Patients with idiopathic pulmonary fibrosis and refractory cough have traction bronchiectasis and distorted airway architecture: a retrospective case review study.

Cough is a common and important sign/symptom in patients with idiopathic pulmonary fibrosis (IPF). However, there have been few reports focusing on cough, and the exact mechanisms for cough in patients with IPF have remained unclear. The objective of this study was to investigate the clinical features of IPF patients with refractory cough and to clarify mechanisms for cough in these patients. We retrospectively reviewed the files of patients with the diagnosis of IPF at Kanazawa University Hospital and compared the clinical features of IPF patients with refractory cough with the clinical features of IPF patients without refractory cough. Among a total of 23 patients with IPF, 10 patients (43.5%) had chronic cough. Of the ten patients, seven patients had concomitant conditions that could lead to cough. Of these seven patients, the cough of four patients was resolved after treatment of their concomitant condition. Finally, among the 23 patients there were 6 (26.1%) with refractory cough associated with IPF. Significant differences were seen between the following clinical features of IPF patients with or without refractory cough, respectively, as follows: lower body mass index (BMI; 18.8±2.5 vs. 22.8±2.5 kg/m2, P<0.01), lower forced vital capacity (FVC; 77.5%±30.4% predicted vs. 99.9%±0.53% predicted, P=0.046), and presence of traction bronchiectasis and distorted airway architecture on high-resolution computed tomography (HRCT; 83.3% vs. 11.8%, P<0.01). The difference between the proportions of patients with or without refractory cough with capsaicin cough sensitivity was not significant. Mechanical stress on the airways due to traction bronchiectasis and distorted airway architecture is a possible mechanism for cough in IPF patients.

Comparing region of interest selection and whole-field analysis for measurement of ciliary beat frequency in high-speed video analysis.

BACKGROUND: Ciliary beat frequency (CBF) is crucial in mucociliary clearance. High-speed video analysis (HSVA) is commonly used to measure CBF but lacks standardization. We compared visual observation and computer-assisted calculation using fast Fourier transformation (FFT) in freshly collected bronchial ciliary epithelial cells and cultured cells. METHODS: Bronchial epithelial cells were obtained from 12 patients who required bronchoscopic examination. Eighty-five videos of ciliary movement of freshly collected and cultured cells were recorded and used to calculate CBF using manual observation, region of interest (ROI) selection, and whole-field analysis. RESULTS: CBF measured by the ROI selection method strongly correlated with that measured using manual observation, especially in freshly collected cells. However, 27.8% of the manual observation method values were doubled in the ROI selection method, probably because a round trip of cilia was calculated as two cycles and needed to be corrected to 1/2 value. Upon increasing the number of ROIs, the results of the ROI selection method came closer to that of WFA. CONCLUSIONS: Computer-assisted calculation using FFT can aid in measuring CBF; however, current methods require visual confirmation. Further automated evaluation techniques are needed to establish more standardized and generalized CBF measurement methods using HSVA.

Prevalence and causes of chronic cough in Japan.

BACKGROUND: Chronic cough is one of the most common symptoms of respiratory diseases and can adversely affect patients' quality of life and interfere with social activities, resulting in a significant social burden. A survey is required to elucidate the frequency and treatment effect of chronic cough. However, clinical studies that cover all of Japan have not yet been conducted. METHODS: Patients who presented with a cough that lasted longer than 8 weeks and visited the respiratory clinics or hospitals affiliated with the Japan Cough Society during the 2-year study period were registered. RESULTS: A total of 379 patients were enrolled, and those who did not meet the definition of chronic cough were excluded. A total of 334 patients were analyzed: 201 patients had a single cause, and 113 patients had two or more causes. The main causative diseases were cough variant asthma in 92 patients, sinobronchial syndrome (SBS) in 36 patients, atopic cough in 31 patients, and gastroesophageal reflux (GER)-associated cough in 10 patients. The time required to treat undiagnosed patients and those with SBS was significantly longer and the treatment success rate for GER-associated cough was considerably poor. CONCLUSIONS: We confirmed that the main causes of chronic cough were cough variant asthma, SBS, atopic cough, and their complications. We also showed that complicated GER-associated cough was more likely to become refractory. This is the first nationwide study in Japan of the causes and treatment effects of chronic cough.

Bronchial Thermoplasty Attenuates Cough Reflex Sensitivity in Severe Asthma : A Single-Center Retrospective Study with 2-year Follow-up.

Despite the relatively short follow-up period in our previous study, we had reported that increased cough reflex sensitivity (CRS) may predict the efficacy of bronchial thermoplasty (BT) for treating asthma. Herein, we examined whether CRS predicts the efficacy of BT 2 years after the final BT treatment. We also investigated the influence of BT on CRS. We reviewed 10 patients 2 years after their final BT treatment. CRS, asthma-related symptoms, asthma exacerbations, and cough-related quality of life were assessed at baseline and 2 years after BT. Five patients responded positively to BT (BT responders) and their asthma control improved. No significant difference in CRS at baseline was detected between the BT responders and nonresponders. In contrast, BT responders exhibited significant improvements in CRS 2 years after BT. CRS at baseline could not predict the BT efficacy after 2 years. This is the first report demonstrating BT desensitized CRS in consecutive case series. J. Med. Invest. 70 : 271-275, February, 2023.

Preoperative assessment of pleural adhesions in patients with lung cancer based on quantitative motion analysis with dynamic chest radiography: A retrospective study.

PURPOSE: Preoperative assessment of pleural adhesion is crucial for appropriate surgical planning. This study aimed to quantitatively evaluate the usefulness of motion analysis using dynamic chest radiography (DCR) for assessing pleural adhesions. METHODS: Sequential chest radiographs of 146 lung cancer patients with or without pleural adhesions (n = 25/121) were obtained using a DCR system during respiration (registration number: 1729). The local motion vector was measured, and the percentage of poor motion area to the maximum expiration lung area (%lung area with poor motion) was calculated. Subsequently, percentage values ≥49.0% were considered to indicate pleural adhesions. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated to assess the prediction performance. The percentage of lung area with poor motion was compared between patients with and without pleural adhesions (p < 0.05). RESULTS: DCR-based motion analysis correctly predicted pleural adhesions in 21 out of 25 patients, with 47 false-positive results (sensitivity, 84.0%; specificity, 61.2%; PPV, 30.9%; NPV, 94.9%). The lung with pleural adhesions showed a significantly greater %lung area with poor motion than the opposite lung in the same patient, similar to the cancerous lung in patients without pleural adhesions. CONCLUSION: On DCR-based motion analysis, pleural adhesions could be indicated by an increase in the percentage of lung area with poor motion. Although the proposed method cannot identify the exact location of pleural adhesions, information regarding the presence or absence of pleural adhesions provided by DCR would help surgeons prepare for challenging surgeries and obtain informed consent from patients.

Primary ciliary dyskinesia with CCDC39 variants displaying specific ciliary ultrastructure and movement concordant with the genotype: A case report.

Primary ciliary dyskinesia (PCD) is a genetic disease with chronic airway infection and inflammation caused by ciliary ultrastructural defects and impairment in ciliary function. We present an adult case of PCD with compound heterozygous nonsense variants in CCDC39. The ciliary ultrastructure findings using electron microscopy and ciliary movement using high-speed video analysis matched the genotype. This is the first case report of PCD with CCDC39 variants in Japan demonstrating specific ciliary ultrastructure and movement related to the genotype.

Tiotropium Add-On and Treatable Traits in Asthma-COPD Overlap: A Real-World Pilot Study.

Purpose: The 'treatable traits' strategy for patients with chronic inflammatory airway diseases, especially asthma and chronic obstructive pulmonary disease (COPD), is a focus of interest, because it implements precision and personalized medicine. Asthma-COPD overlap (ACO), a phenotype involving both asthma and COPD, is an important disease entity because patients with ACO have significantly worse outcomes, conferring greater economical and social burdens. Some guidelines for ACO recommend add-on therapy of long-acting muscarinic antagonists to inhaled corticosteroids and long-acting ß2 agonists. However, this approach is based on extrapolation from patients with asthma or COPD alone. Consequently, a 'treatable traits' approach suitable for ACO remains obscure. Methods: A 12-week open-label cross-over pilot study was conducted in patients with ACO to investigate the effect of tiotropium bromide (TIO) 5 µg/day add-on therapy to fluticasone propionate/formoterol fumarate (FP/FM) 500/20 µg/day compared with FP/FM 500/20 µg/day alone. A 4-week run-in period and two 4-week treatment periods were included. Results: A total of 18 male patients with stable ACO participated in this pilot study. All patients were ex-smokers. Mean values ± standard deviation (SD) for forced expiratory volume in 1 second (FEV1) were 1.21 ± 0.49 L after the run-in period, 1.20 ± 0.51 L after the FP/FM combination therapy period, and 1.30 ± 0.48 L after the TIO add-on therapy to FP/FM period. FEV1 values after the TIO add-on therapy FP/FM period were significantly higher than those after the run-in period (p < 0.01). Conclusion: TIO add-on therapy to FP/FM in patients with ACO, considered difficult to treat because of the presence of both asthma and COPD, resulted in improvements in lung function parameters in this real-world pilot study, indicating the potential value of TIO add-on therapy as a "treatable traits" option for standard treatment for ACO.

Quantitative analysis of changes in lung density by dynamic chest radiography in association with CT values: a virtual imaging study and initial clinical corroboration.

Dynamic chest radiography (DCR) identifies pulmonary impairments as decreased changes in radiographic lung density during respiration (Δpixel values), but not as scaled/standardized computed tomography (CT) values. Quantitative analysis correlated with CT values is beneficial for a better understanding of Δpixel values in DCR-based assessment of pulmonary function. The present study aimed to correlate Δpixel values from DCR with changes in CT values during respiration (ΔCT values) through a computer-based phantom study. A total of 20 four-dimensional computational phantoms during forced breathing were created to simulate both CT and projection images of the same virtual patients. The Δpixel and ΔCT values of the lung fields were correlated on a regression line, and the inclination was statistically evaluated to determine whether there were significant differences among physical types, sex, and breathing methods. The resulting conversion expression was also assessed in the DCR images of 37 patients. The resulting Δpixel values for 30/37 (81%) real patients, 6/7 (86%) normal controls, and 24/30 (80%) chronic obstructive pulmonary disorder patients were within the range of ΔCT values ± standard deviation (SD) reported in a previous study. In addition, no significant differences were detected for each condition of thoracic breathing, suggesting that the same regression line inclination values measured across the entire lung can be used for the conversion of Δpixel values, providing a quantitative analysis that can be correlated with ΔCT values. The developed conversion expression may be helpful for improving the understanding of respiratory changes using radiographic lung densities from DCR-based assessments of pulmonary function.

Kinetic changes in serum KL-6 levels predict disease progression in patients with systemic sclerosis-associated interstitial lung disease.

BACKGROUND: The clinical course of patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD) is highly variable. The Krebs von den Lungen-6 (KL-6) glycoprotein is a promising biomarker for reflecting epithelial injury. However, serum KL-6 and its association with the progression of SSc-ILD have been understudied. METHODS: We reviewed 77 consecutive patients with SSc-ILD seen from 2004 to 2016. A longitudinal study of forced vital capacity (FVC), serum KL-6 levels, and changes in KL-6 levels from baseline (ΔKL-6) was conducted. The progression of ILD was defined as ≥10% relative decline in FVC predicted or 5%-10% decline in FVC predicted along with radiological progression on chest computed tomography. The risk factors for ILD progression were assessed by univariate and multivariate regression. RESULTS: During a 5-year follow-up period, 10 (13%) patients showed rapid progression of ILD within 2 years, 39 (51%) showed overall progression during the 5 years, and 28 (36%) had stable disease. Most patients with progressive ILD showed elevations in serum KL-6 levels over the initial 1-year follow-up period. The best cut-off value for ΔKL-6 that predicted progression of ILD was 193 U/mL (sensitivity 81.6%, specificity 92.9%). Multivariate analysis adjusted by age, sex, smoking status, and immunosuppressant use found that diffuse cutaneous SSc (hazard ratio [HR] 4.51; 95% confidence interval [CI] 1.56-13.04) and ΔKL-6 > 193 U/mL from baseline (HR 7.19; 95% CI 3.30-15.69) were independent predictors for progression of SSc-ILD. CONCLUSION: Changes in the KL-6 level can be useful for predicting disease progression in patients with SSc-ILD.

Antitussive Effect of a Chest Band in Patients with Interstitial Lung Disease: The Preliminary Results from a Pre-post Intervention Study.

Objective Evidence supporting the efficiency of clinically administered therapies against interstitial lung disease (ILD)-related cough is limited. Thus, we conducted a study to evaluate the efficacy of short-term use of chest bands on cough in patients with ILD. Methods This pre-post intervention study was performed at two university hospitals between April 2017 and August 2020. Scores of the visual analog scale (VAS) for cough severity (in terms of frequency and intensity), Leicester Cough Questionnaire (LCQ)-acute, and frequency scale for symptoms of gastroesophageal reflux disease (FSSG) were assessed before and after the use of the chest band (24/48 hours). Patients The study included patients with idiopathic interstitial pneumonias (IIPs) or connective tissue disease-associated interstitial lung disease (CTD-ILD). Results Four patients with IIPs and seven with CTD-ILD were included in the analysis. The cough intensity and LCQ-acute total score improved significantly after the use of the chest band (p=0.007 and p=0.005, respectively), although the cough frequency showed no significant reduction (p=0.074). Furthermore, the FSSG total and acid-reflux symptom scores improved (p=0.018 and p=0.027, respectively), and a negative correlation between the change in LCQ-acute total score and that in FSSG score for acid-reflux symptoms was observed (Spearman rho =-0.841, p=0.001). Conclusion The results of the current study suggest that chest bands might be useful for treating chronic refractory cough in patients with ILD and gastroesophageal reflux disease. However, these results should be interpreted with caution due to methodological limitations associated with this study.

[Paradigm Shift in Respiratory Diagnosis: Current Status and Future Prospects of Dynamic Chest Radiography].

Dynamic chest radiography (DCR) is a flat-panel detector (FPD) -based functional X-ray imaging, which is performed as an additional examination in chest radiography. The large field of view of FPDs permits real-time observation of motion/kinetic findings on the entire lungs, right and left diaphragm, ribs, and chest wall; heart wall motions; respiratory changes in lung density; and diameter of the intrathoracic trachea. Since the dynamic FPDs had been developed in the early 2000s, we focused on the potential of dynamic FPDs for functional X-ray imaging and have launched a research project for the development of an imaging protocol and digital image-processing techniques for the DCR. The quantitative analysis of motion/kinetic findings is helpful for a better understanding of pulmonary function, because the interpretation of dynamic chest radiographs is challenging and time-consuming for radiologists, pulmonologists, and surgeons. Recent clinical studies have demonstrated the usefulness of DCR combined with the digital image processing techniques for the evaluation of pulmonary function and circulation. Especially, there is a major concern in color-mapping images based on dynamic changes in radiographic lung density, where pulmonary impairments can be detected as color defects, even without the use of contrast media or radioactive medicine. Dynamic chest radiography is now commercially available for the use in general X-ray room and therefore can be deployed as a simple and rapid means of functional imaging in both routine and emergency medicine. This review article describes the current status and future prospects of DCR, which might bring a paradigm shift in respiratory diagnosis.

Dynamic chest radiography: clinical validation of ventilation and perfusion metrics derived from changes in radiographic lung density compared to nuclear medicine imaging.

BACKGROUND: Dynamic chest radiography (DCR) is a type of non-contrast-enhanced functional lung imaging with a dynamic flat-panel detector (FPD). This study aimed to assess the clinical significance of ventilation and perfusion metrics derived from changes in radiographic lung density on DCR in comparison to nuclear medicine imaging-derived metrics. METHODS: DCR images of 42 lung cancer patients were sequentially obtained during respiration using a dynamic FPD imaging system. For each subdivided lung region, the maximum change in the averaged pixel value (Δmax), i.e., lung density, due to respiration and cardiac function was calculated, and the percentage of Δmax relative to the total of all lung regions (Δmax%) was computed for ventilation and perfusion, respectively. The Δmax% was compared to the accumulation of radioactive agents such as Tc-99m gas and Tc-99m macro-aggregated albumin (radioactive agents%) on ventilation and perfusion scans in the subdivided lung regions, by Spearman's correlation coefficient (r) and the Dice similarity coefficients (DSC). To facilitate visual evaluation, Δmax% was visualized as a color scaling, where larger Δmax values were indicated by higher color intensities. RESULTS: We found a moderate correlation between Δmax% and radioactive agents% on ventilation and perfusion scans, with perfusion metrics (r=0.57, P<0.001) showing a higher correlation than ventilation metrics (r=0.53, P<0.001). We also found a good or strong correlation (r≥0.5) in 80.9% (34/42) of patients for perfusion metrics (r=0.60±0.16) and in 52.4% (22/42) of patients for ventilation metrics (r=0.53±0.16). DSC indicated a moderate correlation for both metrics. Decreased pulmonary function was observed in the form of reduced color intensities on color-mapping images. CONCLUSIONS: DCR-derived ventilation and perfusion metrics correlated reasonably well with nuclear medicine imaging findings in lung subdivisions, suggesting that DCR could provide useful information on pulmonary function without the use of radioactive contrast agents.

Airway Exposure to Polyethyleneimine Nanoparticles Induces Type 2 Immunity by a Mechanism Involving Oxidative Stress and ATP Release.

Polyethyleneimine (PEI) induced immune responses were investigated in human bronchial epithelial (hBE) cells and mice. PEI rapidly induced ATP release from hBE cells and pretreatment with glutathione (GSH) blocked the response. PEI activated two conductive pathways, VDAC-1 and pannexin 1, which completely accounted for ATP efflux across the plasma membrane. Moreover, PEI increased intracellular Ca2+ concentration ([Ca2+]i), which was reduced by the pannexin 1 inhibitor, 10Panx (50 µM), the VDAC-1 inhibitor, DIDS (100 µM), and was nearly abolished by pretreatment with GSH (5 mM). The increase in [Ca2+]i involved Ca2+ uptake through two pathways, one blocked by oxidized ATP (oATP, 300 µM) and another that was blocked by the TRPV-1 antagonist A784168 (100 nM). PEI stimulation also increased IL-33 mRNA expression and protein secretion. In vivo experiments showed that acute (4.5 h) PEI exposure stimulated secretion of Th2 cytokines (IL-5 and IL-13) into bronchoalveolar lavage (BAL) fluid. Conjugation of PEI with ovalbumin also induced eosinophil recruitment and secretion of IL-5 and IL-13 into BAL fluid, which was inhibited in IL-33 receptor (ST2) deficient mice. In conclusion, PEI-induced oxidative stress stimulated type 2 immune responses by activating ATP-dependent Ca2+ uptake leading to IL-33 secretion, similar to allergens derived from Alternaria.

Two cases of chronic obstructive pulmonary disease evaluated by dynamic-ventilatory digital radiography for pulmonary function and assessment of treatment efficacy.

Spirometry is a crucial test used in the diagnosis and monitoring of patients with chronic obstructive pulmonary disease (COPD). Severe acute respiratory syndrome coronavirus 2 pandemic has posed numerous challenges in performing spirometry. Dynamic-ventilatory digital radiography (DR) provides sequential chest radiography images during respiration with lower doses of radiation than conventional X-ray fluoroscopy and computed tomography. Recent studies revealed that parameters obtained from dynamic DR are promising for evaluating pulmonary function of COPD patients. We report two cases of COPD evaluated by dynamic-ventilatory DR for pulmonary function and treatment efficacy and discuss the potential of dynamic DR for evaluating COPD therapy.

Chest Dynamic-Ventilatory Digital Radiography in Chronic Obstructive or Restrictive Lung Disease.

OBJECTIVE: The aim of this study was to identify the relationships between parameters obtained from dynamic-ventilatory digital radiography (DR) and ventilatory disorders. METHODS: This study comprised 273 participants with respiratory diseases who underwent spirometry and functional residual capacity measurements (104 with normal findings on spirometry as controls, 139 with an obstructive lung disorder, 30 with a restrictive lung disorder) were assessed by dynamic-ventilatory DR. Sequential chest radiography images of the patient's slow and maximum breathing were captured at 15 frames per second by a dynamic flat-panel imaging system. The system measured the following parameters: lung area at maximum inspiration divided by height (lung area_in/height), changes in tracheal diameter due to respiratory motions, rate of tracheal narrowing, diaphragmatic motion, and rate of change in lung area due to respiratory motion. Relationships between these parameters and ventilatory disorders were analyzed. RESULTS: Lung area_in/height in patients with restrictive disorders showed significant decreases. Tracheal diameter change and tracheal narrowing rate in patients with obstructive disorders were significantly increased compared to both the control participants and patients with restrictive disorders. Patients with obstructive disorders and patients with restrictive disorders showed decreased diaphragmatic motion and lung area change rate. With the restrictive disorders as references, the area under the curve (AUC), sensitivity and specificity of lung area_in/height were 0.88, 0.77, and 0.88, respectively. With the obstructive disorders as references, the AUC, sensitivity and specificity of tracheal narrowing rate were 0.67, 0.53 and 0.81, respectively. CONCLUSION: Dynamic-ventilatory DR shows potential as a method for the detection and evaluation of ventilatory disorders in patients with respiratory diseases.

Late-onset programmed cell death protein-1 inhibitor-induced pneumonitis after cessation of nivolumab or pembrolizumab in patients with advanced non-small cell lung cancer: a case series.

Awareness of the immune-related adverse event of programmed cell death protein-1 (PD-1) inhibitor-induced pneumonitis is important. Herein, we report the clinical course of 3 patients suspected to have PD-1 inhibitor-induced pneumonitis after cessation of PD-1 inhibitor treatment. In case 1, a 62-year-old man was diagnosed with stage IVA adenocarcinoma. Nivolumab monotherapy was prescribed as second-line therapy and later discontinued due to financial reasons. Seven months after the final administration of nivolumab, the patient developed what we diagnosed as nivolumab-induced pneumonitis. The patient was immediately prescribed prednisolone (1 mg/kg p.o. daily), and the pneumonitis resolved after 1.5 months. In case 2, a 68-year-old man was diagnosed with stage IVB squamous cell carcinoma. Nivolumab monotherapy was prescribed as fourth-line therapy. After the second administration of nivolumab, the patient developed what we diagnosed as nivolumab-induced pneumonitis; nivolumab was discontinued, and the patient was immediately prescribed prednisolone (1 mg/kg p.o. daily). Eight months after the final administration of nivolumab, the patient again developed nivolumab-induced pneumonitis. The pneumonitis resolved without additional medication. In case 3, a 69-year-old man was diagnosed with stage IVB adenocarcinoma. Pembrolizumab monotherapy was initiated as sixth-line therapy, and it was discontinued after 4 cycles due to disease progression. Four months after the final dose of pembrolizumab, the patient developed what we diagnosed as pembrolizumab-induced pneumonitis. The patient immediately received a high intravenous dose of methylprednisolone (1,000 mg per day for three days). The pneumonitis and respiratory failure progressed, and he died 8 weeks after the onset of the pneumonitis. We report pneumonitis after discontinuation of ICIs in 3 patients. We confirm that, although uncommon, PD-1 inhibitor-induced irAEs can develop after treatment discontinuation. Further accumulation of cases and clarification of the clinical features of patients with irAEs, such as the time of onset, imaging findings, and treatment outcomes are needed.

Molecular features of tumor-derived genetic alterations in circulating cell-free DNA in virtue of autopsy analysis.

In cancer patients, circulating cell-free DNA (cfDNA) includes tumor-derived DNA (tDNA). cfDNA has been used clinically for non-invasive gene mutation testing. The aim of this study was to characterize the features of the genetic alterations detected in cfDNA. This study included 6 patients with primary lung cancer who died due to cancer progression. Tumors were biopsied at autopsy. Genetic alteration profiles were obtained using next generation sequencing. The features of the tDNA genetic alterations detected in cfDNA included a higher frequency of being present in multiple tumors (67% truncal mutations, 36% shared mutations, and 4% individual mutations) and a higher variant allele frequency (VAF; 47.6% versus 4.1% for tDNA alterations detected in cfDNA versus not detected in cfDNA, respectively). The data revealed that the tumor-derived genetic alterations most easily detected in cfDNA were truncal mutations with a high VAF. These results showed that essential genetic alterations enriched in cfDNA could help to characterize cancer cells and that genetic testing using cfDNA has advantages in the detection of fundamental regulatory aberrations occurring during tumorigenesis.