Weight loss and asthma control in severely obese asthmatic females

ARTICLE IN PRESS Respiratory Medicine (2008) 102, 102–108

Weight loss and asthma control in severely obese asthmatic females Mauro Maniscalcoa,b,, Anna Zeddaa, Stanislao Faraonea, Maria Rosaria Cerbonec, Stefano Cristianoc, Cristiano Giardielloc, Matteo Sofiab a

Section of Respiratory Medicine, Hospital S. Maria della Pieta ` Casoria, Naples, Italy Department of Respiratory Medicine, AO Monaldi, University Federico II of Naples, Italy c Department of Surgery, Hospital S. Maria della Pieta ` Casoria, Naples, Italy b

Received 16 May 2007; accepted 26 July 2007 Available online 11 September 2007

KEYWORDS Lung function; Asthma; Exhaled nitric oxide; Inflammation; Surgery; Obesity

Summary Background: Obesity is proposed to represent an important predisposing condition to serious respiratory disturbances including asthma. The effects of consistent weight loss on asthma control are not well known. We investigated the effect of weight reduction induced by bariatric surgery on asthma control in severely obese asthmatic patients. Patients and methods: A consecutive series of 12 asthmatic obese females who had laparoscopic adjustable gastric banding (OB group) and 10 non-operated asthmatic obese females as control group (CG). Body mass index (BMI), Asthma Control Test (ACT), pulmonary function test (PFT), exhaled nitric oxide (NO) were evaluated at baseline and after 1 year. Results: Mean BMI (kg/m2) of OB group decreased from 45.274.7 before surgery to 34.874.2 post-operatively. After surgery the overall ACT score in OB group significantly improved from 18.7 to 22.2 (po0.001), while it remained unchanged in CG (from 18.8 to 18.6, p ¼ 0.73). In particular, in OB group the parameters of shortness of breath and rescue medication use were significantly improved respectively from 3.2 and 3.9 before surgery to 4.2 and 4.6 after surgery (always po0.05). Accordingly, none of the CG who did not experience any weight loss was able to obtain a full asthma control. In the OB group after the surgery PFT significantly improved as compared to CG. No significant difference in exhaled NO was found both in OB group after surgery as compared to before surgery.

Corresponding author. Department of Respiratory Medicine, AO Monaldi, University Federico II of Naples, Largo delle Mimose 1,

80131 Napoli, Italy. Tel./fax: +39 081 7411457. E-mail address: [email protected] (M. Maniscalco). 0954-6111/$ - see front matter & 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.rmed.2007.07.029

ARTICLE IN PRESS Asthma and obesity

103 Conclusion: Consistent weight loss in severely obese patients with asthma is associated to improvement in respiratory symptoms and lung function. However, the mechanisms underlying the effect of large body mass changes on asthma would require further studies. & 2007 Elsevier Ltd. All rights reserved.

Introduction

Measurements

Obesity, the most common nutritional disorder in humans, is a major cause of mortality and morbidity for associated disorders1,2 and it might represent an important predisposing condition to serious respiratory disturbances including asthma. Several studies have reported the association between obesity and asthma prevalence.3–7 In fact, obesity may affect lung function and contribute to an increase in asthma severity.8,9 On the other hand, weight loss may improve lung function and oxygenation in obesity,10,11 and improvement in asthma severity has been reported in adult obese asthmatics after weight loss.12,13 However, only few studies,13–17 mostly retrospective or focused on obesity comorbidities, have evaluated the effects of weight loss attained by bariatric surgery on asthma control, currently defined according to a set of treatment goals, thus giving an assessment of asthma. Recently, attention has focused on the assessment of asthma control with the use of validated questionnaires such as the Asthma Control Test (ACT),18 evaluating activity level, sleep disturbance, the need for rescue albuterol and the global assessment of asthma control. The ACT has been validated as an instrument that can effectively track asthma control status over time.18,19 Similarly, measurement of exhaled nitric oxide (NO) has been increasingly used as a marker of disease activity20–22 and a tool to control to the therapy in asthma.23 Therefore, we investigated whether weight loss induced by bariatric surgery affects lung function, asthma control and exhaled NO in obese patients with asthma.

The weight (kg) and height (m) were determined between 9 and 11 a.m. with the subject barefoot and dressed in very light clothing. From these, the body mass index (BMI) was calculated as the ratio of weight to height squared for each subject.

Materials and methods Patients Twenty-two consecutive severe obese females with previous diagnosis of intermittent or mild to moderate asthma and attending for laparoscopic adjustable gastric banding (LAGB) evaluation to our bariatric surgery clinic were enrolled. All patients were non-smoker or had stopped smoking for 2 years or more. The diagnosis of asthma was conformed to the criteria of the GINA.24 Atopy was determined on the basis of positive wheal responses (43 mm) to 12 common airborne allergen extracts, using a standardized skin prick test kit (Allergopharma, Hamburg, Germany). Exclusion criteria included the following: cardiorespiratory disturbances, obstructive sleep apnea, history of upper respiratory tract infection. Characteristics of the patients and anti-asthmatic medications are presented in Table 1. Twelve patients underwent the laparoscopic adjustable gastric banding by pars flaccida technique25 (OB group) while 10 who refused or were excluded from the surgery represented the control group (CG). No post-operative complications were recorded in OB group. The study protocol was approved by the local ethics committee.

ACT survey To assess the asthma control the ACT survey was used. The ACT survey is a patient-completed questionnaire with five items assessing asthma symptoms (daytime and nocturnal), use of rescue medications, and the effect of asthma on daily functioning. Each item includes five response options corresponding to a five-point Likert-type rating scale. In scoring the ACT survey, responses for each of the five items are summed to yield a score ranging from 5 (poor control of asthma) to 25 (complete control of asthma).

Measurement of exhaled NO NO was detected by a chemiluminescent analyzer (280 NOA Sievers Instruments, Boulder, Sensor Medics, Milan, Italy), characterized by a lower detection limit of 1 (parts per billion) ppb and a NO sampling rate of 200 mL/min. Daily two-point calibration was performed with zero gas (Zero Air Filter, Sievers) and a certified NO gas mixture at 101 ppb (SIAD Osio, Italy). All NO measurements were performed when the patients were fasting. The method recommended for online measurement of the exhaled NO concentration in adults was employed.22 After a full inspiration from room air, subjects exhaled for 10 s through restrictors against positive pressures of 10 cm H2O to generate flow rates of 50 mL/s. This technique allows closing the velum, thus excluding nasal NO during expiration.

Pulmonary function test measurements Lung volumes and flow rates were determined using automated equipment (V Max 22 System SensorMedics, Milan, Italy). Forced inspiratory and expiratory maneuvers were performed three times and the best value obtained from the maximum inspiratory and expiratory flow-volume curves were used for comparison. Recommendation for standardized procedures for various lung function tests was followed.23

Experimental procedure Each person was tested baseline in the run-in period and after 1 year. The PFTs, exhaled NO measurements and ACT questionnaire were performed the same day within 1 month of operation. The PFT and NO measurements and the ACT

ARTICLE IN PRESS 104

Table 1

M. Maniscalco et al.

Baseline characteristics of patients. Sex

Age (years)

Smoke

OB 1 2 3 4

F F F F

53 43 54 34

N N N E

5 6

F F

21 20

7 8

F F

9

BMI (kg/m2)

Atopy

Asthma DUR (years)

GINA classification

Medications (mg)

150 125 114 128

53 43 47 47

P, G, D P, D P P, G

18 12 10 12

Bud 400 bid Bud 200 bid Bud 200 bid Salb prn

N N

120 110

47 40

P, G P

6 10

53 35

E N

103 92

38 40

P, D P, G,

12 22

F

37

N

123

48

P, G, D

30

10

F

55

N

100

44

G

35

11 12

F F

48 56

N E

109 110

43 52

P, G P, G

22 18

Mild per Mild per Mild per Intermittent Mild per Moderate per Mild per Intermittent Moderate per Intermittent Mild per Intermittent

Mean7SD

42.4713

Weight (kg)

115.3715.3 45.274.7

F

43

N

131

45

D

11

2

F

31

N

128

46

P, D

15

3

F

44

N

100

41

D

30

4 5 6 7 8

F F F F F

37 25 24 33 38

E N N E N

128 105 98 122 111

47 43 40 45 47

P, G P P P, D P, G,

18 10 6 8 25

9 10

F F

37 45

N E

113 98

45 42

P, D D

21 30

35.777.0

113713.0

4472.5

Bud 400 bid, salm Salb prn Bud 400 bid Salb prn

17.278.7

CG 1

Mean7SD

Becl 500 bid Bud 400 bid, salm Bud 200 bid Salb prn

Moderate per Intermittent Intermittent Mild per Mild per Mild per Mild per Intermittent Mild per Intermittent

Bud 400 bid, Salm Salb prn Salb prn Becl 500 bid Becl 500 bid Bud 400 bid Bud 200 bid Salb prn Bud 200 bid Salb prn

17.478.8

OB: obese asthmatic who underwent bariatric surgery; CG: obese asthmatic who refused surgery; F: female; N: non-smoker; E: ex smoker; P: parietaria; G: grass pollen; D: dermatophagoides; FVC: forced vital capacity; FEV1: forced expiratory volume in 1 s; per: persistent; bud: budesonide; becl: beclomethasone; salm: salmeterol; salb prn: salbutamol prn as required; bid: bis in die.

questionnaire were repeated 1 year post-operatively in OB group and after 1 year in CG. All measurements were made at lunchtime. All subjects were fasted for 4 h before the tests. The subjects weight and height were measured immediately before the start of the experiment. Patients had been advised not to change their antiasthmatic treatment other than short-acting b2-agonists during the study if the stability of asthma was clinically acceptable. Patients with allergy to pollen were studied out of season. The dose and timing of long-acting b2-agonists were identical at study visits before and after weight loss.

Patients did not consume any short-acting bronchodilators for 4 h before pulmonary function tests.

Statistics Data are presented as means7standard deviation. Twosample paired t-test was used to evaluate differences between patients at baseline and after 1 year. Two-sample unpaired t-test was used to compare OB group and CG. Pearson or Spearman correlation coefficients were used to assess the association between categorical variables,

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105

Table 2 Absolute values (mean7S.D.) and changes (D) in weight, BMI, asthma control test (ACT), exhaled nitric oxide (eNO) and spirometric data for each study group at baseline and after 1 year follow-up. OB group

Weight (kg) DWeight (%) BMI (kg/m2) DBMI (%) ACT score DACT score (%) eNO (ppb) DeNO (%) FEV1 (L) DFEV1 (%) FVC (L) DFVC (%)

Control group

p-Value

Baseline

Follow-up

Baseline

Follow-up

115.3715.3

89.078.5 22 34.874.2 23 22.272.2 +19 36.476.0 +2.0 87.2714.9 +5.1 95.2710.7 +8.4

113.0713.0

118.077.1 +4.4 45.375.1 +2.9 18.671.5 1.1 35.076.1 +6.4 84.5711.3 +2.6 86.1711.5 1.2

45.274.7 18.772.6 35.776.3 83.0714.4 87.8713.5

44.072.5 18.871.6 32.976.4 82.377.5 87.1710.3

anthropometrics measures, spirometric data and exhaled NO. A p-value less than 0.05 was considered significant.

0.2 0.02 0.001

20 15 10 5 0

Baseline

1 year NS

25 20 ACT score

ACT survey Baseline ACT score was not significantly different between OB group before surgery and CG (p ¼ 0.9). Figure 1 displays the overall perception of health status of OB group before and after the surgery. After surgery the overall ACT score significantly improved from 18.7 to 22.2 (po0.001). In eight obese patients before surgery the ACT score was p19, whereas only one patient had a score p19 after surgery. Furthermore, 10 among 12 obese patients after surgery referred a marked improvement of asthma control as compared to the pre-surgery condition referring perceived excellent or good overall health. On the other hand, one reported a worsening and one no changes as compared to before surgery. All five ACT parameters were improved consistently. In particular, the parameters of shortness of breath and rescue medication use were significantly improved respectively from 3.2 and 3.9 before surgery to 4.2 and 4.6 after surgery (always po0.01). No correlation was found between either the overall ACT score or the single ACT parameters and BMI (always p40.05).

o0.001

25

ACT score

No difference in mean weight was found between OB group before surgery and CG at baseline (p ¼ 0.48). Mean weight in the OB group before surgery was 115.3715.3 kg and it significantly decreased 1 year after surgery (89.078.5 kg, po0.0001). At this point, patients had lost at least 20% of their BMI (from 45.274.7 to 34.874.2, po0.0001). In the CG the baseline mean weight was 113.0713.0 kg and no significant difference was found after 1 year (118.0717.1 kg, p ¼ 0.6) (Table 2).

o0.001

∗

Results Weight reduction

o0.001

15 10 5 0

Baseline

1 year

Figure 1 Asthma Control Test (ACT) score in (a) 12 obese subjects affected by asthma before and 1 year after weight loss induced by bariatric surgery, *po0.005; (b) 10 not-operated obese subjects affected by asthma at baseline and after 1 year, NS: not significant.

In the CG no significant changes between baseline value and after 1 year in the overall ACT score (from 18.871.6 at baseline to 18.671.5 after 1 year, p ¼ 0.73) (Figure 1) or in each five ACT parameters were found. In particular, only two reported an improvement of asthma control after 1 year,

ARTICLE IN PRESS 106 whereas four reported no changes and four worsening of asthma control.

Exhaled NO Baseline exhaled NO was not significantly different between OB group before surgery and control group (p ¼ 0.31) (Table 2). Exhaled NO in OB group before surgery was 35.776.3 ppb and it was not affected by weight loss induced by bariatric surgery (36.476.0 ppb, p ¼ 0.42). Similarly, in the CG exhaled NO was not different from baseline after 1 year (from 32.976.4 to 35.076.1 ppb, p ¼ 0.46). No correlation was found between BMI and the absolute value of exhaled NO in OB group before surgery (r ¼ 0.38, p ¼ 0.23) or the reduction in BMI and the difference in exhaled NO after surgery (r ¼ 0.4, p ¼ 0.18). No correlation between exhaled NO and each five ACT parameter was found in either group at baseline or follow-up.

Pulmonary function tests No differences in FEV1 and FVC were found between OB group before surgery and CG at baseline (always p40.7). No correlation between BMI and FEV1 and FVC was found in OB group (always p40.3) In OB group the FEV1 (% of predicted) increased significantly 1 year after the surgery from 83.0714.4 to 87.2714.9 L, p ¼ 0.009. Similarly, the FVC (% of predicted) improved 1 year after the surgery from 87.8713.5 to 95.2710.7 L, p ¼ 0.001. No significant difference in FVC and FEV1 was found in CG after 1 year (FVC 87.1710.3 and 86.1711.5 L, FEV1 82.377.5 and 84.5711.3 L) (Table 2).

Discussion This study shows that the weight reduction in severe obese females with asthma is associated to improvement of respiratory symptoms, rescue medication use and lung function. To assess the symptoms and the use of rescue medication in our study we have used the ACT.18 ACT is a clinically valid measure that can be useful to clinicians and might be useful in assessing asthma control in the same patient populations, which requires only that the patients properly report their symptoms and rescue medication use.19 There have been numerous reports in the literature suggesting an association in adults and children between wheezing, asthma and obesity, and a number of explanatory hypotheses have been generated.6,26–28 Moreover, it has been documented that weight gain more than 25 kg increases fourfold the relative risk of asthma.29 In contrast only few studies have examined the effect of a consistent weight loss in severely obese asthmatics. Spivak et al.30 evaluated the improvement of obesity related illness including asthma following bariatric surgery. In that study analyzing the post-surgical follow-up of a large cohort of patients, the effect of weight loss on obesity related illness

M. Maniscalco et al. status was assessed by examining the reduction of drugs prescription for each comorbidities before surgery and during follow-up. Dixon et al.13 in an uncontrolled study reported improvement in clinical scores of 32 asthmatics obese after bariatric surgery. There was a highly significant reduction at follow-up with significant improvements in all aspects of asthma assessed, including severity, daily impact, medications needed, hospitalization, sleep and exercise. In the present study, both ACT and exhaled NO as a marker of airway inflammation were obtained and compared to a control group of asthmatic obese not receiving the surgical procedure with similar lung function abnormalities and in the absence of significant other cardio-respiratory comorbidities. We found a resolution of respiratory symptoms in 10 among 12 patients. Interestingly only patients in the OB group were able to reach a full improvement of respiratory symptoms in comparison to none of the obese asthmatics who did not experience any weight loss. This result obtained after weight reduction may depend on several factors. First, in asthmatic patients, airway obstruction causes early airway closure during expiration. This feature is accentuated by obesity, especially when patients are lying down.31 Noticeably, we did not find any correlation between BMI and lung volumes in our female subjects at a variance with recent study of Santana et al.32 who evaluated non-asthmatic subjects with severe morbid obesity with even higher BMI and a significant smoker prevalence; however, weight reduction reduces closing capacity, which tends to increase the forced expiratory volume in 1 s (FEV1) and the forced vital capacity (FVC); this may also lead to a reduction in clinical symptoms in asthmatic people. Second, it has been proposed that the narrowed peripheral airways in obesity may cause increased airway responsiveness, as may the rapid shallow breathing pattern observed in the morbidly obese, thus weight reduction may reduce airway responsiveness. As obesity is associated with both reduced chest wall compliance and increased elastic load on respiratory muscle, improvement in lung function with weight loss might be dependent on reduction of these elastic loads independently from changes in airway obstruction.33 Other proposed links between obesity and asthma include gastro-oesophageal reflux,34 which is increased in obesity. Gastro-oesophageal reflux may worsen asthma symptoms, and reduction of fat around the abdomen may reduce reflux, thus alleviating symptoms. However, none of our patients referred gastroesophageal symptoms and preoperative endoscopy resulted negative for lower esophageal sphincter abnormalities. Also the psychological benefit of having lost weight may also reduce symptoms.35 Finally, a low intake of antioxidants, and the production of pro-inflammatory mediators from adipose tissue, causing airway inflammation has been proposed as factors linking obesity and asthma.36 The weight reduction induced by bariatric surgery may have influenced these factors. However, in our obese patients after surgery, exhaled NO, which is a common marker of airways inflammation in asthma, remained unchanged. This may reflect the fact that, whereas the overall clinical picture of the asthma was improved by the weight reduction, airway inflammation persisted.

ARTICLE IN PRESS Asthma and obesity Alternatively, the confounding factor of weight reduction on exhaled NO should be considered. In fact in a previous study we have shown that severe uncomplicated obese subjects demonstrate low exhaled NO levels which normalize after consistent weight loss.37 Therefore, a reduced exhaled NO in our obese subjects after surgery might be counterbalanced by the increase in NO due to the weight reduction. Accordingly, Komakula et al.38 have showed that in asthmatics, exhaled NO declines with increasing BMI, and showing that increased airway oxidative stress may explain the reductions in NO. Consequently, NO may not be a good marker of airway inflammation in the obese as it may be produced at normal or elevated levels but then degraded by oxidative stress. The improvement in the ACT score observed in the OB group might be linked to the improvement in the overall respiratory symptoms and not to the specific disease, as we found an improvement in the global lung function after surgery. In fact both FEV1 and FVC increased in symmetric fashion, suggesting an improvement in restrictive lung disease. However, both baseline and after surgery lung function did not demonstrate marked impairment; moreover, it is unlikely that the ACT may have simply been changed due to reduction in obesity related dyspnea as rescue brochodilatators were effective into symptom relieving. Actually, a modified ACT with the three first questions administrated to a large group of non-asthmatic obese scheduled for bariatric surgery did not show any significant score decrease (data not shown). Finally, as recently reported in post-hoc analysis of pharmacology trials, while BMI may influence the response to controller drugs in asthma, there was no correlation between BMI and use of beta stimulants.39 Our study has some limitations. It was unblinded and not randomised as the control group was represented by subjects who decided to delay the scheduled operation for reasons unrelated to their asthma or other health problems. Furthermore, we did not evaluate if the improvement in the control of the asthma was related to the reduction in the airway hyper-reactivity. However, in a previous study persistence in airways hyper-reactivity after weight reduction has been reported.27 Finally, the patients presented mostly intermittent or mild persistent asthma with lung function nearly normal and this of course reduced the room for improvement. This bias was due to the protocol of our surgical department, which excludes from the list of bariatric surgery patients with more severe asthma. In conclusion, the weight reduction induced by bariatric surgery in severely obese females with asthma is associated to improvement of respiratory symptoms, use of rescue medication and lung function. The mechanisms underlying the effects of consistent weight loss on asthma in severe obese subjects would require further studies.

Conflict of interest None of the authors have a conflict of interest to declare in relation to this work.

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