Role of mast cells in the pathogenesis of severe lung damage in COVID-19 patients.

BACKGROUND: There is still insufficient knowledge with regard to the potential involvement of mast cells (MCs) and their mediators in the pathology of coronavirus disease-2019 (COVID-19). Therefore, our study aimed to investigate the role of MCs, their activation and protease profiles in the pathogenesis of early and late lung damage in COVID-19 patients. METHODS: Formalin-fixed and paraffin embedded lung specimens from 30 patients who died from COVID-19 and 9 controls were used for histological detection of MCs and their proteases (tryptase, chymase) followed by morphometric quantification. RESULTS: Our results demonstrated increased numbers of MCs at early stage and further augmentation of MCs number during the late stage of alveolar damage in COVID-19 patients, as compared to the control group. Importantly, the percentage of degranulated (activated) MCs was higher during both stages of alveolar lesions in comparison to the controls. While there was no prominent alteration in the profile of tryptase-positive MCs, our data revealed a significant elevation in the number of chymase-positive MCs in the lungs of COVID-19 patients, compared to the controls. CONCLUSIONS: MCs are characterized by dysregulated accumulation and increased activation in the lungs of patients suffering from COVID-19. However, future profound studies are needed for precise analysis of the role of these immune cells in the context of novel coronavirus disease.

Breathing pattern, accessory respiratory muscles work, and gas exchange evaluation for prediction of NIV failure in moderate-to-severe COVID-19-associated ARDS after deterioration of respiratory failure outside ICU: the COVID-NIV observational study.

BACKGROUND: Data on the efficacy of non-invasive ventilation (NIV) after progression of respiratory failure in patients who have already received oxygen therapy, or CPAP outside ICU is limited. The study aimed to find predictors of NIV failure based on breathing pattern, gas exchange, and accessory respiratory muscles evaluation in patients who progressed to moderate-to-severe COVID-19 ARDS. METHODS: This was a prospective observational study in patients with moderate-to-severe COVID-19-ARDS on NIV (n = 80) admitted to COVID-ICU of Sechenov University. The combined success rate for conventional oxygen and CPAP outside ICU was 78.6% (440 of 560 patients). The primary endpoints were intubation rate and mortality. We measured respiratory rate, exhaled tidal volume (Vte), mean peak inspiratory flow (PIF), inspiratory time (Ti), PaO2, SpO2, end-tidal carbon dioxide (PETCO2), and Patrick score, and calculated ROX index, PaO2/FiO2, ventilatory ratio, and alveolar dead space (Vdalv/Vt) on Days 1, 3, 5, 7, 10, and 14. For all significant differences between NIV success and failure groups in measured data, we performed ROC analysis. RESULTS: NIV failure rate in ICU after deterioration of respiratory failure outside ICU was 71.3% (n = 57). Patients with the subsequent NIV failure were older at inclusion, more frail, had longer duration of disease before ICU admission, and higher rate of CPAP use outside ICU. ROC-analysis revealed that the following respiratory parameters after 48 h of NIV can serve as a predictors for NIV failure in moderate-to-severe COVID-19-associated ARDS: PaO2/FiO2 < 112 mmHg (AUROC 0.90 (0.93-0.97), p < 0.0001); PETCO2 < 19.5 mmHg (AUROC 0.84 (0.73-0.94), p < 0.0001); VDalv/VT > 0.43 (AUROC 0.78 (0.68-0.90), p < 0.0001); ROX-index < 5.02 (AUROC 0.89 (0.81-0.97), p < 0.0001); Patrick score > 2 points (AUROC 0.87 (0.78-0.96), p = 0.006). CONCLUSION: In patients who progressed to moderate-to-severe COVID-19-ARDS probability of NIV success rate was about 1/3. Prediction of the NIV failure can be made after 48 h based on ROX index < 5.02, PaO2/FiO2 < 112 mmHg, PETCO2 < 19.5 mmHg, and Patrick score > = 2. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04667923 , registered on 16/12/2020.

Potential for the lung recruitment and the risk of lung overdistension during 21 days of mechanical ventilation in patients with COVID-19 after noninvasive ventilation failure: the COVID-VENT observational trial.

BACKGROUND: Data on the lung respiratory mechanics and gas exchange in the time course of COVID-19-associated respiratory failure is limited. This study aimed to explore respiratory mechanics and gas exchange, the lung recruitability and risk of overdistension during the time course of mechanical ventilation. METHODS: This was a prospective observational study in critically ill mechanically ventilated patients (n = 116) with COVID-19 admitted into Intensive Care Units of Sechenov University. The primary endpoints were: «optimum¼ positive end-expiratory pressure (PEEP) level balanced between the lowest driving pressure and the highest SpO2 and number of patients with recruitable lung on Days 1 and 7 of mechanical ventilation. We measured driving pressure at different levels of PEEP (14, 12, 10 and 8 cmH2O) with preset tidal volume, and with the increase of tidal volume by 100 ml and 200 ml at preset PEEP level, and calculated static respiratory system compliance (CRS), PaO2/FiO2, alveolar dead space and ventilatory ratio on Days 1, 3, 5, 7, 10, 14 and 21. RESULTS: The «optimum¼ PEEP levels on Day 1 were 11.0 (10.0-12.8) cmH2O and 10.0 (9.0-12.0) cmH2O on Day 7. Positive response to recruitment was observed on Day 1 in 27.6% and on Day 7 in 9.2% of patients. PEEP increase from 10 to 14 cmH2O and VT increase by 100 and 200 ml led to a significant decrease in CRS from Day 1 to Day 14 (p < 0.05). Ventilatory ratio was 2.2 (1.7-2,7) in non-survivors and in 1.9 (1.6-2.6) survivors on Day 1 and decreased on Day 7 in survivors only (p < 0.01). PaO2/FiO2 was 105.5 (76.2-141.7) mmHg in non-survivors on Day 1 and 136.6 (106.7-160.8) in survivors (p = 0.002). In survivors, PaO2/FiO2 rose on Day 3 (p = 0.008) and then between Days 7 and 10 (p = 0.046). CONCLUSION: Lung recruitability was low in COVID-19 and decreased during the course of the disease, but lung overdistension occurred at «intermediate¼ PEEP and VT levels. In survivors gas exchange improvements after Day 7 mismatched CRS. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04445961 . Registered 24 June 2020-Retrospectively registered.

Anti-IL-17 monoclonal antibodies in hospitalized patients with severe COVID-19: A pilot study.

BACKGROUND: One of the main pathophysiological mechanisms underlying the severe course of COVID-19 is the hyper-inflammatory syndrome associated with progressive damage of lung tissue and multi-organ dysfunction. IL-17 has been suggested to be involved in hyper-inflammatory syndrome. OBJECTIVE: To evaluate the efficacy and safety of the IL-17 inhibitor netakimab in patients with severe COVID-19. STUDY DESIGN: In our retrospective case-control study we evaluated the efficacy of netakimab in hospitalized patients with severe COVID-19 outside the intensive care unit (ICU). Patients in the experimental group were treated with standard of care therapy and netakimab at a dose of 120 mg subcutaneously. RESULTS: 171 patients with severe COVID-19 were enrolled in our study, and 88 of them received netakimab. On the 3 day of therapy, body temperature, SpO2/FiO2, NEWS2 score, and CRP improved significantly in the netakimab group compared to the control group. Other clinical outcomes such as transfer to ICU (11.4% vs 9.6%), need for mechanical ventilation (10.2% vs 9.6%), 28-day mortality (10.2% vs 8.4%), did not differ between the groups. CONCLUSION: In hospitalized patients with severe COVID-19, anti-IL-17 therapy might mitigate the inflammatory response and improve oxygenation, but do not affect the need for mechanical ventilation and mortality.

Noninvasive ventilation for acute hypoxemic respiratory failure in patients with COVID-19.

AIM: Noninvasive ventilation (NIV) is known to reduce intubation in patients with acute hypoxemic respiratory failure (AHRF). We aimed to assess the outcomes of NIV application in COVID-19 patients with AHRF. MATERIALS & METHODS: In this retrospective cohort study, patients with confirmed diagnosis of COVID-19 and AHRF receiving NIV in general wards were recruited from two university-affiliated hospitals. Demographic, clinical, and laboratory data were recorded at admission. The failure of NIV was defined as intubation or death during the hospital stay. RESULTS: Between April 8 and June 10, 2020, 61 patients were enrolled into the final cohort. NIV was successful in 44 out of 61 patients (72.1%), 17 patients who failed NIV therapy were intubated, and among them 15 died. Overall mortality rate was 24.6%. Patients who failed NIV were older, and had higher respiratory rate, PaCO2, D-dimer levels before NIV and higher minute ventilation and ventilatory ratio on the 1-st day of NIV. No healthcare workers were infected with SARS-CoV-2 during the study period. CONCLUSIONS: NIV is feasible in patients with COVID-19 and AHRF outside the intensive care unit, and it can be considered as a valuable option for the management of AHRF in these patients.

Influence of Anxiety/Depression on the Subjective Evaluation of Cough in Patients with Chronic Obstructive Pulmonary Disease and Obesity.

Background and objectives: Obesity and anxiety and/or depression are common comorbidities in patients with chronic obstructive pulmonary disease (COPD). For doctors treating COPD, cough has a certain importance as a symptom. The purpose of this study was to figure out how obesity and anxiety/depression may influence the subjective assessment of cough. Materials and Methods: 110 patients with COPD participated in the study. The patients were divided into two groups, one including obese patients, and the other including patients with normal body weight. All patients filled out the hospital anxiety and depression scale (HADS) questionnaire, evaluated the severity of their cough by using visual analogue scale (VAS) on the 1st and 10th day of treatment, and underwent a 12 hour cough monitoring with a special cough monitoring device both on the 1st and the 10th day of treatment. Results: The severity of anxiety according to the HADS in patients with COPD and normal body weight was significantly higher than in patients with COPD and obesity, corresponding to 9.25 ± 1.37 and 8.20 ± 1.18 points, respectively (p = 0.0063). The patients with normal body weight and obesity, but without anxiety and depression, subjectively noted an improvement in their well-being on the 10th day of treatment (p = 0.0022, p = 0.0021, respectively). In subgroups with normal body weight and obesity with anxiety and/or depression, the mean values for VAS on day 10 did not change significantly (p = 0.1917, p = 0.1921, respectively). Also, patients from the subgroup with normal body weight and anxiety/depression had a significantly higher assessment of their cough on day 10 than obese patients with anxiety/depression (p = 0.0411). The VAS values correlated positively with the actual amount of cough (r = 0.42, p = 0.0122 and r = 0.44, p = 0.0054, respectively) in patients without anxiety and/or depression, while in patients with anxiety and/or depression, there was an inverse correlation between VAS values and cough (r = -0.38, p = 0.0034 and r = -0.40, p = 0.0231). Conclusions: It is important to diagnose and treat anxiety and depression in patients with COPD for a better prognosis and higher efficacy of medical treatments. While treating such patients, it is preferable to use a cough monitoring device for objective assessments, since the patients may exaggerate or underestimate their symptoms.

Mapping the Common Barriers to Optimal COPD Care in High and Middle-Income Countries: Qualitative Perspectives from Clinicians.

Purpose: Chronic obstructive pulmonary disease (COPD) poses a significant global health burden despite being largely preventable and treatable. Despite the availability of guidelines, COPD care remains suboptimal in many settings, including high-income countries (HICs) and upper-middle-income countries (UMICs), with varied approaches to diagnosis and management. This study aimed to identify common and unique barriers to COPD care across six countries (Australia, Spain, Taiwan, Argentina, Mexico, and Russia) to inform global policy initiatives for improved care. Methods: COPD care pathways were mapped for each country and supplemented with epidemiological, health-economic, and clinical data from a targeted literature review. Semi-structured interviews with 17 respiratory care clinicians were used to further validate the pathways and identify key barriers. Thematic content analysis was used to generate the themes. Results: Six themes were common in most HICs and UMICs: "Challenges in COPD diagnosis", "Strengthening the role of primary care", "Fragmented healthcare systems and coordination challenges", "Inadequate management of COPD exacerbations", "Limited access to specialized care" and, "Impact of underfinanced and overloaded healthcare systems". One theme, "Insurance coverage and reimbursement challenges", was more relevant for UMICs. HICs and UMICs differ in patient and healthcare provider awareness, primary care involvement, spirometry access, and availability of specialized care. Both face issues with healthcare fragmentation, guideline adherence, and COPD exacerbation management. In addition, UMICs also grapple with resource limitations and healthcare infrastructure challenges. Conclusion: Many challenges to COPD care are the same in both HICs and UMICs, underscoring the pervasive nature of these issues. While country-specific issues require customized solutions, there are untapped possibilities for implementing global respiratory strategies that support countries to manage COPD effectively. In addition to healthcare system-level initiatives, there is a crucial need for political prioritization of COPD to allocate the essential resources it requires.

Rate of severe exacerbations, healthcare resource utilisation and clinical outcomes in patients with COPD in low-income and middle-income countries: results from the EXACOS International Study.

INTRODUCTION: The EXAcerbations of Chronic obstructive lung disease (COPD) and their OutcomeS (EXACOS) International Study aimed to quantify the rate of severe exacerbations and examine healthcare resource utilisation (HCRU) and clinical outcomes in patients with COPD from low-income and middle-income countries. METHODS: EXACOS International was an observational, cross-sectional study with retrospective data collection from medical records for a period of up to 5 years. Data were collected from 12 countries: Argentina, Brazil, Chile, Colombia, Costa Rica, Dominican Republic, Guatemala, Hong Kong, Mexico, Panama, Russia and Taiwan. The study population comprised patients ≥40 years of age with COPD. Outcomes/variables included the prevalence of severe exacerbations, the annual rate of severe exacerbations and time between severe exacerbations; change in lung function over time (measured by the forced expiratory volume in 1 s (FEV1)); peripheral blood eosinophil counts (BECs) and the prevalence of comorbidities; treatment patterns; and HCRU. RESULTS: In total, 1702 patients were included in the study. The study population had a mean age of 69.7 years, with 69.4% males, and a mean body mass index of 26.4 kg/m2. The mean annual prevalence of severe exacerbations was 20.1%, and 48.4% of patients experienced ≥1 severe exacerbation during the 5-year study period. As the number of severe exacerbations increased, the interval between successive exacerbations decreased. A statistically significant decrease in mean (SD) FEV1 from baseline to post-baseline was observed in patients with ≥1 severe exacerbation (1.23 (0.51) to 1.13 (0.52) L; p=0.0000). Mean BEC was 0.198 x109 cells/L, with 64.7% of patients having a BEC ≥0.1 x109 cells/L and 21.3% having a BEC ≥0.3 x109 cells/L. The most common comorbidity was hypertension (58.3%). An increasing number of severe exacerbations per year was associated with greater HCRU. DISCUSSION: The findings presented here indicate that effective treatment strategies to prevent severe exacerbations in patients with COPD remain a significant unmet need in low-income and middle-income countries.

Involvement of Mast Cells in the Pathology of COVID-19: Clinical and Laboratory Parallels.

Recent studies suggested the potential role of mast cells (MCs) in the pathology of coronavirus disease 2019 (COVID-19). However, the precise description of the MCs' activation and the engagement of their proteases is still missing. The objective of this study was to further reveal the importance of MCs and their proteases (chymase, tryptase, and carboxypeptidase A3 (CPA3)) in the development of lung damage in patients with COVID-19. This study included 55 patients who died from COVID-19 and 30 controls who died from external causes. A histological analysis of the lung parenchyma was carried out to assess the protease profiles and degranulation activity of MCs. In addition, we have analyzed the general blood test, coagulogram, and C-reactive protein. The content of tryptase-positive MCs (Try-MCs) in the lungs of patients with COVID-19 was higher than in controls, but their degranulation activity was lower. The indicators of chymase-positive MCs (Chy-MCs) were significantly lower than in the controls, while the content of CPA3-positive MCs (CPA3-MCs) and their degranulation activity were higher in patients with COVID-19. In addition, we have demonstrated the existence of correlations (positive/negative) between the content of Try-MCs, Chy-MCs, and CPA3-MCs at different states of their degranulation and presence (co-adjacent/single) and the levels of various immune cells (neutrophils, eosinophils, basophils, and monocytes) and other important markers (blood hemoglobin, activated partial thromboplastin time (aPTT), international normalized ratio (INR), and fibrinogen). Thus, the identified patterns suggest the numerous and diverse mechanisms of the participation of MCs and their proteases in the pathogenesis of COVID-19, and their impact on the inflammatory process and coagulation status. At the same time, the issue requires further study in larger cohorts of patients, which will open up the possibility of using drugs acting on this link of pathogenesis to treat lung damage in patients with COVID-19.

Pulmonary Fibrosis and Progressive Pulmonary Fibrosis in a Prospective Registry of Interstitial Lung Diseases in Eastern Siberia.

Interstitial lung diseases (ILD) are part of a large heterogeneous group of diseases that differ in many ways (in their cause, clinical presentation, and response to therapy, etc.), but there are similar pathophysiological mechanisms involved in the development of the inflammation and/or fibrosis of the lungs. Currently, several criteria for pulmonary fibrosis (PF) and progressive pulmonary fibrosis (PPF) are proposed, and the information on the prevalence and characteristics of these conditions is limited. The aim of this study was to evaluate the spectrum of PF and PPF according to the registry of patients with ILD in eastern Siberia. Materials and methods: The study included patients with ILD from all of the medical institutions in the Irkutsk region (eastern Siberia). Each case of ILD (n = 270) was reviewed by a multidisciplinary discussion panel. The ILD patient registry included information on the clinical findings, history, pulmonary function tests, high-resolution computed tomography (HRCT), and histological findings. The follow-up period for the patients varied from 1 to 5 years. Results: Pulmonary fibrosis was detected by HRCT in 104 patients with ILD (38.5%). PF was present in 100% of the patients with IPF and SS-ILD, in 90.9% of the patients with CHP, in 71.4% of the patients with NSIP, and in 60% of the patients with RA-ILD. Sixty-two patients met the criteria for PPF (23.0% of the entire ILD cohort and 59.6% of the patients with PF). PPF occurred most often in the patients with IPF, CHP, IPAF, and SSc-ILD: 100%, 72.7%, 40%, and 38.5% of them, respectively. The variables associated with fibrosis progression included Velcro crackles (OR 18.3, p < 0.001) and late diagnosis (OR 4.1, p < 0.001). Conclusion: Pulmonary fibrosis and progressive pulmonary fibrosis are common in patients with ILD. The high mortality rate of PPF dictates the need for the active, early detection of a progressive fibrosing course of a wide range of ILD and suggests that further studies assessing the effectiveness of the interventions might be warranted.

Combined Pulmonary Fibrosis and Emphysema: When Scylla and Charybdis Ally.

Combined pulmonary fibrosis and emphysema (CPFE) is a recently recognized syndrome that, as its name indicates, involves the existence of both interstitial lung fibrosis and emphysema in one individual, and is often accompanied by pulmonary hypertension. This debilitating, progressive condition is most often encountered in males with an extensive smoking history, and is presented by dyspnea, preserved lung volumes, and contrastingly impaired gas exchange capacity. The diagnosis of the disease is based on computed tomography imaging, demonstrating the coexistence of emphysema and interstitial fibrosis in the lungs, which might be of various types and extents, in different areas of the lung and several relative positions to each other. CPFE bears high mortality and to date, specific and efficient treatment options do not exist. In this review, we will summarize current knowledge about the clinical attributes and manifestations of CPFE. Moreover, we will focus on pathophysiological and pathohistological lung phenomena and suspected etiological factors of this disease. Finally, since there is a paucity of preclinical research performed for this particular lung pathology, we will review existing animal studies and provide suggestions for the development of additional in vivo models of CPFE syndrome.