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Introduction

Thoracoscopic segmental lung resection has become a frequently employed procedure in pediatric thoracic surgery due to its minimally invasive nature and enhanced recovery outcomes. This technique utilizes one-lung ventilation (OLV) to isolate and safeguard the operative lung, concurrently optimizing surgical field visibility and facilitating precise anatomical dissection.¹ However, OLV presents significant physiological challenges, particularly in children. It can inadvertently induce absorption atelectasis in the non-ventilated lung and may exacerbate or precipitate the formation of atelectatic regions within the dependent, ventilated lung due to gravitational effects and altered mechanics. These alterations result in intrapulmonary shunts, impaired gas exchange, and ventilation-perfusion (V/Q) mismatch, which are primary contributors to intraoperative hypoxemia.

The consequences extend beyond gas exchange abnormalities. The collapse-reexpansion cycle and the inflammatory response to regional hypoxia can trigger the activation and release of various inflammatory cytokines, including interleukins (eg, IL-6, IL-8) and tumor necrosis factor-alpha (TNF-α). These cytokines play a pivotal role in mediating the pathophysiological cascade associated with lung ischemia-reperfusion injury, potentially leading to perioperative pulmonary complications such as pneumonia, persistent atelectasis, and hypoxemia, which can prolong hospital stay and increase morbidity.²

Research conducted in adults indicates that implementing stepwise lung recruitment as a lung-protective ventilation strategy during thoracoscopic segmental lung resection under OLV may lead to a reduction in the severity of acute lung injury and a decrease in postoperative pulmonary complications.³ The conventional recruitment method, often employed in pediatric cases, serves as a useful comparator but has limitations in achieving sustained recruitment in lower lung zones. Indeed, the efficacy of stepwise lung recruitment has been well-documented in adults. However, its impact on pediatric populations remains an area open for further investigation and exploration. In comparison to adults, pediatric populations exhibit reduced lung functional residual capacities and elevated closing volumes. Consequently, this physiological difference heightens the susceptibility to atelectasis subsequent to anesthesia induction.

This single-center study aimed to assess the effects of a stepwise lung recruitment strategy on intraoperative oxygenation and postoperative lung outcomes in pediatric patients undergoing thoracoscopic segmentectomy with OLV.

Materials and Methods

Study Participants

A total of 78 pediatric patients undergoing elective general anesthesia for thoracoscopic lung segmentectomy were meticulously chosen from the period spanning April 2021 to September 2022. The cohort consisted of 42 males and 36 females ranging in age from 1 to 5 years with a weight median between 7.5 to 23.5 kg. The participants were allocated through a computer-based randomization method, resulting in two distinct groups: the stepwise lung recruitment group (SR) and the controlled lung inflation recruitment group (CR). Before the procedures, informed consent forms were duly signed by the families of the pediatric participants. This study was conducted in accordance with the declaration of Helsinki and approved by the Ethics Committee of Children’s Hospital of Henan.

The sample size was estimated based on a pilot dataset targeting a detectable 15% difference in oxygenation index with 80% power at α = 0.05, resulting in a required minimum of 35 patients per group.

Inclusion and Exclusion Criteria

Inclusion Criteria

(1) American Society of Anesthesiologists (ASA) classification of I to II; (2) Preoperative hemoglobin level ≥ 10 gm/dl, no severe cardiac arrhythmias; (3) Selected procedure of unilateral segmental lung resection under thoracoscopy; (4) No significant impairments in liver, kidney, or coagulation/bleeding functions; (5) Informed consent form signed by relatives.

Exclusion Criteria

(1) Children with severe heart or lung diseases; (2) Presence of a bronchial fistula; (3) History of pulmonary resection; (4) Presence of pulmonary bullae, pneumothorax, or other conditions contraindicating lung re-expansion; (5) Recent systemic infection.

Elimination Criteria

(1) Violation of study protocol requirements; (2) Withdrawal from the study at the request of the child; (3) Occurrence of severe complications and/or adverse events.

Anesthesia and Surgical Methods

Both cohorts of pediatric participants were instructed to observe a 6-hour fasting period and refrain from consuming clear liquids for two hours prior to the surgical procedure. To identify the specific lung segment harboring the lesion, preoperative enhanced chest computed tomography (CT) scans were conducted, incorporating 3D reconstruction techniques. The surgical procedures were consistently performed by a single physician throughout the study. Following anesthesia induction and airway management by the anesthesiologist, the surgical team proceeded with positioning and thoracoscopic access. To maintain stable anesthetic depth and minimize variability in neuroinflammatory response, anesthesia was guided by bispectral index monitoring, maintaining the index values between 40 and 60 throughout surgery.

Simultaneously, the child was carefully positioned on the healthy side at a precise 90-degree angle. The surgical procedure employed a three-port technique, wherein the viewing port was precisely positioned along the mid-axillary line between the 7th or 8th ribs. Simultaneously, the working ports were strategically placed at the anterior axillary line between the 4th or 5th ribs, and the infra-scapular line between the 8th or 9th ribs. Utilizing preoperative 3D-CT brachial angiography images, the surgical team dissected and severed the vessels and bronchi of the target lung segment, progressing from superficial to deep layers.

During the surgical procedure, electrocoagulation or an ultrasonic scalpel was employed to meticulously sever the smaller branches of pulmonary arteries and veins. In contrast, the larger branches were securely clamped using medium Hem lock clips before being incised. Furthermore, the segmental bronchus was clamped with large Hem lock clips prior to its precision cut using an ultrasonic scalpel. The intersegmental planes underwent evaluation, relying on the demarcation between expanded and collapsed lung tissue or, alternatively, following arterial ischemia. Following that, these planes were meticulously separated through the precise application of electrocoagulation.

All patients observed standard preoperative fasting protocols (solid foods for 6 hours, clear liquids for 2 hours). General anesthesia was administered and managed exclusively by attending pediatric anesthesiologists, not the surgical team. Induction was performed using intravenous propofol (2–3 mg/kg), fentanyl (2 µg/kg), and rocuronium (0.6–1.0 mg/kg) to facilitate endotracheal intubation. A cuffed endotracheal tube was used in all patients, and the size was selected based on the standard formula: endotracheal tube size (mm internal diameter) = (age/4) + 3.5. Intubation was performed under direct laryngoscopy, and placement was confirmed by end-tidal CO₂ and bilateral chest auscultation. A pediatric fiberoptic bronchoscope (2.8 mm outer diameter) was used to guide the accurate placement of the bronchial blocker. A 5 Fr bronchial blocker (Arndt or equivalent) was used for lung isolation. The anesthesia was maintained using sevoflurane (MAC 1.0–1.2) in an oxygen-air mixture (FiO₂ 0.5), with additional fentanyl boluses as needed. Muscle relaxation was maintained with intermittent doses of rocuronium. Depth of anesthesia was continuously monitored using bispectral index (BIS), with target values maintained between 40 and 60.

Lung Recruitment Technique

During bilateral lung mechanical ventilation, both groups employed a pressure-limited ventilation (PCV) approach. For OLV, the following calibrations were used: the tidal volume was set at 8–10 mL/kg, positive end expiratory pressure (PEEP) at 5 cm H₂O, the inspiratory to expiratory ratio at 1:2, respiratory rate at 25 breaths per minute, the end-tidal carbon dioxide (P_etCO₂) maintained between 35 and 45 mmHg and the maximum airway pressure (Pmax) was set at 28 cm H₂O.

In the SR group, stepwise lung recruitment was executed twice: just before the initiation of OLV and immediately upon the restoration of bilateral lung ventilation. The stepwise lung recruitment technique involved setting the inspiratory peak pressure at 28 cm H₂O, then increasing PEEP by 3–5 cm H₂O every 15 seconds over three breathing cycles until PEEP reached 15 cm H₂O. This level was then maintained for three cycles. Following this, PEEP was gradually reduced by 2–3 cm H₂O per breathing cycle until the oxygen saturation dropped by more than 1% compared to the previous cycle. The PEEP was then meticulously adjusted back to the value from the previous step. This PEEP value was considered the optimal PEEP, which maintained consistently throughout the remainder of the surgical procedure.

For the CR group, administration of controlled lung re-expansion occurred immediately prior to the initiation of the OLV and was repeated upon the restoration of bilateral lung ventilation. The CR group was selected as a comparator because it represents a conventional and widely used lung recruitment method in pediatric surgical practice. The procedure was as follows: under the manual control mode of the anesthesia machine, the inspiratory peak pressure was set at 28 cm H₂O and was maintained for 15–20 seconds, followed by switching to the PCV mode until the end of the surgery.

Both the CR and SR groups underwent lung ultrasound assessments guided by a 7–13 Hz linear array probe performed by anesthesiologists. It was conducted five minutes after the intubation and the commencement of the mechanical ventilation. It was repeated again at the end of the surgery. For this diagnostic procedure, the child was placed in a supine position, with the arm on the examined side elevated. Following that, a probe was positioned vertically within the intercostal space to acquire a standardized “bat sign” image, referring to an image resembling a bat, formed by the pleural line and the upper and lower ribs. Following the initial positioning, the probe was meticulously slid horizontally along the intercostal spaces, systematically scanning each area. In regions where atelectasis was identified, precise lung re-expansion maneuvers were conducted.

Observation Indicators

(1) The following general information and surgical details were observed: The changes in anesthesia time, surgery time, one-lung ventilation time, and fluid replacement volume were monitored. (2) The observation points were set at post-anesthesia induction pre-OLV (T0), 20 minutes after OLV lung re-expansion (T1), and 20 minutes after full lung re-expansion post-OLV (T2), recording changes in each parameter. Hemodynamic parameters included HR, MAP; respiratory parameters included oxygenation index (OI) = (PaO₂/FiO₂), CO, V_T, peak airway pressure (Ppeak), Pmean, Cdyn, and PaCO₂. (4) Recording of pulmonary complications (pneumonia, hypoxemia, atelectasis, pneumothorax) occurring within 7 days post-surgery.

Statistical Methods

SPSS software version 25.0 was used for data analysis. Quantitative data were represented in means and standard deviations (). Normally distributed quantitative data were analyzed using the t-test, intra-group differences over time were analyzed using repeated measures analysis of variance, and count data were analyzed using the χ² test. A P-value < 0.05 was considered statistically significant.

Results

General Information

Baseline characteristics including age, gender, and weight were similar between the two groups, with no statistically significant differences (P > 0.05), as shown in Table 1. A CONSORT flow diagram was shown in Supplementary Figure 1.

Table 1 Comparative Analysis of General Characteristics Across Cohorts

Surgical Details

There were no statistically significant differences in surgical details (anesthesia time, surgery time, one-lung ventilation time, fluid replacement volume) between the two groups (P > 0.05, Table 2).

Table 2 Comparative Analysis of Surgical Parameters Across Cohorts ()

Comparison of Hemodynamic Parameters Between Groups

At T1, the SR experimental group showed lower Ppeak and higher levels of Pmean, Cdyn, OI, and V_T compared to the control group [(20.12±1.41) vs (24.03±1.33), P = 0.000; (19.79±1.52) vs (16.48±1.47), P = 0.000; (4.32±0.63) vs (3.11±0.49), P = 0.000; (177.09±17.34) vs (130.64±15.78), P = 0.000; (309.83±20.25) vs (286.21±18.63), P = 0.000]. These suggest better compliance, gas exchange, and alveolar recruitment. At T2, the SR group maintained a more stable hemodynamic profile with return of HR and CO toward baseline faster than CR. Refer to Table 3.

Table 3 Comparative Analysis of Hemodynamic and Respiratory Parameters Across Cohorts ()

Comparison of Pulmonary Complications Between Groups

Postoperative complications were significantly lower in the SR experimental group. The incidence of pneumonia dropped from 25.6% (CR) to 0% (SR), and atelectasis from 25.6% to 5.1%. Pneumothorax also declined markedly (23.1% vs 2.6%, P = 0.007). Although hypoxemia trended lower in SR, it did not reach statistical significance (P = 0.104). Refer to Table 4.

Table 4 Comparative Analysis of Pulmonary Complications Between Cohorts [n (%)]

Discussion

Lung re-expansion procedures are important in general anesthesia surgery. These interventions serve the purpose of opening collapsed alveoli, enhancing oxygenation, optimizing lung compliance, and mitigating any adverse effects on patient cardiopulmonary function.⁴ While both groups aimed to restore lung volume after OLV, the SR group employed a gradual increase in PEEP, minimizing hemodynamic fluctuations and improving postoperative outcomes. To our knowledge, this is one of the first studies comparing SR to CR in pediatric thoracoscopic segmentectomy.

In the context of this study, during OLV at T1, observed reductions in MAP and CO, coupled with an elevated HR, indicate alterations in lung compliance. These changes are directly associated with the diminished oxygen supply during OLV in infants. However, by T2, the MAP, CO, and HR values in the SR experimental group had largely returned to pre-intervention levels, indicating that the stepwise lung recruitment technique has a minimal impact on hemodynamic parameters and allows for faster postoperative recovery. Importantly, all anesthesia procedures were conducted by qualified pediatric anesthesiologists using a standardized protocol. This controlled for any confounding impact of anesthetic depth or agent variability on hemodynamic stability and inflammatory responses. These findings offer robust evidence supporting the importance of sustaining perioperative oxygen delivery in pediatric patients.

The rationale behind this phenomenon may stem from the fact that the stepwise lung recruitment technique avoids imposing excessive and prolonged pressure, affording the body adequate time to self-regulate cardiovascular parameters and chemoreceptor responses. Consequently, this mitigates the reflexive effects on HR and prevents dilation under elevated vascular pressure, thereby promoting stability in pediatric blood circulation.^5,6

In the context of this study, at time point T1, the SR experimental group demonstrated a decrease in Ppeak compared to the CR control group and increases in Pmean, Cdyn, OI, and V_T (P < 0.05). This observation implies that stepwise lung recruitment has the potential to reduce peak airway pressure during surgical procedures, elevate mean airway pressure, and improve dynamic lung compliance. Our analysis suggests that stepwise lung recruitment, achieved by incrementally increasing the level of PEEP, stabilizes intrathoracic and pulmonary pressures. This gradual approach prevents abrupt spikes and ensures a consistent transition. This steady increase in Pmean subsequently reduces intrapulmonary shunt, facilitates the re-expansion of collapsed alveoli, improves ventilation, and decreases dead space ventilation.^7,8

Simultaneously, stepwise lung recruitment can swiftly restore the child’s hemodynamics, dampen the excitability of the pulmonary vagal reflex, and prevent changes in CO caused by increase in intrathoracic pressure, thereby mitigating cardiovascular suppression’s impact on improving lung oxygenation and compliance.^9,10 Furthermore, compared to the CR control group, the SR experimental group showed increased levels of V_T and Cdyn, and a reduced incidence of postoperative pulmonary complications. This phenomenon can be attributed to the gradual elevation of lung re-expansion pressure, which facilitates a systematic increase in lung pressure. Consequently, this approach effectively mitigates lung shear injuries, prevents direct harm to the alveolar endothelium and epithelium, and mitigates the release of inflammatory factors. Additionally, it contributes to a reduction in the number of ischemia-reperfusion alveoli on the non-ventilated side, thereby diminishing pulmonary oxidative stress and preventing excessive secretion of inflammatory mediators.¹¹ A uniform size of 5 Fr bronchial blocker and 2.8 mm pediatric fiberoptic bronchoscope was used in all cases to maintain consistency and ensure safe and accurate lung isolation.

Cardiac Troponin T (cTnT) serves as a biomarker for myocardial ischemia; however, it does not directly correlate with the severity of myocardial injury. Subsequently, High-sensitivity cardiac troponin T (hs-cTnT) provides greater sensitivity, which is detectable in the early stages, and positively correlates with the severity of the pathological condition.¹²

TNF-α and IL-6 are pivotal inflammatory cytokines present in serum.¹³ They play crucial roles in systemic inflammatory responses and contribute to the pathogenesis of various diseases.¹⁴ They can exacerbate inflammation and tissue damage.¹⁵ Furthermore, heightened expression of inflammatory factors may facilitate the aggregation of lung tissue mast cells, intensify histamine activity, and result in the liberation of a substantial number of eosinophils. These processes contribute to the development of hyperreactive airways, which, in turn, have the potential to precipitate airway spasms or obstruction. Ultimately, this intricate interplay further compromises cardiopulmonary function during OLV.¹⁶

Inflammatory factors have the potential to disrupt the integrity of cardiomyocyte membranes, leading to structural damage within the myocardium and consequent reduction in cardiac function.¹⁷ Following surgery, the incidence rates of pneumonia, pneumothorax, and atelectasis are reduced. This favorable outcome can be attributed to the gradual elevation of pulmonary pressure. This approach activates endogenous protective mechanisms, mitigates reperfusion injury resulting from ischemia during ventilation in segmental lung resection, and consequently diminishes the release of inflammatory factors.¹⁸ The CR group served as the control group in this study, representing the conventional method of lung re-expansion widely practiced in pediatric thoracic anesthesia, thus offering a valid clinical benchmark for comparison.

Furthermore, controlled lung re-expansion may result in a swift elevation of intrapulmonary pressure, potentially compromising the integrity of the pulmonary interstitial capillary membrane. This process, in turn, triggers the expression of inflammatory factors, increasing the risk of myocardial injury.¹⁹ In contrast, the stepwise lung recruitment technique effectively mitigates the abrupt elevation in intrapulmonary pressure that is typically associated with controlled lung re-expansion and as a result, it affords myocardial protection.²⁰

Stepwise lung recruitment maneuver has also been considered a safe and well tolerated technique in hemodynamically stable children with acute respiratory distress syndrome (ARDS) and in adult patients with early ARDS.^21,22 In lung resection, stepwise lung recruitment is primarily used to assess lung function after surgical resection, while in ARDS, it is used to treat and improve lung function. During lung resection, stepwise lung recruitment aims to evaluate and optimize the function of the remaining lung tissue, maintain hemodynamic stability, and improve the function of the healthy lung, which may experience small airway closure due to the chest wall being soft and functional residual capacity being low. In ARDS, the focus is on alleviating symptoms and improving lung function. The stepwise lung recruitment maneuver is also being investigated for its potential use in pediatric patients following cardiac surgery.²³ The use of this technique in other population warrants further investigation.

To summarize, the stepwise lung recruitment technique proves advantageous in safeguarding lung function and minimizing the occurrence of pulmonary complications in infants. Nevertheless, this study is constrained by certain limitations, including a small sample size, single-center design, and the absence of long-term follow-up. These factors may potentially introduce bias into the obtained results. Moreover, the presence of ETT cuff is a protective factor against pneumonia, therefore it could have generated a bias in analysis. In future investigations, researchers should explore the protective effects of stepwise lung recruitment on lung function in infants undergoing segmental lung resection with OLV. This could be achieved by either expanding the sample size or conducting a multicenter study.

Funding

Henan Province medical science and technology breakthrough project. Key projects jointly built by provinces and ministries (NO. SBGJ202102210). Henan Province medical science and technology breakthrough project. Joint construction project (NO. 2018020653).

Disclosure

The authors report no conflicts of interest in this work.

References

1. Hung WT, Wang YC, Huang HH, et al. Surgical resection for congenital lung malformation: lessons learned from thoracotomy to biportal thoracoscopy under one-lung ventilation. Formos Med Assoc. 2022;121(11):2152–2160. doi:10.1016/j.jfma.2022.03.003

2. Li P, Kang X, Miao M, et al. Individualized positive end-expiratory pressure (PEEP) during one-lung ventilation for prevention of postoperative pulmonary complications in patients undergoing thoracic surgery: a meta-analysis. Medicine. 2021;100(28):e26638. doi:10.1097/MD.0000000000026638

3. Spadaro S, Grasso S, Karbing DS, et al. Physiological effects of two driving pressure-based methods to set positive end-expiratory pressure during one lung ventilation. J Clin Monit Comput. 2021;35(5):1149–1157. doi:10.1007/s10877-020-00582-z

4. Hartland BL, Newell TJ, Damico N. Alveolar recruitment maneuvers under general anesthesia: a systematic review of the literature. Respir Care. 2015;60(4):609–620. doi:10.4187/respcare.03488

5. Torre Oñate T, Romero Berrocal A, Bilotta F, et al. Impact of stepwise recruitment maneuvers on cerebral hemodynamics: experimental study in neonatal model. J Pers Med. 2023;13(8):1184. doi:10.3390/jpm13081184

6. Serrano Zueras C, Guilló Moreno V, Santos González M, et al. Safety and efficacy evaluation of the automatic stepwise recruitment maneuver in the neonatal population: an in vivo interventional study. Can anesthesiologists safely perform automatic lung recruitment maneuvers in neonates? Paediatr Anaesth. 2021;31(9):1003–1010. doi:10.1111/pan.14243

7. Cui Y, Cao R, Li G, et al. The effect of lung recruitment maneuvers on post-operative pulmonary complications for patients undergoing general anesthesia: a meta-analysis. PLoS One. 2019;14(5):e0217405. doi:10.1371/journal.pone.0217405

8. Peel JK, Funk DJ, Slinger P, Srinathan S, Kidane B. Positive end-expiratory pressure and recruitment maneuvers during one-lung ventilation: a systematic review and meta-analysis. J Thorac Cardiovasc Surg. 2020;160(4):1112–1122.e3. doi:10.1016/j.jtcvs.2020.02.077

9. Pensier J, de Jong A, Hajjej Z, et al. Effect of lung recruitment maneuver on oxygenation, physiological parameters and mortality in acute respiratory distress syndrome patients: a systematic review and meta-analysis. Intensive Care Med. 2019;45(12):1691–1702. doi:10.1007/s00134-019-05821-9

10. Jung K, Kim S, Kim BJ, et al. Comparison of positive end-expiratory pressure versus tidal volume-induced ventilator-driven alveolar recruitment maneuver in robotic prostatectomy: a randomized controlled study. J Clin Med. 2021;10(17):3921. doi:10.3390/jcm10173921

11. Cheng MJ, Ji HY, Xia R, et al. Research status and dilemma of lung protective ventilation strategy in pediatric general anesthesia. Int J Anesthesiol Resuscit. 2022;43(9):968–972. doi:10.3760/cma.j.cn321761-20220427-00636

12. Clerico A, Aimo A, Cantinotti M. High-sensitivity cardiac troponins in pediatric population. Clin Chem Lab Med. 2021;60(1):18–32. doi:10.1515/cclm-2021-0976

13. Goshi N, Lam D, Bogguri C, et al. Direct effects of prolonged TNF-α and IL-6 exposure on neural activity in human iPSC-derived neuron-astrocyte co-cultures. Front Cell Neurosci. 2025;19:1512591. doi:10.3389/fncel.2025.1512591

14. Hirano T. IL-6 in inflammation, autoimmunity and cancer. Int Immunol. 2021;33(3):127–148. doi:10.1093/intimm/dxaa078

15. Takeuchi T, Yoshida H, Tanaka S. Role of interleukin-6 in bone destruction and bone repair in rheumatoid arthritis. Autoimmun Rev. 2021;20(9):102884. doi:10.1016/j.autrev.2021.102884

16. Yang SB, Tang XN, Yang XX, Zhang L, Wang P, Chen Y. Effects of L-carnitine assisted mechanical ventilation therapy on inflammatory response and cardiac function in children with heart failure. Pract J Cardiac Cerebral Pneum Vasc Dis. 2022;30(7):96–99. doi:10.12114/j.issn.1008-5971.2022.00.134

17. Chang X, Liu R, Li R, Peng Y, Zhu P, Zhou H. Molecular mechanisms of mitochondrial quality control in ischemic cardiomyopathy. Int J Biol Sci. 2023;19(2):426–448. doi:10.7150/ijbs.76223

18. Kim HJ, Seo JH, Park KU, et al. Effect of combining a recruitment maneuver with protective ventilation on inflammatory responses in video-assisted thoracoscopic lobectomy: a randomized controlled trial. Surg Endosc. 2019;33(5):1403–1411. doi:10.1007/s00464-018-6415-6

19. Santiago VR, Rzezinski AF, Nardelli LM, et al. Recruitment maneuver in experimental acute lung injury: the role of alveolar collapse and edema. Crit Care Med. 2010;38(11):2207–2214. doi:10.1097/CCM.0b013e3181f3e076

20. Zhuang JK, Chen YL, Guo YQ, Xie WQ. Effect of lung recruitment maneuvers with different oxygen concentrations combined with positive end-expiratory pressure on postoperative pulmonary complications in patients undergoing thoracoscopic radical resection of lung cancer. J Clin Anesthesiol. 2022;38(4):361–364. doi:10.12089/jca.2022.04.005

21. Galassi MS, Arduini RG, Araújo OR, Sousa RMK, Petrilli AS, Silva DCBD. Alveolar recruitment maneuvers for children with cancer and acute respiratory distress syndrome: a feasibility study. Rev Paul Pediatr. 2021;39:e2019275. doi:10.1590/1984-0462/2021/39/2019275

22. Kung SC, Hung YL, Chen WL, Wang CM, Chang HC, Liu WL. Effects of stepwise lung recruitment maneuvers in patients with early acute respiratory distress syndrome: a prospective, randomized, controlled trial. J Clin Med. 2019;8(2):231. doi:10.3390/jcm8020231

23. Gu M, Deng N. Xia W, et alStudy protocol for a single-centre randomised controlled trial to investigate the effect of lung recruitment in paediatric patients after cardiac surgery. BMJ Open. 2022;12:e063278. doi:10.1136/bmjopen-2022-063278

Introduction

Chronic obstructive pulmonary disease (COPD) is a group of progressive respiratory disorders caused by chronic airway inflammation, and it is characterized by airway obstruction or persistent airflow limitation.¹ Major symptoms of this disease include chronic cough, sputum production, and dyspnea. Clinically, COPD often exhibits recurrent exacerbations and is difficult to cure, and the common diseases of COPD include asthma, emphysema, and chronic bronchitis.² Progressive decline in lung function leads to reduced physical activity (PA) in individuals with COPD and multiple complications, including congestive heart failure (CHF) and diabetes, as well as psychological issues (such as severe anxiety and depression). These factors severely impair patients’ quality of life and can be life-threatening. The World Health Organization reports that nearly 299 million individuals worldwide suffer from COPD. It stands as the fourth major cause of death worldwide,³ with incidence rates rising every year. For example, in 2017, the prevalence of COPD in the United States was 15.2% among current cigarette smokers, 7.6% among former smokers, and 2.8% among adults who had never smoked.⁴ COPD typically develops insidiously and is often overlooked during the early stages. Patients usually receive medical attention only after symptoms become pronounced, thereby resulting in a poor prognosis.^5,6 COPD also requires substantial healthcare resources, imposing a considerable burden on global medical and public health systems. Therefore, identifying factors influencing COPD and developing effective prevention strategies to reduce its incidence is of great importance in alleviating this global health and socioeconomic burden.

Obesity, a prevalent metabolic disorder, is linked to a range of systemic complications. It can cause functional impairments in organs and tissues, ultimately resulting in organic lesions. The relationship between obesity and COPD has received growing attention.⁷ In particular, the accumulation of visceral fat (VF) in individuals with obesity may elevate the risk of COPD.⁸ Obesity may trigger pulmonary disease by inducing oxidative stress (OS) and systemic inflammation.^7,9 Thus, a reliable indicator for assessing VF is essential for effective chronic disease control and enhancing quality of life.

The Body Roundness Index (BRI), a novel anthropometric metric based on waist circumference (WC) and height, can comprehensively reflect visceral adiposity and body fat percentage.¹⁰ Increasing evidence demonstrates that BRI holds great potential for disease risk stratification. Elevated BRI levels are associated with many chronic diseases, such as chronic kidney disease (CKD), diabetes, and cardiovascular diseases (CVD), including atherosclerosis and hypertension (HP).^11,12 Nonetheless, the relationship between BRI and COPD remains unclear. Using data from the National Health and Nutrition Examination Survey (NHANES) 2013–2018, this study aims to examine the association between BRI and COPD.

Materials and Methods

Study Design and Population

Conducted by the National Center for Health Statistics (NCHS), the NHANES employs a stratified, multistage sampling design and various data collection methods to analyze the nutritional and health status of American children and adults. All NHANES protocols were approved by the Ethics Review Board of NCHS. Written informed consent was provided by all enrolled individuals. To ensure participant confidentiality, all data were de-identified. According to the Ethical Review Methods for Life Science and Medical Research Involving Human Participants, Article 32 exempts certain research from requiring ethical approval under specific conditions. Research utilizing legally obtained public data or data derived from non-intrusive observation of public behavior does not require ethical approval.

Data from three consecutive NHANES cycles (2013–2018) were collected. A total of 29,400 individuals were initially included. Individuals were excluded if they were under 20 years of age (n = 12,343), had incomplete BRI data (n = 1766), or lacked information on key covariates, including smoking status (n = 9), alcohol consumption (n = 1011), educational background (n = 9), marital status (n = 3), and PA (n = 5). Ultimately, 14,254 individuals were enrolled (Figure 1).

COPD Outcomes

COPD was defined according to affirmative responses to any of the following self-reported questions: “Have you been diagnosed with emphysema?”, “Have you been diagnosed with chronic bronchitis?”, or “Has a doctor ever informed you that you have COPD?” Individuals who answered “no” to all three questions were considered non-COPD.

Calculation of Anthropometric Indices

BRI was treated as the independent variable. According to the BRI calculation formula proposed by Tomas et al,¹⁰ data on WC and height were extracted from the anthropometric measurements in NHANES for the calculation.

Assessment of Covariates

A wide range of lifestyle, demographic, and health-related variables were collected: alcohol consumption, poverty income ratio (PIR), sex, total cholesterol, educational background, total energy intake (TEI), race/ethnicity, high-density lipoprotein cholesterol (HDL), protein, total sugar, age, HP, marital status, height, carbohydrate, dietary fiber (DF), CVD, total fat, smoking status, vigorous and moderate recreational activities, weight, eosinophil count, diabetes, white blood cell count, monocyte count, WC, and BMI.

Smoking status was categorized as never smoked, current smoker, or former smoker based on whether the individuals had smoked more than 100 cigarettes over a lifetime and their duration since quitting. Individuals were defined as having diabetes according to the following criteria: self-reported physician diagnosis of diabetes, fasting blood glucose >126 mg/dL, administration of glucose-lowering medication or insulin, or glycated hemoglobin (HbA1c) ≥6.5%.¹³ HP was defined according to the following criteria: self-reported HP, current use of antihypertensive medication, average systolic blood pressure ≥130 mmHg or average diastolic blood pressure ≥80 mmHg across three measurements.¹⁴ CVD was defined if individuals reported the following physician diagnoses: coronary heart disease, CHF, heart attack, or stroke.¹³

Statistical Analysis

Following NHANES methodological guidelines, this study applied the recommended multistage probability sampling weights to account for the complex survey design during statistical analyses. BRI was divided into four quartiles based on its distribution: Q1 (1.167–3.965), Q2 (3.965–5.282), Q3 (5.282–6.940), and Q4 (6.940–23.482). The Kolmogorov–Smirnov test was used to assess the normality of continuous variables. Given that these continuous variables were non-normally distributed, they were expressed as medians and interquartile ranges, and between-group comparisons were conducted using the Kruskal–Wallis test. Categorical variables were expressed as frequencies and percentages, and between-group comparisons were made using weighted Chi-square tests. Multicollinearity among covariates was examined, and variables with a variance inflation factor (VIF) ≥ 5 were excluded. Weighted logistic regression (WLR) models were employed to investigate the association between BRI and COPD prevalence. Three models were constructed: Model 1 was unadjusted; Model 2 was adjusted for race, sex, and age; Model 3 was further adjusted for educational background, marital status, PIR, TEI, DF, smoking status, alcohol consumption, moderate PA, diabetes, HP, CVD,¹⁵ direct HDL cholesterol, and eosinophil percentage. Restricted cubic spline (RCS) analysis with five knots was employed to investigate the dose-response relationship between BRI and COPD prevalence. Subgroup analyses stratified by sex, smoking status (never, current, former), alcohol consumption, diabetes, HP, and CVD were conducted to test the robustness of the findings. Statistical significance was defined as two-sided p-values less than 0.05. R version 4.4.2 was used to conduct statistical analysis.

Result

Baseline Characteristics of Study Population

Table 1 illustrates the basic characteristics of the included 14,254 individuals (stratified by BRI quartiles). The overall prevalence of COPD was 8.3%, corresponding to a weighted estimate of 210,015,248 individuals. The median age of individuals was 48 years, with 49% men and 51% women. BRI was divided into four quartiles: Q1 (1.167–3.965), Q2 (3.965–5.282), Q3 (5.282–6.940), and Q4 (6.940–23.482).

Table 1 Baseline Characteristics of Participants

The highest BRI quartile had a greater proportion of women and Mexican Americans in comparison to the lowest BRI quartile. Moreover, higher BRI levels were associated with lower engagement in vigorous PA, older age, and being widowed. Moreover, the highest BRI group exhibited a greater prevalence of CVD and diabetes.

Associations Between BRI and the Likelihood of COPD

The association between BRI and COPD prevalence was examined using WLR models (Table 2). For continuous BRI, the results indicated that BRI was positively associated with COPD prevalence. In Model 1 (unadjusted), each unit increase in BRI was associated with a 16.8% increase in the likelihood of COPD (P < 0.001). In model 2 (adjusted for race/ethnicity, sex, and age), this association remained stable (OR = 1.141, 95% CI: 1.106–1.176, P < 0.001). In model 3 (further adjusted for comorbidities, dietary intake, and laboratory indicators), the association persisted, although slightly attenuated (OR = 1.085; 95% CI: 1.036–1.136; P = 0.002).

Table 2 WLR Analysis of BRI and COPD

For categorical BRI, Model 1 demonstrated that individuals in the highest BRI quartile had a 2.972-fold higher likelihood of COPD in comparison to those in the lowest quartile (P < 0.001). This association remained significant in Model 2 (OR = 2.162; 95% CI: 1.728–2.706; P < 0.001) and Model 3 (OR = 1.466; 95% CI: 1.091–1.969; P = 0.015).

RCS Analysis

RCS analysis examined the dose-response relationship between BRI and the likelihood of developing COPD. The results revealed an approximately linear positive association between BRI and the likelihood of developing COPD (P for nonlinearity = 0.155) (Figure 2).

Figure 2 The association between BRI and the likelihood of developing COPD through RCS analysis. The RCS curve was adjusted for race/ethnicity, sex, PIR, educational background, marital status, age, TEI, DF, smoking status, alcohol consumption, diabetes, HP, moderate PA, direct HDL cholesterol, and eosinophil percentage.

Subgroup Analysis

The robustness of the association between BRI and COPD prevalence was assessed by subgroup analyses based on sex, smoking status, alcohol consumption, age, diabetes, HP, and CVD. The results demonstrated a significant association between BRI and the likelihood of developing COPD in all subgroups except for former smokers and individuals with CVD. In addition, interaction tests revealed substantial differences in COPD prevalence across subgroups stratified by sex, HP, and CVD (Figure 3).

Figure 3 The association between BRI and COPD prevalence through subgroup analyses.

Discussion

This cross-sectional study, which involved 14,254 individuals, suggested that higher BRI levels were positively associated with COPD prevalence in the US adult population. This association was confirmed to be linear based on RCS analysis. Although no threshold effect was detected in the RCS analysis, it was observed that when BRI exceeded 5.332, COPD prevalence increased significantly with rising BRI. Subgroup analyses further supported the robustness of these findings. Interaction tests indicated that sex, HP, and CVD significantly modified this association. These results suggest that maintaining an appropriate BRI level is particularly important for COPD prevention. Moreover, BRI, due to its cost-effectiveness and efficiency, may hold substantial value in large-scale COPD screening and risk stratification.

Obesity, as a major contributor to the risk of COPD, has garnered increasing research interest. Prior studies mainly employed BMI to quantify obesity, but BMI cannot differentiate between fat mass (FM) and fat-free mass (FFM). Since FFM and FM exert distinct effects on pulmonary physiology, Zhang et al highlighted the necessity of investigating the association between fat distribution and COPD risk.¹⁶ Although WC reflects abdominal fat accumulation (AFA), it does not distinguish between subcutaneous and visceral fat. The A Body Shape Index may outperform BMI and WC in predicting ACM, but is less reliable for predicting chronic diseases.^17–19 In contrast, BRI, which integrates WC and height into a cylindrical model, more accurately estimates abdominal obesity.^20–22 Current studies have demonstrated relationships between BRI and obstructive respiratory diseases. BRI is a superior predictor of obstructive sleep apnea.²³ Xu et al demonstrated that both weight-adjusted waist index (WWI) and BRI are independent factors influencing asthma risk, with BRI exhibiting better predictive performance than WWI.²⁴ These conclusions support the utility of BRI in early COPD detection and risk stratification. Therefore, timely identification and intervention in individuals with elevated BRI may help slow disease progression and improve their quality of life.

Several mechanisms may underlie the association between BRI and COPD. Individuals with high BRI tend to have significant AFA, which increases the COPD risk. This finding has been supported by previous research.^25,26 Lam et al reported that central obesity is associated with both obstructive and restrictive ventilatory impairments in COPD.²⁶ This may be attributed to obesity-induced systemic inflammation, which can impair the normal structure and function of lung tissue.²⁷ Abnormal accumulation of visceral adipose tissue (VAT) can cause adipocyte hypoxia by impairing ventilation and reducing tissue oxygenation,^7,15 ultimately triggering inflammatory responses. The activation of immune cells (such as neutrophils, macrophages, and eosinophils) contributes to pulmonary inflammation.^28,29 Furthermore, VAT is recognized as an active endocrine organ.²⁸ In individuals with obesity, VAT homeostasis is disrupted, thereby leading to abnormal secretion of adipokines. This includes elevated levels of pro-inflammatory mediators such as leptin, IL-6, and TNF-α, and decreased levels of anti-inflammatory factors such as adiponectin. These imbalances can further stimulate the NOD-like receptor family pyrin domain-containing 3 inflammasome and IL-1β signaling,^28,30,31 potentially accelerating airway remodeling, impairing lung function, and ultimately contributing to COPD progression.

Furthermore, elevated levels of chronic low-grade inflammatory mediators related to obesity, such as TNF-α, leptin, and IL-6 secreted by adipose tissue, are associated with neutrophil-mediated OS responses.⁹ Neutrophil activation contributes to the depletion of systemic antioxidants by releasing reactive oxygen species (ROS),³² thereby reducing pulmonary defense capacity. Moreover, it can exacerbate damage to the alveolar wall by releasing proteases. In addition, ROS can activate inflammation-related signaling pathways,^32,33 alter the extracellular matrix, and stimulate goblet cell activation, thereby resulting in mucus hypersecretion and subsequent airway obstruction. Current evidence demonstrates that neutrophil elastases damage elastic fibers and mucociliary structures in the lungs, ultimately impairing mucus clearance and promoting goblet cell metaplasia and mucin production.⁹ These effects further reduce pulmonary compliance and increase airway resistance, thereby elevating COPD risk.

Moreover, inadequate PA also contributes to COPD progression among individuals with obesity. In individuals with COPD, obesity may further impair ventilation through such mechanical constraints as limited diaphragmatic movement and increased chest wall resistance.^7,34,35 Additionally, these constraints can elevate the risk of comorbid conditions, including metabolic syndrome and CVD, thus indirectly accelerating disease deterioration.^15,30

According to subgroup analyses, no significant association between BRI and COPD was observed in participants with CVD or in former smokers, suggesting that the generalizability of BRI may vary across populations. The lack of a significant association in the CVD subgroup may be attributable to residual confounding from unmeasured factors, such as medication interventions or complications, or to potential reverse causality.³⁶ After smoking cessation, systemic inflammation persisted in patients with COPD, whereas it declined in healthy former smokers.³⁷ This difference may affect the BRI–COPD relationship through pathways involving fat and lung function. Existing research reveals that although smoking cessation is frequently accompanied by weight gain, it does not lead to an elevated risk of COPD.³⁸ These findings warrant further investigation in prospective cohort studies. In addition, sex, HP, and CVD significantly modified the association between BRI and the odds of having COPD. The association between obesity and CVD may be mediated by shared intermediate metabolic risk factors, including impaired glucose tolerance, insulin resistance, HP, and hypertriglyceridemia, all of which contribute to adverse cardiovascular events.^39,40 In the CVD subgroup, several plasma markers are linked to obesity.⁴¹ For example, abnormally low natriuretic peptide levels are associated with an increase in total white adipose tissue mass.⁴² These factors may partly disrupt the BRI–COPD relationship, distinguishing this subgroup from individuals without CVD. A U.S.-based study suggests that men are more prone to exhibit AFA.⁴³ Abdominal fat, particularly VAT, increases COPD risk through metabolic and inflammatory mechanisms.⁴⁴

This study has several strengths. First, the generalizability of our results was enhanced by incorporating a nationally representative sample and applying a complex multistage probability sampling design. Second, this study systematically analyzed the association between BRI and COPD and adjusted for multiple covariates to minimize confounding. Moreover, regression and subgroup analyses further reinforced the reliability of the observed associations.

Nevertheless, some limitations should be acknowledged. First, a causal relationship between BRI and COPD cannot be established because of the cross-sectional design. Second, since the data were derived from a US population, the generalizability of the findings is uncertain and warrants further validation. Third, compared with standardized diagnoses based on lung function tests, self-reported diagnoses may substantially underestimate the true prevalence of COPD, resulting in underdiagnosis. Consequently, self-report diagnosis is an imprecise tool for identifying COPD patients,⁴⁵ potentially affecting the interpretation of the findings. Hence, these findings should be confirmed by prospective cohort studies.

Conclusion

This study observed a positive linear association between BRI and the likelihood of developing COPD. This result suggests that BRI could serve as a potential marker for assessing the likelihood of COPD and may help reduce the cost of early COPD screening. In addition, BRI has been shown to be more accurate and sensitive than BMI and WC. Therefore, these findings hold significant implications for clinical practice and epidemiological research. Future studies should further investigate whether BRI-based interventions can improve clinical outcomes in individuals with COPD, as well as explore the potential threshold value of BRI.

Data Sharing Statement

The datasets analysed during the current study are available in the National Center for Health Statistics (NCHS), https://www.cdc.gov/nchs/nhanes/about/index.html.

Ethics Approval and Informed Consent

All NHANES protocols obtained approval from the Ethics Review Board of NCHS. Written informed consent was offered by enrolled individuals.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work..

Funding

The authors declare that they did not receive any funding from any source.

Disclosure

The authors declare that they have no competing interests.

References

1. Patel N. An update on COPD prevention, diagnosis, and management: the 2024 GOLD report. Nurse Pract. 2024;49:29–36. doi:10.1097/01.NPR.0000000000000180

2. Sandelowsky H, Weinreich UM, Aarli BB, et al. COPD – do the right thing. BMC Fam Pract. 2021;22:244. doi:10.1186/s12875-021-01583-w

3. James SL, Abate D, Abate KH, et al. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990–2017: a systematic analysis for the global burden of disease study 2017. Lancet. 2018;392:1789–1858. doi:10.1016/S0140-6736(18)32279-7

4. Wheaton AG, Liu Y, Croft JB, et al. Chronic obstructive pulmonary disease and smoking status – United States, 2017. MMWR Morb Mortal Wkly Rep. 2019;68:533–538. doi:10.15585/mmwr.mm6824a1

5. Ho T, Cusack RP, Chaudhary N, et al. Under- and over-diagnosis of COPD: a global perspective. Breathe. 2019;15:24–35. doi:10.1183/20734735.0346-2018

6. Martinez FJ, Han MK, Allinson JP, et al. At the root: defining and halting progression of early chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2018;197:1540–1551. doi:10.1164/rccm.201710-2028PP

7. Palma G, Sorice GP, Genchi VA, et al. Adipose tissue inflammation and pulmonary dysfunction in obesity. Int J Mol Sci. 2022;23(13):7349. doi:10.3390/ijms23137349

8. Furutate R, Ishii T, Wakabayashi R, et al. Excessive visceral fat accumulation in advanced chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis. 2011;6:423–430. doi:10.2147/COPD.S22885

9. Rahman I. Oxidative stress in pathogenesis of chronic obstructive pulmonary disease: cellular and molecular mechanisms. Cell Biochem Biophys. 2005;43:167–188. doi:10.1385/CBB:43:1:167

10. Thomas DM, Bredlau C, Bosy-Westphal A, et al. Relationships between body roundness with body fat and visceral adipose tissue emerging from a new geometrical model. Obesity. 2013;21:2264–2271. doi:10.1002/oby.20408

11. Huang C, Gao Z, Huang Z, et al. Nonlinear association between body roundness index and metabolic dysfunction associated steatotic liver disease in nondiabetic Japanese adults. Sci Rep. 2025;15:15442. doi:10.1038/s41598-025-99540-5

12. Yang L, Huang S, Sheng S, et al. Association of obesity-related indices with rapid kidney function decline and chronic kidney disease, a study from a large longitudinal cohort in China. Obes Facts;2025. 1–27. doi:10.1159/000545356

13. Wang K, Mao Y, Lu M, et al. Association between serum Klotho levels and the prevalence of diabetes among adults in the United States. Front Endocrinol. 2022;13:1005553. doi:10.3389/fendo.2022.1005553

14. Cai Y, Chen M, Zhai W, et al. Interaction between trouble sleeping and depression on hypertension in the NHANES 2005–2018. BMC Public Health. 2022;22:481. doi:10.1186/s12889-022-12942-2

15. Naik D, Joshi A, Paul TV, et al. Chronic obstructive pulmonary disease and the metabolic syndrome: consequences of a dual threat. Indian J Endocrinol Metab. 2014;18:608–616. doi:10.4103/2230-8210.139212

16. Zhang Q, Wang Z, Liu W, et al. Elucidating the relationship between body fat index and pulmonary health: insights from cross-sectional analysis and mendelian randomization. Int J Chron Obstruct Pulmon Dis. 2025;20:869–882. doi:10.2147/COPD.S488523

17. Verhulst SL, Schrauwen N, Haentjens D, et al. Sleep-disordered breathing in overweight and obese children and adolescents: prevalence, characteristics and the role of fat distribution. Arch Dis Child. 2007;92:205–208. doi:10.1136/adc.2006.101089

18. Ji M, Zhang S, An R. Effectiveness of A Body Shape Index (ABSI) in predicting chronic diseases and mortality: a systematic review and meta-analysis. Obes Rev. 2018;19:737–759. doi:10.1111/obr.12666

19. Song X, Jousilahti P, Stehouwer CD, et al. Comparison of various surrogate obesity indicators as predictors of cardiovascular mortality in four European populations. Eur J Clin Nutr. 2013;67:1298–1302. doi:10.1038/ejcn.2013.203

20. Cao H, Shi C, Aihemaiti Z, et al. Association of body round index with chronic kidney disease: a population-based cross-sectional study from NHANES 1999–2018. Int Urol Nephrol. 2025;57:965–971. doi:10.1007/s11255-024-04275-3

21. Wei C, Zhang G. Association between body roundness index (BRI) and gallstones: results of the 2017–2020 national health and nutrition examination survey (NHANES). BMC Gastroenterol. 2024;24:192. doi:10.1186/s12876-024-03280-1

22. Qiu L, Xiao Z, Fan B, et al. Association of body roundness index with diabetes and prediabetes in US adults from NHANES 2007–2018: a cross-sectional study. Lipids Health Dis. 2024;23:252. doi:10.1186/s12944-024-02238-2

23. Pan X, Liu F, Fan J, et al. Association of body roundness index and a body shape index with obstructive sleep apnea: insights from NHANES 2015–2018 data. Front Nutr. 2024;11:1492673. doi:10.3389/fnut.2024.1492673

24. Xu J, Xiong J, Jiang X, et al. Association between body roundness index and weight-adjusted waist index with asthma prevalence among US adults: the NHANES cross-sectional study, 2005–2018. Sci Rep. 2025;15:9781. doi:10.1038/s41598-025-93604-2

25. Leone N, Courbon D, Thomas F, et al. Lung function impairment and metabolic syndrome: the critical role of abdominal obesity. Am J Respir Crit Care Med. 2009;179:509–516. doi:10.1164/rccm.200807-1195OC

26. Lam KB, Jordan RE, Jiang CQ, et al. Airflow obstruction and metabolic syndrome: the Guangzhou Biobank Cohort Study. Eur Respir J. 2010;35:317–323. doi:10.1183/09031936.00024709

27. Lenártová P, Habánová M, Mrázová J, et al. Analysis of visceral fat in patients with chronic obstructive pulmonary disease (COPD). Rocz Panstw Zakl Hig. 2016;67:189–196.

28. Huang JX, Xiao BJ, Yan YX, et al. Association between visceral adipose tissue and chronic respiratory diseases: a two-sample multivariable mendelian randomization study in European population. Int J Chron Obstruct Pulmon Dis. 2025;20:919–928. doi:10.2147/COPD.S510828

29. Para O, Cassataro G, Fantoni C, et al. Prognostic role of blood eosinophils in acute exacerbations of chronic obstructive pulmonary disease: systematic review and meta-analysis. Monaldi Arch Chest Dis. 2025. doi:10.4081/monaldi.2025.3298

30. Hughes MJ, McGettrick HM, Sapey E. Shared mechanisms of multimorbidity in COPD, atherosclerosis and type-2 diabetes: the neutrophil as a potential inflammatory target. Eur Respir Rev. 2020;29:190102. doi:10.1183/16000617.0102-2019

31. Ren Y, Zhao H, Yin C, et al. Adipokines, hepatokines and myokines: focus on their role and molecular mechanisms in adipose tissue inflammation. Front Endocrinol. 2022;13:873699.

32. Uchida K, Shiraishi M, Naito Y, et al. Activation of stress signaling pathways by the end product of lipid peroxidation. 4-hydroxy-2-nonenal is a potential inducer of intracellular peroxide production. J Biol Chem. 1999;274:2234–2242. doi:10.1074/jbc.274.4.2234

33. Tsukagoshi H, Kawata T, Shimizu Y, et al. 4-Hydroxy-2-nonenal enhances fibronectin production by IMR-90 human lung fibroblasts partly via activation of epidermal growth factor receptor-linked extracellular signal-regulated kinase p44/42 pathway. Toxicol Appl Pharmacol. 2002;184:127–135. doi:10.1006/taap.2002.9514

34. Suzuki M, Makita H, Östling J, et al. Lower leptin/adiponectin ratio and risk of rapid lung function decline in chronic obstructive pulmonary disease. Ann Am Thorac Soc. 2014;11:1511–1519. doi:10.1513/AnnalsATS.201408-351OC

35. Ruvuna L, Hijazi K, Guzman DE, et al. Dynamic and prognostic proteomic associations with FEV(1) decline in chronic obstructive pulmonary disease. medRxiv. 2024. doi:10.1101/2024.08.07.24311507

36. Strain T, Wijndaele K, Sharp SJ, et al. Impact of follow-up time and analytical approaches to account for reverse causality on the association between physical activity and health outcomes in UK Biobank. Int J Epidemiol. 2020;49:162–172. doi:10.1093/ije/dyz212

37. Willemse BW, ten Hacken NH, Rutgers B, et al. Effect of 1-year smoking cessation on airway inflammation in COPD and asymptomatic smokers. Eur Respir J. 2005;26:835–845. doi:10.1183/09031936.05.00108904

38. Sahle BW, Chen W, Rawal LB, et al. Weight gain after smoking cessation and risk of major chronic diseases and mortality. JAMA Network Open. 2021;4:e217044. doi:10.1001/jamanetworkopen.2021.7044

39. Saxton SN, Clark BJ, Withers SB, et al. Mechanistic links between obesity, diabetes, and blood pressure: role of perivascular adipose tissue. Physiol Rev. 2019;99(4):1701–1763. doi:10.1152/physrev.00034.2018

40. Piché ME, Tchernof A, Després JP. Obesity phenotypes, diabetes, and cardiovascular diseases. Circ Res. 2020;126:1477–1500. doi:10.1161/CIRCRESAHA.120.316101

41. Neeland IJ, Poirier P, Després JP. Cardiovascular and metabolic heterogeneity of obesity: clinical challenges and implications for management. Circulation. 2018;137:1391–1406. doi:10.1161/CIRCULATIONAHA.117.029617

42. Nyberg M, Terzic D, Ludvigsen TP, et al. A state of natriuretic peptide deficiency. Endocr Rev. 2023;44:379–392. doi:10.1210/endrev/bnac029

43. Power ML, Schulkin J. Sex differences in fat storage, fat metabolism, and the health risks from obesity: possible evolutionary origins. Br J Nutr. 2008;99:931–940. doi:10.1017/S0007114507853347

44. Mafort TT, Rufino R, Costa CH, et al. Obesity: systemic and pulmonary complications, biochemical abnormalities, and impairment of lung function. Multidiscip Respir Med. 2016;11:28. doi:10.1186/s40248-016-0066-z

45. Abrham Y, Zeng S, Lin W, et al. Self-report underestimates the frequency of the acute respiratory exacerbations of COPD but is associated with BAL neutrophilia and lymphocytosis: an observational study. BMC Pulm Med. 2024;24:433. doi:10.1186/s12890-024-03239-8