[National Survey on the Activity of Lung Function Laboratories. Effects During the SARS-COV-2 Pandemic]. / Encuesta sobre la actividad de los laboratorios de función pulmonar. Efectos durante la pandemia por SARS-CoV-2.

Introduction: Following the SARS-CoV-2 pandemic in March 2020, pulmonary function testing (PFT) laboratories underwent a transformation, with a reduction in the number of tests or closure in some cases. The aim of this work was to know the activity of PFT in Spain and the modification of this activity due to the pandemic. Material and methods: A protocolised survey was carried out to members of the PFT laboratories through the Spanish Society of Pneumology and Thoracic Surgery (SEPAR). Results: Thirty-nine hospitals in Spain responded. The pulmonary function tests most frequently performed in the PFT laboratories were forced spirometry with bronchodilator test (100%), body plethysmography (97.4%), CO transfer capacity (97.4%), respiratory muscle strength measured in the mouth (97.4%), 6-minute walking test (94.7%), measurement of exhaled fraction of nitric oxide (92.3%) and incremental exercise test (71.8%).The pandemic led to a significant decrease in the number of tests (35.4%) during 2020 with subsequent recovery in 2021, without reaching pre-pandemic values.The most important changes were increased examination times, working with personal protective equipment and ventilation of the rooms. The performance of the nasopharyngeal swab for SARS-CoV2 testing prior to the tests was not homogeneous in the PFT laboratories. Conclusions: Most hospitals are sufficiently equipped to perform the most common pulmonary function tests. The pandemic resulted in a loss of activity in all hospitals.

Predictors and changes of physical activity in idiopathic pulmonary fibrosis.

BACKGROUND: Different clinical predictors of physical activity (PA) have been described in idiopathic pulmonary fibrosis (IPF), but studies are lacking evaluating the potential role of muscle strength and anxiety and depression symptoms in PA limitation. Moreover, little is known about the impact of changes in PA in the course of the disease. The aim of the present study was to investigate the relationship between baseline PA and a wide range of variables in IPF, to assess its longitudinal changes at 12 months and its impact on progression free-survival. METHODS: PA was assessed by accelerometer and physiological, clinical, psychological factors and health-related quality of life were evaluated in subjects with IPF at baseline and at 12 month follow-up. Predictors of PA were determined at baseline, evolution of PA parameters was described and the prognostic role of PA evolution was also established. RESULTS: Forty participants with IPF were included and 22 completed the follow-up. At baseline, subjects performed 5765 (3442) daily steps and spent 64 (44) minutes/day in moderate to vigorous PA. Multivariate regression models showed that at baseline, a lower six-minute walked distance, lower quadriceps strength (QMVC), and a higher depression score in the Hospital Anxiety and Depression scale were associated to lower daily step number. In addition, being in (Gender-Age-Physiology) GAP III stage, having a BMI ≥ 25 kg/m2 and lower QMVC or maximum inspiratory pressure were factors associated with sedentary behaviour. Adjusted for age, gender and forced vital capacity (FVC) (%pred.) a lower progression-free survival was evidenced in those subjects that decreased PA compared to those that maintained, or even increased it, at 12 months [HR 12.1 (95% CI, 1.9-78.8); p = 0.009]. CONCLUSION: Among a wide range of variables, muscle strength and depression symptoms have a predominant role in PA in IPF patients. Daily PA behaviour and its evolution should be considered in IPF clinical assessment and as a potential complementary indicator of disease prognosis.

Higher mortality and intubation rate in COVID-19 patients treated with noninvasive ventilation compared with high-flow oxygen or CPAP.

The effectiveness of noninvasive respiratory support in severe COVID-19 patients is still controversial. We aimed to compare the outcome of patients with COVID-19 pneumonia and hypoxemic respiratory failure treated with high-flow oxygen administered via nasal cannula (HFNC), continuous positive airway pressure (CPAP) or noninvasive ventilation (NIV), initiated outside the intensive care unit (ICU) in 10 university hospitals in Catalonia, Spain. We recruited 367 consecutive patients aged ≥ 18 years who were treated with HFNC (155, 42.2%), CPAP (133, 36.2%) or NIV (79, 21.5%). The main outcome was intubation or death at 28 days after respiratory support initiation. After adjusting for relevant covariates and taking patients treated with HFNC as reference, treatment with NIV showed a higher risk of intubation or death (hazard ratio 2.01; 95% confidence interval 1.32-3.08), while treatment with CPAP did not show differences (0.97; 0.63-1.50). In the context of the pandemic and outside the intensive care unit setting, noninvasive ventilation for the treatment of moderate to severe hypoxemic acute respiratory failure secondary to COVID-19 resulted in higher mortality or intubation rate at 28 days than high-flow oxygen or CPAP. This finding may help physicians to choose the best noninvasive respiratory support treatment in these patients.Clinicaltrials.gov identifier: NCT04668196.

Respiratory and Peripheral Muscle Weakness and Body Composition Abnormalities in Non-Cystic Fibrosis Bronchiectasis Patients: Gender Differences.

As demonstrated in COPD, bronchiectasis patients may experience respiratory and peripheral muscle dysfunction. We hypothesized that respiratory and peripheral (upper and lower limbs) muscle function and nutritional status may be more significantly altered in female than in males for identical age and disease severity. In mild-to-moderate bronchiectasis patients (n = 150, 114 females) and 37 controls (n = 37, 21 females), radiological extension, maximal inspiratory and expiratory pressures (MIP and MEP), sniff nasal inspiratory pressure (SNIP), hand grip and quadriceps muscle strengths, body composition, and blood analytical biomarkers were explored. Compared to the controls, in all bronchiectasis patients (males and females), BMI, fat-free mass index (FFMI), fat tissue, upper and lower limb muscle strength, and respiratory muscle strength significantly declined, and FFMI, fat tissue, and quadriceps muscle function were significantly lower in female than male patients. In patients with mild-to-moderate bronchiectasis, respiratory and peripheral muscle function is significantly impaired and only partly related to lung disease status. Quadriceps muscle strength was particularly weakened in the female patients and was negatively associated with their exercise tolerance. Muscle weakness should be therapeutically targeted in bronchiectasis patients. Body composition and peripheral muscle function determination should be part of the comprehensive clinical assessment of these patients.

Incidence of pulmonary embolism in patients with non-invasive respiratory support during COVID-19 outbreak.

While the incidence of thrombotic complications in critically ill patients is very high, in patients under non-invasive respiratory support (NIS) is still unknown. The specific incidence of thrombotic events in each of the clinical scenarios within the broad spectrum of severity of COVID-19, is not clearly established, and this has not allowed the implementation of thromboprophylaxis or anticoagulation for routine care in COVID-19. Patients admitted in a semi-critical unit treated initially with NIS, especially Continuous-Positive Airway Pressure (CPAP), were included in the study. The cumulative incidence of pulmonary embolism was analyzed and compared between patients with good response to NIS and patients with clinical deterioration that required orotracheal intubation. 93 patients were included and 16% required mechanical ventilation (MV) after the NIS. The crude cumulative incidence of the PE was 14% (95%, CI 8-22) for all group. In patients that required orotracheal intubation and MV, the cumulative incidence was significantly higher [33% (95%, CI 16-58)] compared to patients that continued with non-invasive support [11% (CI 5-18)] (Log-Rank, p = 0.013). Patients that required mechanical ventilation were at higher risk of PE for a HR of 4.3 (95%CI 1.2-16). In conclusion, cumulative incidence of PE is remarkably higher in critically patients with a potential impact in COVID-19 evolution. In this context, patients under NIS are a very high-risk group for developing PE without a clear strategy regarding thromboprophylaxis.

[Could Inspiratory Muscle Function Be an Equivalent of Lung Hyperinflation in COPD Patients?] / ¿La función muscular inspiratoria podría ser un equivalente de la insuflación pulmonar en los pacientes con EPOC?

Introduction: Chronic obstructive pulmonary disease (COPD) is the respiratory disease that causes the greatest morbidity and mortality worldwide. Lung function parameters and systemic manifestations have been defined as prognostic factors; however, they have limitations. The aim of this study was to analyze whether inspiratory muscle strength could reflect lung hyperinflation, and therefore serve as a prognostic factor in COPD patients. Method: We selected COPD patients who had performed a non-invasive respiratory muscle strength assessment and lung function testing between January 2015 and October 2017. Mortality was subsequently followed up until March 1, 2020. Results: We included 140 COPD patients (GOLD stage I 5%, II 73.4%, and III 21.6%), of whom 10% died during follow-up. Bronchial obstruction, defined by FEV1, was a good predictor of mortality (p = 0.004). Lung hyperinflation, defined as inspiratory capacity (IC)/total lung capacity less than 25 and IC less than 65% of predicted increased mortality in COPD patients (p = 0.001 and p = 0.06, respectively). In this cohort, inspiratory muscle strength, measured by SNIP, was not a prognostic factor (p = 0.629). Conclusion: In COPD patients, lung hyperinflation is a prognostic factor, but inspiratory muscle function is not. Inspiratory muscle function in COPD patients depends not only on lung mechanics but also on intrinsic muscle factors.

Feasibility, tolerability, and effects of exercise-based prehabilitation after neoadjuvant therapy in esophagogastric cancer patients undergoing surgery: an interventional pilot study.

Patients requiring surgery for locally advanced esophagogastric cancer often require neoadjuvant therapy (NAT), which may have a detrimental impact on cardiorespiratory reserve. The aims of this study were to investigate the feasibility and tolerability of a 5-week preoperative high-intensity interval training program after NAT, and to assess the potential effects of the training protocol on exercise capacity, muscle function, and health-related quality of life (HRQL). We prospectively studied consecutive patients with resectable locally advanced esophageal and gastric cancer in whom NAT was planned (chemo- or chemoradiotherapy). Feasibility was assessed with the TELOS (Technological, Economics, Legal, Operational, and Scheduling) components, and data on exercise tolerability (attendance and occurrence of adverse or unexpected events). Exercise capacity was assessed with peak oxygen uptake (VO2peak) in a cardiopulmonary exercise test at baseline, post-NAT, and following completion of a high-intensity interval exercise training (25 sessions). Changes in muscle strength and HRQL were also assessed. Of 33 recruited subjects (mean age 65 years), 17 received chemoradiotherapy and 16 chemotherapy. All the TELOS components were addressed before starting the intervention; from a total of 17 questions considered as relevant for a successful implementation, seven required specific actions to prevent potential concerns. Patients attended a mean of 19.4 (6.4) exercise sessions. The predefined level of attendance (≥15 sessions of scheduled sessions) was achieved in 27 out of 33 (81.8%) patients. Workload progression was adequate in 24 patients (72.7%). No major adverse events occurred. VO2peak decreased significantly between baseline and post-NAT (19.3 vs. 15.5 mL/Kg/min, P < 0.05). Exercise led to a significant improvement of VO2peak (15.5 vs. 19.6 mL/kg/min, P < 0.05). Exercise training was associated with clinically relevant improvements in some domains of HRQL, with the social and role function increasing by 10.5 and 11.6 points, respectively, and appetite loss and fatigue declining by 16 and 10.5, respectively. We conclude that a structured exercise training intervention is feasible and safe following NAT in patients with esophagogastric cancer, and it has positive effects to restore exercise capacity to baseline levels within 5 weeks with some improvements in HRQL.

Deficient muscle regeneration potential in sarcopenic COPD patients: Role of satellite cells.

Sarcopenia is a major comorbidity in chronic obstructive pulmonary (COPD). Whether deficient muscle repair mechanisms and regeneration exist in the vastus lateralis (VL) of sarcopenic COPD remains debatable. In the VL of control subjects and severe COPD patients with/without sarcopenia, satellite cells (SCs) were identified (immunofluorescence, specific antibodies, anti-Pax-7, and anti-Myf-5): activated (Pax-7+/Myf-5+), quiescent/regenerative potential (Pax-7+/Myf-5-), and total SCs, nuclear activation (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling [TUNEL]), and muscle fiber type (morphometry and slow- and fast-twitch, and hybrid fibers), muscle damage (hematoxylin-eosin staining), muscle regeneration markers (Pax-7, Myf-5, myogenin, and MyoD), and myostatin levels were identified. Compared to controls, in VL of sarcopenic COPD patients, myostatin content, activated SCs, hybrid fiber proportions, TUNEL-positive cells, internal nuclei, and muscle damage significantly increased, while quadriceps muscle strength, numbers of Pax-7+/Myf-5- and slow- and fast-twitch, and hybrid myofiber areas decreased. In the VL of sarcopenic and nonsarcopenic patients, TUNEL-positive cells were greater, whereas muscle regeneration marker expression was lower than in controls. In VL of severe COPD patients regardless of the sarcopenia level, the muscle regeneration process is triggered as identified by SC activation and increased internal nuclei. Nonetheless, a lower regenerative potential along with significant alterations in muscle phenotype and damage, and increased myostatin were prominently seen in sarcopenic COPD.

Respiratory muscle senescence in ageing and chronic lung diseases.

Ageing is a progressive condition that usually leads to the loss of physiological properties. This process is also present in respiratory muscles, which are affected by both senescent changes occurring in the whole organism and those that are more specific for muscles. The mechanisms of the latter changes include oxidative stress, decrease in neurotrophic factors and DNA abnormalities. Ageing normally coexists with comorbidities, including respiratory diseases, which further deteriorate the structure and function of respiratory muscles. In this context, changes intrinsic to ageing become enhanced by more specific factors such as the impairment in lung mechanics and gas exchange, exacerbations and hypoxia. Hypoxia in particular has a direct effect on muscles, mainly through the expression of inducible factors (hypoxic-inducible factor), and can result in oxidative stress and changes in DNA, decrease in mitochondrial biogenesis and defects in the tissue repair mechanisms. Intense exercise can also cause damage in respiratory muscles of elderly respiratory patients, but this can be followed by tissue repair and remodelling. However, ageing interferes with muscle repair by tampering with the function of satellite cells, mainly due to oxidative stress, DNA damage and epigenetic mechanisms. In addition to the normal process of ageing, stress-induced premature senescence can also occur, involving changes in the expression of multiple genes but without modifications in telomere length.

Ten Research Questions for Improving COPD Care in the Next Decade.

With the 60th anniversary of the CIBA symposium, it is worth evaluating research questions that should be prioritized in the future. Coming research initiatives can be summarized in 10 main areas. (1) From epidemiology the impact of new forms of electronic cigarettes on prevalence and mortality of COPD will be sought. (2) The study of the disease endotypes and its relationship phenotypes will have to be unraveled in the next decade. (3) Diagnosis of COPD faces several challenges opening the possibility of a change in the definition of the disease itself. (4) Patients' classification and risk stratification will need to be clarified and reassessed. (5) The asthma-COPD overlap dilemma will have to be clarified and define whether both conditions represent one only chronic airway disease again. (6) Integrating comorbidities in COPD care will be key in a progressively ageing population to improve clinical care in a chronic care model. (7) Nonpharmacological management have areas for research including pulmonary rehabilitation and vaccines. (8) Improving physical activity should focus research because of the clear prognostic impact. (9). Pharmacological therapies present several challenges including efficacy and safety issues with current medications and the development of biological therapy. (10) The definition, identification, categorization and specific therapy of exacerbations will also be an area of research development. During the next decade, we have a window of opportunity to address these research questions that will put us on the path for precision medicine.

Is iron deficiency modulating physical activity in COPD?

There is evidence that iron plays a key role in the adequate functioning of skeletal muscle. While it has been demonstrated that nonanemic iron deficiency (NAID) affects exercise tolerance and response to exercise training in patients with COPD, the impact on daily physical activities (DPAs) remains unknown. Eighteen COPD patients with NAID (ferritin <100 ng/mL or ferritin 100-299 ng/mL with a transferrin saturation <20%) and 18 COPD patients without this abnormality, matched for age, gender, and the degree of airflow limitation (control group), were enrolled to the study. The primary outcome was the level of DPA assessed by accelerometers. Patients were (mean [SD]) 66 (7) years and were mostly male (70%) and former smokers (52%). Their forced expiratory volume at 1 second was 41 (16)% predicted, carbon monoxide diffusing capacity was 47 (14)% predicted and oxygen arterial pressure reached 70 (11) mmHg. DPA and the number of steps per day were lower in NAID COPD patients compared with controls (physical activity level 1.39 vs 1.59, P<0.05; and 4,402 vs 6,975 steps/day, P<0.05, respectively). The percentage of patients with increased time spent sitting per day (>6 hours) was higher in patients with NAID compared with controls (73% vs 37%, P<0.05). In addition, the percentage of patients doing moderate to vigorous physical activity per day (>3 metabolic equivalents of task, at least 30 minutes) was lower in this group (66% vs 100%, P<0.05). The presence of iron deficiency was associated with reduced DPA in COPD patients. Further studies are needed to evaluate iron reposition and their impact on the level of physical activity in these patients.

Isolated DLco/VA reduction in systemic sclerosis patients: a new patient subset?

INTRODUCTION: Diffusing capacity for carbon monoxide (DLco) reduction is the first detectable pulmonary functional test (PFT) change in systemic sclerosis (SSc)-related pulmonary complications. reduction in patients without cardiopulmonary alterations has also been observed; a good characterisation of these patients is lacking. The objective of this study is to describe the characteristics of SSc patients with isolated DLco reduction and compare these patients to SSc patients with DLco reduction with a known cause. METHODS: SSc patients with DLco < 80% predicted were included and classified into cases (isolated DLco reduction) and controls (DLco reduction in the presence of known pulmonary pathology). SSc clinico-serological data, PFT and echocardiography features were collected and analysed. RESULTS: From a total SSc cohort of 115 patients, 75 patients were included: 20 cases (26.7%) and 55 controls (73.3%). Cases were predominantly limited skin subset (90% vs 60%, p < 0.001), were anti-centromere antibody (ACA)-positive (95% vs 40%, p < 0.001) and had an infrequent oesophageal involvement (45% vs 74%; p = 0.016). The mean DLco reduction of cases was mild (65.60% ± 10.56). Only 1 out of 20 patients had normal DLco/VA values, and tricuspid regurgitation was more frequent (85% vs 53.8%, p = 0.014). CONCLUSION: There is a subgroup of SSc patients with mild isolated DLco and DLco/VA reduction, predominantly limited SSc with ACA seropositivity, which could identify a particular SSc subset. We hypothesise that isolated DLco/VA reduction could indicate a pulmonary vascular involvement. Nevertheless, a close follow-up is mandatory, as a pre-PAH situation cannot be excluded.

Inspiratory muscle activation increases with COPD severity as confirmed by non-invasive mechanomyographic analysis.

There is a lack of instruments for assessing respiratory muscle activation during the breathing cycle in clinical conditions. The aim of the present study was to evaluate the usefulness of the respiratory muscle mechanomyogram (MMG) for non-invasively assessing the mechanical activation of the inspiratory muscles of the lower chest wall in both patients with chronic obstructive pulmonary disease (COPD) and healthy subjects, and to investigate the relationship between inspiratory muscle activation and pulmonary function parameters. Both inspiratory mouth pressure and respiratory muscle MMG were simultaneously recorded under two different respiratory conditions, quiet breathing and incremental ventilatory effort, in 13 COPD patients and 7 healthy subjects. The mechanical activation of the inspiratory muscles was characterised by the non-linear multistate Lempel-Ziv index (MLZ) calculated over the inspiratory time of the MMG signal. Subsequently, the efficiency of the inspiratory muscle mechanical activation was expressed as the ratio between the peak inspiratory mouth pressure to the amplitude of the mechanical activation. This activation estimated using the MLZ index correlated strongly with peak inspiratory mouth pressure throughout the respiratory protocol in both COPD patients (r = 0.80, p<0.001) and healthy (r = 0.82, p<0.001). Moreover, the greater the COPD severity in patients, the greater the level of muscle activation (r = -0.68, p = 0.001, between muscle activation at incremental ventilator effort and FEV1). Furthermore, the efficiency of the mechanical activation of inspiratory muscle was lower in COPD patients than healthy subjects (7.61±2.06 vs 20.42±10.81, respectively, p = 0.0002), and decreased with increasing COPD severity (r = 0.78, p<0.001, between efficiency of the mechanical activation at incremental ventilatory effort and FEV1). These results suggest that the respiratory muscle mechanomyogram is a good reflection of inspiratory effort and can be used to estimate the efficiency of the mechanical activation of the inspiratory muscles. Both, inspiratory muscle activation and inspiratory muscle mechanical activation efficiency are strongly correlated with the pulmonary function. Therefore, the use of the respiratory muscle mechanomyogram can improve the assessment of inspiratory muscle activation in clinical conditions, contributing to a better understanding of breathing in COPD patients.

Sex differences in function and structure of the quadriceps muscle in chronic obstructive pulmonary disease patients.

Chronic obstructive pulmonary disease (COPD) is a complex disorder with extrapulmonary manifestations. Even though there is some knowledge regarding sex differences in the lung disease, little is known about extrapulmonary manifestations. Our aim was to analyze the specific profile of muscle dysfunction, structure, and biology in COPD women. Twenty-one women and 19 men with stable COPD as well as 15 controls were included. Nutritional status, physical activity, lung and muscle function, exercise capacity, and quality of life were assessed. In addition, blood, breath condensate, and quadriceps muscle samples were tested for inflammatory markers. Moreover, fiber phenotype, signs of damage-regeneration, and the expression of key genes linked to myogenesis and inflammation were assessed in the muscle. Inflammatory markers were increased in all body compartments but no correlation was found among them. Muscle dysfunction was present in both COPD groups but was more marked in women. The opposite occurred with the increase in the percentage of type II fibers that was lower in women despite a similar level of airway obstruction as in men. Female COPD also showed higher signs of muscle damage than COPD men who, in contrast, exhibited slightly higher signs of regeneration. We conclude that sex influences muscle phenotype and function in COPD.