w/ HPN 2 (9)2 (9) 4 (18)4 (18)

Subj. w/ DM 2Subj. w/ DM 2 1 (4.5)1 (4.5) 2 (9)2 (9)

Subj. w/ GERDSubj. w/ GERD 2 (9)2 (9) 3 (13.6)3 (13.6)

Ex. smokersEx. smokers 6 (27.3)6 (27.3) 8 (36.4)8 (36.4)

BMIBMI 37.2 37.2 ± 5.7± 5.7 37.0 37.0 ± 5.8± 5.8

σσ waist-hip ratio waist-hip ratio 0.88 0.88 ± 0.09± 0.09 0.88 0.88 ± 0.09± 0.09

σσ waist circ. waist circ. 109.5 ± 16.2109.5 ± 16.2 107.3 ± 12.4107.3 ± 12.4

Subj. w/ atopySubj. w/ atopy 21 (95.5)21 (95.5) 15 (68.2)15 (68.2)

Table 1Table 1

n = 44 (SABAs)n = 44 (SABAs)

n =44 (ICS)n =44 (ICS)

σσ dose of ICS in obese= 827±282 dose of ICS in obese= 827±282

σσ dose of ICS in non-obese = 814±282 dose of ICS in non-obese = 814±282

Total ACQ ScoresTotal ACQ ScoresSignificantly higher for the obese subjects Significantly higher for the obese subjects than non-obese (p=0.005).than non-obese (p=0.005).Obese subjects significantly more activity Obese subjects significantly more activity limitation (p=0.003) and limitation (p=0.003) and wheezing (p=0.005).wheezing (p=0.005).No significant different: No significant different: - No.of awakenings/night (p=0.15)- No.of awakenings/night (p=0.15)- - ƒ of presence of symptoms on waking ƒ of presence of symptoms on waking (p=0.10).(p=0.10).- amt. of SABA use (p=0.11)- amt. of SABA use (p=0.11)

ACQ total score was positively correlated ACQ total score was positively correlated w/ BMI (p=0.01, r=0.27)w/ BMI (p=0.01, r=0.27)

- waist circumference (p=0.03, r=0.24)- waist circumference (p=0.03, r=0.24)

- not to waist-to-hip ratio- not to waist-to-hip ratio

Table 2Table 2

Table 2 – Spirometry, Lung Volumes, & Methacholine Test Table 2 – Spirometry, Lung Volumes, & Methacholine Test ResultsResults

NON-OBESENON-OBESE

VARIABLESVARIABLES SABAs SABAs (n=22)(n=22) SABAs + ICSSABAs + ICS (n=22) (n=22)

σσ FEV1 % predicted FEV1 % predicted 98 ± 1398 ± 13 90 ± 1790 ± 17

σσ FVC % predicted FVC % predicted 111 111 ± 15± 15 101 101 ± 15± 15

σσ FEV/FVC FEV/FVC 92 ± 1092 ± 10 88 ± 1188 ± 11

σσ FEF FEF25-75% 25-75% % %

predictedpredicted73 73 ± 23± 23 56 56 ± 24± 24

σσ TLC % predicted TLC % predicted 113 113 ± 18± 18 115 115 ± 15± 15

σσ RV % predicted RV % predicted 125 125 ± 33± 33 119 119 ± 28± 28

σσ ERV % predicted ERV % predicted 108 108 ± 44± 44 117 117 ± 33± 33

σσ IC % predicted IC % predicted 108 108 ± 25± 25 106 106 ±± 20 20

σσ change % predicted change % predicted reversibble FEV1reversibble FEV1

6.5 6.5 ± 7.0± 7.0 5.7 5.7 ± 4.6± 4.6

PCPC20 20 mg/mL mg/mL 1.32 (0.79-2.20)1.32 (0.79-2.20) 1.03 (0.66-1.61)1.03 (0.66-1.61)

OBESEOBESE

VARIABLESVARIABLES SABAs SABAs (n=22)(n=22) SABAs + ICSSABAs + ICS (n=22) (n=22)

σσ FEV1 % predicted FEV1 % predicted 100 ± 18100 ± 18 81 ± 1681 ± 16

σσ FVC % predicted FVC % predicted 111 111 ± 18± 18 92 ± 1392 ± 13

σσ FEV/FVC FEV/FVC 94 ± 794 ± 7 90 ± 1290 ± 12

σσ FEF FEF25-75% 25-75% % %

predictedpredicted79 ± 2579 ± 25 50 50 ± 22± 22

σσ TLC % predicted TLC % predicted 104 ± 13104 ± 13 109 109 ± 12± 12

σσ RV % predicted RV % predicted 90 ± 2390 ± 23 117 117 ± 25± 25

σσ ERV % predicted ERV % predicted 78 ± 3678 ± 36 67 67 ± 61± 61

σσ IC % predicted IC % predicted 124 ± 24124 ± 24 127 127 ± 24± 24

σσ change % predicted change % predicted reversibble FEV1reversibble FEV1

4.9 ± 5.24.9 ± 5.2 6.3 6.3 ± 5.6± 5.6

PCPC20 20 mg/mL mg/mL 1.36 (0.77-1.61)1.36 (0.77-1.61) 0.96 (0.55-1.68)0.96 (0.55-1.68)

Methacholine Challenge:Methacholine Challenge:

airway responsiveness to methacholine airway responsiveness to methacholine was higher in subject w/ ICS treatment.was higher in subject w/ ICS treatment.No significant difference bet.the the airway No significant difference bet.the the airway responsiveness to obese & non-obese.responsiveness to obese & non-obese.

20% fall in FEV20% fall in FEV11 in obese & non-obese in obese & non-obese subjects has the same amt. of wheezing subjects has the same amt. of wheezing (p=0.22), phlegm production (p=0.11), (p=0.22), phlegm production (p=0.11), chest tightness (p=0.35), breathlessness chest tightness (p=0.35), breathlessness (p=0.64), cough (p=0.21)(p=0.64), cough (p=0.21)

Despite similar expiratory flows, Despite similar expiratory flows, bronchodilator response, airways responsiveness bronchodilator response, airways responsiveness to methacholine, and symptom perception scores, to methacholine, and symptom perception scores, asthma control was poorer in obese subjects than asthma control was poorer in obese subjects than in non-obese subjects (p=0.005).in non-obese subjects (p=0.005).

Total Lung capacity (p=0.01), expiratory Total Lung capacity (p=0.01), expiratory reserve volume (p<0.0001), functional residual reserve volume (p<0.0001), functional residual capacity (p<0.0001), and residual volume capacity (p<0.0001), and residual volume (p=0.006) were lower in obese subjects than in (p=0.006) were lower in obese subjects than in non-obese subjects.non-obese subjects.

Table 3: Differential Cell Count in Induced SputumTable 3: Differential Cell Count in Induced Sputum

NON-OBESENON-OBESE

VARIABLESVARIABLES SABAs SABAs SABAs + ICSSABAs + ICS

Eosinophils Eosinophils 2.6 (3.7)2.6 (3.7) 15.2 (19.6)15.2 (19.6)

MacrophagesMacrophages 54.5 (30.1)54.5 (30.1) 40.6 (19.4)40.6 (19.4)

LymphocystesLymphocystes 1.3 (0.9)1.3 (0.9) 1.5 (1.3)1.5 (1.3)

NeutrophilsNeutrophils 31.6 (21.8)31.6 (21.8) 40.9 (17.1)40.9 (17.1)

Metachromatic Metachromatic cellscells

10.5 (17.1)10.5 (17.1) 1.9 (2.1)1.9 (2.1)

OBESEOBESE

VARIABLESVARIABLES SABAs SABAs SABAs + ICSSABAs + ICS

Eosinophils Eosinophils 4.6 (12.9)4.6 (12.9) 5.1 (8.8)5.1 (8.8)

MacrophagesMacrophages 42.1 (19.8)42.1 (19.8) 48.7 (23.9)48.7 (23.9)

LymphocystesLymphocystes 1.3 (1.2)1.3 (1.2) 1.5 (1.0)1.5 (1.0)

NeutrophilsNeutrophils 48.6 (21.3)48.6 (21.3) 41.5 (26.7)41.5 (26.7)

Metachromatic Metachromatic cellscells

3.6 (3)3.6 (3) 3.2 (4.1)3.2 (4.1)

OBESEOBESE NON-OBESENON-OBESE

Serum IgESerum IgE

(p=0.96)(p=0.96)

216 216 ± 367 ± 367 IU/mLIU/mL

219 219 ± 245 ± 245 IU/mLIU/mL

σσ serum CRP serum CRP (p=0.001)(p=0.001)

4.3 4.3 ± 3.2 mg/L± 3.2 mg/L 2.4 2.4 ± 3.4 mg/L± 3.4 mg/L

Serum level of Serum level of Fibrinogen Fibrinogen (p=0.0002)(p=0.0002)

3.7 3.7 ± 0.7 g/L± 0.7 g/L 3.1 3.1 ± 0.6 g/L± 0.6 g/L

Induced-sputum eosinophil and Induced-sputum eosinophil and neutrophil counts were similar in both neutrophil counts were similar in both groups, although there was an inverse groups, although there was an inverse correlation between sputum eosinophils and correlation between sputum eosinophils and waist circumference and a trend for a similar waist circumference and a trend for a similar relationship for BMI.relationship for BMI.

Blood serum C-reactive protein Blood serum C-reactive protein (p=0.009) and fibrinogen (p=0.0004) levels (p=0.009) and fibrinogen (p=0.0004) levels were higher in obese subjects than in non-were higher in obese subjects than in non-obese subjects.obese subjects.

DISCUSSIONDISCUSSION

Airway hyperresponsiveness was Airway hyperresponsiveness was comparable in both groups, but differences comparable in both groups, but differences in airway & systemic inflammatory in airway & systemic inflammatory parameters, & changes in pulmonary parameters, & changes in pulmonary function w/ obesity is suggestive of a function w/ obesity is suggestive of a particular asthma phenotype in obese particular asthma phenotype in obese subjects.subjects.

The blood level of CRP & waist The blood level of CRP & waist circumference were correlated w/ lung circumference were correlated w/ lung vol.changes & w/ decrease induced-vol.changes & w/ decrease induced-sputum eosinophil, which could indicate a sputum eosinophil, which could indicate a possible impact of fat distribution & possible impact of fat distribution & systemic inflammatory state in people who systemic inflammatory state in people who are obese on the dev’t & clinical are obese on the dev’t & clinical presentation of asthma.presentation of asthma.

Based on the results, obese subjects have Based on the results, obese subjects have poorer asthma control than non-obese poorer asthma control than non-obese subject, Lavoie et al. found a significant subject, Lavoie et al. found a significant association between BMI & a total ACQ association between BMI & a total ACQ score in 382 asthmatics.score in 382 asthmatics.

Poor asthma control in obese individuals Poor asthma control in obese individuals could also have been due to their having could also have been due to their having an altered perception of asthma an altered perception of asthma symptoms. However in this study, they symptoms. However in this study, they found no significant difference in asthma found no significant difference in asthma symptoms perception between in both symptoms perception between in both groups w/ the same degree of groups w/ the same degree of bronchoconstriction.bronchoconstriction.

A different phenotype of asthma, reduced A different phenotype of asthma, reduced response to treatment, or more severe response to treatment, or more severe asthma could explain the poorer asthma asthma could explain the poorer asthma control in obese asthmatics.control in obese asthmatics.

Obesity & insulin resistance may be the Obesity & insulin resistance may be the the common pathways underlying lung the common pathways underlying lung function impairment & metabolic function impairment & metabolic syndrome. syndrome.

LIMITATION OF THE STUDYLIMITATION OF THE STUDY

Difficulty in determining how much of the Difficulty in determining how much of the observed abnormalities is related to the observed abnormalities is related to the mechanical effect of obesity or to an mechanical effect of obesity or to an altered immune response that could have altered immune response that could have influenced bronchoreactivity.influenced bronchoreactivity.

The type of systemic inflammatory The type of systemic inflammatory markers are nonspecific.markers are nonspecific.

More enrolled obese subjects are female.More enrolled obese subjects are female.

Obese subjects have more comorbid Obese subjects have more comorbid illness.illness.

Diferent smoking history of 2 groups.Diferent smoking history of 2 groups.

Obese people with asthma had poorer Obese people with asthma had poorer asthma control than non-obese asthmatic asthma control than non-obese asthmatic despite similar symptoms perception. despite similar symptoms perception.

Bronchial and systemic inflammatory Bronchial and systemic inflammatory characteristics and the specific pattern of characteristics and the specific pattern of pulmonary function changes suggest a pulmonary function changes suggest a different phenotype of asthma in these different phenotype of asthma in these subjects.subjects.

CONCLUSIONCONCLUSION

RECOMMENDATIONSRECOMMENDATIONS

Modulate a particular type of airway Modulate a particular type of airway inflammation in various organs such as the inflammation in various organs such as the airway in the subject w/ abdominal obesity.airway in the subject w/ abdominal obesity.

Further studies w/ more specific markers Further studies w/ more specific markers of bronchial & systemic inflammation are of bronchial & systemic inflammation are needed to confirm these results.needed to confirm these results.

The impact of weight distribution & body The impact of weight distribution & body composition between women & men could composition between women & men could have different effect to lung volumes & have different effect to lung volumes & level of systemic inflammation, also level of systemic inflammation, also hormonal effects could also influence hormonal effects could also influence these parameters.these parameters.

The impact of comorbid illness to obese The impact of comorbid illness to obese asthmatics needs further research.asthmatics needs further research.