Background/Objectives: Coronavirus disease 2019 (COVID-19) course may differ among individuals-in particular, those with comorbidities may have severe pneumonia, requiring oxygen supplementation or mechanical ventilation. Post-COVID-19 long-term structural changes in imaging studies can contribute to persistent respiratory disturbance. This study aimed to investigate COVID-19 sequels affecting the possibility of persistent structural lung tissue abnormalities and their influence on the respiratory function of peripheral airways and gas transfer. Methods: Patients were divided into two groups according to severity grades described by the World Health Organization. Among the 176 hospitalized patients were 154 patients with mask oxygen supplementation and 22 patients with high-flow nasal cannula (HFNC) or mechanical ventilation. All tests were performed at 3, 6, and 9 months post-hospitalization. Results: Patients in the severe/critical group had lower lung volumes in FVC, FVC%, FEV1, FEV1%, LC, TLC%, and DLCO% at three months post-hospitalization. At 6 and 9 months, neither group had significant FVC and FEV1 value improvements. The MEF 25-75 values were not significantly higher in the mild/moderate group than in the severe/critical group at three months. There were weak significant correlations between FVC and FEV1, MEF50, MEF 75, plethysmography TLC, disturbances in DLCO, and total CT abnormalities in the severe/critical group at three months. In a mild/moderate group, there was a significant negative correlation between the spirometry, plethysmography parameters, and CT lesions in all periods. Conclusions: Persistent respiratory symptoms post-COVID-19 can result from fibrotic lung parenchyma and post-infectious stenotic small airway changes not visible in CT, probably due to persistent inflammation.

OBJECTIVE: The use of small airway parameters generated by spirometry, namely forced expiratory flow between 25% and 75% of forced vital capacity (FVC) (FEF25%-75%) and forced expiratory flow at 50% and 75% of FVC (FEF50% and FEF75%, respectively), is widely discussed. We evaluated the importance of these spirometric parameters in a large Chinese population.
METHODS: We conducted a cross-sectional observational study in which spirometry and bronchodilator responsiveness (BDR) data were collected in a healthcare centre from May 2021 to August 2022 and in a tertiary hospital from January 2017 to March 2022. Discordance was assessed between the classification of test results by the large airway parameters of forced expiratory volume in 1 second (FEV1) and FEV1/FVC ratio and by the small airway parameters of FEF25%-75%, FEF75% and FEF50%. The predictive power of Z-scores of spirometric parameters for airflow limitation and BDR was assessed using receiver operating characteristic curves.
RESULTS: Our study included 26,658 people. Among people with a normal FVC (n = 14,688), 3.7%, 4.5% and 3.6% of cases exhibited normal FEV1/FVC ratio but impaired FEF25%-75%, FEF75% and FEF50%, respectively, while 6.8%-7.0% of people exhibited normal FEV1 but impaired FEF25%-75%, FEF75% and FEF50%. Using the Z-scores of combining both large and small airway parameters in spirometry showed the best area under the curve for predicting airflow limitation (0.90; 95% CI 0.87-0.94) and predicting BDR (0.72; 95% CI 0.71-0.73).
CONCLUSIONS: It is important to consider both large and small airway parameters in spirometry to avoid missing a diagnosis of airflow obstruction.

OBJECTIVE: To investigate the impact of type 2 inflammation markers blood eosinophils (EOS) and fractional exhaled nitric oxide (FeNO) on bronchodilator responsiveness (BDR) in patients with chronic obstructive pulmonary disease (COPD).
METHODS: This study was conducted among 389 patients with an established diagnosis of COPD in our hospital from October, 2019 to October, 2023, who all underwent bronchial dilation test (BDT) of the large and small airways. Based on smoking history, blood EOS, and FeNO, these patients were divided group A (blood EOS < 300/μL + FeNO < 35 ppb + smoking history < 20 pack-years), group B (blood EOS < 300/μL+FeNO < 35 ppb+smoking history ≥20 pack-years), group C (blood EOS ≥300/μL or FeNO≥35 ppb+smoking history ≥20 pack-years), and group D (blood EOS ≥300/μL or FeNO ≥35 ppb+smoking history < 20 pack-years) for analyzing the relationship between clinical indexes and BDR.
RESULTS: BDR evaluation based on forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and maximum mid-expiratory flow (MMEF) yielded consistent results, all showing a younger mean age, higher FeNO levels, and higher blood EOS counts and percentages in patients positive for BDT (P < 0.05). The improvement value and improvement rate of FEV1 were significantly lower in group A than in group D. The improvement value and improvement rate of FEV1 as well as the improvement rate of MMEF were significantly lower in group B than in group D. In the overall patients, age and FeNO were significantly correlated with the improvement value and improvement rate of FEV1 and the improvement rate of MMEF (P < 0.05).
CONCLUSIONS: Type 2 inflammation markers have different effects on BDR in the large and small airways of COPD patients, and their clinical significance needs further investigation.

UNASSIGNED: Childhood Asthma Control Test (C-ACT) is a well-validated questionnaire for asthma controls among 4-11 years old children. This study aims to examine if longitudinal C-ACT score changes could also reflect lung pathophysiologic changes.
UNASSIGNED: Thirty-seven children (43% female) aged 5 to 10 years old with mild or moderate asthma were followed up for 6 weeks with bi-weekly assessments of C-ACT, airway mechanics, lung function and respiratory inflammation. Associations of longitudinal changes in C-ACT score with lung pathophysiologic indicators were evaluated using linear mixed-effects models.
UNASSIGNED: A two-point worsening of total C-ACT score (sum of child and caregiver-reported) was associated with significant decreases in forced expiratory volume during the 1st second (FEV1) by 1.7% (P=0.04) and forced vital capacity (FVC) by 1.6% (P=0.01) and increased total airway resistance [airway resistance at 5 Hz (R5)] by 3.8% (P=0.05). A two-point worsening in child-reported score was significantly associated with 3.1% and 2.5% reductions in FEV1 and FVC, respectively, and with increases in R5 by 6.5% and large airway resistance [airway resistance at 20 Hz (R20)] by 5.5%. In contrast, a two-point worsening of caregiver-reported score was associated with none of the concurrent lung pathophysiologic measurements. Worsening of total C-ACT score was significantly associated with increased respiratory inflammation [fractional exhaled nitric oxide (FeNO)] in a subset (n=23) of children without eosinophilic airway inflammation. C-ACT scores were associated with none of the small airway measures.
UNASSIGNED: In children with mild or moderate asthma, longitudinal C-ACT score changes could reflect acute changes in large airway resistance and lung function. Measures of small airway physiology would provide valuable complementary information for asthma control. Asthma phenotype may affect whether C-ACT score could reflect respiratory inflammation.

Bronchiolitis obliterans (BO) is a progressive fibrotic process that predominantly affects the small airways and is identified as constrictive bronchiolitis by pathologists. It is commonly associated with allogeneic hematopoietic stem cell transplant (HSCT), lung transplant, exposure to inhaled toxins, post-infectious processes, autoimmune diseases, and sometimes, no known cause. In the latter case, it is referred to as cryptogenic bronchiolitis obliterans. A 52-year-old Hispanic man with a medical history of hypertension, diabetes mellitus, and coronary artery disease was referred to the pulmonary department due to experiencing dyspnea on exertion, intermittent dry cough, and progressive limitation of activities of daily living. Spirometry revealed severe obstructive changes, and chest high-resolution computed tomography showed ground-glass opacities with nodular infiltrates in the upper lobes, leading to a presumptive diagnosis of hypersensitivity pneumonitis. The patient underwent a lung surgical biopsy of the right upper and lower lobes, which revealed extensive constrictive bronchiolitis. Due to the patient\'s worsening general condition, bilateral lung transplantation succeeded without any further complications. Following the transplantation, the patient showed good recovery and functional improvement. Bronchiolitis obliterans, or constrictive bronchiolitis, has a variable natural history. It is associated with a higher risk of mortality in allogenic HSCT. When BO is secondary to inhalation of toxic gases, it is usually nonprogressive and limited to toxin exposure. Autoimmune diseases or cryptogenic bronchiolitis are rare and have a heterogeneous clinical course. To make a proper diagnosis, clinical history, radiologic and histologic findings must be considered.

The small airway, present since the origins of humanity and described barely a century ago, has recently been discovered as the anatomical site where inflammation begins in some obstructive lung diseases, such as asthma and Chronic Obstructive Pulmonary Disease (COPD), per se. Small airway dysfuction was identified in up to 91% of asthmatic patients and in a large proportion of COPD patients. In subjects without pathology, small airway represent 98.8% (approximately 4500 ml) of the total lung volume, contributing only between 10-25% of the total lung resistance; however, in subjects with obstruction, it can represent up to 90% of the total resistance. Despite this, its morphological and functional characteristics allow its dysfunction to remain undetected by conventional diagnostic methods, such as spirometry. Hence the importance of this review, which offers an overview of the tools available to assess small airway dysfunction and the possible therapies that act in this silent zone.
La vía aérea pequeña, presente desde los orígenes de la humanidad y descrita hace apenas un siglo, se ha descubierto recientemente como el sitio anatómico donde inicia la inflamación provocada por algunas enfermedades pulmonares obstructivas: asma y enfermedad pulmonar obstructiva crónica (EPOC), per se. Se ha identificado disfunción de la vía aérea pequeña en el 91% de los pacientes asmáticos y en una gran proporción de quienes padecen EPOC. En los pacientes sin enfermedad, la vía aérea pequeña representa el 98.8% (4500 mL) del volumen pulmonar total, y solo aporta del 10 al 25% de la resistencia pulmonar total; sin embargo, en sujetos con obstrucción puede suponer el 90% de la resistencia total. A pesar de esto, sus características morfológicas y funcionales permiten que la disfunción pase inadvertida por métodos diagnósticos convencionales, por ejemplo la espirometría. Con base en lo anterior, el objetivo de este estudio fue revisar el panorama general de los métodos disponibles para evaluar la vía aérea pequeña y los posibles tratamientos asociados con esta zona silente.

COPD is a common disease characterized by respiratory airflow obstruction. TGF-β1 and SMAD pathway is believed to play a role in COPD pathogenesis by driving epithelial mesenchymal transition (EMT).
We investigated TGF-β1 signalling and pSmad2/3 and Smad7 activity in resected small airway tissue from patients with; normal lung function and a smoking history (NLFS), current smokers and ex-smokers with COPD GOLD stage 1 and 2 (COPD-CS and COPD-ES) and compared these with normal non-smoking controls (NC). Using immunohistochemistry, we measured activity for these markers in the epithelium, basal epithelium, and reticular basement membrane (RBM). Tissue was also stained for EMT markers E-cadherin, S100A4 and vimentin.
The Staining of pSMAD2/3 was significantly increased in the epithelium, and RBM of all COPD groups compared to NC (p <0.0005). There was a less significant increase in COPD-ES basal cell numbers compared to NC (p= 0.02). SMAD7 staining showed a similar pattern (p <0.0001). All COPD group levels of TGF-β1 in the epithelium, basal cells, and RBM cells were significantly lower than NC (p <0.0001). Ratio analysis showed a disproportionate increase in SMAD7 levels compared to pSMAD2/3 in NLFS, COPD-CS and COPD-ES. pSMAD negatively correlated with small airway calibre (FEF25-75%; p= 0.03 r= -0.36). EMT markers were active in the small airway epithelium of all the pathological groups compared to patients with COPD.
Activation of the SMAD pathway via pSMAD2/3 is triggered by smoking and active in patients with mild to moderate COPD. These changes correlated to decline in lung function. Activation of the SMADs in the small airways is independent of TGF-β1, suggesting factors other than TGF-β1 are driving these pathways. These factors may have implications for small airway pathology in smokers and COPD through the process of EMT, however more mechanistic work is needed to prove these correlations.

The diagnosis of cough-variant asthma (CVA) is based on bronchial provocation test, which is challenging to be conducted. Most CVA patients have type 2 airway inflammation and small airway dysfunction. FeNO200, reflecting small airway inflammation, may be used to diagnose CVA.
This study aimed to explore and compare the value of lower airway exhaled nitric oxide (FeNO50, FeNO200, and CaNO) combined with small airway parameters for diagnosing CVA.
Chronic cough patients who attended the clinic from September 2021 to August 2022 were enrolled and divided into CVA group (n = 71) and non-CVA (NCVA) group (n = 212). The diagnostic values of FeNO50, FeNO200, concentration of alveolar nitric oxide (CaNO), maximal mid-expiratory flow (MMEF), forced expiratory flow at 75% of forced vital capacity (FEF75%) and forced expiratory flow at 50% of forced vital capacity (FEF50%) for CVA were evaluated.
FeNO50 [39(39) ppb versus 17(12) parts per billion (ppb), p < 0.01], FeNO200 [17(14) ppb versus 8(5) ppb, p < 0.01] and CaNO [5.0(6.1) ppb versus 3.5(3.6) ppb, p < 0.01] in CVA group were significantly higher than those in NCVA group. The optimal cut-off values of FeNO50, FeNO200, and CaNO for diagnosis of CVA were 27.00 ppb [area under the curve (AUC) 0.88, sensitivity 78.87%, specificity 79.25%], 11.00 ppb (AUC 0.92, sensitivity 88.73%, specificity 81.60%) and 3.60 ppb (AUC 0.66, sensitivity 73.24%, specificity 52.36%), respectively. For diagnosing CVA, the value of FeNO200 was better than FeNO50 (p = 0.04). The optimal cut-off values of MMEF, FEF75%, and FEF50% for the diagnosis of CVA were 63.80% (AUC 0.75, sensitivity 53.52%, specificity 86.32%), 77.9% (AUC 0.74, sensitivity 57.75%, specificity 83.49%) and 73.50% (AUC 0.75, sensitivity 60.56%, specificity 80.19%), respectively. The AUCs of FeNO50 combined with MMEF, FEF75%, and FEF50% for the diagnosis of CVA were all 0.89. The AUCs of FeNO200 combined with MMEF, FEF75%, and FEF50% for the diagnosis of CVA were all 0.93.
FeNO200 > 11 ppb contributed strongly for differentiating CVA from chronic cough, especially in patients with small airway dysfunction.

BACKGROUND: Small airway dysfunction (SAD) is a widespread but less typical clinical manifestation of respiratory dysfunction. In lung diseases, SAD can have a higher-than-expected impact on lung function. The aim of this study was to explore risk factors for SAD and to establish a predictive model.
METHODS: We included 1233 patients in the pulmonary function room of TangDu Hospital from June 2021 to December 2021. We divided the subjects into a small airway disorder group and a non-small airway disorder group, and all participants completed a questionnaire. We performed univariate and multivariate analyses to identify the risk factors for SAD. Multivariate logistic regression was performed to construct the nomogram. The performance of the nomogram was assessed and validated by the Area under roc curve (AUC), calibration curves, and Decision curve analysis (DCA).
RESULTS: One. The risk factors for small airway disorder were advanced age (OR = 7.772,95% CI 2.284-26.443), female sex (OR = 1.545,95% CI 1.103-2.164), family history of respiratory disease (OR = 1.508,95% CI 1.069-2.126), history of occupational dust exposure (OR = 1.723,95% CI 1.177-2.521), history of smoking (OR = 1.732,95% CI 1.231-2.436), history of pet exposure (OR = 1.499,95% CI 1.065-2.110), exposure to O3 (OR = 1.008,95% CI 1.003-1.013), chronic bronchitis (OR = 1.947,95% CI 1.376-2.753), emphysema (OR = 2.190,95% CI 1.355-3.539) and asthma (OR = 7.287,95% CI 3.546-14.973). 2. The AUCs of the nomogram were 0.691 in the training set and 0.716 in the validation set. Both nomograms demonstrated favourable clinical consistency. 3.There was a dose‒response relationship between cigarette smoking and SAD; however, quitting smoking did not reduce the risk of SAD.
CONCLUSIONS: Small airway disorders are associated with age, sex, family history of respiratory disease, occupational dust exposure, smoking history, history of pet exposure, exposure to O3, chronic bronchitis, emphysema, and asthma. The nomogram based on the above results can effectively used in the preliminary risk prediction.

UNASSIGNED: Glycopyrronium bromide has a quaternary ammonium structure and a low oral bioavailability, which reduces its systemic effects; it acts through a bronchodilating blockade of muscarinic receptors. The aim of this retrospective study was to analyze a possible relationship between the changes in the small airways and the efficacy of a bronchodilation with glycopyrronium bromide; exercise tolerance was also assessed, by performing the six-minute walking test.
UNASSIGNED: Forty-one patients were identified (23 females/18 males; mean age 66.82 ± 9.75 years), with a normal forced expiratory volume in 1 s (FEV1)/forced vital capacity ratio of 77.45% ± 4.86%, a reduced forced mid-expiratory flow between 25% and 75% of forced vital capacity (FEF25-75) of 42.9% ± 10.5%, with an increased residual volume/total lung capacity ratio of 132.68% ± 6.41%, FEV1 1.85 ± 0.54 L, forced vital capacity 2.39 ± 0.71 L, airway resistance (sR tot) 168.18% ± 42.5%, total lung capacity 98.28% ± 8.9%, six-minute walking test distance 318.3 ± 36.6 m, modified British Medical Research Council dyspnea scale 1.48 ± 0.77. All patients were initiated with glycopyrronium bromide 50 μg/die and reassessed after 4 months.
UNASSIGNED: After the treatment with glycopyrronium bromide, a significant improvement was noted regarding forced vital capacity (p = 0.04), FEF25-75 (p < 0.001), sR tot (p < 0.001), residual volume/total lung capacity ratio (p < 0.001) with reduction of dynamic hyperinflation, the significant increase of the distance covered during the six-minute walking test (p < 0.001), and modified British Medical Research Council (p < 0.001) showed enhanced exercise tolerance. FEV1 improved, but the difference was not statistically significant.
UNASSIGNED: Small airway dysfunction is associated with bronchodilator responsiveness. Glycopyrronium bromide has proven to be capable of inducing favorable effects on lung hyperinflation and its functional and clinical consequences, with a decrease in dyspnea and an increase in exercise capacity. The use of anticholinergic drugs is useful in the management of small airway disease.