Real world experience on the effectiveness and safety of pirfenidone in patients with idiopathic pulmonary fibrosis in Taiwan.

Introduction: Randomized controlled trials have demonstrated a reduction in the decline of lung function and a reduced risk of acute exacerbation in patients with idiopathic pulmonary fibrosis treated with the antifibrotic prifenidone. The present study aimed to investigate the real-world effectiveness and safety profile of pirfenidone treatment for patients with IPF in Taiwan. Methods: Between January 1, 2019 and December 31, 2020, we enrolled 50 patients who were newly diagnosed with IPF and had at least 12 months follow-up period after pirfenidone administration. Result: The primary outcome of pharmacologic effect showed that the mean differences in the absolute values of forced vital capacity from baseline were 0.2 liter (n = 36), 0.13 liter (n = 32), 0.04 liter (n = 26), and - 0.004 liter (n = 26) after 3, 6, 9, and 12 months of administration, respectively. A slight improvement in quality of life, including scores of chronic obstructive pulmonary disease assessment test and St. George's respiratory questionnaire scores. The most common adverse effects were gastrointestinal upset and dermatological problems. No new safety concerns were observed in the present study. Conclusion: Our real-world study describe for the first time in Taiwan, the use of pirfenidone over a 12 months period. This drug preserves the lung function and improves quality of life with tolerable side effects.

Angiotensin-(1-7) attenuates SARS-CoV2 spike protein-induced interleukin-6 and interleukin-8 production in alveolar epithelial cells through activation of Mas receptor.

BACKGROUND: SARS-CoV-2 spike proteins (SP) can bind to the human angiotensin-converting enzyme 2 (ACE2) in human pulmonary alveolar epithelial cells (HPAEpiC) and trigger an inflammatory process. Angiotensin-(1-7) may have an anti-inflammatory effect through activation of Mas receptor. This study aims to investigate whether SARS-CoV-2 SP can induce inflammation through ACE2 in the alveolar epithelial cells which can be modulated through angiotensin-(1-7)/Mas receptor axis. METHODS: HPAEpiC were treated with SARS-CoV-2 SP in the presence or absence of ACE2 antagonist-dalbavancin and Mas receptor agonist-angiotensin-(1-7). Proinflammatory cytokine production (IL-6 and IL-8) were measured at mRNA and protein levels. MAP kinase phosphorylation and transcription factor activation was determined by Western Blot. Mas receptor was blocked by either antagonist (A779) or knockdown (specific SiRNA). Experiments were replicated using A549 cells. FINDINGS: SARS-CoV-2 SP (5 µg/mL) significantly induced MAP kinase (ERK1/2) phosphorylation, downstream transcription factor (activator protein-1, AP-1) activation and cytokine production (IL-6 and IL-8) at both mRNA and protein levels. Pretreatment with dalbavancin (10 µg/mL), or angiotensin-(1-7) (10 µM) significantly reduced ERK1/2 phosphorylation, AP-1 activation, and cytokine production. However, these angiotensin-(1-7)-related protective effects were significantly abolished by blocking Mas receptor with either antagonist (A799,10 µM) or SiRNA knockdown. INTERPRETATION: SARS-CoV-2 SP can induce proinflammatory cytokine production, which can be inhibited by either ACE2 antagonist or Mas receptor agonist-angiotensin-(1-7). Angiotensin-(1-7)-related protective effect on cytokine reduction can be abolished by blocking Mas receptor. Our findings suggest that ACE2/angiotensin-(1-7)/Mas axis may serve as a therapeutic target to control inflammatory response triggered by SARS-CoV-2 SP.

Functional parameters of small airways can guide bronchodilator use in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) may present comorbid obstructive lung diseases with small airway dysfunction (SAD). Existing guidelines suggest that inhaled bronchodilators should be used if the ratio of forced expiratory volume in the 1st second and forced vital capacity (FEV1/FVC) < 0.7 in IPF. However, most IPF patients have FEV1/FVC > 0.7 even with coexisting emphysema. We retrospectively enrolled IPF patients who were registered at our outpatient clinic. At baseline, 63 patients completed computed tomography (CT) scans, lung function measurements, and symptom questionnaires. Among these patients, 54 (85.71%) underwent antifibrotic treatment and 38 (60.32%) underwent long-acting bronchodilator treatment. The median FEV1/FVC was 0.86. Not all patients treated with bronchodilators showed significant changes in lung function. IPF patients with SAD, determined by IOS parameters, showed significant improvement in FEV1, FEF25-75%, and symptom scores after bronchodilator treatment. Bronchodilator efficacy was not observed in patients without SAD. CT-confirmed emphysema was seen in 34.92% of patients. There were no changes in lung function or symptom scores after bronchodilator treatment in patients with emphysema. In conclusion, FEV1/FVC cannot reflect the airflow limitation in IPF. Emphysema in IPF is not a deciding factor in whether patients should receive bronchodilator treatment. IOS parameters may be useful to guide bronchodilator therapy in patients with IPF coexisting with SAD.

Mucolytic Agents and Statins Use is Associated with a Lower Risk of Acute Exacerbations in Patients with Bronchiectasis-Chronic Obstructive Pulmonary Disease Overlap.

BACKGROUND: Bronchiectasis-chronic obstructive pulmonary disease (COPD) overlap (BCO) is a neglected area of trials, and it is not covered by guidelines for clinical practice. METHODS: Using the National Health Insurance Research Database of Taiwan, COPD patients with or without bronchiectasis from 2000 to 2009 were enrolled as the BCO and COPD alone cohorts, respectively. Patients followed for <28 days, diagnosed with COPD who were not prescribed with COPD medications, and those diagnosed with bronchiectasis who did not receive a chest X-ray or computed tomography were excluded. The primary endpoints were acute exacerbations and mortality. RESULTS: There were 831 patients in the BCO cohort and 3321 patients in the COPD alone cohort, covering 3763.08 and 17,348.95 person-years, respectively, from 2000 to 2011. The BCO cohort had higher risk for exacerbations (adjusted hazard ratio (HR) 2.26, 95% confidence interval (CI) 1.94⁻2.63) and mortality (HR 1.46, 95% CI 1.24⁻1.73) than the COPD alone cohort. In the patients overall, the use of statins, macrolides, and mucolytic agents was associated with significantly lower risks of acute exacerbations (statins, HR 0.37, 95% CI 0.29⁻0.46; macrolides, HR 0.65, 95% CI 0.45⁻0.93; mucolytic agents, HR 0.68, 95% CI 0.59⁻0.78). Statins were associated with a significantly lower risk of mortality (HR 0.32, 95% CI 0.25⁻0.41). In the BCO group, statins and mucolytic agents use was associated with significantly lower risks of acute exacerbations (statins, HR 0.44, 95% CI 0.29⁻0.65; mucolytic agents, HR 0.58, 95% CI 0.45⁻0.75). CONCLUSION: Statins and mucolytic agents use may lower risk of acute exacerbation in patients with BCO.