Non-exercise Activity Thermogenesis Correlated With Clinical Parameters in Patients With or At-Risk for Chronic Obstructive Pulmonary Disease (COPD): A Pilot Study

Background: Attention to physical activity has grown in patients with chronic obstructive pulmonary disease (COPD), as it serves as a robust indicator for mortality associated with COPD. Non-exercise activity thermogenesis (NEAT) is the energy expenditure due to physical activities besides active sports-like exercises and resistance training in daily life, and decreased NEAT may be related to physical inactivity in patients with COPD. We examined whether NEAT assessed using a questionnaire reflects clinical parameters in patients with or at risk for COPD. Methods: The study participants consisted of 36 male patients (COPD=28; stage1=6, stage2=14, stage3/4=8, and at-risk for COPD=8) older than 50 years of age. The participants underwent anthropometric measurements, lung function testing, a six-minute walk test, muscle strength testing, and questionnaires, e.g., the COPD assessment test (CAT), modified Medical Research Council (mMRC) dyspnea scale, and Hospital Anxiety and Depression Scale. Image analysis with chest computed tomography (CT) included the number of trunk muscles, bronchial wall thickening, and emphysema (percentage of the lung ﬁeld occupied by low attenuation area <-950 HU). We evaluated the relationship between these clinical parameters and NEAT questionnaire scores using Pearson correlation analysis and the Tukey-Kramer test. Results: The NEAT score was correlated with the severity of airflow limitation and airway wall thickness measured by chest CT, symptoms evaluated by the mMRC dyspnea scale and CAT, and inspiratory muscle strength and pectoralis muscle area assessed by CT. Conclusion: Our study revealed the significance of NEAT as a valuable indicator in assessing the health status of patients with or at risk for COPD. The NEAT score was correlated with various clinical traits, suggesting that incorporating NEAT assessments using a questionnaire can contribute to a comprehensive understanding of the clinical condition in these patients. Further large-scale studies are warranted to validate and generalize these findings across diverse COPD populations.


Introduction
Chronic obstructive pulmonary disease (COPD) is a progressive lung disorder characterized by irreversible airflow obstruction and alveolar destruction, mostly attributable to smoking.The degree of symptoms and functional limitations caused by COPD can differ from person to person, often resulting in delayed diagnosis.COPD also progresses with weight loss and skeletal muscle deficits [1], which limits pulmonary ventilation and increases ventilatory burden during exercise.Patients with COPD tend to avoid exerciseassociated dyspnea and fatigue, leading to an inactive lifestyle.This process is called a "dyspnea-inactivity vicious cycle," and this may happen at any stage of COPD to a certain degree [2][3][4].
Non-exercise activity thermogenesis (NEAT) is the energy expenditure of all physical activities other than volitional sporting-like exercise [5].It includes various activities in daily life, such as walking to work, attending school, singing, dancing, washing clothes, and cleaning floors.Since patients with COPD are apt to have less exercise activity thermogenesis, their activity energy expenditure is considered to be mainly composed of NEAT.We have recently reported that the total NEAT score evaluated by a questionnaire was correlated with the physical activity level (PAL) assessed by the doubly labeled water method and indirect calorimetry in patients with or at risk for COPD [6].However, only a few previous studies have investigated the relationship between NEAT and clinical traits of COPD, including lung functions, body composition, muscle strength, and features of computed tomography (CT) images.
Therefore, we examined the NEAT score in patients with COPD using the questionnaire designed to evaluate physical activity related to NEAT and investigated how NEAT correlates with these clinical traits.We thought it might be possible to better understand the disease and develop a new treatment strategy by examining which clinical parameters are associated with the NEAT score in COPD patients.

Study design and population
In total, 37 consecutive patients with (n=28) or at risk for COPD (n=9, with chronic respiratory symptoms and smoking history≥10 pack-years, and FEV 1 /FVC≥0.7)who visited the outpatient clinic of Saitama Medical University Hospital between June 2017 and February 2018 participated in this study.COPD was defined by a post-bronchodilator FEV 1 /FVC < 70% according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines [7].Patients at risk for COPD had similar COPD assessment test (CAT) scores to those of the patients with COPD (9.6 ± 4.0 versus 10.2 ± 6.7) and most of them (six patients) improved their symptoms by administration of inhaled bronchodilators.Exclusion criteria were infectious diseases, diabetes mellitus with medication, dysphagia, or other serious diseases that would interfere with movement; treatment with drugs affecting energy expenditure (thyroid hormone, beta-blocker, glucagon-like peptide-1 receptor agonist) or water balance (sodium-glucose cotransporter-2 blocker); and weight loss of ≥5% of their body weight (BW) during the previous three months.After one at-risk COPD patient had to discontinue the study because of acute bronchitis, the data from the remaining 36 participants were used for analysis.

Data collection
All patients underwent anthropometric measurements, pulmonary function tests, a 6-minute walk test (6MWT), calf circumference (CC) measurement, hand grip strength (HGS), CAT, modified Medical Research Council (mMRC) dyspnea scale, and chest CT.The Hospital Anxiety and Depression Scale (HADS) was used to measure the emotional state of patients and their degree of anxiety and depression [8].BW was measured to the nearest 0.1 kg using a digital scale with patients wearing light clothing.The height of each patient was measured to the nearest 0.1 cm using a horizontal headboard with an attached wall-mounted metric scale.
Body mass index was calculated using these measurements (BW in kg/height in m 2 ).Fat free mass and skeletal muscle mass were measured by bioelectrical impedance analysis using an SFB7 (ImpediMed, Queensland, Australia).

Assessment of NEAT using a questionnaire
We asked participants about their daily activities to evaluate NEAT using a questionnaire (NEAT score), which was modified from a compendium of physical activities [9].It consists of 11 questions about locomotive activities and 25 questions about non-locomotive activities [10] and is available in the online supplementary material.Each questionnaire item was evaluated with a score of 1-3 points according to the activity levels, and these points were summed to determine the total NEAT score.

Pulmonary function testing
After bronchodilator inhalation, spirometry was performed by trained and certified spirometry technicians using a FUDAC-7 instrument (Fukuda Denshi Co., Ltd., Tokyo, Japan).Lung volume subdivisions and diffusing capacity of carbon monoxide (DLco) were measured in all participants.As indices of respiratory muscle strength, maximal expiratory pressure (PEmax) and maximal inspiratory pressure (PImax) were measured with an AutospiroAS-507 spirometer (Minato Medical Science, Co., Ltd., Osaka, Japan).The predicted pulmonary function values were calculated according to the Japanese Respiratory Society equation 2014 [11].

Computed tomography scan acquisition and analysis
Details regarding trunk muscle measurements have been provided in our previous report [12].In brief, we performed an analysis of three trunk muscles on a single-slice axial chest CT image.The pectoralis muscle area (PMA) at the top of the aortic arch, rectus abdominis muscle area at the first lumbar vertebra, and erector spinae muscle area (ESMA) at the level of the Th12 lumbar vertebra were measured.Intra-observer agreement and inter-observer reliability were previously confirmed [11].The percentage of low attenuation area was determined using a cutoff value of <-950 Hounsfield units.The lumen area (LA) and wall area (WA) of the segmental right apical (RB1) were automatically measured.Then, the PMA and LA were normalized to the body surface area (BSA).The wall area percentage (WA%) was calculated using the following formula: 100×WA/(sum of the LA and WA).We used SYNAPSE VINCENT volume analyzer software (FUJIFILM Medical Co., Ltd., Tokyo, Japan) for all CT image analyses.Representative cross-sectional CT images are shown in Figure 1.

Statistical analysis
The data pertaining to the continuous variables are expressed as the mean ± standard deviation (SD) unless otherwise specified.Pearson correlation analysis was used to evaluate the associations between the NEAT score and clinical parameters.To determine the extent to which the locomotive NEAT score or the nonlocomotive NEAT score affects each other, a partial correlation analysis with adjustment for the nonlocomotive NEAT score was performed between the locomotive NEAT score and clinical parameters, and vice versa.Multiple comparisons were performed using the Tukey-Kramer test.The Jonckheere-Terpstra trend test was performed for a trend analysis of the continuous variables.All statistical analyses were performed using the EZR 4.1.2(R, open-source, Saitama Medical Centre, Jichi Medical University, Saitama, Japan).Statistical significance was set at p<0.05.

Distributions of the NEAT scores
The distributions of the total, locomotive, and non-locomotive NEAT scores by the GOLD stage are shown in Table 2.Although the values of patients with COPD tended to be lower as the disease severity increased, there were no significant differences among the GOLD stages.When the data of the patients classified as atrisk for COPD were excluded, trend analyses revealed that patients with higher GOLD stage displayed lower non-locomotive score (p=0.038)although there were no significant differences in the total NEAT score (p=0.069) and locomotive NEAT score (p=0.217).NEAT: Non-exercise activity thermogenesis; GOLD: Global Initiative for Chronic Obstructive Lung Disease; COPD: chronic obstructive pulmonary disease   Figure 2 shows the relationships between the total NEAT scores and representative clinical parameters.When we examined the relationship between locomotive /non-locomotive NEAT scores and clinical parameters, similar trends were observed in the correlations between the non-locomotive NEAT scores and the clinical parameters, except for %DLco/VA (r=0.286,p=0.091) and %PImax (r=0.303,p=0.072).In contrast, the clinical parameters correlated with locomotive NEAT scores were limited to %DLco/VA (r=0.349,p=0.037), %PImax (r=0.411,p=0.013), 6MWD (r=0.353,p=0.035), and mMRC dyspnea scale score (r=-0.560,p=0.0004).Partial correlation analysis revealed a significant correlation between mMRC and locomotive NEAT scores (r=-0.560,p=0.012).

Discussion
To the best of our knowledge, this is the first report to describe the relationship between the NEAT score and clinical traits in patients with COPD.Our findings showed that the NEAT score that reflects NEAT was correlated with the severity of airflow limitation, inspiratory muscle strength, COPD-specific symptoms, and several parameters on chest CT images.
A previous study suggested that patients with COPD are physically inactive and have increased sedentary time from early stages, and the tendency became clearer as the disease worsened [4].Although the NEAT score we obtained in this study did not show evident differences among the GOLD stages, the score was significantly correlated with %FEV 1 in the total population.It should be noted that seven parameters, i.e., %FEV 1 , % 50 , CAT, mMRC dyspnea scale score, Borg scale score (fatigue), PMA, and WA%5 th , were correlated with the total and non-locomotive NEAT scores, while %DLco/VA, %PImax, and mMRC were correlated with the total and locomotive NEAT scores.The 6MWD was solely correlated with the locomotive NEAT scores and not with the total and non-locomotive scores.These observations imply that airflow limitation may lead to a decrease in non-locomotive NEAT rather than locomotive NEAT, while exercise capacity may parallel locomotive NEAT.
The NEAT score was also associated with not only %FEV 1 but also % 50 on lung function testing and WA%5 th on CT images.Since those variables are indicators of peripheral airway obstruction, this questionnaire may be useful and helpful for detecting early peripheral airway obstruction.In addition, our finding that there was no relationship between the NEAT score and the fat free mass index or skeletal muscle mass index may indicate that decreased scores on this questionnaire reflect less physical activity caused by respiratory dysfunction rather than overall muscle weakness due to aging.
In the present study, the NEAT score was also correlated with inspiratory muscle strength and PMA, which is the inspiratory accessory muscle.Respiratory muscles are essential for alveolar ventilation and work against increased mechanical loads due to impaired diaphragm function and airflow limitation.In fact, several studies have shown a correlation between respiratory muscle strength and lung function, including FEV 1 [12][13][14][15].Vyas et al. inferred that impaired muscle function results in a lower FEV 1 , although the mechanism remains unknown [16].Amelioration of respiratory muscle strength has been reported to be correlated with improved physical activity, dyspnea, exercise tolerance, and disease-specific quality of life (QOL) [17], and PMA was also correlated with disease severity, QOL, exercise tolerance, and physical activity [12,18].Therefore, if activities like inspiratory muscle training improve respiratory muscle strength and PMA, the NEAT score would increase, resulting in better exercise tolerance and improved QOL associated with the disease.
Finally, the NEAT score was correlated with COPD-specific symptoms evaluated by the mMRC dyspnea scale and CAT.The mMRC dyspnea scale score had a similar correlation with the locomotive NEAT score to that with the non-locomotive score, while CAT was only correlated with the non-locomotive NEAT score and not with the locomotive score.In other words, the mMRC dyspnea scale score reflects locomotive and nonlocomotive NEAT, whereas CAT weakly and solely reflects non-locomotive NEAT.
We have recently demonstrated that the NEAT score was correlated with PAL in patients with COPD [6].In addition, the present study indicated that the NEAT score reflected other COPD traits including airflow limitation, reduced inspiratory muscle strength and volume, and subsequent dyspnea and impaired QOL.Therefore, we believe that the NEAT score could function as a valuable and comprehensive questionnaire for assessing the health status of patients with COPD and providing personalized treatment.For example, future studies exploring the impact of rehabilitation interventions, particularly inspiratory muscle training, on NEAT scores may offer insights into improving exercise tolerance and disease-specific QOL.In addition, further investigation into the predictive value of the NEAT score for COPD prognosis may be a promising avenue for advancing patient care and management.
This study has several limitations.First, the sample size was relatively small, and only two patients with very severe COPD were included.Second, female patients were not included because several studies demonstrated that the majority of Japanese COPD patients are male [19,20].Therefore, the present findings may not be applicable to them.Third, the correlations between the NEAT questionnaire and COPD-related clinical parameters were not strong.This may mean the need for further refinement to tailor the questionnaire more specific to the characteristics of COPD patients.

Conclusions
Our pilot study has provided valuable insights into the potential of the NEAT questionnaire as a comprehensive indicator in the assessment of COPD.The observed correlations with COPD-specific symptoms, inspiratory muscle strength, and peripheral airway limitations on CT imaging highlighted the multifaceted utility of the NEAT score.Incorporating the NEAT score into routine clinical practice may not only enhance our understanding of COPD but also contribute to more effective and personalized management strategies.However, the generalizability of our findings warrants validation through largerscale studies to establish the broader applicability and reliability of the NEAT score in a diverse COPD population.

Appendices Non-exercise activity thermogenesis (NEAT) score
Three points are scored when subjects answer "A lot".
Two points are scored when subjects answer "Sometimes".
One point is scored when subjects answer "Hardly ever" or "No".
In question No. 4, Three points are scored when subjects answer "Faster than most people".Two points are scored when subjects answer "About the same as other people".
One point is scored when subjects answer "I get passed by other people".

FIGURE 1 :
FIGURE 1: Representative cross-sectional computed tomography images.(A) The pectoralis muscle area is shown in green.(B) Lumen area (green) and wall area (between green and red) of the segmental right apical (third-generation of the segmental right apical).

BMI:
Body mass index; GOLD: Global Initiative for Chronic Obstructive Lung Disease; VC: vital capacity; FEV 1 : forced expiratory volume in 1 second; % 50 :percentage of velocity of expiratory airflow at 50%; SpO 2 : peripheral capillary oxygen saturation; %RV: percentage of residual volume; DL CO /VA: diffusing capacity of carbon monoxide/alveolar volume; mMRC: modified Medical Research Council; CAT: chronic obstructive pulmonary disease assessment test; FFMI: fat free mass index; SMI: skeletal muscle mass; HGS: hand grip strength; CC: calf circumference; PMA: pectoralis muscle area; RAMA: rectus abdominis muscle area; ESMA: erector spinae muscle area; LA3: lumen area of the third-generation bronchus; LA5: lumen area of the fifthgeneration bronchus; WA%3 rd : wall area percent of the third-generation bronchus; WA%5 th : wall area percent of the fifth-generation bronchus; LAA%: percentage of the lung field occupied by the low attenuation area; HU: Hounsfield unit.

1 .
Do you walk on the way to work?A lot (over 30 minutes one way) Sometimes (30 minutes or less) Hardly ever (or do not travel to work) 2. Do you use a train or a bus (not including taxis or private cars)?A lot (almost every day) 2024 Yogi et al.Cureus 16(1): e53019.DOI 10.7759/cureus.53019

TABLE 1 : Clinical biochemical and physiological data of all participants.
: wall area percent of the third generation bronchus; WA%5 th : wall area percent of the fifth generation bronchus; LAA%: percentage of the lung field occupied by the low attenuation area; HU: Hounsfield unit; NEAT: non-exercise activity thermogenesis.
M: Male; F: female; BMI: body mass index; GOLD: Global Initiative for Chronic Obstructive Lung Disease; VC: vital capacity; FEV 1: forced expiratory volume in 1 second; DL CO /VA: diffusing capacity of carbon monoxide/alveolar volume; PImax: maximal inspiratory pressure; mMRC: modified Medical Research Council; CAT: chronic obstructive pulmonary disease assessment test; HAD-A: Hospital Anxiety and Depression Scale-Anxiety; HAD-D: Hospital Anxiety and Depression Scale-Depression; FFMI: mass index; SMI: skeletal muscle mass index; HGS: hand grip strength; CC: calf circumference; PMA: pectoralis muscle area; RAMA: rectus abdominis muscle area; ESMA: erector spinae muscle area; LA3: lumen area of the third generation bronchi; LA5: lumen area of the fifth generation bronchus; WA%3 rd