TLR/WNT: A Novel Relationship in Immunomodulation of Lung Cancer.

The most frequent cause of death by cancer worldwide is lung cancer, and the 5-year survival rate is still very poor for patients with advanced stage. Understanding the crosstalk between the signaling pathways that are involved in disease, especially in metastasis, is crucial to developing new targeted therapies. Toll-like receptors (TLRs) are master regulators of the immune responses, and their dysregulation in lung cancer is linked to immune escape and promotes tumor malignancy by facilitating angiogenesis and proliferation. On the other hand, over-activation of the WNT signaling pathway has been reported in lung cancer and is also associated with tumor metastasis via induction of Epithelial-to-mesenchymal-transition (EMT)-like processes. An interaction between both TLRs and the WNT pathway was discovered recently as it was found that the TLR pathway can be activated by WNT ligands in the tumor microenvironment; however, the implications of such interactions in the context of lung cancer have not been discussed yet. Here, we offer an overview of the interaction of TLR-WNT in the lung and its potential implications and role in the oncogenic process.

Effects of Inhaled Corticosteroids on the Innate Immunological Response to Pseudomonas aeruginosa Infection in Patients with COPD.

Inhaled corticosteroids (ICS) use is associated with an increased risk of Pseudomonas aeruginosa (PA) infection in patients with COPD. We aimed to evaluate the effects of ICS on alveolar macrophages in response to PA in COPD patients with and without baseline ICS treatment (COPD and COPD + ICS, respectively) as well as smoker and nonsmoker controls. To do so, cells were infected with PA and cotreated with budesonide (BUD) or fluticasone propionate (FLU). The analysis of NF-κB and c-jun activity revealed a significant increase in both factors in response to PA cotreated with BUD/FLU in smokers but not in COPD or COPD + ICS patients when compared with PA infection alone. The expression of Toll-like receptor 2 (TLR2) and the transcription factor c-jun were induced upon PA infection in nonsmokers only. Moreover, in the smoker and COPD groups, there was a significant increase in TLR2 and a decrease in c-jun expression when treated with BUD/FLU after PA infection, which were not observed in COPD + ICS patients. Therefore, the chronic use of ICS seemingly makes the macrophages tolerant to BUD/FLU stimulation compared with those from patients not treated with ICS, promoting an impaired recognition of PA and activity of alveolar macrophages in terms of altered expression of TLR2 and cytokine production, which could explain the increased risk of PA infection in COPD patients under ICS treatment.

Obstructive Sleep Apnea in School-Aged Children Presented with Nocturnal Enuresis.

OBJECTIVES: We aimed to detect obstructive sleep apnea (OSA) among school-age children presented with nocturnal enuresis (NE) and to identify the possible risk factors for OSA in them. METHODS: Sixty-six children aged > 5-16 years presented with NE were enrolled in the study. Children with urinary tract anatomical abnormalities or infection, intellectual disabilities, genetic syndromes, psychological issues, and diabetes mellitus were excluded. They were clinically examined, scored using sleep clinical record score (SCR), and subjected for full-night polysomnogram (PSG). Children with obstructive apnea/hypopnea index (AHI) ≥ 2 episodes/hour (h) were considered as OSA. RESULTS: Fifty-four children (81.8% of the recruited children) aged 8.3 ± 2.8 years agreed to undergo PSG as 68.5% had OSA with median obstructive AHI of 6.1 (3.7-13.2) episodes/h, median oxygen saturation of 97% and nadir of 88%. Thirty-three percent were obese with significantly higher AHI [7.0 (3.7-12.4) vs. 2.4 (1.3-6.1) episodes/h; p = 0.023]. SCR score correlated significantly with AHI (r2 = 0.462, p = 0.001) with 91% sensitivity in detecting OSA ≥ 5 episodes/h. Nasal obstruction, adenoid/adult facial phenotype, and arched palate were associated with OSA (p < 0.05). CONCLUSION: NE is commonly associated with OSA especially in obese children. Nasal obstruction, abnormal facial phenotype, and high-arched palate were common risk factors.

Usefulness of Bronchoscopic Probe-Based Confocal Laser Endomicroscopy in the Diagnosis of Pneumocystis jirovecii Pneumonia.

BACKGROUND: Probe-based confocal laser endomicroscopy (pCLE) is a novel technique that provides in vivo microscopic imaging of the distal lung. We hypothesized that the intra-alveolar exudates characterizing Pneumocystis jirovecii pneumonia (PJP) can be identified by pCLE in vivo and help in its diagnosis. OBJECTIVES: We aimed to assess the usefulness of pCLE for the in vivo diagnosis of PJP. METHODS: Thirty-two human immunodeficiency virus (HIV)-positive patients with new pulmonary infiltrates and fever were studied using pCLE. Real-time alveolar images were recorded during the bronchoscopy for off-line analysis by two independent observers. Bronchoalveolar lavage samples were also obtained and processed for microbiology and cytological evaluation, including Grocott stain for P. jirovecii. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of pCLE for the diagnosis of PJP in these patients were calculated. RESULTS: Fourteen patients (44%) were confirmed to have PJP by cultures/staining. pCLE was well tolerated in all patients. It identified intra-alveolar exudates in 13 of them (41%), where 11 of them (85%) had positive Grocott stain for P. jirovecci, with 93% concordance between observers. Sensitivity, specificity, PPV and NPV of pCLE for the diagnosis of PJP were 79, 89, 85 and 84%, respectively. In smokers, these figures improved to be 92, 88, 85 and 94%. CONCLUSIONS: pCLE is a quick and safe procedure for on-site diagnosis of PJP in HIV+ patients with excellent specificity and sensitivity mainly in smokers.

Haemophilus influenzae induces steroid-resistant inflammatory responses in COPD.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is an inflammatory disorder partially resistant to glucocorticoids. A reduced histone deacetylase (HDAC) activity has been proposed to explain this resistance. Haemophilus influenzae frequently colonizes the airways of COPD patients, where it enhances inflammation. The effects of Haemophilus influenzae on HDAC activity have not been investigated before. METHODS: The effects of the presence or absence of Haemophilus influenzae ex-vivo and in vitro were studied. To this end, we determined: (1) cytokine release in alveolar macrophages (AM) from 7 patients with COPD, 5 healthy smokers, 6 healthy non-smokers and (2) HDAC activity, nuclear factor kappa B (NF-κB) activation in a macrophage-like cell line (PMA-transformed U937 cells) co-cultured with epithelial cells. Experiments were repeated with dexamethasone (1 µM) and/or the HDAC enhancer theophylline (10 µM). RESULTS: Haemophilus influenzae induced a steroid-resistant inflammatory response in AM from COPD and controls and decreased HDAC activity, activated NF-κB and induced the secretion of several cytokines (IL-6, IL-8, IL-1ß, IL-10 and TNF-α) (p < 0.001 for all comparisons) in the macrophage-like cell line. Dexamethasone reduced NF-κB activation but it did not modify HDAC activity. The addition of theophylline to dexamethasone increased HDAC activity and suppressed cytokine release completely, without modifying NF-κB activation. CONCLUSIONS: These results indicate that Haemophilus influenzae reduces HDAC activity and induces a NF-κB mediated inflammatory response that is only partially suppressed by glucocorticoids irrespective of having COPD. Yet, the latter can be fully restored by targeting HDAC activity.

Structure-function relationship in COPD revisited: an in vivo microscopy view.

BACKGROUND: Fibred confocal fluorescence microscopy (FCFM) is a novel technology that allows the in vivo assessment and quantification during bronchoscopy of the bronchial wall elastic fibre pattern, alveolar and vessel diameters and thickness of the elastic fibre in the alveolar wall. AIMS: To relate these structural characteristics with lung function parameters in healthy subjects, smokers with normal spirometry and patients with chronic obstructive pulmonary disease (COPD). METHODS: We performed FCFM in 20 never smokers, 20 smokers with normal spirometry and 23 patients with COPD who required bronchoscopy for clinical reasons. The bronchial wall elastic fibre pattern was classified as lamellar, loose and mixed pattern, and later confirmed pathologically. Airspace dimensions and extra-alveolar vessel diameters were measured. Lung function measurements and pulmonary CT scans were obtained in all participants. RESULTS: Patients with COPD were characterised by a significantly higher prevalence of loose fibre bronchial deposition pattern and larger alveolar diameter which correlated inversely with several lung function parameters (forced expiratory volume in 1 s (FEV1) , FEV1/forced vital capacity ratio, maximum expiratory flow, carbon monoxide transfer factor and carbon monoxide transfer coefficient; p<0.05). Increased alveolar macrophages were demonstrated in active smokers with or without COPD. CONCLUSIONS: This is the first FCFM study to describe in vivo microscopic changes in the airways and alveoli of patients with COPD that are related to lung function impairment. These findings open the possibility of assessing the in vivo effects of therapeutic interventions for COPD in future studies.

Probe-based confocal laser endomicroscopy imaging of endobronchial hamartomas.

Probe-based confocal laser endomicroscopy (pCLE) is a new technique that can microscopically image the airways in vivo during ordinary flexible bronchoscope procedures. pCLE can visualize the basement membrane of the bronchial epithelium, allowing the study of the different changes in benign or malignant/premalignant bronchial lesions. We present 2 cases of pathology-proven endobronchial hamartoma diagnosed by biopsy which show characteristic images under pCLE examination. The tumor was removed in both cases by rigid bronchoscopy using a diathermy loop and a cryoprobe.

ERS International Congress 2023: highlights from the Clinical Techniques, Imaging and Endoscopy Assembly.

The Clinical Techniques, Imaging and Endoscopy Assembly is involved in the diagnosis and treatment of several pulmonary diseases, as demonstrated at the 2023 European Respiratory Society (ERS) International Congress in Milan, Italy. From interventional pulmonology, the congress included several exciting results for the use of bronchoscopy in lung cancer, including augmented fluoroscopy, robotic-assisted bronchoscopy and cryobiopsies. In obstructive lung disease, the latest results on bronchoscopic treatment of emphysema with hyperinflation and chronic bronchitis were presented. Research on using cryobiopsies to diagnose interstitial lung disease was further explored, with the aims of elevating diagnostic yield and minimising risk. For imaging, the latest updates in using artificial intelligence to overcome the increased workload of radiologists were of great interest. Novel imaging in sarcoidosis explored the use of magnetic resonance imaging, photon-counting computed tomography and positron emission tomography/computed tomography in the diagnostic work-up. Lung cancer screening is still a hot topic and new results were presented regarding incorporation of biomarkers, identifying knowledge gaps and improving screening programmes. The use of ultrasound in respiratory medicine is an expanding field, which was demonstrated by the large variety in studies presented at the 2023 ERS Congress. Ultrasound of the diaphragm in patients with amyotrophic lateral sclerosis and myasthenia gravis was used to assess movements and predict respiratory fatigue. Furthermore, studies using ultrasound to diagnose or monitor pulmonary disease were presented. The congress also included studies regarding the training and assessment of competencies as an important part of implementing ultrasound in clinical practice.

Validation of a Pathological Score for the Assessment of Bronchial Biopsies in Severe Uncontrolled Asthma: Beyond Blood Eosinophils.

BACKGROUND: Blood eosinophil count (BEC) is currently used as a surrogate marker of T2 inflammation in severe asthma but its relationship with tissue T2-related changes is elusive. Bronchial biopsy could add reliable information but lacks standardization. OBJECTIVES: To validate a systematic assessment of the bronchial biopsy for the evaluation of severe uncontrolled asthma (SUA) by standardizing a pathological score. METHODS: A systematic assessment of submucosal inflammation, tissue eosinophilic count/field (TEC), goblet cells hyperplasia, epithelial changes, basement membrane thickening, prominent airway smooth muscle and submucosal mucous glands was initially agreed and validated in representative bronchial biopsies of 12 patients with SUA by 8 independent pathologists. In a second phase, 62 patients with SUA who were divided according to BEC≥300cells/mm3 or less underwent bronchoscopy with bronchial biopsies and the correlations between the pathological findings and the clinical characteristics were investigated. RESULTS: The score yielded good agreement among pathologists regarding submucosal eosinophilia, TEC, goblet cells hyperplasia and mucosal glands (ICC=0.85, 0.81, 0.85 and 0.87 respectively). There was a statistically significant correlation between BEC and TEC (r=0.393, p=0.005) that disappeared after correction by oral corticosteroids (OCS) use (r=0.170, p=0.307). However, there was statistically significant correlation between FeNO and TEC (r=0.481, p=0.006) that was maintained after correction to OCS use (r=0.419, p=0.021). 82.4% of low-BEC had submucosal eosinophilia, 50% of them moderate to severe. CONCLUSION: A standardized assessment of endobronchial biopsy is feasible and could be useful for a better phenotyping of SUA especially in those receiving OCS.

Redefining the Role of Bronchoscopy in the Workup of Severe Uncontrolled Asthma in the Era of Biologics: A Prospective Study.

BACKGROUND: Severe uncontrolled asthma (SUA) is frequently treated with biologic therapy if a T2 phenotype is found. Bronchoscopy is not routinely recommended in these patients unless a specific indication to rule out comorbidities is present. RESEARCH QUESTION: Is routine bronchoscopy safe and useful in phenotyping and endotyping patients with SUA before the indication of a biologic therapy? STUDY DESIGN AND METHODS: Prospective study of consecutive patients with SUA who were referred to a specialized asthma clinic to assess the indication of a biologic therapy. Patients were clinically phenotyped as T2-allergic, T2-eosinophilic, and non-T2. All patients underwent bronchoscopy, and systematic data collection of endoscopic findings, microbiology of bronchial aspirate, and presence of eosinophils in bronchial biopsy were recorded and compared between asthma phenotypes. Cluster analysis was performed accordingly. RESULTS: One hundred patients were recruited and classified as T2-allergic (28%), T2-eosinophilic (64%), and non-T2 (8%). On bronchoscopy, signs of gastroesophageal reflux disease were detected in 21%, vocal cord dysfunction in 5%, and tracheal abnormalities in 3%. Bronchial aspirate culture isolated bacteria in 27% of patients and fungi in 14%. Three clusters were identified: nonspecific, upper airway, and infection, the latter being less frequently associated with submucosal eosinophilia. Eosinophils were detected in 91% of bronchial biopsies. Despite a correlation to blood eosinophils, five patients with T2-phenotypes showed no eosinophils in bronchial biopsy, and three patients with non-T2 showed eosinophils in bronchial biopsy. Only one patient had moderate bleeding. INTERPRETATION: Routine bronchoscopy in SUA eligible for biologic therapy is a safe procedure that can help to better phenotype and personalize asthma management.

Effects of different exercise training programs on the functional performance in fibrosing interstitial lung diseases: A randomized trial.

OBJECTIVES: We aimed to compare the effects of different aerobic exercise training (ET) programs on respiratory performance, exercise capacity, and quality of life in fibrosing interstitial lung diseases (f-ILD). METHODS: A case-control study where 31 patients with f-ILD diagnosis based on chest high-resolution computed tomography were recruited from Main Alexandria University hospital-Egypt. Ten patients were randomly assigned for only lower limbs (LL) endurance training program, and 10 patients for upper limbs, lower limbs, and breathing exercises (ULB) program for consecutive 18 sessions (3 sessions/week for 6 consecutive weeks). Eleven patients who refused to participate in the ET program were considered as control. All patients were subjected for St George's respiratory questionnaire (SGRQ), 6-minute walk test (6-MWT), forced spirometry and cardiopulmonary exercise testing (CPET) before and after ET programs. RESULTS: Fibrosing non-specific interstitial pneumonia (NSIP) and collagenic associated-ILD were the commonest pathologies among the ET groups (30% each) with mean age of 44.4±12.25 and 41.90±7.58 years for LL and ULB groups respectively and moderate-to-severe lung restriction. 6-MWT and SGRQ significantly improved after both ET programs (p<0.001). Peak oxygen consumption (VO2) improved significantly after both LL training (median of 22 (interquartile range (IQR) = 17.0-24.0) vs. 17.5 (IQR = 13.0-23.0) ml/kg/min, p = 0.032) and ULB training (median of 13.5 (IQR = 11.0-21.0) vs. 10.5 (IQR = 5.0-16.0) ml/kg/min, p = 0.018). Further, maximal work load and minute ventilation (VE) significantly improved after both types of ET training (p<0.05); however, neither ventilation equivalent (VE/VCO2) nor FVC% improved after ET (p = 0.052 and 0.259 respectively). There were no statistically significant important differences between LL and ULB training programs regarding 6-MWT, SGRQ or CPET parameters (p>0.05). CONCLUSIONS: ET was associated with improvements in exercise capacity and quality of life in f-ILD patients irrespective of the type of ET program provided.

Hsa-Mir-320c, Hsa-Mir-200c-3p, and Hsa-Mir-449c-5p as Potential Specific miRNA Biomarkers of COPD: A Pilot Study.

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disease commonly induced by cigarette smoke. The expression of miRNAs can be altered in patients with COPD and could be used as a biomarker. We aimed to identify a panel of miRNAs in bronchoalveolar lavage (BAL) to differentiate COPD patients from smokers and non-smokers with normal lung function. Accordingly, forty-five subjects classified as COPD, smokers, and non-smokers (n = 15 per group) underwent clinical, functional characterization and bronchoscopy with BAL. The mean age of the studied population was 61.61 ± 12.95 years, BMI 25.72 ± 3.82 Kg/m2, FEV1/FVC 68.37 ± 12.00%, and FEV1 80.07 ± 23.63% predicted. According to microarray analysis, three miRNAs of the most upregulated were chosen: miR-320c, miR-200c-3p, and miR-449c-5p. These miRNAs were validated by qPCR and were shown to be differently expressed in COPD patients. ROC analysis showed that these three miRNAs together had an area under the curve of 0.89 in differentiating COPD from controls. Moreover, in silico analysis of candidate miRNAs by DIANA-miRPath showed potential involvement in the EGFR and Hippo pathways. These results suggest a specific 3-miRNA signature that could be potentially used as a biomarker to distinguish COPD patients from smokers and non-smoker subjects.

Effect of nocturnal hypoxemia on glycemic control among diabetic Saudi patients presenting with obstructive sleep apnea.

Background: Obstructive sleep apnea (OSA) is a prevalent disease that is associated with an increased incidence of type II diabetes mellitus (DM) if left untreated. We aimed to determine the association between glycosylated hemoglobin (HbA1c) levels and both nocturnal hypoxemia and apnea-hypopnea index (AHI) among a Saudi patients with OSA. Methods: A cross-sectional study that enrolled 103 adult patients diagnosed with DM and confirmed to have OSA by full night attended polysomnography between 2018 and 2021. Those who presented with acute illness, chronic obstructive pulmonary disease (COPD)/restrictive lung diseases causing sleep-related hypoxemia, or no available HbA1c level within 6 months before polysomnography were excluded from the study. Univariate and multivariate linear regression analyses between HbA1c levels and parameters of interest were tested. Results: Sixty-seven (65%) of the studied population had uncontrolled DM (HbA1c ≥7%). In univariate regression analysis, there was a significant positive association between HbA1c, and sleep time spent with an oxygen saturation below 90% (T90), female gender, and body mass index (BMI) (p<0.05) but not AHI, or associated comorbidities (p>0.05). In the multivariate analysis, HbA1c was positively associated with increasing T90 (p<0.05), and ODI (p<0.05), but not with AHI (p>0.05). Conclusion: Nocturnal hypoxemia could be an important factor affecting glycemic control in patients with OSA suffering from DM irrespective of the severity of both diseases.

Predicting mortality for patients with heart failure beyond oxygen consumption: a prognostic risk score.

Cardiopulmonary exercise test (CPET) is a crucial tool for the functional evaluation of cardiac patients. We hypothesized that maximal oxygen consumption (V̇o2max) and ventilatory efficiency-minute ventilation to carbon dioxide production (V̇e/V̇co2) slope are not the only parameters of CPET able to predict major cardiac events (mortality or cardiac transplantation urgently or elective). We aimed to identify the best CPET predictors of major cardiac events in patients with severe chronic heart failure and to propose an integrated score that could be applied for their prognostic evaluation. We evaluated 140 patients with chronic heart failure who underwent CPET between 2011 and 2019. Major cardiac events were evaluated during follow-up. Univariate and multivariate logistic regression analyses were applied to study the predictive value of different clinical, echocardiographic, and CPET parameters in relation to the major cardiac events. A score was generated, and c-statistic was used for the comparisons. Thirty-nine patients (27.9%) died or underwent cardiac transplantation over a median follow-up of 48 mo. Five parameters (maximal workload, breathing reserve, left ventricular ejection fraction, diastolic dysfunction, and nonidiopathic cardiomyopathy) were used to generate a risk score that had better risk discrimination than the New York Heart Association dyspnea scale, V̇o2max, V̇e/V̇co2 slope > 35 alone, and combined V̇o2max and V̇e/V̇co2 slope (P = 0.009, 0.004, <0.001, and 0.005, respectively) in predicting major cardiac events. A composite score of CPET and clinical/echocardiographic data is more reliable than the single use of V̇o2max or combined with V̇e/V̇co2 slope to predict major cardiac events.NEW & NOTEWORTHY This is a cohort study with a follow-up of maximum of 8 years of patients with chronic heart failure that demonstrates a simple integrated score consisting of CPET (breathing reserve, workload at maximal exercise), echocardiographic (LVEF, diastolic dysfunction), and clinical (etiology of cardiac disease) data. The generated score was a better predictor of major cardiac events (mortality or cardiac transplantation) than Weber classification (V̇o2max classification) or NYHA functional class as single factors.

Implementation of an Integrated Care Model for Frequent-Exacerbator COPD Patients: A Controlled Prospective Study.

INTRODUCTION: Frequent-exacerbator COPD (fe-COPD) associated with frequent hospital admissions have high morbidity, mortality and use of health resources. These patients should be managed in personalized integrated care models (ICM). Accordingly, we aimed to evaluate the long-term effectiveness of a fe-COPD ICM on emergency room (ER) visits, hospital admissions, days of hospitalization, mortality and improvement of health status. METHODS: Prospective-controlled study with analysis of a cohort of fe-COPD patients assigned to ICM and followed-up for maximally 7 years that were compared to a parallel cohort who received standard care. All patients had a confirmed diagnosis of COPD with a history of ≥2 hospital admissions due to exacerbations in the year before enrollment. The change in CAT score and mMRC dyspnea scale, hospital admissions, ER visits, days of hospitalization, and mortality were analyzed. RESULTS: 141 patients included in the ICM were compared to 132 patients who received standard care. The ICM reduced hospitalizations by 38.2% and ER visits by 69.7%, with reduction of hospitalizations for COPD exacerbation, ER visits and days of hospitalization (p<0.05) compared to standard care. Further, health status improved among the ICM group after 1 year of follow-up (p=0.001), effect sustained over 3 years. However, mortality was not different between groups (p=0.117). Last follow-up CAT score>17 was the strongest independent risk factor for mortality and hospitalization among ICM patients. CONCLUSIONS: An ICM for fe-COPD patients effectively decreases ER and hospital admissions and improves health status, but not mortality.

Characterization of COPD Admissions During the First COVID-19 Outbreak.

Purpose: Exacerbations of COPD (ECOPD) are a frequent cause of hospitalization that seemed to ameliorate during the COVID outbreak. We aimed to evaluate the clinical characteristics of COPD-related hospital admissions and mortality in relation to the presence of COVID-19. Patients and Methods: We conducted a case-control study of patients admitted in four teaching hospitals throughout Spain between March 15 and April 30, 2020. Hospital admissions of respiratory cause with and without PCR-proven SARS-CoV-2 infection in patients with COPD were evaluated. Baseline and episode-related clinical characteristics were analyzed. Logistic regression analysis was performed to evaluate the risk for mortality. Results: During the study period, 2101 patients were admitted for respiratory worsening, 1200 (57.1%) with COVID-19. A total of 228 (10.8%) were admitted due to COPD worsening, of whom 52 (22.8%) tested positive for COVID-19. COPD patients with COVID-19, when compared to those without COVID-19, were more frequently males with better lung function (FEV1 postbronchodilator 71% vs 46% respectively, p<0.001) and had higher mortality (44.9% vs 13.6% respectively, p<0.001) despite similar age, comorbidities, total days of hospitalization and admission to intensive care unit. COVID-19 and eosinopenia were the strongest risk factors for mortality in the multivariate analysis in the overall COPD population. Inhaled corticosteroid use was not associated to mortality. Conclusion: Hospitalizations for ECOPD without COVID-19 were more frequent than COPD with COVID-19 during the first outbreak, but the latter were associated with higher mortality and low eosinophil counts that warrant further analysis.

Inhaled corticosteroid dose is associated with Pseudomonas aeruginosa infection in severe COPD.

INTRODUCTION: Patients with chronic obstructive pulmonary disease (COPD) with frequent exacerbations (ExCOPD) are commonly treated with inhaled corticosteroids (ICS) and are at risk of infections caused by potential pathogenic bacteria (PPB) including Pseudomonas aeruginosa (PsA). OBJECTIVES: To investigate the association between the use of ICS and PsA infection among ExCOPD. METHODS: Case-control study with longitudinal follow-up that recruited ExCOPD after a hospitalisation due to exacerbation between 2012 and 2020. Patients with isolation of PsA (COPD-PsA) in sputum either during admission or follow-up were compared with those with other or no PPB. Clinical, functional characteristics, DDD, use of ICS and survival were evaluated. Cox regression analysis was performed to evaluate the risk factors associated to PsA infection and mortality. RESULTS: 358 patients (78% male, mean age 73±9 years) were enrolled and followed up for a median of 4 years (IQR=3-8). 173 patients (48.3%) had at least a positive culture for PsA. COPD-PsA had more frequent exacerbations, more severe airflow limitation and higher mortality (69.4% vs 46.5%, p<0.001). There were no differences in the use of ICS between groups but the dose of ICS was significantly higher among COPD-PsA (median of 500 µg fluticasone propionate equivalents (IQR=250-1000) vs 400 µg (IQR=200-1000), p=0.007). Blood eosinophil count (BEC) was not different between ICS users and non-users. In multivariate analysis, the dose of ICS was an independent risk factor for PsA infection and mortality but not ICS use. CONCLUSIONS: ICS dose, but not its use, could be a risk factor for PsA infection in patients with severe COPD regardless of BEC.

Implementation of an Integrated Care Model for Frequent-Exacerbator COPD Patients: A Controlled Prospective Study.

INTRODUCTION: Frequent-exacerbator COPD (fe-COPD) associated with frequent hospital admissions have high morbidity, mortality and use of health resources. These patients should be managed in personalized integrated care models (ICM). Accordingly, we aimed to evaluate the long-term effectiveness of a fe-COPD ICM on emergency room (ER) visits, hospital admissions, days of hospitalization, mortality and improvement of health status. METHODS: Prospective-controlled study with analysis of a cohort of fe-COPD patients assigned to ICM and followed-up for maximally 7 years that were compared to a parallel cohort who received standard care. All patients had a confirmed diagnosis of COPD with a history of ≥2 hospital admissions due to exacerbations in the year before enrollment. The change in CAT score and mMRC dyspnea scale, hospital admissions, ER visits, days of hospitalization, and mortality were analyzed. RESULTS: 141 patients included in the ICM were compared to 132 patients who received standard care. The ICM reduced hospitalizations by 38.2% and ER visits by 69.7%, with reduction of hospitalizations for COPD exacerbation, ER visits and days of hospitalization (p<0.05) compared to standard care. Further, health status improved among the ICM group after 1 year of follow-up (p=0.001), effect sustained over 3 years. However, mortality was not different between groups (p=0.117). Last follow-up CAT score>17 was the strongest independent risk factor for mortality and hospitalization among ICM patients. CONCLUSIONS: An ICM for fe-COPD patients effectively decreases ER and hospital admissions and improves health status, but not mortality.

Diaphragmatic motor cortex hyperexcitability in patients with chronic obstructive pulmonary disease.

BACKGROUND AND OBJECTIVES: Respiratory muscles dysfunction has been reported in COPD. Transcranial magnetic stimulation (TMS) has been used for assessing the respiratory corticospinal pathways particularly of diaphragm. We aimed to study the cortico-diaphragmatic motor system changes in COPD using TMS and to correlate the findings with the pulmonary function. METHODS: A case control study recruited 30 stable COPD from the out-patient respiratory clinic of Main Alexandria University hospital- Egypt and 17 healthy control subjects who were subjected to spirometry. Cortical conduction of the diaphragm was performed by TMS to all participants followed by cervical magnetic stimulation of the phrenic nerve roots. Diaphragmatic resting motor threshold (DRMT), cortical motor evoked potential latency (CMEPL), CMEP amplitude (CMEPA), peripheral motor evoked potential latency (PMEPL), PMEP amplitude (PMEPA) and central motor conduction time (CMCT) were measured. RESULTS: 66.7% of COPD patients had severe and very severe COPD with median age of 59 (55-63) years. There was statistically significant bilateral decrease in DRMT, CMEPA and PMEPA in COPD group versus healthy subjects and significant increase in CMEPL and PMEPL (p <0.01). Left CMCT was significantly prolonged in COPD group versus healthy subjects (p <0.0001) but not right CMCT. Further, there was significant increase in CMEPL and CMCT of left versus right diaphragm in COPD group (p = 0.003 and 0.001 respectively) that inversely correlated with FEV1% and FVC% predicted. Right and left DRMT were insignificantly different in COPD group (p >0.05) but positively correlated with FEV1/FVC, FEV1% and FVC% predicted. CONCLUSION: Central cortico-diaphragmatic motor system is affected in COPD patients with heterogeneity of both sides that is correlated with pulmonary function. SIGNIFICANCE: Coticospinal pathway affection could be a factor for development of diaphragmatic dysfunction in COPD patients accordingly its evaluation could help in personalization of COPD management especially pulmonary rehabilitation programs.