Spontaneous pneumomediastinum (SPM) is a rare and self-limiting condition characterized by the presence of air in the mediastinum not related to trauma or surgical procedures [1]. Described by Laennec in 1819 as a complication of trauma, Hamman 120 years later published his case series of SPM. This condition typically affects young adults aged 20-30 years, with a male preponderance of 8:1. SPM is associated with other medical conditions, including asthma, connective tissue disease, interstitial lung disease, diabetic ketoacidosis, chronic obstructive airway disease, and influenza-like syndrome. [1] SPM is reported to develop in 10% of cases of intubated COVID-19 with acute respiratory distress syndrome (ARDS) even with low tidal volume strategies [2,3]. One unmatched case control study of 271 patients showed the incidence of SPM among non-intubated acute COVID-19 patients at 3.3%, similar to our patient [4]. The case we described would fit into this group. 

The cause of COVID-19, SARS-CoV 2, is a novel coronavirus associated with wide heterogeneity in clinical presentation ranging from asymptomatic to critical illness. The first infection was detected in late 2019 in Wuhan, China, after which it rapidly spread worldwide. Mortality was high among those with advanced age and significant comorbidities. The acute phase of COVID-19 infection lasts approximately three to four weeks. After four weeks of infection, SARS-CoV 2 no longer has the capability to replicate, and residual illness in this stage is called the post-acute COVID-19 syndrome [5]. Symptoms associated with the infection may persist, such as lethargy, easy fatigability, and shortness of breath, with some requiring prolonged supplemental oxygenation. To our knowledge, the incidence and risk factors of SPM among patients who have recovered from COVID-19 infection, i.e., patients in the post-acute phase, is yet to be studied.

We present a case of SPM in a patient with post-acute COVID-19 syndrome who received high flow nasal oxygen therapy in the acute stages of the disease.

The patient was a 58-year-old Chinese gentleman who never smoked. He had a BMI of 29.4kg/m2 and was fully vaccinated for COVID-19 (last dose was given three months prior to admission). He was admitted to the emergency room complaining of a productive cough accompanied by shortness of breath. A nasal pharyngeal swab for polymerase chain reaction (PCR) detecting SARS‐CoV‐2 ribonucleic acid (RNA) resulted in a positive. His significant medical history included hypertension and hyperlipidemia. He had no prior trauma, asthma history, diabetes, pulmonary tuberculosis, or connective tissue disease.

On admission, physical examination showed decreased breath sounds on both lungs and diffuse systolic murmur. He was febrile at 38 degrees Celsius, with a blood pressure of 114/77mmHg, heart rate of 143 per minute, and respiratory rate of 35 per minute. Oxygen saturation was at 89% on 100% non-rebreather mask. Arterial blood gas showed type 1 respiratory failure with a P/F ratio of 46. Therefore, we decided to start oxygen therapy with a high-flow nasal cannula (HFNC) (FiO2: 100%, flow: 60 L/min with SpO2: 96%). Initial chest X-ray (CXR) revealed right middle and lower zone patchy airspace opacities without pleural effusion or pneumothorax (Figure 1).

The full blood count showed a white blood cell count (WBC) of 6.95x10^9/L, hemoglobin 15.2g/dL, platelets 191x10^9/L, C-Reactive protein (CRP) 151.1mg/L (N=1.0-5.0mg/L), procalcitonin 1.2ng/mL (N=0.5 to 2.0ng/mL), serum lactate 1.9mmol/L (N=0.6-1.4mmol/L), serum urea 6.8mmol/L (N=2.4 to 6.6mmol/L) and beta-hydroxybutyrate 0.35mmol/L (N=0.02-0.27). His International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC) 4C score was nine, signifying high risk and an in-hospital mortality of 31.4 to 34.9%. The patient was prescribed intravenous dexamethasone before transferring to medical intensive care unit (MICU).

In the medical intensive care unit, he received empiric intravenous amoxicillin-clavulanic acid and oral doxycycline. Blood cultures and sputum cultures, which were taken from endotracheal tube (ETT), were all reported as no bacterial growths. Fever persisted, and a repeat chest X-ray showed worsening bilateral airspace opacities. Antibiotics were escalated to intravenous piperacillin-tazobactam while on intravenous dexamethasone therapy. Blood cultures and sputum cultures were repeated and were negative. On day six of illness, he received the first dose of a five-day course of intravenous remdesivir. Due to persistent hypoxia, he received two doses of intravenous tocilizumab on day six and day 26 of illness.

He also developed starvation ketosis and revealed newly diagnosed diabetes mellitus with HbA1c of 8.1%. Subcutaneous (SC) intermediate-acting insulin (Insulatard) was prescribed. Thromboprophylaxis with subcutaneous enoxaparin was given during the pulmonary phase of the illness. The HFNC setting for the first 15 days was on maximum flow of 60L/min, with a taper to 40L/min on the remaining seven days. Initial FiO2 on HFNC was at 100%, with subsequent gradual weaning to 40% on day 28 of illness. On day 10 of illness, he received a trial of continuous positive airway pressure ventilation (CPAP), but HFNC was resumed as no significant improvement was seen on oxygenation. CRP levels improved from 151mg/L to 72.8mg/L, and by day 28 of illness, the CRP was at 4.4mg/L. The patient performed awake prone positioning to improve oxygenation.

On day 30 of illness, he was weaned off to a non-rebreather mask and managed to sustain adequate oxygen saturation on nasal cannula oxygenation at 5-liter oxygen. He was transferred to the general ward for rehabilitation. He remained afebrile and normotensive with a resting tachycardia at 100-110/min. Despite mild dyspnea and easy fatigability, oxygen saturations were at 98% on 4-liter oxygen nasal cannula. Intravenous dexamethasone was gradually tapered down.

On day 34 of illness, COVID-19 PCR with cycle threshold (CT) ratio was 33.34/33.37. Despite this, his saturations dropped to 77% while on 4-liter oxygen nasal cannula. He was put on 100% non-rebreather mask, and oxygen saturations increased to 96-99%. Repeat CXR showed stable bilateral diffuse airspace opacities with no evidence of pneumothorax. Repeat arterial blood gas revealed type 1 respiratory failure with a P/F ratio of 119 and CRP of 0.7mg/L. An electrocardiogram showed normal sinus rhythm at 73/min. A computed tomography pulmonary angiogram (CTPA) was arranged to rule out acute pulmonary embolism. SC enoxaparin was restarted at a therapeutic dose. The scan was negative for pulmonary embolism but detected a pneumomediastinum (PM), pneumopericardium (PP), and subcutaneous emphysema (Figure 2, 3). Respiratory medicine service recommended keeping him on non-rebreather mask oxygenation, and he was deemed a poor candidate for positive pressure ventilation in the event of current deterioration. On examination, he was alert tachypneic with bilateral scattered crackles in the middle and lower zones on auscultation. He developed subcutaneous emphysema at the neck but no change in the quality of his voice. After discussion with the patient and his family, he opted for maximum ward management in the event of further deterioration. The family was hopeful for his full recovery. On day 36 of illness, he developed atrial flutter with a pulse rate of 160bpm on 12-lead electrocardiography (ECG) with a blood pressure of 109/79mmHg. He received rate control measures, including intravenous amiodarone, oral bisoprolol, and digoxin, and his heart rate improved to sinus rhythm at 76bpm on 12-lead ECG.

On day 40 of illness, the patient was found unresponsive with pulseless electrical activity on the cardiac monitor. Cardiopulmonary resuscitation (CPR) was initiated and he was intubated by the on-call airway team. Despite the resuscitation team’s best efforts, no return of spontaneous circulation was achieved, and the patient was pronounced demised.

There are a number of mechanisms that lead to the development of spontaneous pneumomediastinum. First is the alveolar rupture secondary to inflammation and diffuse alveolar pressures due to coughing. The escaping air from the ruptured alveoli tracks along the bronchovascular sheaths, dissecting into the pulmonary hila and escaping into the mediastinal space. This is seen on thoracic computed tomography scans demonstrating the Macklin effect, described as linear collections of air continuous to the bronchovascular sheaths dissecting into the pulmonary hilum [6]. Second is the direct viral invasion of the lung parenchyma, visceral and parietal pleura causing disruption of the parenchymal and pleural integrity or ruptured alveoli leading to subsequent air leak [7]. Third is the prothrombotic effect of COVID-19 infection-causing pulmonary vascular thrombosis and subsequent necrosis in the alveolar membranes. Fourth is cytokine storm-induced diffuse alveolar injury or direct viral infection of type 1 and type 2 pneumocytes increasing the risk of alveolar rupture [3].

COVID-19 related SPM affects an older population aged 38-72 years of age versus 5-34 years for non-COVID SPM [8]. COVID-19 related SPM has been associated with a more severe course of the disease and a mortality rate of 28.5% versus non-COVID SPM, which has an estimated mortality rate of 5.6% [1].

We highlight the risk of SPM, PP, and subcutaneous emphysema developing in COVID-19 patients without the usually associated conditions who did not receive invasive positive pressure ventilation at the post-acute phase of the disease. We also hope this launches further investigations comparing the non-invasive and invasive modalities of oxygen supplementation and the respective settings for severe COVID-19 to achieve the optimal oxygenation profile while minimizing the risk of barotrauma and PP and PM. We also anticipate more studies that look into developing multidisciplinary treatment protocols for patients who develop COVID-19 related PP and PM. The question is: which modality achieves optimal oxygenation while minimizing the risk of barotrauma and SPM? 



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Huajing Yang,1,* Zihui Wang,1,* Shan Xiao,1 Cuiqiong Dai,1 Xiang Wen,1 Fan Wu,1,2 Jieqi Peng,1 Heshan Tian,1 Yumin Zhou,1,2 Pixin Ran1,2

1National Center for Respiratory Medicine, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of China; 2Guangzhou Laboratory, Bio-Island, Guangzhou, People’s Republic of China

Correspondence: Pixin Ran; Yumin Zhou, National Center for Respiratory Medicine, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of China, Tel +86 2083205187, Fax +86 20-81340482, Email [email protected]; [email protected]

Background: The effect of serum uric acid (SUA) levels on lung function in chronic obstructive pulmonary disease (COPD) people remained unclear. We aimed to investigate the association between SUA and lung function.
Methods: A cross-sectional study was performed to measure the SUA levels and lung function in 2797 consecutive eligible individuals. Of these, individuals in our study were divided into two groups, the COPD group (n=1387) and the non-COPD group (n=1410). The diagnosis of COPD is defined as post-bronchodilator first second of forced expiratory volume (FEV1)/forced vital capacity (FVC) ratio of less than 0.70. Multivariable adjustment linear models were applied to estimate the effect of SUA levels on FEV1% predicted, FVC% predicted, and FEV1/FVC stratified by COPD status.
Results: After multivariable adjustment, each 1 mg/dL increase of SUA was significantly associated with a decrease in FEV1% predicted (− 1.63%, 95% confidence interval [CI] − 2.37 to − 0.90), FVC % predicted (− 0.89%, 95% CI − 1.55 to − 0.24), and FEV1/FVC (− 0.70%, 95% CI − 1.10 to − 0.30). In the COPD group, each 1 mg/dL increase of SUA was significantly associated with decreases in FEV1% predicted (− 1.87%, 95% CI − 2.91 to − 0.84), FVC% predicted (− 1.35%, 95% CI − 2.35 to − 0.34), and FEV1/FVC (− 0.63%, 95% CI − 1.18 to − 0.08). However, no significant association between lung function and SUA was found among people without COPD.
Conclusion: High SUA levels were associated with lower lung function, especially in COPD patients. However, no statistically significant effect of SUA on lung function was found in people without COPD.

Introduction

Serum uric acid (SUA) is the final breakdown product of purines or purine-containing compounds and is present at high concentrations in the epithelial lining fluid of the airway and in plasma.1–3 SUA has the double-edged characteristic of having antioxidant properties as well as pro-oxidant and pro-inflammatory properties.4,5 Based on these characteristics, there are complicated interpretations of whether SUA has a beneficial or noxious effect on lung function.6–8 An experimental study revealed that high SUA levels could improve emphysematous phenotype and lung dysfunction by reducing oxidative stress in mice with chronic obstructive pulmonary disease (COPD), and also found no significant effects of SUA on the lung function in non-diseased mice.9 What they found suggests that SUA levels may only affect lung function in individuals with impaired lung tissue but not normal lung structure.

Impairment of lung tissue reduces oxygen intake, which may result in tissue hypoxia. Tissue hypoxia elevates the SUA levels by inducing the degradation of adenosine.10 Previous studies have found a negative association between SUA levels and measures of lung function, such as forced vital capacity (FVC) and the first second of forced expiratory volume (FEV1) in individuals with COPD.8,11 Another study found no effect of SUA on lung function in the same population.12

For the population with normal lung structure, the effect of high SUA levels on lung function have been conflicting in cross-sectional studies; while a positive effect was found in a large Korean population (n=69,928) without any clinical diseases,6 a negative effect was observed in the Korean National Health and Nutrition Examination Survey,13 and also no significant effect was found in young adults aged 22–29 years.14

Current researchers have paid greater attention to differential effects of SUA on lung function stratified by smoking status15 or gender status,13 but no attention to respiratory disease status. To the best of our knowledge, this is the first epidemiological study focusing on the different effects of SUA on lung function in individuals with or without COPD. In currently available research, the relationships between SUA and lung function stratified by COPD status are not well-characterized for reasons of different populations and the heterogeneous analysis methods among others.

Based on this, our study aimed to identify the relationship between SUA and lung function in individuals with or without COPD.

Methods

Study Population and Blood Tests

Our study applied the baseline data set of a cohort study of people with chronic airway disease in Guangdong, China (ChiCTR1900024643), which was a population-based, multicenter randomized survey of COPD, conducted from June 2019 to June 2021. This study included people: 1) people aged over 30 years old; 2) people who had signed informed consent; 3) who returned complete COPD-related questionnaires; 4) who had undergone the standardized spirometry; 5) who had completed blood tests. Exclusion criteria were the following: 1) a history of malignancy; 2) acute inflammatory diseases or infectious diseases (such as pneumonia, bronchiectasis with infection and active pulmonary tuberculosis); 3) acute exacerbation of COPD within four weeks; 4) cardiovascular or chronic pulmonary diseases (such as hypertension, asthma, bronchiectasis, pneumoconiosis, and interstitial lung diseases), which can affect SUA levels.

Initially, a total of 3160 study subjects were considered as eligible subjects and included in our study. After excluding those without a laboratory examination (n=118), without a complete questionnaire (n=62) and lacking available spirometry data (n=183), 2797 participants were enrolled in our study (Figure 1). Invited participants were required to undergo anthropometric measurement, the spirometer examination, laboratory assessment, and also answered COPD related-questionnaires. The study protocol was approved by the Ethics Committee of the First Affiliated Hospital of Guangzhou Medical University (No.2018–53). All participants gave written informed consent. This present study was in line with the principles of the Declaration of Helsinki.

Figure 1 Study flow chart.

Blood samples were obtained from invited participants after 12 h of fasting. SUA levels were determined by the uricase-peroxidase method and by the creatinase-peroxidase method, respectively.16

Outcome Definitions

Invited participants were required to complete a questionnaire based on the questionnaires from the International Burden of Obstructive Lung Disease Study17 and a 2007 Chinese epidemiological study,18 that included potential risk factors for COPD and also chronic respiratory symptoms (such as cough, phlegm production, and dyspnoea). The technicians who were responsible for administering this questionnaire had been strictly trained and also passed a training test. The presence of cough was assessed with “Do you usually cough for three consecutive months or more per year for two years? ” Phlegm production was assessed with “Do you usually bring up phlegm for three consecutive months or more per year for two years?” Dyspnoea was assessed with “Have you had shortness of breath either when walking up a slight hill or brisk walking on the level?”

Lung Function Measures

Participants aged over 30 years were required to finish standardized spirometry. Participants who were physically incapable of taking standardized spirometry (ie, thoracic, abdominal, or eye surgery, retinal detachment or myocardial infarction in past three months; pregnant or breastfeeding; antibacterial chemotherapy for tuberculosis) were excluded.19 Before and after bronchodilator spirometries were performed by using a portable spirometer (CareFusion MasterScreen Pneumo, Germany) according to the European Respiratory Society/American Thoracic Society standards (ERS/ATS 2005).19 Manoeuvre of American Thoracic Society quality grade C or above were acceptable for analysis.20 Standardized spirometry was conducted during the summer, from 2019 to 2020. The diagnosis of COPD is defined by post-bronchodilator (Salbutamol Sulfate Aerosol, 400 μg, 20 min later) FEV1/FVC ratio of less than 0.70.21 The predicted value for FVC and FEV1 is calculated according to the Report Working Party Standardization of lung function tests,22 adjusted by an equation obtained in a representative Chinese population.23

Covariate Definitions

We collected demographic data, including sex, age, and also body index mass (BMI). Never smokers were defined as adults who reported having smoked less than 100 cigarettes in their lifetime. Current smokers were defined as adults who reported having smoked more than 100 cigarettes in their lifetime and also currently smoke some days or every day. Former smokers were defined as adults who reported having smoked more than 100 cigarettes in their lifetime but quit smoking more than three months.

Statistical Analyses

The normality of distribution of variables was evaluated with the Kolmogorov–Smirnov test. Continuous variables were exhibited as the mean ± SD when in a normal distribution, and as medians (interquartile ranges) when in a skewed distribution. Student’s t-test was applied to compare differences among individuals with and without COPD. Categorical variables were expressed as numbers (percentages), and the Chi-square test or Fisher’s exact test were used to assess the inter-group difference. Continuous SUA values were also transformed into categorical variables according to their terciles. The ANOVA test was applied to investigate the significant differences between different SUA- levels groups.

Binary logistic models were applied to investigate the relationships between the SUA levels, the presence of COPD, and the chronic respiratory symptoms (cough, phlegm production, and dyspnea), either adjusted or unadjusted sex, age, smoking status, cumulative tobacco smoking, and body mass index (BMI). To investigate the different effects of SUA on lung function, we also conducted a multivariate analysis among individuals with or without COPD. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated to estimate the strength of this association.

Multivariable adjustment linear models were implied to estimate the effect of SUA levels on FEV1%, FVC%, and FEV1/FVC. We also tested the assumptions of normality, linearity, and homoscedasticity graphically by using plots of observed versus predicted values as well as also plots of residuals versus predicted values or the observed exposure values. No major violations were found.

In the sensitivity analysis, the same analyses were performed in the different groups by smoking statuses to explore any differential effects of SUA based on smoking status. Analyses of the gender subgroups were also conducted. The relationship between SUA and spirometer measurement after bronchodilators was also estimated.

All tests were two-sided, and p-values less than 0.05 were considered statistically significant. Data were analyzed using R statistical software (version 4.1.0).

Results

Study Population

A total of 2797 participants who met inclusion criteria and had available data were enrolled in our study, including 1410 (50.41%) non-COPD subjects and 1387 (49.58%) COPD patients. The clinical characteristics and biochemical biomarkers of invited participants are presented in Table 1. Participants were divided into two groups based on their current status of COPD. Significant differences between the two groups were found, such as sex, age, BMI, smoking status, pre-bronchodilator spirometric values, and also chronic respiratory symptoms. Additionally, overall SUA levels were higher in individuals with COPD, as 4.17 ± 1.10 mg/dl, versus 3.79 ± 1.14 mg/dl in the non-COPD group (Table 1; Figure 2). Individuals with high SUA levels were older, with higher values of BMI, and more likely to be current smokers compared to individuals in the lowest SUA group. Those in the highest terciles were also more likely to have lower FEV1% predicted, lower FVC % predicted, and low FEV1/FVC. Compared to the lowest SUA tertiles, individuals in the two highest terciles were more likely to report a risk of cough, phlegm production, and also dyspnoea.

Table 1 The Association of Baseline Participant Characteristics with SUA and COPD (N=2797)

Figure 2 Serum uric acid levels in people with and without chronic obstructive pulmonary disease. ***p value less than 0.001.

Abbreviations: COPD, chronic obstructive pulmonary disease; Non-COPD, without chronic obstructive pulmonary disease.

Uric Acid and COPD

Unadjusted logistic regression analysis showed no significant effect of SUA on the prevalence of COPD (unadjusted OR,1.33; 95% CI 1.25 to 1.44) (Table 2). After multivariable adjustment, the OR (95% CI) of the prevalence of COPD was 1.15 (95% CI 1.06 to 1.25) with p-value less than 0.001 per 1 mg/dL increase of SUA (Table 2; Figure 3). Similar results were also found both in the never-smoker and ever-smoker groups (online supplementary Figure A1), but not in the female population (online supplementary Figure A2).

Table 2 Association Between SUA, Lung Function and Chronic Respiratory Symptom in People with or Without COPD

Figure 3 Association of SUA levels with study outcomes. Shown are odds ratio or estimate effect for each outcome for each 1 mg/dl increase in serum uric acid, adjusted for age, sex, BMI, smoking status, and cumulative tobacco consumption. Bold values means that all participants were in the analysis. *p value less than 0.05.

Abbreviations: COPD, chronic obstructive pulmonary disease; Non-COPD, without chronic obstructive pulmonary disease; FEV1% predicted, percent predicted forced expiratory volume in 1 s; FVC% predicted, percent predicted forced vital capacity; 95% CI, 95% confidence interval.

Uric Acid and Lung Function

After multivariable adjustment, each 1 mg/dl increase of SUA was associated with a 1.63% decrease in FEV1% predicted (95% CI −2.37 to −0.90) (Table 2; Figure 3; Figure 4). Each 1 mg/dl increase of SUA was significantly associated with a 1.87% (95% CI −2.91 to −0.84) decrease in FEV1% predicted, but no significant relationship was found in the non-COPD group (0.39%,95% CI −1.18 to 0.40). After multivariable adjustment, each 1 mg/dl increase of SUA levels was associated with a −0.89% decrease (95% CI −1.55 to−0.24) in FVC % predicted. Similar results were found in the COPD group, (−1.35% [95% CI −2.35 to −0.34]) but not in the non-COPD group (−0.42% [95% CI −1.26 to 0.43]). Additionally, after multivariable adjustment, each 1 mg/dL increase in SUA levels was associated with a −0.7% (95% CI −1.10 to −0.30) decrease in FEV1 /FVC. Each 1 mg/dl increase in SUA was associated with a 0.63% decrease in FEV1 /FVC in the COPD group, while no significant association between SUA levels and FEV1 /FVC was found in the Non-COPD group (p-value 0.987). The associations between SUA levels and lung function after using bronchodilators were also evaluated, with similar results were found (online supplementary Figure A3.).

Figure 4 Regression of lung function on SUA in people with or without COPD. The analysis was multi-variable adjusted for age, sex, BMI, smoking status, and cumulative tobacco consumption. Regression values in the top and 95% CIs were shown as the shaded area around the regression line.

Abbreviations: COPD, chronic obstructive pulmonary disease; Non-COPD, without chronic obstructive pulmonary disease; FEV1% predicted, percent predicted forced expiratory volume in 1 s; FVC% predicted, percent predicted forced vital capacity.

Uric Acid and Symptoms of Airway Disease

The OR of dyspnea was 1.12 (95% CI 1.05 to 1.21) with each 1 mg/dl higher SUA (Table 2; Figure 3). This association remained significant after adjustment for potential confounders. People with COPD had a higher risk of dyspnea than did those without COPD (adjusted ORs, 1.11 in the COPD group and 1.07 in the non-COPD group). No significant effect of SUA on dyspnoea was found in the non-COPD group (adjusted OR,1.00; 95% CI 0.88 to 1.13).

Discussion

This observational study analyzed 1387 individuals (49.58%) with COPD. Individuals with COPD had significantly higher SUA levels than did individuals without COPD (4.17 ± 1.10 vs 3.79 ± 1.14, respectively). In addition, we found that increased SUA levels were significantly associated with decreased in FEV1% predicted, FVC% predicted, and FEV1/FVC, and with increased risk of COPD as well as chronic respiratory symptoms. Negative associations between SUA and FEV1% predicted, FVC% predicted, and FEV1/FVC were found in the COPD group, but no significant association between lung function and SUA levels was found in the non-COPD group. To the best of our knowledge, this is the first epidemiological study focusing on the different effects of SUA on lung function based on individuals with or without COPD.

Cross-sectional studies have estimated that higher SUA levels were positively6 and inversely24 associated with lung function. Previous epidemiological results have been rather inconsistent whether in COPD populations or healthy populations. Two studies found that increased SUA levels accelerated lung function decline in COPD patients,12,25 while another found no significant effect of SUA on lung function in individuals with COPD.12 Similarly, the contradictory effect of SUA on lung function was found in individuals without COPD. In comparison, a positive effect was observed in a large Korean population (n=69,928) of healthy subjects,6 a negative effect was reported in the Korean National Health and Nutrition Examination Survey,13 and another analysis of young adults aged 22–29 years found no significant effect.14 With the heterogeneity of the above studies, such as in term of demographic data and statistical analysis, and so on, it is difficult to draw a clear relationship between SUA and lung function and to explore potential mechanisms, which may explain the discrepancy in current epidemiological studies.

The potentially different effects of SUA on lung function may depend on differential mechanisms. Shaheen suggested that interpretation of previous studies need to be careful26 and provided several possible mechanisms, such as the pro-oxidant and pro-inflammatory properties of SUA, a poor proxy for epithelial lining fluid concentrations, and also potential for confounding. Previous studies have demonstrated that SUA levels were inversely correlated with lung function in the female general population but not the male population.13,24 Though the cause of these sex differences between SUA and lung function remain uncertain, one study has suggested that sex hormones may affect SUA metabolism, making the relative health effect of SUA may be stronger in female generations.27 Further, our study provides a new insight to explain the contradictory relationship between SUA and lung function, the health effect of SUA levels on lung function, which is that health effect of SUA levels on lung function could be influenced by COPD status.

Previous experimental studies have estimated that high SUA levels do not affect reactive oxygen species levels, which can initiate inflammation or airway remodeling26,28–30 under normal conditions, and do not affect lung function under the same condition.9 Experimentally induced hypoxia models found that SUA levels were higher in hypoxia status compared to normal status in lung tissue,31 which means that hypoxia may promote purine catabolism,32,33 which could increase the levels of SUA, and those elevated SUA levels can cause systemic inflammation, potentially damaging lung function. A previous epidemiological study revealed that SUA levels were higher in people with more severe airflow limitation, and were also increased in the presence of hypoxia and systemic inflammation.25 Braghiroli et al suggested that compared to the healthy population, SUA levels were significantly increased in individuals with COPD in hypoxia status but not in those without.32 In a cross-sectional study, Nicks et al found that lower SUA levels were associated with COPD severity in the cross-sectional study.7

This is consistent with our findings; high SUA levels impaired the lung function in the COPD patients but not in non-COPD people with normal oxygen saturation.34,35 Although oxygen saturation values were not collected in our studies, we identified the positive correlation between the high SUA levels and the risk of dyspnoea. As people with the symptom of dyspnoea have different levels of hypoxia,36 that may support our assumptions. Meanwhile, further research is needed to explore the relationships among SUA, lung function, and oxygen saturation in respiratory disease, especially in COPD patients.

A variety of factors such as air pollution and smoking are suggested to have more influence on lung function in COPD patients and therefore have attracted significant attention. Quitting smoking and avoiding air pollution are important suggestions to prevent decreased lung function in COPD patients, but blood biomarkers such as higher SUA levels cannot be ignored. A meta-analysis demonstrated that SUA levels might be a useful biomarker for COPD,37 and an independent predictor of mortality, and are associated with a higher risk of acute exacerbation of COPD.25,38 For better management of COPD, further research about the effect of SUA on lung function, especially in COPD patients, is required.

The strengths of this study include its large sample size and also the amount of data available. Subjects in our study were enrolled from the community but not the clinic, without any severity underlying disease except COPD. Additionally, we were also able to analyze the effect of SUA on lung function after bronchodilation, which could not observed in the previous studies. Similar results were found when compared to SUA levels and lung function before bronchodilation.

Some limitations in our study should be considered. First, the population in our study consisted mostly of males (71.9%), and the percentage of females (28.1%) was lower than in other studies,6,39 which may have influenced the overall results. Nonetheless, the observed association between SUA and lung function persisted in a gender-adjusted model. Second, several possible factors that may influence SUA levels were not completely ruled out, including chronic kidney disorders, alcohol consumption, food intake, metabolic syndrome, and also cardiovascular disease. However, after adjustment for major confounders (age, gender, BMI, smoking status, and cumulative tobacco consumption), logistic regression analysis showed that SUA levels continued to be a significant predictor of COPD risk. Similar results were seen in the linear regression model. Based on this, we believe that the influence of biases from unknown confounding that the model did not adjust for did not significantly affect the outcome. Thirdly, though SUA levels have been suggested to be an imperfect proxy for epithelial lining fluid concentration,1 SUA from epithelial lining fluid concentration is thought to be secreted by submucosal nasal glands after uptake from plasma.3 Lastly, because the design of our study was retrospective and cross-sectional, the causal relationship between uric acid and lung function could not be determined.

Conclusion

In conclusion, the high SUA level was associated with a higher risk of COPD and chronic respiratory symptoms, and lower lung function. What’s more, significant effects of SUA on lung function were found in individuals with COPD, but not individuals without COPD.

Abbreviations

SUA, serum uric acid; COPD, chronic obstructive pulmonary disease; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; BMI, body mass index; ORs, odds ratios.

Data Sharing Statement

With the permission of the corresponding authors, we can provide participant data without names and identifiers. The corresponding authors have the right to decide whether to share the data based on the research objectives and plan provided. Data will be immediately available after publication. No end date. Please contact correspondence author for data requests.

Ethics Approval and Informed Consent

The study protocol was approved by the Ethics Committee of the First Affiliated Hospital of Guangzhou Medical University. All participants gave written informed consent.

Consent for Publication

This article has not been published elsewhere in whole or in part. All authors have read and approved the content, and agree to submit it for consideration for publication in your journal. There are no ethical/legal conflicts involved in the article.

Acknowledgments

We thank all the participants who contributed to this study. Thanks are due to Zhishan Deng, Youlan Zheng, Lifei Lu, Ningning Zhao, Jianwu Xu, Peiyu Huang, Xiaopeng Ling, Shaodan Wei, Qiaoyi He, Wenjun Lai and Yunsong Chen (National Center for Respiratory Medicine, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou. Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Nan shan Medical Development Foundation of Guangdong Province) for Data collection.

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 present study was supported by The National Key Research and Development Program of China (Grant number 2016YFC1304101), the Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program (2017BT01S155), the National Natural Science Foundation of China (81970045), Zhongnanshan Medical Foundation of Guangdong Province (ZNSA2020003, ZNSA-2021012, and ZNSA-2020013) Basic and Applied Basic Research Fund of Guangdong Province (2020A 1515110915) and National Natural Science Foundation of China (82000044).

Disclosure

We declare that there are no financial or personal competing interests associated with the study.

References

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Introduction

Chronic obstructive pulmonary disease (COPD) is the third leading cause of death and it is a global health problem with increasing prevalence.1 COPD is characterized by coughing or wheezing, excess sputum production, and shortness of breath.1 A subgroup of patients of COPD have progressive disease and results in the deterioration of cardiopulmonary function.1 These patients tend to have poor exercise capacity and health-related quality of life (HRQL).

Some patients of COPD experience difficulty with physical activity and unpleasant symptoms even under optimal medical treatment. Pulmonary rehabilitation (PR) may help improve physical activity and HRQL in these patients with COPD and the Global Initiative for Chronic Obstructive Disease (GOLD) guideline recommends that PR should be an integral part of COPD treatment. PR is a cornerstone in COPD management but not all patients benefit from PR,2 and this could relate to pre-PR work efficiency (WE). We want to investigate this systematically.

Cardiopulmonary exercise testing (CPET) is used to evaluate exercise intolerance. WE, one parameter of CPET, measures an individual’s oxygen consumption (VO2) during exercise workload (WR).3 WE is a measure of overall oxygen consumption efficiency during exercise. We previously reported that COPD patients with a poor WE also had early anaerobic metabolism, lower exercise capacity, more exertional dyspnea, and poorer HRQL.4 However, whether WE affects the effect of PR in COPD patients with a poor WE remain unknown.

Since no studies to date have examined the effects of PR in patients with a poor WE, here we aimed to investigate the effects of PR in COPD patients with a normal versus poor WE. Specifically, we aimed to determine how different WE affects PR.

Materials and Methods

Study Design

Patients with COPD were recruitment from the outpatient department in Taipei Tzu-Chi Hospital. These patients underwent pre-PR assessments by CPET, questionnaire of HRQL, respiratory muscle strength. They then received a 12-week PR. After PR, they underwent post-PR assessment by CPET, questionnaire of HRQL, respiratory muscle strength again.

In this study, we aimed to investigate whether patients with different WE respond differently to PR. The normal range of WE is 8.6–10.1 mL/min/watt.3 Wasserman et al suggested that a WE <8.6 mL/min/watt indicates a poor WE.3 We therefore divided the patients into two groups: group 1 (Gr 1) were patients with a normal WE and group 2 (Gr 2) were patients with a poor WE. The primary outcome was to assess the changes in WE in patients with a normal WE versus those with a poor WE. The secondary outcomes were to assess circulatory responses, ventilatory responses, gas exchanges, exercise capacity and HRQL in patients with a normal WE versus those a with poor WE.

Patient Recruitment

Forty-five patients with stable COPD were recruited. The diagnosis and severity of COPD was defined according to GOLD guideline.5 The inclusion criteria were absence of acute exacerbations for 3 months before recruitment, ability to ambulate for completion of CPET and PR, and willingness to be included in the study. The exclusion criteria were a history of other lung diseases such as asthma, pulmonary tuberculosis, etc., orthopedic or neurological impairment that unable to perform CPET and PR, unwilling to participate in the PR programs and those had ever participated in a PR program. The ethics committee of Taipei Tzu-Chi Hospital approved the study. All patients provided informed consent.

Pulmonary Function Test

According to the standards of the American Thoracic Society (ATS), the patients used a spirometer (Medical Graphics Corporation; St Paul, MN, USA) for the pulmonary function tests.6 According to the GOLD guidelines,7 we used the percentage of forced expiratory volume in 1 second (FEV1%) to evaluate the degree of airflow obstruction.

Cardiopulmonary Exercise Test

All participants underwent the CPET using a bike ergometer (Lode Corival, Netherlands) through a progressive protocol. Their exhaled air was analyzed by breath analysis (Breeze Suite 6.1; Medical Graphics Corporation, St Paul, MN, USA) to assess their oxygen consumption (VO2), carbon dioxide output (VCO2), end tidal PCO2 (PETCO2) and tidal volume (VT). Their oxygen saturation (SpO2), respiratory frequency (Rf), electrical heart function, blood pressure (BP), and heart rate (HR) were continuously monitored during the CPET.

Peak VO2 (VO2peak) was measured at exercise capacity. WE is the relationship between VO2 and WR during exercise.8 WE is defined as the slope of VO2/WR and determined using linear regression analysis. The VO2 at the anaerobic threshold (AT) was determined by the VCO2 versus VO2 graph.9 The predicted VO2 at AT less than 40% of predicted VO2max indicates a poor AT%.3 Oxygen pulse (O2P) was defined as VO2 divided by HR (O2P = VO2/HR). An O2P at a peak exercise level lower than 80% of the predicted value is considered poor.3 Respiratory gas exchange (RER) is defined as VCO2/VO2.3

Respiratory Muscle Strength

Maximum inspiratory pressure (MIP) and maximum expiratory pressure (MEP) were measured five times with a pressure gauge (Respiratory Pressure Meter; Micro Medical Corp, England), and the highest value was recorded.4,10 For the measurement of MIP, the patients exhaled to the residual volume and then perform a rapid maximal inspiration. For the measurement of MEP, the patients inhaled to the total lung capacity and then exhaled with maximal effort.

Exertional Dyspnea and Leg Fatigue Scores

The dyspnea and leg fatigue scores were evaluated using a modified version of Borg scale at peak exercise during CPET, which is scored 0–10 points; higher scores indicate more severe dyspnea or leg fatigue.11 Dyspnea and leg scores are determined at peak exercise during the CPET.

Health-Related Quality of Life

The Chinese version of the COPD Assessment Test (CAT) was used to assess HRQL. The CAT consists of eight items (cough, phlegm, chest tightness, dyspnea, activity, confidence to leave home, sleeplessness, and energy). The score for each item ranges from 0 to 5,12 and the total score ranges from 0 (best) to 40 (worst) points.12 A total CAT score ≥10 is classified as a high-level symptom.12 The minimum clinically important difference of CAT is 2 points.12

PR Program

All patients performed a 12-week twice-weekly hospital-based PR program. In each training session, formal education, including proper use of medications, breathing exercise (purse-lip and diaphragm breathing), and self-management skills were provided. The exercise training was performed by cycle ergometer. Patients were encouraged to achieve their maximal exercise as possible. The exercise intensity was targeted to 50–100% of peak VO2 as patients’ tolerance. During the exercise training, respiratory therapists monitored the WR, SpO2, Rf, HR, BP, dyspnea, and leg fatigue.

Statistical Analysis

The parameters are shown as mean and standard deviation. A paired t-test was used to compare parameters before and after PR. An independent sample t test was used to compare the pre- and post-PR parameters between the two groups. The changes in parameters were defined as differences between pre- and post-PR and were analyzed by the independent sample t test between the two groups. We perform Normality test of variables to identify the parametric test that is used to analyze normal distribution variables. A statistically significant difference was set at p < 0.05. The statistical analyses were performed using SPSS version 24.0 (SPSS, Inc., Chicago, IL, USA).

Results

Baseline Clinical and Demographic Characteristics

Table 1 shows the demographic and clinical characteristics of all patients. Among the 45 COPD patients, 21 had a normal WE (Gr 1) and 24 had a poor WE (Gr 2). No significant differences were noted in body weight, body height, body mass index, age, gender, smoking status, COPD severity, duration of diagnosis of COPD, comorbidities of congestive heart failure, hypertension and diabetes mellitus between these two groups. Most enrolled patients were COPD group B.

Table 1 Baseline Demographic Characteristics

Effects of PR on Circulatory Parameters of Patients with a Normal versus Poor WE

At baseline, the WE, AT, and O2P were significantly lower in Gr 2 than in Gr 1 (Table 2) but mean blood pressure (MBP) and HR did not differ significantly between Gr 1 and Gr 2. For Gr 1, at post-PR, significant improvement was seen in AT but not in WE, O2P, HR, or MBP. For Gr 2, at post-PR, significant improvement was seen in WE, AT, O2P, and MBP at rest. The improvement in circulatory parameters after PR for each group is shown in Figure 1. The improvements in WE, AT, and O2P after PR were significantly greater in Gr 2 than in Gr 1.

Table 2 Effects of PR on Circulatory Parameters of Patients with a Normal and Poor WE

Figure 1 Degree of changes in circulatory parameters after PR in patients by study groups. The changes of WE (A), AT (B) and O2P (C) of Gr 2 were significantly higher than those of Gr 1. However, changes in MBP at rest (D), MBP during exercise (E), and HR during exercise (F) were not significantly different between the two groups.*p < 0.05, ***p < 0.001, ns: p > 0.05. Yellow and blue dots are outliers.

Abbreviations: AT, anaerobic threshold; Gr, group; HR, heart rate; MBP, mean blood pressure; ns, non-significance; O2P, oxygen pulse; WE, work efficiency.

Effects PR on Ventilatory Parameters of Patients with a Normal and Poor WE

At baseline, the FVC%, FEV1%, FEV1/FVC, MIP, and MEP were significantly lower in Gr 2 than in Gr 1 (Table 3). For Gr 1, there were no significant differences in FVC, FEV1, MIP, MEP, Rf, or VT at pre- versus post-PR. For Gr 2, there were no significant differences in FVC, FEV1, MIP, MEP, and VT at pre- versus post-PR, but Rf at exercise was significantly lower at post- than pre-PR. The improvement in ventilatory parameters at post-PR for each group is shown in Figure 2. No significant intergroup difference in FVC, FEV1, MIP, MEP, Rf, or VT was noted at post-PR.

Table 3 Effects of PR on Ventilatory Parameters of Patients with a Normal and Poor WE

Figure 2 Degree of changes in ventilatory parameters after PR of patients by study groups. The changes of FEV1 (A), FVC (B), MIP (C), MEP (D), Rf at rest (E), Rf at exercise (F), VT at rest (G) and VT at exercise (H) were not significantly different between the two groups. p > 0.05. Yellow and blue dots are outliers.

Abbreviations: FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; Gr, group; MEP, maximal expiratory pressure; MIP, maximal inspiratory pressure; ns, non-significance; Rf, respiratory frequency; VT, tidal volume.

Effects PR on Gas Exchanges of Patients with a Normal versus Poor WE

At baseline, the PETCO2, SpO2 at rest or during exercise and the RER were similar between Gr 1 and 2 (Table 4). The PETCO2 and SpO2 at rest or during exercise and the RER did not differ. The changes in PETCO2, SpO2 at rest or during exercise after PR for each group are shown in Figure 3. The changes in SpO2and PETCO2 after PR were similar between Gr 1 and Gr 2.

Table 4 Effects of PR on Gas Exchanges of Patients with a Normal and Poor WE

Figure 3 Degree of changes in gas exchange after PR in patients by study groups. The changes of SpO2 at rest (A) or exercise (B), and PETCO2 at rest (C) or exercise (D) were not significantly different between the two groups. p > 0.05. Yellow and blue dots are outliers.

Abbreviations: Gr, group; ns, non-significance; PETCO2, end tidal carbon dioxide; SpO2, blood oxygen saturation by pulse oximeter.

Effects of PR on Exercise Capacity of Patients with a Normal versus Poor WE

At baseline, the mean exercise capacity (VO2 and WR at peak exercise) was significantly greater in Gr 1 than in Gr 2 (Table 5). PR significantly improved VO2 and WR at peak exercise in patients of both groups. The changes in VO2 and WR at peak exercise after PR for both groups are shown in Figure 4. The changes in VO2 and WR at peak exercise after PR were similar between groups.

Table 5 Effects of PR on Exercise Capacity of Patients with a Normal and Poor WE

Figure 4 Degree of change in exercise capacity after PR in patients by study groups. The changes of WR (A) and peak VO2 (B) were not significantly different between the two groups. p > 0.05. Yellow and blue dots are outliers.

Abbreviations: Gr, group; ns, non-significance; VO2, oxygen consumption; WR, work rate.

Effects of PR on HRQL, Exertional Dyspnea, and Leg Fatigue Scores of Patients with a Normal versus Poor WE

At baseline, the phlegm, breathlessness, activities, CAT total score, and modified British Medical Research Council (mMRC) score were significantly poorer in Gr 1 than in Gr 2 (Table 6). For patients in Gr 1, PR significantly improved breathlessness, CAT total score, mMRC score, dyspnea, and fatigue at peak exercise. For patients in Gr 2, PR significantly improved phlegm, chest tightness, breathlessness, activities, sleep, CAT total score, mMRC score, dyspnea, and leg fatigue during exercise.

Table 6 Effects of PR on HRQL, Exertional Dyspnea and Leg Fatigue Score of Patients with a Normal and Poor WE

The changes in CAT, mMRC score, dyspnea, and leg fatigue during exercise after PR for each group are shown in Figure 5. The changes in breathlessness, activity, CAT total score, and mMRC score after PR were significantly greater in Gr 1 than in Gr 2.

Figure 5 Degree of change in HRQL after PR in patients by study group. There were no significant differences in the changes of cough (A), sputum (B) and chest tightness (C) between the two groups. The improvement of dyspnea (D) and activity (E) were significantly more in the Gr 2 than those in the Gr 1. Changes of confidence (F), sleep (G) and energy (H) were without significant difference between the two groups. The decreases in CAT total score (I) and mMRC (J) were significantly more in the Gr 1 than those in the Gr 1. The changes of dyspnea (K) and leg fatigue (L) Borg scale at peak exercise did not differ between the two groups.*p < 0.05, **p < 0.01, ns: p > 0.05. Yellow and blue dots are outliers.

Abbreviations: CAT, COPD assessment test; Gr, group; mMRC, modified British Medical Research Council; ns, non-significance.

Subgroups Analysis of Patients with Poor WE

Among the 24 patients with a poor WE, WE returned to normal in 7 patients (29%), and WE did not return to normal in 17 patients (71%). We compared the baseline data and response to PR of these two groups of patients, as shown in Table 7. For baseline data, WE, VO2 at AT and O2P were significantly higher in patients with normalized WE than those without normalized WE. However, age, gender, body mass index, exercise capacity, and CAT total score at baseline did not show significant difference between the two groups.

Table 7 Subgroup Analysis of Patients with a Poor WE

Discussion

This is the first study to assess the different effects of PR in COPD patients with a normal versus poor WE. There are some important and novel findings in this study. Compared to COPD patients with a normal WE, those with a poor WE had decreased exercise capacity, more exertional dyspnea, poor HRQL, and poor circulatory parameters. Our PR program was efficient to improve exercise capacity, exertional dyspnea, HRQL, and circulatory parameters for COPD patients with both normal or poor WE. However, greater improvements in VO2 at AT, exercise capacity, and CAT were found in patients with a poor WE than those with a normal WE. Furthermore, improvements in WE, O2P, and Rf in peak exercise, chest tightness, activity, and sleep quality were found only in patients with a poor WE, but not in patients with a normal WE.

In our study, we used high intensity (50–100%) of exercise training and these patients had improvement of exercise capacity and HRQL after such training. Patients with a poor WE further had improvement of WE and O2P. However, it is not known about the effect of low intensity (<50%) exercise training on WE. Besides, most enrolled patients were COPD group B in the current study. This was because that we enrolled stable COPD for PR and we excluded acute exacerbations within three months. Since the majority of patients were COPD group B, it is unclear whether patients of other groups would get the same results after exercise training.

The overall VO2 dynamics during exercise depend on the gas exchange by the respiratory system, oxygen delivery by the circulatory system, and oxygen extraction for exercise by the musculoskeletal system.13 Oxygen extraction further depends on the muscle mass of the limbs, muscular capillary contents, and mitochondrial function of muscle cells.8 A poor WE suggests a poor overall oxygen consumption efficiency that indicates poor oxygen delivery or impaired muscular extraction of oxygen.14

In the current study, patients with a poor WE had early AT, poorer exercise capacity, and poorer HRQL than those with a normal WE. The consequence of a poor WE is early anaerobic metabolism during exercise.14 Anaerobic glycolysis produces lactic acidosis, which further leads to excessive ventilation responses to acidosis-stimulating chemoreceptors.14,15 Hyperventilation during early exercise further results in exertional dyspnea sensation, exercise intolerance, and a poor HRQL.15 This explained that the COPD patients with a poor WE experience early anaerobic metabolism during exercise and are therefore prone to exercise intolerance and poor HRQL.

Wasserman et al previously suggested that trained and untrained patients would have a similar WE regardless of age or gender.8 However, we found that PR improved WE in COPD patients with a poor WE but not in those with a normal WE. Therefore, exercise training is not unable to change WE. It is for patients with a normal WE, exercise training will not increase their WE. But for patients with a poor WE, exercise training will still increase their WE. Patients with a normal WE indicated good oxygen delivery and extraction. Therefore, for patients with a normal WE, there is little room for improvement in WE. Patients with a poor WE indicated poor oxygen delivery or extraction. Exercise training improves their oxygen delivery or extraction.

The mechanisms of the improvement in WE after PR are multiple. One previous study suggested that PR improved the central cardiovascular response such as stroke volume during exercise in COPD.16 We here also showed that O2P, a reliable surrogate marker of stroke volume, was improved in patients with a poor WE. Nasis et al also showed that PR improved cardiac output in patients with COPD.17 The reduction in dynamic hyperinflation after PR is related to the improvement in stroke volume.16 Besides, exercise training is known to improve contractile capacity of cardiomyocyte.18

Skeletal muscle and mitochondrial dysfunction is a systemic manifestation in some patients with COPD.19 Vogiatzis et al revealed that PR increased muscle cross-sectional area and capillary contents.20 Marillier et al also found that exercise training increased muscle cell mitochondrial function.19 According to these studies, exercise training increases muscle mass, muscular capillary contents, and mitochondrial function, which are important factors of oxygen extraction. The improvement in oxygen extraction also resulted in an increase in WE. Although we did not examine mitochondrial function and muscle mass after PR, it is plausible based on these studies that PR leads to improve peripheral muscle mass and mitochondrial function.

There is one previous study about the impact of PR on severe physical inactivity in patients with COPD.2 In this study, most patients of severe physical inactivity (78%) did not change activity level after PR. The result seems to contradict our results that we showed the improvement of WE in patients with a poor WE. However, the two studies aimed at different outcomes. Thyregod et al focused on physical inactivity and we focused on WE. WE is determined by multiple factors. Physical inactivity with muscle deconditioning may be one possible reason of a poor WE, but not all patients in severe physical inactivity result in a poor WE. Most of our enrolled patients also self-reported physical inactivity, but only 24 of 45 patients had a poor WE.

Clinical Implication

Exercise intolerance, exertional dyspnea, poor HRQL are common in patients with COPD.15 An individual’s overall oxygen consumption efficiency depends on oxygen delivery, oxygen extraction, and mitochondrial function.8 WE is a good parameter that provides information about circulatory and tissue oxygen consumption function during exercise. We suggested here that COPD patients with a poor WE have more severe exertional dyspnea, lower exercise capacity, poor circulatory function, earlier anaerobic metabolism, and poorer HRQL. PR improved their exercise capacity, circulatory function, anaerobic metabolism, and HRQL.

Study Limitations

Although our research has many important findings, it still has some limitations. First, patients with a poor WE had poor circulatory function, more severe exercise intolerance, and poorer HRQL. However, the value of WE for predicting long-term outcomes such as the survival of patients with COPD is unclear. Therefore, the long-term impact of PR for improving WE is unknown. Further, PR improved WE in our study, but we could not determine whether this was due to improved circulatory, muscular, or mitochondrial function for these patients. However, it is difficult to determine muscular and mitochondrial function in patients with COPD. Therefore, WE is still an available, effective, and non-invasive parameter for monitoring an individual’s overall cardiovascular, muscular, and mitochondrial function after PR.8

Conclusions

Patients with a poor WE had poor circulatory parameters, exercise capacity and HRQL. PR improved exercise capacity, HRQL, and VO2 at AT in patients of both normal or poor WE. However, greater improvements in VO2 at AT, exercise capacity, and HRQL were found in COPD patients with a poor WE than those with a normal WE. Furthermore, improvements in WE, O2P, and Rf at peak exercise, chest tightness, activity, and sleep quality were found only in patients with a poor WE.

Data Sharing Statement

The datasets used during the current study are available from the corresponding author on reasonable request.

Ethics Approval and Informed Consent

The ethics committee of Taipei Tzu-Chi Hospital approved the study. All participants were informed about the purpose of the study, in accordance with the Declaration of Helsinki. Patient’s written consent has been obtained.

Funding

This study was supported by grants from the Taipei Tzu Chi Hospital and the Buddhist Tzu Chi Medical Foundation (TCRD-TPE-109-59 and TCRD-TPE-109-24(2/3), respectively).

Disclosure

The authors disclose no financial or other potential conflicts of interest in this work.

References

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Torreon, Coahuila. /

The covid-19 virus and its variants has modified not only its behavior, but also its clinical manifestationsbecause in 2019 when this new type of coronavirus appeared the sequelae were particularly respiratory.

Arnulfo Portales Castanedo, an internist and specialist in cardiopulmonary medicine, states that Initially, the most important sequelae were respiratory with an advanced state of pulmonary inflammation..

“Let’s remember that there were no vaccines, so the covids we had were relatively more aggressive, many had a pretty good time and others out of nowhere had a serious respiratory compromise and we ended up with them in intensive care, they were the ones with the most sequelae.”

At that moment it was thought that this type of sequelae would be unique, pulmonary fibrosis, difficulty breathing and the need for chronic use of oxygen and even steroids and cortisone to continue deflating the lung.

“We saw that the patient did not improve, we tried to use antifibrosing drugs of the lung, probably already in very late stages, some respond, others do not and we thought that this was going to be our only sequel.”

The specialist mentioned that Over time and as they saw the different variants of the virus and the transmission capacity, they realized that the population was becoming more vulnerable. and more susceptible to the ravages of transmissibility. The virus became more contagious, although with less lethality and affectation in degrees of severitywhich was modifying their behavior and clinical manifestations.

“We are presented with a challenge to say that it is not covid and although within the same medical environment there are very coined phrases to say, everything is covid and not everything is covid, those are two phrases that pose us a very serious dilemma.”

He considered that a person with a very serious health problem may not be cared for, thinking that it is covid and the time it takes to define whether or not it can be vital for the patient.

“Personally, with the challenge that I have faced the most, it is the first answer that I have to give to see in which area of ​​the hospital I am going to attend to this patient or if I am going to attend to this patient in my consultation or in a unit respiratory, due to the risk it represents for other patients and the second is the diversity of clinical manifestations”.

These are diverse, since in the first variants the affectation was mainly respiratory, while in the latest variants there have been other presentations.

Any infectious process, be it viral, bacterial, fungal, mycobacterial or parasitic, which are what is included in the pathogen, produces an infection and the body as part of the general response is going to inflame.

He explains that this inflammatory response has counterweights, factors that promote it, self-regulatory factors to stop it, and each person responds differently to the same stimulus, in this In the case of an infectious process such as the covid virus, we would only have to see what variant we are facing.

“Each one has its particularities, in this variability and this particular susceptibility of each person, this inflammatory response can be perpetual, it can be replicated or modified depending on the genome, what you have risk factors for developing or simply and simply even if you do not have them. you, you are the family chain that is going to start the change because the virus itself modified that genome.”

It is there where the manifestations of a new disease derived from or as a result of a detonation by the covid infection are triggeredwhich he considered terribly interesting from a medical point of view, but from a health point of view a serious problem.

in different presentations

Armando Abraham de Pablos Leal, an infectious disease doctor, stated that as new variants have existed, they have had a different clinical presentationbecause in the last two variants there have been behaviors at the level of the central nervous system.

Transverse myelitis as well as Guillain-Barré syndrome became more common and although not as frequentbegan to see more cases in the last 2 variants and have even had patients with suicidal ideation.

Anxiety and depression

“We have had many patients with depression who have probably had a very mild flu-like illness, but the patients come to me two weeks later with a lot of anxiety, with easy crying and who go only for this symptom.”

He explained that patients with pericarditis, tachycardia, thyroiditis and encephalitis have frequently been received, which has become more common. “I have come to have the same residents with encephalitis and pericarditis at the same time, this presentation became more and more common.”

He explained that the last two variants had this capacity, due to a protein called Neurofeline that makes it easy to enter the central nervous system. Variants have different presentations at the level of the nervous systembut each time they have had more access capacity.

Although it is true, he indicated, the inflammatory capacity is different in each variant and especially in the last one, which is omicron, which is said to have less inflammatory capacity and was greatly influenced by the vaccine. He mentioned that another problem is immunosuppression, patients with superinfection, aspergillosis, coccidioidomycosis and not only pulmonary tuberculosis, but the body’s response was not sufficient to stop it at the lung level and it is also disseminated.

“The immunosuppressive effect is also going to bring us even more things, perhaps we are just waiting for the latest variants, especially omicron, about what else can be activating us.”

ANDIn the case of older adults, he assured that at first they were the most affected, however, it had a lot to do with the fact that they were the first to be covered with the vaccine and that currently it is what has helped everyone.

Before and after covid Elida Moran Guel, a specialist in emergency medicine and intensive care, pointed out that the history of medicine will have a before and after covid-19 due to what is currently being experienced in the world. “It is a totally different change from what we learned at school, it is a disease that we all had to learn together, students, teachers, we all went hand in hand and I think we continue to learn”.

The specialist commented that with the sequelae that occur in the different variants, a patient can last up to 6 months inflamed, however, something new comes out daily and there are new reports. She indicated that in these two years people have written about her experience and that is what has greatly enriched her.

“Although at first one wrote what was going through his head, they are now more structured studies with greater statistical weight, with greater methodological weight, they are already studies so well done that we can already get an idea of ​​what could be done or what was done on the other side of the world in the face of covid.”

EGO



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