- Email: [email protected]
Beneficial impact of weight loss on respiratory function in interstitial lung disease patients with obesity
respiratory investigation xxx (xxxx) xxx
Available online at www.sciencedirect.com
Respiratory Investigation journal homepage: www.elsevier.com/locate/resinv
Original article
Beneficial impact of weight loss on respiratory function in interstitial lung disease patients with obesity Akimasa Sekine a,*, Satoshi Wasamoto a, Eri Hagiwara a, Hideaki Yamakawa a,b, Satoshi Ikeda a, Hiroko Okabayashi a, Tsuneyuki Oda a, Ryo Okuda a, Hideya Kitamura a, Tomohisa Baba a, Shigeru Komatsu a, Takashi Ogura a a b
Department of Respiratory Medicine, Kanagawa Cardiovascular and Respiratory Center, Japan Department of Respiratory Medicine, Saitama Red Cross Hospital, Japan
article info
abstract
Article history:
Background: Interstitial lung disease (ILD) patients commonly become obese or overweight
Received 3 March 2020
due to deteriorated daily living activities and the adverse effects of prednisolone. This
Received in revised form
study aimed to clarify the effect of weight loss on pulmonary function test (PFT) in ILD
14 September 2020
patients with obesity.
Accepted 9 October 2020
Methods: Among all consecutive ILD patients with a body mass index (BMI) 27 kg/m2 who
Available online xxx
received nutrition education for improving obesity between June 2014 and December 2018, we retrospectively included patients who successfully decreased their body weight by over
Keywords:
2 kg and underwent follow-up PFT within 6 months. The results of PFT at baseline and
Interstitial lung disease
follow-up and the level of Krebs von den Lungen-6 (KL-6) were compared.
Obesity
Results: Eleven patients (5 men and 6 women; median BMI of 34.1 kg/m2), were enrolled. For
Diet
PFT at baseline, the percentages of forced vital capacity (%FVC), functional residual ca-
Vital capacity
pacity (%FRC), and diffusing capacity of the lung for carbon monoxide (%DLCO) were 69.3%,
DLCO
59.9%, and 54%, respectively. The median KL-6 was 1035 U/mL. The median interval from baseline to the follow-up PFTs was 41 days. Compared to the baseline results of PFT, %FVC, %FRC, and %DLCO significantly increased (p ¼ 0.018, 0.0006, and 0.024, respectively), and the changes in body weight and FVC were strongly correlated (p ¼ 0.0004). In addition, the median serum level of KL-6 at follow-up tended to decrease by 206.5 U/mL (p ¼ 0.083). Conclusion: In ILD patients with obesity, weight loss is important and potentially improves their disease course. © 2020 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.
* Corresponding author. 236-0051, Tomiokahigashi 6-16-1, Kanazawa-ku, Yokohama City, Japan. E-mail addresses: [email protected], [email protected] (A. Sekine). https://doi.org/10.1016/j.resinv.2020.10.002 2212-5345/© 2020 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved. Please cite this article as: Sekine A et al., Beneficial impact of weight loss on respiratory function in interstitial lung disease patients with obesity, Respiratory Investigation, https://doi.org/10.1016/j.resinv.2020.10.002
2
1.
respiratory investigation xxx (xxxx) xxx
Introduction
Interstitial lung disease (ILD) is characterized by various degrees of fibrosis and inflammation of the lung parenchyma [1]. Idiopathic pulmonary fibrosis (IPF) is the most common type of ILD and presents with a poor prognosis. In IPF patients, the forced vital capacity (FVC) annually decreases by 150e200 mL [2], and the decrease of FVC is correlated with disease activity and mortality [3]. More recently, progressive fibrosing ILD other than IPF has been reported as a phenotype associated with a decline in lung function, aggravated symptoms, and early mortality [4]. Therefore, changes in FVC were used as a primary endpoint in some clinical trials of IPF [5] and non-IPF fibrosing ILD [6,7]. ILD patients commonly become obese or overweight because of deteriorated activities of daily living (ADLs) and adverse effects of prednisolone. Generally, obesity can negatively affect respiratory physiology and cause FVC reduction [8,9]. However, an official ATS/ERS/JRS/ALAT statement in 2011 declared that it remains unclear whether it is meaningful to improve the obese state in IPF patients [1]. However, the effect of weight loss on the pulmonary function test (PFT) result was reported in ILD patients with severe obesity who underwent bariatric surgery. In that study, the median body mass index (BMI) decreased from 39 kg/m2 to 30 kg/m2 in one year, and %FVC was dramatically improved from 62% to 74% [10]. These results strongly indicate that weight loss is important in ILD patients with severe obesity. However, in clinical practice, bariatric surgery is not easy for ILD patients, and the effect of weight loss through nutrition education and exercise therapy on PFT remains unclear. To investigate this research question, we performed a retrospective study.
2.
Patients and methods
All patients who were given nutritional guidance and education about dietary restrictions for improving obesity by registered nutritionists were investigated. The World Health Organization defines obesity as BMI 30 kg/m2 and overweight as BMI 25e30 kg/m2. However, in Asians, obesity is defined as BMI 25 kg/m2 because of differences in physique between Asians and Europeans. Because some studies defined obesity as BMI 27 kg/m2 [11,12], we investigated all ILD patients who had BMI 27 kg/m2 and received nutrition education in the period from June 2014 to December 2018. Patients with a weight loss of less than 2 kg or no PFT at baseline or follow-up within 6 months were excluded. Patients who received additional treatment for ILD or surgical lung biopsy between baseline and follow-up PFTs were also excluded. The serum level of KL-6 and the results of PFT, including FVC, %FVC, %diffusing capacity of the lung for carbon monoxide (DLCO), and %functional residual capacity (FRC), were compared between the baseline and follow-up. In addition, the correlation between the changes in FVC and body weight was investigated.
2.1.
Wilcoxon signed-rank test. The correlation between the changes in FVC and weight loss was analyzed using Pearson and Spearman’s rank correlation coefficients. P-values of less than 0.05 were considered statistically significant. All analyses were performed using JMP 10 software (SAS Institute, Cary, NC, USA). This study was approved by the Institutional Ethical Review Board (IRB: KCRC-19-0039).
3.
Results
3.1.
Patient characteristics at baseline (Table 1)
The study profile is shown in Fig. 1. Among the 110 patients who received nutrition education, 43 had ILD. Among the 33 patients with BMI 27 kg/m2, 22 patients were excluded because of lack of follow-up PFT, lack of weight loss 2 kg, or additional treatment. Finally, 11 patients, including five men and six women, with a median age of 67 years, were enrolled (Table 1). Seven patients had smoking histories, and the median weight and BMI were 87.6 kg and 34.1 kg/m2, respectively. Regarding the clinical diagnosis of ILD, 10 patients had idiopathic interstitial pneumonia with IPF (6 patients), NSIP (2 patients), and unclassifiable (2 patients). At baseline, seven patients did not receive any treatment for ILD, while the remaining four patients were treated with prednisolone, tacrolimus, pirfenidone, and/or cyclosporin. The serum level of KL-6 was evaluated in all patients and found to be elevated, with a median value of 1035 U/mL (normal value < 500 U/mL). Regarding PFT, the median FVC and %FVC were as low as 2310 mL and 69.3%, respectively, although the median FEV1.0% was within the normal range. The %DLCO and %FRC were remarkably low at the median values of 54% and 59.9%, respectively, whereas the predicted ratio of DLCO adjusted for alveolar ventilation (%DLCO/VA) was within the normal range.
3.2.
Changes from baseline (Table 2)
The interval from baseline PFT to follow-up PFT ranged from 14e182 days, with a median of 41 days. During the follow-up
Statistical analysis
The parameters of FVC, %FVC, %DLCO, and %FRC were compared between baseline and follow-up using the paired
Fig. 1 e Study profile. BMI, body mass index; PFT, pulmonary function test.
Please cite this article as: Sekine A et al., Beneficial impact of weight loss on respiratory function in interstitial lung disease patients with obesity, Respiratory Investigation, https://doi.org/10.1016/j.resinv.2020.10.002
3
respiratory investigation xxx (xxxx) xxx
Table 1 e Patient characteristics at baseline. Pulmonary functional analysis Case no.
Age/ Sex
Smoking history
Body weight BMI (kg) (kg/ m2)
1
47/M
Ex
102.7
35.8
2 3 4 5 6 7 8 9
59/M 61/M 67/M 72/M 47/F 58/F 71/F 74/F
Current Ex Ex Ex Never Never Never Ex
117.7 104.7 97 87.6 121 69.9 77.4 75.7
38.3 35.1 34.1 30.5 44.1 29.7 36.6 32.7
10 11
78/F 79/F
Ex Never
65.4 73
29.5 32.5
Median
67
87.6
34.1
Clinical diagnosis
Treatment KL-6 (U/ mL)
SjS related
PSL 9 mg Tac 6 mg Unclassifiable Observation IPF Observation IPF Observation IPF Observation NSIP Observation NSIP Observation IPF PFD 1200 mg Unclassifiable PSL10 mg CyA 150 mg IPF Observation IPF PSL 5 mg Tac 4 mg
FVC (mL)
% % % %DLCO/ % FVC FEV1 DLCO VA FRC
1064
2310
55
64.2
23.2
49.5
70.6
829 1035 615 528 733 1103 1262 2577
3410 3780 2400 2770 3050 1690 1470 1360
82 94.5 65 76.7 96.8 66.3 69.3 61.7
67 89.2 62.3 75.7 98.1 67.1 76.8 71.3
69.5 52.6 51.1 67.8 48.6 69.2 51.1 60.6
97.5 70.9 80.8 102.1 96.9 138.0 117.4 132.9
73.5 63.3 66.3 59.6 59.9 61.5 48.1 49.0
641 1640
1250 1950
61.7 59.1 94.7 108.3
68.7 54
152.2 111.6
49.9 44.3
1035
2310
69.3 71.3
54
102.1
59.9
BMI, body mass index; UIP, usual interstitial pneumonia; KL-6, Krebs von den Lungen-6; FVC, forced vital capacity; FEV1, forced expiratory volume in 1 s; FRC, functional residual capacity; DLCO, diffusing lung capacity for carbon monoxide; PSL, prednisolone; Tac, tacrolimus; PFD, € gren’s syndrome; VA, pirfenidone; CyA, cyclosporin A; NSIP, non-specific interstitial pneumonia; IPF, idiopathic pulmonary fibrosis; SjS, Sjo alveolar volume.
period, nine patients were admitted to our hospital for dietary restriction and were given exercise therapy to prevent immobilization syndrome due to the decreased activity during their admission. One patient (Case 4) was admitted to another hospital due to bacterial pneumonia complicated with cardiac failure. The amount of weight loss was 2.2e16.5 kg, with a median of 5.9 kg. Of note, KL-6 decreased in almost all evaluated patients (8/10, 80%), although the difference was not significant (Fig. 2A, p ¼ 0.083). The PFT showed that the median DFVC, D%FVC, and D%FEV1 were 80 mL, 3.8%, and 4.9%, respectively. FVC, %FVC, and %FEV significantly improved (Fig. 2B, p ¼ 0.012, 0.018, and 0.032). In addition, %DLCO and % FRC improved with a median DDLCO of 5.2% (Fig. 2C, p ¼ 0.024) and D%FRC of 7.9% (Fig. 2D, p ¼ 0.006); meanwhile, there was
no significant improvement of %DLCO/VA (p ¼ 0.79). The correlation between the amount of weight loss and FVC increase was significant (Fig. 3, r2 ¼ 0.77, p ¼ 0.0004).
4.
Discussion
This study showed the following two findings. First, %FVC, % DLCO, and %FRC significantly improved after short-term obesity treatment, and a significant positive correlation between the amount of weight loss and FVC increase was observed. Second, the level of KL-6 tended to decrease after weight loss.
Table 2 e Changes from baseline. Pulmonary functional analysis Case no.
Age/ Sex
Duration (days)
Exercise therapy
DBW (kg)
1 2 3 4 5 6 7 8 9 10 11 Median
47/M 59/M 61/M 67/M 72/M 47/F 58/F 71/F 74/F 78/F 79/F 67
35 14 136 182 69 17 129 61 22 18 41 41
Yes* Yes* Yes* No Yes* Yes* No Yes* Yes* Yes* Yes*
6.4 8.6 13.2 16.5 3.9 9.5 5.9 3.6 4.2 2.2 4.5 5.9
DBMI DKL-6 (kg/ (U/ m2) mL) 2.2 2.8 4.4 5.8 1.4 3.5 2.5 1.7 1.8 1.0 2.0 2.2
222.0 N.E. 755 525.0 103.0 7.0 260.0 131.0 512.0 191.0 496.0 206.5
DFVC (mL)
D% FVC
D% FEV1
D% DLCO
D%DLCO/ VA
D% FRC
460 540 460 1000 0 140 70 40 80 10 40 80
11.0 13.0 11.2 27.8 0.7 4.5 3.5 0.6 3.8 0.3 1.9 3.8
5.5 13.2 7.5 20.6 4.9 8.0 1.6 0.9 1.8 0.6 0.7 4.9
5.2 6 2.2 7.8 17 9.7 8.9 0.2 4.9 2.9 12.6 5.2
4.3 1.0 1.3 3.9 5.7 4.3 17.3 5.4 6.0 2.3 11.3 2.3
2.8 7.9 13.8 27.2 23.8 16.3 2.4 0.4 3.3 7.2 9.9 7.9
BW, body weight; KL-6, Krebs von den Lungen-6; VC, vital capacity; FVC, forced vital capacity; FEV1, forced expiratory volume in 1 s. RV, residual volume; DLCO, diffusing lung capacity for carbon monoxide; VA, alveolar volume; *during admission for diet therapy.
Please cite this article as: Sekine A et al., Beneficial impact of weight loss on respiratory function in interstitial lung disease patients with obesity, Respiratory Investigation, https://doi.org/10.1016/j.resinv.2020.10.002
4
respiratory investigation xxx (xxxx) xxx
Fig. 2 e Changes in serum levels of Krebs von den Lungen-6 and results of respiratory functional test. KL-6, Krebs von den Lungen-6.
Generally, it is not surprising that FVC and FRC improve in individuals with obesity after weight loss. However, it remains unclear whether ILD patients with obesity present the same results after weight loss [1]. The effect of obesity on respiratory function is complex. The increase in adipose tissue around the rib cage and abdomen results in decreased chest wall compliance and increased resistance, which increases the mass load on the respiratory musculature and leads to reduced FVC, TLC, and FRC [8,9]. In addition, a recent report showed that adipose tissues were present below the bronchial mucosa in patients with bronchial asthma and obesity, which contribute to direct obstruction of the airways [13]. An important finding of the present study is that %DLCO also significantly improved after short-term obesity treatment. Generally, %DLCO is normal even in indivisuals with morbid obesity and shows no change after improvement in obesity [9,14]. However, a previous study on bariatric surgery for ILD patients showed that %DLCO improved from 53% to 60% a year after bariatric surgery [10]. Taking this report together with this study’s results, weight loss in ILD patients with obesity
Fig. 3 e Correlation between the decrease in body weight and the increase in forced vital capacity. FVC, forced vital capacity.
would improve %DLCO. We believe that ILD itself improved through weight loss because of decreased KL-6 and increased %DLCO. In ILD patients, an increase in KL-6 is considered a result of an increase in KL-6 production by regenerated alveolar type 2 pneumocytes and/or enhanced permeability following destruction of the air-blood barrier in the affected lungs [15]. Considering the short follow-up period in this study, we believe that the KL-6 decrease in our patients resulted from the improvement of the impaired permeability of the air-blood barrier. Generally, FRC in individuals with obesity decreases and finally approaches the closing capacity of the small airways, which causes collapse and atelectasis. This repeated opening and closing of the small airways potentially cause lung injury [9]. Because ILD patients have low %FRC, the improvement of obesity in ILD patients is more likely to increase FRC and finally improve lung injury during tidal breathing. This hypothesis would be supported by the improvement of FRC after short-term obesity treatment. In clinical practice, ILD patients commonly become obese because of ADLs reduction and the adverse effects of prednisolone. Many clinical trials and studies showed that ILD patients were overweight (median BMI, 25e30 kg/m2), which indicates a substantial number of patients have obesity [16]. In IPF patients, a decline in FVC and DLCO is correlated with decreased survival, and DLCO at baseline is a reliable predictor of survival. Considering the results of this study, weight loss may improve the disease course of ILD patients with obesity. In addition, two antifibrotic agents, pirfenidone and nintedanib, can improve annual FVC decline but frequently cause anorexia and/or diarrhea, which results in weight loss [2,7,17]. Therefore, chest physicians should be aware of the weight loss influence on PFT in ILD patients with obesity when evaluating the effect of antifibrotic agents. Despite the important findings in this study, there are several limitations. First, this is a retrospective, single-center study that included only 11 patients with no control group. It will be more supportive to compare the results between obese patients with and without weight loss with a larger
Please cite this article as: Sekine A et al., Beneficial impact of weight loss on respiratory function in interstitial lung disease patients with obesity, Respiratory Investigation, https://doi.org/10.1016/j.resinv.2020.10.002
respiratory investigation xxx (xxxx) xxx
scale study. Second, this study evaluated short-term outcomes within 6 months of the included patients, and therefore, the long-term effect of weight loss on pulmonary function needs to be elucidated.
5.
Conclusions
In ILD patients with obesity, short-term weight loss improved PFT results, including %FVC, %FRC, and %DLCO, and led to decreased KL-6 levels. Weight loss may improve the disease course of ILD patients with obesity.
Conflict of Interest Dr. Ogura received honoraria from Boehringer Ingelheim and Shionogi Co. Ltd. The remaining authors have no conflict of interest to declare.
Acknowledgment We want to thank Editage (www.editage.com) for English language editing.
references
[1] Raghu G, Collard HR, Egan JJ, Martinez FJ, Behr J, Brown KK, et al. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med 2011;183:788e824. [2] Wuyts WA, Wijsenbeek M, Bondue B, Bouros D, Bresser P, Robalo Cordeiro C, et al. Idiopathic pulmonary fibrosis: best practice in monitoring and managing a relentless fibrotic disease. Respr Int Rev Thor Disease 2019;99:1e10. [3] Paterniti MO, Bi Y, Rekic D, Wang Y, Karimi-Shah BA, Chowdhury BA. Acute exacerbation and decline in forced vital capacity are associated with increased mortality in idiopathic pulmonary fibrosis. Ann Am Thorac Soc 2017;14:1395e402.
5
[4] Wells AU, Brown KK, Flaherty KR, Kolb M, Thannickal VJ. Group IPFCW What’s in a name? That which we call IPF, by any other name would act the same. Eur Respir J 2018;51. [5] Raghu G. Idiopathic pulmonary fibrosis: lessons from clinical trials over the past 25 years. Eur Respir J 2017;50. [6] Distler O, Highland KB, Gahlemann M, Azuma A, Fischer A, Mayes MD, et al. Nintedanib for systemic sclerosisassociated interstitial lung disease. N Engl J Med 2019;380:2518e28. [7] Flaherty KR, Wells AU, Cottin V, Devaraj A, Walsh SLF, Inoue Y, et al. Nintedanib in progressive fibrosing interstitial lung diseases. N Engl J Med 2019;381:1718e27. [8] Ashburn DD, DeAntonio A, Reed MJ. Pulmonary system and obesity. Crit Care Clin 2010;26:597e602. [9] Salome CM, King GG. Berend N Physiology of obesity and effects on lung function. J Appl Physiol 1985;108:206e11. 2010. [10] Ardila-Gatas J, Sharma G, Nor Hanipah Z, Tu C, Brethauer SA, Aminian A, et al. Bariatric surgery in patients with interstitial lung disease. Surg Endosc 2019;33:1952e8. [11] Koike H, Fujino T, Koike M, Shinohara M, Kitahara K, Kinoshita T, et al. Obesity is associated with the development of interstitial pneumonia under long-term administration of amiodarone in refractory atrial fibrillation patients. Int Heart J 2016;57:30e4. [12] Goh VH, Tain CF, Tong TY, Mok HP, Wong MT. Are BMI and other anthropometric measures appropriate as indices for obesity? A study in an Asian population. J Lipid Res 2004;45:1892e8. [13] Elliot JG, Donovan GM, Wang KCW, Green FHY, James AL. Noble PB fatty airways: implications for obstructive disease. Eur Respir J 2019;54:1900857. [14] Wei YF, Tseng WK, Huang CK, Tai CM, Hsuan CF, Wu HD. Surgically induced weight loss, including reduction in waist circumference, is associated with improved pulmonary function in obese patients. Surg Obes Relat Dis 2011;7:599e604. [15] Yokoyama A, Kondo K, Nakajima M, Matsushima T, Takahashi T, Nishimura M, et al. Prognostic value of circulating KL-6 in idiopathic pulmonary fibrosis. Respirology 2006;11:164e8. [16] Khor YH, Glaspole I. Goh NSL Therapeutic burden in interstitial lung disease: lessons to learn. Respirology 2019;24:566e71. [17] Richeldi L, du Bois RM, Raghu G, Azuma A, Brown KK, Costabel U, et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med 2014;370:2071e82.
Please cite this article as: Sekine A et al., Beneficial impact of weight loss on respiratory function in interstitial lung disease patients with obesity, Respiratory Investigation, https://doi.org/10.1016/j.resinv.2020.10.002
Available online at www.sciencedirect.com
Respiratory Investigation journal homepage: www.elsevier.com/locate/resinv
Original article
Beneficial impact of weight loss on respiratory function in interstitial lung disease patients with obesity Akimasa Sekine a,*, Satoshi Wasamoto a, Eri Hagiwara a, Hideaki Yamakawa a,b, Satoshi Ikeda a, Hiroko Okabayashi a, Tsuneyuki Oda a, Ryo Okuda a, Hideya Kitamura a, Tomohisa Baba a, Shigeru Komatsu a, Takashi Ogura a a b
Department of Respiratory Medicine, Kanagawa Cardiovascular and Respiratory Center, Japan Department of Respiratory Medicine, Saitama Red Cross Hospital, Japan
article info
abstract
Article history:
Background: Interstitial lung disease (ILD) patients commonly become obese or overweight
Received 3 March 2020
due to deteriorated daily living activities and the adverse effects of prednisolone. This
Received in revised form
study aimed to clarify the effect of weight loss on pulmonary function test (PFT) in ILD
14 September 2020
patients with obesity.
Accepted 9 October 2020
Methods: Among all consecutive ILD patients with a body mass index (BMI) 27 kg/m2 who
Available online xxx
received nutrition education for improving obesity between June 2014 and December 2018, we retrospectively included patients who successfully decreased their body weight by over
Keywords:
2 kg and underwent follow-up PFT within 6 months. The results of PFT at baseline and
Interstitial lung disease
follow-up and the level of Krebs von den Lungen-6 (KL-6) were compared.
Obesity
Results: Eleven patients (5 men and 6 women; median BMI of 34.1 kg/m2), were enrolled. For
Diet
PFT at baseline, the percentages of forced vital capacity (%FVC), functional residual ca-
Vital capacity
pacity (%FRC), and diffusing capacity of the lung for carbon monoxide (%DLCO) were 69.3%,
DLCO
59.9%, and 54%, respectively. The median KL-6 was 1035 U/mL. The median interval from baseline to the follow-up PFTs was 41 days. Compared to the baseline results of PFT, %FVC, %FRC, and %DLCO significantly increased (p ¼ 0.018, 0.0006, and 0.024, respectively), and the changes in body weight and FVC were strongly correlated (p ¼ 0.0004). In addition, the median serum level of KL-6 at follow-up tended to decrease by 206.5 U/mL (p ¼ 0.083). Conclusion: In ILD patients with obesity, weight loss is important and potentially improves their disease course. © 2020 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.
* Corresponding author. 236-0051, Tomiokahigashi 6-16-1, Kanazawa-ku, Yokohama City, Japan. E-mail addresses: [email protected], [email protected] (A. Sekine). https://doi.org/10.1016/j.resinv.2020.10.002 2212-5345/© 2020 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved. Please cite this article as: Sekine A et al., Beneficial impact of weight loss on respiratory function in interstitial lung disease patients with obesity, Respiratory Investigation, https://doi.org/10.1016/j.resinv.2020.10.002
2
1.
respiratory investigation xxx (xxxx) xxx
Introduction
Interstitial lung disease (ILD) is characterized by various degrees of fibrosis and inflammation of the lung parenchyma [1]. Idiopathic pulmonary fibrosis (IPF) is the most common type of ILD and presents with a poor prognosis. In IPF patients, the forced vital capacity (FVC) annually decreases by 150e200 mL [2], and the decrease of FVC is correlated with disease activity and mortality [3]. More recently, progressive fibrosing ILD other than IPF has been reported as a phenotype associated with a decline in lung function, aggravated symptoms, and early mortality [4]. Therefore, changes in FVC were used as a primary endpoint in some clinical trials of IPF [5] and non-IPF fibrosing ILD [6,7]. ILD patients commonly become obese or overweight because of deteriorated activities of daily living (ADLs) and adverse effects of prednisolone. Generally, obesity can negatively affect respiratory physiology and cause FVC reduction [8,9]. However, an official ATS/ERS/JRS/ALAT statement in 2011 declared that it remains unclear whether it is meaningful to improve the obese state in IPF patients [1]. However, the effect of weight loss on the pulmonary function test (PFT) result was reported in ILD patients with severe obesity who underwent bariatric surgery. In that study, the median body mass index (BMI) decreased from 39 kg/m2 to 30 kg/m2 in one year, and %FVC was dramatically improved from 62% to 74% [10]. These results strongly indicate that weight loss is important in ILD patients with severe obesity. However, in clinical practice, bariatric surgery is not easy for ILD patients, and the effect of weight loss through nutrition education and exercise therapy on PFT remains unclear. To investigate this research question, we performed a retrospective study.
2.
Patients and methods
All patients who were given nutritional guidance and education about dietary restrictions for improving obesity by registered nutritionists were investigated. The World Health Organization defines obesity as BMI 30 kg/m2 and overweight as BMI 25e30 kg/m2. However, in Asians, obesity is defined as BMI 25 kg/m2 because of differences in physique between Asians and Europeans. Because some studies defined obesity as BMI 27 kg/m2 [11,12], we investigated all ILD patients who had BMI 27 kg/m2 and received nutrition education in the period from June 2014 to December 2018. Patients with a weight loss of less than 2 kg or no PFT at baseline or follow-up within 6 months were excluded. Patients who received additional treatment for ILD or surgical lung biopsy between baseline and follow-up PFTs were also excluded. The serum level of KL-6 and the results of PFT, including FVC, %FVC, %diffusing capacity of the lung for carbon monoxide (DLCO), and %functional residual capacity (FRC), were compared between the baseline and follow-up. In addition, the correlation between the changes in FVC and body weight was investigated.
2.1.
Wilcoxon signed-rank test. The correlation between the changes in FVC and weight loss was analyzed using Pearson and Spearman’s rank correlation coefficients. P-values of less than 0.05 were considered statistically significant. All analyses were performed using JMP 10 software (SAS Institute, Cary, NC, USA). This study was approved by the Institutional Ethical Review Board (IRB: KCRC-19-0039).
3.
Results
3.1.
Patient characteristics at baseline (Table 1)
The study profile is shown in Fig. 1. Among the 110 patients who received nutrition education, 43 had ILD. Among the 33 patients with BMI 27 kg/m2, 22 patients were excluded because of lack of follow-up PFT, lack of weight loss 2 kg, or additional treatment. Finally, 11 patients, including five men and six women, with a median age of 67 years, were enrolled (Table 1). Seven patients had smoking histories, and the median weight and BMI were 87.6 kg and 34.1 kg/m2, respectively. Regarding the clinical diagnosis of ILD, 10 patients had idiopathic interstitial pneumonia with IPF (6 patients), NSIP (2 patients), and unclassifiable (2 patients). At baseline, seven patients did not receive any treatment for ILD, while the remaining four patients were treated with prednisolone, tacrolimus, pirfenidone, and/or cyclosporin. The serum level of KL-6 was evaluated in all patients and found to be elevated, with a median value of 1035 U/mL (normal value < 500 U/mL). Regarding PFT, the median FVC and %FVC were as low as 2310 mL and 69.3%, respectively, although the median FEV1.0% was within the normal range. The %DLCO and %FRC were remarkably low at the median values of 54% and 59.9%, respectively, whereas the predicted ratio of DLCO adjusted for alveolar ventilation (%DLCO/VA) was within the normal range.
3.2.
Changes from baseline (Table 2)
The interval from baseline PFT to follow-up PFT ranged from 14e182 days, with a median of 41 days. During the follow-up
Statistical analysis
The parameters of FVC, %FVC, %DLCO, and %FRC were compared between baseline and follow-up using the paired
Fig. 1 e Study profile. BMI, body mass index; PFT, pulmonary function test.
Please cite this article as: Sekine A et al., Beneficial impact of weight loss on respiratory function in interstitial lung disease patients with obesity, Respiratory Investigation, https://doi.org/10.1016/j.resinv.2020.10.002
3
respiratory investigation xxx (xxxx) xxx
Table 1 e Patient characteristics at baseline. Pulmonary functional analysis Case no.
Age/ Sex
Smoking history
Body weight BMI (kg) (kg/ m2)
1
47/M
Ex
102.7
35.8
2 3 4 5 6 7 8 9
59/M 61/M 67/M 72/M 47/F 58/F 71/F 74/F
Current Ex Ex Ex Never Never Never Ex
117.7 104.7 97 87.6 121 69.9 77.4 75.7
38.3 35.1 34.1 30.5 44.1 29.7 36.6 32.7
10 11
78/F 79/F
Ex Never
65.4 73
29.5 32.5
Median
67
87.6
34.1
Clinical diagnosis
Treatment KL-6 (U/ mL)
SjS related
PSL 9 mg Tac 6 mg Unclassifiable Observation IPF Observation IPF Observation IPF Observation NSIP Observation NSIP Observation IPF PFD 1200 mg Unclassifiable PSL10 mg CyA 150 mg IPF Observation IPF PSL 5 mg Tac 4 mg
FVC (mL)
% % % %DLCO/ % FVC FEV1 DLCO VA FRC
1064
2310
55
64.2
23.2
49.5
70.6
829 1035 615 528 733 1103 1262 2577
3410 3780 2400 2770 3050 1690 1470 1360
82 94.5 65 76.7 96.8 66.3 69.3 61.7
67 89.2 62.3 75.7 98.1 67.1 76.8 71.3
69.5 52.6 51.1 67.8 48.6 69.2 51.1 60.6
97.5 70.9 80.8 102.1 96.9 138.0 117.4 132.9
73.5 63.3 66.3 59.6 59.9 61.5 48.1 49.0
641 1640
1250 1950
61.7 59.1 94.7 108.3
68.7 54
152.2 111.6
49.9 44.3
1035
2310
69.3 71.3
54
102.1
59.9
BMI, body mass index; UIP, usual interstitial pneumonia; KL-6, Krebs von den Lungen-6; FVC, forced vital capacity; FEV1, forced expiratory volume in 1 s; FRC, functional residual capacity; DLCO, diffusing lung capacity for carbon monoxide; PSL, prednisolone; Tac, tacrolimus; PFD, € gren’s syndrome; VA, pirfenidone; CyA, cyclosporin A; NSIP, non-specific interstitial pneumonia; IPF, idiopathic pulmonary fibrosis; SjS, Sjo alveolar volume.
period, nine patients were admitted to our hospital for dietary restriction and were given exercise therapy to prevent immobilization syndrome due to the decreased activity during their admission. One patient (Case 4) was admitted to another hospital due to bacterial pneumonia complicated with cardiac failure. The amount of weight loss was 2.2e16.5 kg, with a median of 5.9 kg. Of note, KL-6 decreased in almost all evaluated patients (8/10, 80%), although the difference was not significant (Fig. 2A, p ¼ 0.083). The PFT showed that the median DFVC, D%FVC, and D%FEV1 were 80 mL, 3.8%, and 4.9%, respectively. FVC, %FVC, and %FEV significantly improved (Fig. 2B, p ¼ 0.012, 0.018, and 0.032). In addition, %DLCO and % FRC improved with a median DDLCO of 5.2% (Fig. 2C, p ¼ 0.024) and D%FRC of 7.9% (Fig. 2D, p ¼ 0.006); meanwhile, there was
no significant improvement of %DLCO/VA (p ¼ 0.79). The correlation between the amount of weight loss and FVC increase was significant (Fig. 3, r2 ¼ 0.77, p ¼ 0.0004).
4.
Discussion
This study showed the following two findings. First, %FVC, % DLCO, and %FRC significantly improved after short-term obesity treatment, and a significant positive correlation between the amount of weight loss and FVC increase was observed. Second, the level of KL-6 tended to decrease after weight loss.
Table 2 e Changes from baseline. Pulmonary functional analysis Case no.
Age/ Sex
Duration (days)
Exercise therapy
DBW (kg)
1 2 3 4 5 6 7 8 9 10 11 Median
47/M 59/M 61/M 67/M 72/M 47/F 58/F 71/F 74/F 78/F 79/F 67
35 14 136 182 69 17 129 61 22 18 41 41
Yes* Yes* Yes* No Yes* Yes* No Yes* Yes* Yes* Yes*
6.4 8.6 13.2 16.5 3.9 9.5 5.9 3.6 4.2 2.2 4.5 5.9
DBMI DKL-6 (kg/ (U/ m2) mL) 2.2 2.8 4.4 5.8 1.4 3.5 2.5 1.7 1.8 1.0 2.0 2.2
222.0 N.E. 755 525.0 103.0 7.0 260.0 131.0 512.0 191.0 496.0 206.5
DFVC (mL)
D% FVC
D% FEV1
D% DLCO
D%DLCO/ VA
D% FRC
460 540 460 1000 0 140 70 40 80 10 40 80
11.0 13.0 11.2 27.8 0.7 4.5 3.5 0.6 3.8 0.3 1.9 3.8
5.5 13.2 7.5 20.6 4.9 8.0 1.6 0.9 1.8 0.6 0.7 4.9
5.2 6 2.2 7.8 17 9.7 8.9 0.2 4.9 2.9 12.6 5.2
4.3 1.0 1.3 3.9 5.7 4.3 17.3 5.4 6.0 2.3 11.3 2.3
2.8 7.9 13.8 27.2 23.8 16.3 2.4 0.4 3.3 7.2 9.9 7.9
BW, body weight; KL-6, Krebs von den Lungen-6; VC, vital capacity; FVC, forced vital capacity; FEV1, forced expiratory volume in 1 s. RV, residual volume; DLCO, diffusing lung capacity for carbon monoxide; VA, alveolar volume; *during admission for diet therapy.
Please cite this article as: Sekine A et al., Beneficial impact of weight loss on respiratory function in interstitial lung disease patients with obesity, Respiratory Investigation, https://doi.org/10.1016/j.resinv.2020.10.002
4
respiratory investigation xxx (xxxx) xxx
Fig. 2 e Changes in serum levels of Krebs von den Lungen-6 and results of respiratory functional test. KL-6, Krebs von den Lungen-6.
Generally, it is not surprising that FVC and FRC improve in individuals with obesity after weight loss. However, it remains unclear whether ILD patients with obesity present the same results after weight loss [1]. The effect of obesity on respiratory function is complex. The increase in adipose tissue around the rib cage and abdomen results in decreased chest wall compliance and increased resistance, which increases the mass load on the respiratory musculature and leads to reduced FVC, TLC, and FRC [8,9]. In addition, a recent report showed that adipose tissues were present below the bronchial mucosa in patients with bronchial asthma and obesity, which contribute to direct obstruction of the airways [13]. An important finding of the present study is that %DLCO also significantly improved after short-term obesity treatment. Generally, %DLCO is normal even in indivisuals with morbid obesity and shows no change after improvement in obesity [9,14]. However, a previous study on bariatric surgery for ILD patients showed that %DLCO improved from 53% to 60% a year after bariatric surgery [10]. Taking this report together with this study’s results, weight loss in ILD patients with obesity
Fig. 3 e Correlation between the decrease in body weight and the increase in forced vital capacity. FVC, forced vital capacity.
would improve %DLCO. We believe that ILD itself improved through weight loss because of decreased KL-6 and increased %DLCO. In ILD patients, an increase in KL-6 is considered a result of an increase in KL-6 production by regenerated alveolar type 2 pneumocytes and/or enhanced permeability following destruction of the air-blood barrier in the affected lungs [15]. Considering the short follow-up period in this study, we believe that the KL-6 decrease in our patients resulted from the improvement of the impaired permeability of the air-blood barrier. Generally, FRC in individuals with obesity decreases and finally approaches the closing capacity of the small airways, which causes collapse and atelectasis. This repeated opening and closing of the small airways potentially cause lung injury [9]. Because ILD patients have low %FRC, the improvement of obesity in ILD patients is more likely to increase FRC and finally improve lung injury during tidal breathing. This hypothesis would be supported by the improvement of FRC after short-term obesity treatment. In clinical practice, ILD patients commonly become obese because of ADLs reduction and the adverse effects of prednisolone. Many clinical trials and studies showed that ILD patients were overweight (median BMI, 25e30 kg/m2), which indicates a substantial number of patients have obesity [16]. In IPF patients, a decline in FVC and DLCO is correlated with decreased survival, and DLCO at baseline is a reliable predictor of survival. Considering the results of this study, weight loss may improve the disease course of ILD patients with obesity. In addition, two antifibrotic agents, pirfenidone and nintedanib, can improve annual FVC decline but frequently cause anorexia and/or diarrhea, which results in weight loss [2,7,17]. Therefore, chest physicians should be aware of the weight loss influence on PFT in ILD patients with obesity when evaluating the effect of antifibrotic agents. Despite the important findings in this study, there are several limitations. First, this is a retrospective, single-center study that included only 11 patients with no control group. It will be more supportive to compare the results between obese patients with and without weight loss with a larger
Please cite this article as: Sekine A et al., Beneficial impact of weight loss on respiratory function in interstitial lung disease patients with obesity, Respiratory Investigation, https://doi.org/10.1016/j.resinv.2020.10.002
respiratory investigation xxx (xxxx) xxx
scale study. Second, this study evaluated short-term outcomes within 6 months of the included patients, and therefore, the long-term effect of weight loss on pulmonary function needs to be elucidated.
5.
Conclusions
In ILD patients with obesity, short-term weight loss improved PFT results, including %FVC, %FRC, and %DLCO, and led to decreased KL-6 levels. Weight loss may improve the disease course of ILD patients with obesity.
Conflict of Interest Dr. Ogura received honoraria from Boehringer Ingelheim and Shionogi Co. Ltd. The remaining authors have no conflict of interest to declare.
Acknowledgment We want to thank Editage (www.editage.com) for English language editing.
references
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Please cite this article as: Sekine A et al., Beneficial impact of weight loss on respiratory function in interstitial lung disease patients with obesity, Respiratory Investigation, https://doi.org/10.1016/j.resinv.2020.10.002