Annalisa Frizzelli

Purpose: Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder that generally predisposes to pulmonary emphysema with or without chronic obstructive pulmonary disease (COPD). Despite the lack of spirometric obstruction, early Small Airways Dysfunction (SAD) may occur in AATD patients preceding lung damage. Methods: We conducted a retrospective, single-center study on 60 AATD patients without airflow obstruction (FEV₁/FVC ≥ 0.70). SAD was defined as: reduced spirometric flows (≥2 of FEF25–75, FEF50, FEF75 <65% predicted) and/or IOS R5–R20 value greater than 0.07 kPa•s•L⁻¹. Correlation and agreement between spirometry and IOS were assessed, as well as associations with Modified Medical Research Council (mMRC) dyspnea scores. Results: SAD was detected in 23% of patients by spirometry, 10% by IOS, and 13% by both methods. A slight agreement was found between spirometric and IOS criteria (κ = 0.22). Only IOS-defined SAD was significantly associated with dyspnea (mMRC ≥2; p = 0.05), and R5–R20 values correlated with mMRC scores (r = 0.38, p = 0.003). No association was observed between spirometry-defined SAD and symptoms. Conclusions: These findings support IOS as a partially complementary tool for the early detection of peripheral airway impairment in AATD. Moreover, IOS but not spirometry criteria were related to breathlessness perception in AATD patients without airflow obstruction, with IOS proving to be a clinically more sensitive measure.

Introduction: Respiratory muscle function may be evaluated using non-invasive tests, including parasternal or diaphragm surface electromyography (EMG_para, EMG_di) and thoracic ultrasound (US). The relationship between respiratory muscle EMG and US indices has not previously been evaluated. Methods: Healthy subjects performed spirometry, sniff, maximal inspiratory and expiratory mouth pressures (SNIP, MIP, MEP). Tidal and sniff US_di excursion and end-tidal inspiratory parasternal thickness were assessed. EMG_para and US-guided EMG_di were performed to measure neural respiratory drive index (NRDI). Data are reported as mean (±SD) or median (IQR). Pearson or Spearman correlation analyses were performed as appropriate. Results: Twenty subjects (12 females, mean age 33.45±8.97 years) had: FEV₁ 99±12%pred, FVC 102±13%pred, SNIP 89±30 cmH₂O, MIP 86±35 cmH₂O, MEP 102±47 cmH₂O. NRDI_para was 113 (59-251)%·bpm and NRDI_di was 90 (40-184)%·bpm. Sniff US_di excursion was 2.48 (1.90-2.90) cm, tidal US_di was ­­­­­­1.97 (1.47-2.10) cm. Right and left parasternal thickness were 0.36±0.15 and 0.33±0.14 cm, respectively. Inverse correlations were found between NRDI_para and sniff US_di excursion (r=-0.58, p=0.01) and SNIP (r=-0.69, p=0.001), and NRDI_di and sniff US_di (r=-0.45, p=0.04) and SNIP (r=-0.46, p=0.04). SNIP was positively correlated to sniff US_di excursion (r=0.57, p=0.01). Conclusion: In healthy subjects, surface electromyography of parasternal intercostal muscles and diaphragm is related to US-measured diaphragm excursion. Evaluation of these non-invasive tests of respiratory muscle function in disease states where there is load capacity imbalance of the respiratory muscle pump is warranted.

Background and Objectives: In adults, 150 to 300 min a week of moderate-intensity physical activity is the recommended daily level to maintain or improve fitness. In subjects with chronic obstructive pulmonary disease (COPD), reductions in daily physical activity (DPA) amounts are related to clinically significant outcomes. In this study, we ascertain whether or not COPD patients, when clustered into active (DPA ≥ 30 min a day, 5 days a week) and inactive (DPA < 30 min a day, 5 days a week), may differ in exercise capacity, as assessed by a cardiopulmonary exercise test (CPET). Materials and Methods: A large sample of clinically stable COPD patients was retrospectively recruited and then underwent spirometry and an incremental ramp protocol 5–15 watts/min CPET. DPA was assessed by a questionnaire. Results: A total of 83 (female 25%, age range 41–85 y) active and 131 (female 31%, age range 49–83 y) inactive participants were enrolled. They were similar in age, sex distribution, body mass index (BMI) and in spirometry. The two groups were significantly different in dyspnea on exertion, as assessed by the modified Medical Research Council (mMRC), and in cardio-metabolic parameters, but not in ventilatory ones, as confirmed by the CPET. Conclusions: COPD patients experiencing physical activity of at least 30 min a day, 5 days a week, showed a greater exercise capacity and an improved cardiovascular response to exercise, when compared to inactive ones. Active and inactive participants did not differ in terms of airflow obstruction severity as well as in dynamic hyperinflation and ventilatory inefficiency during exercise. This study further suggests the benefits of regular physical activity in COPD.

Background: There is no gold standard in diagnosing SAD. Indicators of SAD are considered: (a) a value 0.07 kPa·s·L−1 (R5-R20+). Aim and Objectives: The aim of the study was to ascertain, in asthmatic patients, whether spirometry and IOS indicators agree in detecting SAD. We also assessed the relationship between spirometry and IOS indicators and clinical features of asthma. Methods: We prospectively recruited adult asthmatic patients. Anthropometric and clinical characteristics were recorded. All patients performed spirometry and IOS tests. Results: We enrolled 301 asthmatic patients (179 females; mean age 50 ± 16 years) with normal to moderately severe degree of airway obstruction; 91% were non-smokers, 74% were atopic, 28% had an exacerbation in the previous year, and 18% had a poor asthma control by ACT. SAD was diagnosed in 62% of patients through FEF+, in 40% through FEV3/FEV6+ and in 41% through R5-R20+. κ values were 0.49 between FEF+ and FEV3/FEV6+, 0.20 between FEF+ and R5-R20+, 0.07 between FEV3/FEV6+ and R5-R20+. R5-R20+ but not FEF+ and FEV3/FEV6+ was significantly associated with ACT score (p < 0.05). Conclusions: Our study shows that in mild to moderately severe asthmatic patients, spirometry and IOS indicators are complementary in diagnosing SAD. Additionally, IOS indicator, but not spirometry ones, was related to asthma control.

Article: The interplay between diabetes mellitus and chronic obstructive pulmonary disease. An overview - Minerva Medica 2022 Feb 09 - Minerva Medica - Journals

The BNT162b2 COVID-19 vaccine is composed of lipid-nanoparticles (LNP) containing the mRNA that encodes for SARS-CoV-2 spike glycoprotein. Bronchospasm has been reported as an early reaction after COVID-19 mRNA vaccines in asthmatic patients. The aim of this study was to investigate the acute impact of BNT162b2 in a human ex vivo model of severe eosinophilic asthma. Passively sensitized human isolated bronchi were challenged with the platelet-activating factor to reproduce ex vivo the hyperresponsiveness of airways of patients suffering from severe eosinophilic asthma. BNT162b2 was tested on the contractile sensitivity to histamine and parasympathetic activation via electrical field stimulation (EFS); some experiments were performed after mRNA denaturation. BNT162b2 increased the resting tone (+11.82 ± 2.27%) and response to histamine in partially contracted tissue (+42.97 ± 9.64%) vs. the control (p < 0.001); it also shifted the concentration-response curve to histamine leftward (0.76 ± 0.09 logarithm) and enhanced the response to EFS (+28.46 ± 4.40%) vs. the control. Denaturation did not significantly modify (p > 0.05) the effect of BNT162b2. BNT162b2 increases the contractile sensitivity to histamine and parasympathetic activation in hyperresponsive airways, a detrimental effect not related to the active component but to some excipient. A possible candidate for the bronchospasm elicited by BNT162b2 could be the polyethylene glycol/macrogol used to produce LNP.

Background: Long-term sequelae, called Long-COVID (LC), may occur after SARS-CoV-2 infection, with unexplained dyspnoea as the most common symptom. The breathing pattern (BP) analysis, by means of the ratio of the inspiratory time (T_I) during the tidal volume (V_T) to the total breath duration (T_I/T_TOT) and by the V_T/T_I ratio, could further elucidate the underlying mechanisms of the unexplained dyspnoea in LC patients. Therefore, we analysed T_I/T_TOT and V_T/T_I at rest and during maximal exercise in LC patients with unexplained dyspnoea, compared to a control group. Methods: In this cross-sectional study, we enrolled LC patients with normal spirometry, who were required to perform a cardio-pulmonary exercise test (CPET) for unexplained dyspnoea, lasting at least 3 months after SARS-CoV-2 infection. As a control group, we recruited healthy age and sex-matched subjects (HS). All subjects performed spirometry and CPET, according to standardized procedures. Results: We found that 42 LC patients (23 females) had lower maximal exercise capacity, both in terms of maximal O₂ uptake (VO₂peak) and workload, compared to 40 HS (22 females) (p < 0.05). LC patients also showed significantly higher values of T_I/T_TOT at rest and at peak, and lower values in V_T/T_I at peak (p < 0.05). In LC patients, values of T_I/T_TOT at peak were significantly related to ∆PETCO₂, i.e., the end-tidal pressure of CO₂ at peak minus the one at rest (p < 0.05). When LC patients were categorized by the T_I/T_TOT 0.38 cut-off value, patients with T_I/T_TOT > 0.38 showed lower values in VO₂peak and maximal workload, and greater values in the ventilation/CO₂ linear relationship slope than patients with T_I/T_TOT ≤ 0.38 (p < 0.05). Conclusions: Our findings show that LC patients with unexplained dyspnoea have resting and exertional BP more prone to diaphragmatic fatigue, and less effective than controls. Pulmonary rehabilitation might be useful to revert this unpleasant condition.

Inhaled corticosteroids (ICS) remain the mainstay of asthma treatment, along with bronchodilators serving as control agents in combination with ICS or reliever therapy. Although current pharmacological treatments improve symptom control, health status, and the frequency and severity of exacerbations, they do not really change the natural course of asthma, including disease remission. Considering the highly heterogeneous nature of asthma, there is a strong need for innovative medications that selectively target components of the inflammatory cascade. The aim of this review was to systematically assess current investigational agents in Phase I and II randomised controlled trials (RCTs) over the last five years. Sixteen classes of novel therapeutic options were identified from 19 RCTs. Drugs belonging to different classes, such as the anti-interleukin (IL)-4Rα inhibitors, anti-IL-5 monoclonal antibodies (mAbs), anti-IL-17A mAbs, anti-thymic stromal lymphopoietin (TSLP) mAbs, epithelial sodium channel (ENaC) inhibitors, bifunctional M₃ receptor muscarinic antagonists/β₂-adrenoceptor agonists (MABAs), and anti-Fel d 1 mAbs, were found to be effective in the treatment of asthma, with lung function being the main assessed outcome across the RCTs. Several novel investigational molecules, particularly biologics, seem promising as future disease-modifying agents; nevertheless, further larger studies are required to confirm positive results from Phase I and II RCTs.

Atemwege mit einem Durchmesser von weniger als 2 mm werden als kleine Atemwege bezeichnet. Sie sind essenziell für den Transport und Austausch von Sauerstoff und Kohlendioxid und spielen gleichzeitig eine wichtige Rolle in der Lungenmechanik und tragen zur Unterteilung des Lungenvolumens bei. Die Messung der Funktion der kleinen Atemwege ist daher bei Patienten mit Atemwegs­erkrankungen von entscheidender Bedeutung. Dieser Überblick konzentriert sich auf die physiologischen Aspekte der kleinen Atemwege, die sowohl als Luftkanäle als auch als Determinanten der Lungenmechanik betrachtet werden, den gebräuchlichsten Instrumenten zur Bewertung ihrer Funktion und Behandlungsimplikationen.