Efficacy of dupilumab for severe chronic rhinosinusitis with nasal polyps and asthma: A prospective study.

BACKGROUND: Dupilumab exerts clinical effects, including improved sinus opacification, olfactory function, and quality of life, in patients with severe chronic rhinosinusitis with nasal polyps (CRSwNP). Meanwhile, only a few studies have reported its effects on nasal airway resistance and olfactory function, particularly in the Japanese population. Predictors of response remain unclear. OBJECTIVE: In this prospective, observational study, we assessed the comprehensive efficacy and therapeutic response to dupilumab in severe CRSwNP patients with comorbid asthma. METHODS: In 16 adult severe CRSwNP patients with comorbid asthma, the efficacy of 48-week dupilumab treatment, including olfactory function measured by a T&T olfactometer, nasal airway resistance measured by rhinomanometry, nasal polyp score, Lund-Mackay computed tomography score (LMS), and 22-item Sinonasal Outcome Test (SNOT-22), was assessed. Regarding asthma, the annualized rate of exacerbations, 7-item Asthma Control Questionnaire (ACQ-7), and spirometry were assessed. Treatment responsiveness was analyzed. RESULTS: With 48-week dupilumab treatment, olfactory function, nasal airway resistance, nasal polyp score, LMS, and SNOT-22 scores improved significantly. Regarding comorbid asthma, the rate of exacerbations decreased, and ACQ-7 scores and lung function improved significantly. According to the European Position Paper on Rhinosinusitis and Nasal Polyps 2022/European Forum for Research and Education in Allergy and Airway Diseases criteria, 15 patients (94%) were moderate-to-excellent responders at 48 weeks of treatment. Patients with higher SNOT-22 scores, ACQ-7 scores, rates of asthma exacerbation in the previous year, and blood eosinophil counts benefited more from treatment. CONCLUSION: Dupilumab improved upper and lower airway outcomes especially in severe CRSwNP patients with comorbid, poorly controlled asthma.

Prevalence and clinical relevance of comorbid pertussis infection in adult patients with asthma: A prospective, cross-sectional study.

BACKGROUND: Viral or atypical bacterial respiratory infections are involved in the new development and the pathogenesis of asthma. Though an association between pertussis and asthma has been expected, few studies have reported it consistently. We assessed the prevalence and clinical relevance of pertussis infection in adult patients with asthma. METHODS: In this prospective, cross-sectional study, newly referred, adult patients with asthma (n = 107) and with non-asthmatic subacute/chronic cough (n = 31) were enrolled. The prevalence of pertussis in patients with asthma and in those with non-asthmatic subacute/chronic cough was assessed. Next, the prevalence of newly diagnosed asthma was compared between asthmatic patients with and without pertussis. Finally, demographic characteristics of patients, blood test results, pulmonary function test results, and questionnaire scores were compared between the two patient groups. RESULTS: The prevalence of pertussis infection was significantly higher in patients with asthma than in those with non-asthmatic subacute/chronic cough (36% vs 10%; P = 0.004). The prevalence of newly diagnosed asthma was significantly higher in asthmatic patients with pertussis than in those without (74.4% vs 50.0%; P = 0.014). The physical, psychological, and total scores of the Leicester Cough Questionnaire were significantly lower in asthmatic patients with pertussis than in those without (all P < 0.05). The acid-reflux, dyspeptic, and total scores of the Frequency Scale for Symptoms of Gastroesophageal Reflux Disease (GERD) (FSSG) were significantly higher in asthmatic patients with pertussis than in those without (all P ≤ 0.05). The FSSG acid-reflux score was negatively correlated with the cough-specific quality of life (QOL) score only in asthmatic patients with pertussis (rho = -0.68, P = 0.01). CONCLUSIONS: The prevalence of pertussis infection was significantly higher in adult patients with asthma than in those with non-asthmatic subacute/chronic cough. In patients with asthma, comorbid pertussis infection may play a role in newly diagnosed asthma and may contribute to impaired cough-specific QOL partly due to worsening acid-reflux symptoms of GERD.

A rare case of a huge malignant pleural mesothelioma presenting in the posterior mediastinum.

We report a case of a 69-year-old woman with pleural mesothelioma presenting in the posterior mediastinum with a maximum diameter of 25 cm. She had a chronic cough and a pleural effusion was noted on chest X-ray. The examination of the effusion showed high hyaluronic acid levels, and mesothelioma was suspected. A chest computed tomography scan showed a huge mediastinal mass, which caused rapid progression of respiratory failure and compression of the heart. Sufficient tissue samples could not be obtained before death. The patient died approximately 1 month after the initial visit, and a pathological autopsy was performed. The diagnosis of malignant pleural mesothelioma was made. Malignant pleural mesothelioma with a huge posterior mediastinal mass such as in this case is considerably rare; however, it is a rapidly progressing form of the disease and is reported here as an important differential diagnosis for mediastinal tumours.

Comorbid functional dyspepsia reflects IL-33-mediated airway neuronal dysfunction in asthma.

BACKGROUND: Neuronal dysfunction is implicated in the pathophysiology of asthma and functional dyspepsia (FD). However, the relationship between these diseases remains unclear. OBJECTIVE: This study aimed to clarify the clinical implications of comorbid FD in asthma and to explore the unified pathway between asthma and FD by focusing on airway neuronal dysfunction. METHODS: Clinical indices and biomarkers, including capsaicin cough sensitivity (C-CS), were compared between patients with asthma with and without FD. C-CS was determined on the basis of capsaicin concentration that induced at least 2 coughs (C2) or 5 coughs (C5). Additionally, the associations of airway inflammation with airway innervation and gastrointestinal motility were evaluated in mouse models of type 2 airway inflammation. RESULTS: Patients with asthma with FD had worse asthma control and cough severity and lower C2 and C5 thresholds than those without FD. The severity of FD symptoms was negatively correlated with C2 and C5 thresholds. FD and poor asthma control were predictors of heightened C-CS (defined as C5 ≤ 2.44 µmol) in asthma. A mouse model of papain-induced airway inflammation developed airway hyperinnervation and gastrointestinal dysmotility, and both pathologies were ameliorated by an anti-IL-33 antibody. Moreover, papain-induced gastrointestinal dysmotility was mitigated by silencing the airway sensory neurons using QX-314, a sodium channel blocker. Furthermore, sputum IL-33 levels were significantly elevated in patients with asthma with FD or heightened C-CS compared to their counterparts. CONCLUSION: FD is significantly associated with airway neuronal dysfunction in asthma. IL-33-mediated airway neuronal dysfunction may contribute to the interaction between asthma and FD.

Efficacy of dupilumab for airway hypersecretion and airway wall thickening in patients with moderate-to-severe asthma: A prospective, observational study.

BACKGROUND: Dupilumab has clinical effects in patients with moderate-to-severe asthma. When considering interleukin (IL)-4 and IL-13 signaling, effects of dupilumab on airway mucus hypersecretion and airway remodeling are expected, but they have been reported in only a few short-term studies. Its efficacy for airway hyperresponsiveness (AHR) remains unknown. We comprehensively assessed the efficacy of dupilumab, especially for subjective and objective measures of airway mucus hypersecretion and airway dimensions in moderate-to-severe asthmatic patients. METHODS: In 28 adult patients with moderate-to-severe uncontrolled asthma, the comprehensive efficacy of 48-week dupilumab treatment, including the Cough and Sputum Assessment Questionnaire (CASA-Q), radiological mucus scores and airway dimensions on computed tomography (CT), was assessed prospectively. Treatment responsiveness to dupilumab was analyzed. RESULTS: With 48-week dupilumab treatment, all four cough and sputum domain scores of CASA-Q improved significantly. Radiological mucus scores and airway wall thickening on CT were significantly decreased. The decreases in mucus scores were significantly associated with improvements in Asthma Control Questionnaire scores, Asthma Quality of Life Questionnaire (AQLQ) overall scores, airway obstruction, and airway type 2 inflammation. When defined by > 0.5 improvement in AQLQ overall scores, 18 patients (64%) were identified as responders. CONCLUSIONS: Dupilumab reversed subjective and objective measures of airway mucus hypersecretion and some aspects of airway remodeling in patients with moderate-to-severe uncontrolled asthma.

Low Daily Step Count Associated with Small Erector Spine Muscle Area and Sarcopenia in Idiopathic Pulmonary Fibrosis.

Objective The daily step count is associated with mortality in idiopathic pulmonary fibrosis (IPF). However, the factors associated with this phenomenon are not yet fully understood. We therefore clarified its association with clinical parameters. Methods Fifty-nine patients with IPF with available data for daily step counts; 6-minute walk distance (6MWD); chest, abdominal, and pelvic computed tomography (CT); pulmonary function; psychological evaluations; and sarcopenia assessments were prospectively enrolled. The daily step count was measured continuously for seven consecutive days. The cross-sectional areas of the erector spinae muscles at the level of the 12th vertebra (ESMCSA) and psoas major muscle volume (PMV) obtained by CT were assessed. Results The average age of the patients was 73.3±8.1 years old, and the percent predicted forced vital capacity was 81.6% ±15.8%. The average daily step count was 4,258 (2,155-6,991) steps. The average 6MWD, ESMCSA, and PMV were 413±97 m, 25.5±6.7 cm2, and 270±75.6 cm3, respectively. A linear regression analysis for daily step count showed that the ESMCSA and 6MWD were independent factors for the daily step count, whereas the PMV and skeletal muscle index were not. The daily step count, ESMCSA, and 6MWD were lower in patients with sarcopenia than in those without sarcopenia. Conclusions A lower daily step count was associated with a smaller erector spinae muscle area and sarcopenia in patients with IPF. Further studies are warranted to confirm the importance of physical therapy for muscle strengthening in patients with IPF.

Bronchial thermoplasty improves cough hypersensitivity and cough in severe asthmatics.

BACKGROUND: Cough is a troublesome symptom of asthma because it is associated with disease severity and poor asthma control. Bronchial thermoplasty (BT) may be effective in improving cough severity and cough-related quality of life in severe uncontrolled asthma. OBJECTIVE: To evaluate the efficacy of BT for cough in severe uncontrolled asthma. METHODS: Twelve patients with severe uncontrolled asthma were enrolled in this study between 2018 May and March 2021 and arbitrarily divided into cough-predominant [cough severity Visual Analog Scale (VAS) ≥ 40 mm, n = 8] and typical asthma (cough VAS <40 mm, n = 4) groups. Clinical parameters, such as capsaicin cough sensitivity [C-CS: the concentrations to inhaled capsaicin required to induce at least two (C2) and five (C5) coughs], lung function, and type-2-related biomarkers (fractional nitric oxides and absolute eosinophil counts) and cough-related indices [cough severity VAS and the Leicester Cough Questionnaire (LCQ)] were evaluated before and 3 months after performing BT. RESULTS: BT significantly improved both cough-related indices and C-CS in the cough-predominant group. Changes in C-CS were significantly correlated with changes in the LCQ scores (C5: r = 0.65, p = 0.02 for all patients, and r = 0.81, p = 0.01 for the cough-predominant group). CONCLUSIONS: BT may be effective for cough in severe uncontrolled asthma by improving C-CS. However, further larger cohort studies are necessary to confirm the effect of BT for cough in asthma. CLINICAL TRIAL REGISTRATION: This study was registered in the UMIN Clinical Trials Registry (Registry ID UMIN: 000031982).

Tiotropium for refractory cough in asthma via cough reflex sensitivity: A randomized, parallel, open-label trial.

BACKGROUND: We previously reported in an uncontrolled study that tiotropium alleviated chronic cough in asthma refractory to inhaled corticosteroids and long-acting ß2 agonists (ICS/LABA) by modulating capsaicin cough reflex sensitivity (C-CRS). OBJECTIVE: We sought to determine the antitussive effects of tiotropium for refractory cough in asthma in a randomized, parallel, open-label trial. METHODS: A total of 58 patients with asthma having chronic cough refractory to ICS/LABA were randomized in a 2:1 ratio to add tiotropium 5 µg (39 patients) or theophylline 400 mg (19 patients) for 4 weeks. Patients underwent workups, including capsaicin cough challenge test and subjective measures such as cough severity visual analog scales (VAS). We adopted C5, the lowest capsaicin concentration to induce at least 5 coughs, as an index of C-CRS. We also performed a posthoc analysis to identify factors predicting tiotropium responders, who found an improvement of at least 15 mm in cough severity VAS. RESULTS: A total of 52 patients (tiotropium, 38; theophylline, 14) completed the study. Both tiotropium and theophylline significantly improved cough severity VAS and cough-specific quality of life. Tiotropium, but not theophylline, significantly increased C5, whereas pulmonary function did not change in either group. In addition, changes in cough severity VAS correlated with changes in C5 values in the tiotropium group. A posthoc analysis revealed that heightened C-CRS (C5 ≤1.22 µM) before the addition of tiotropium was an independent predictor for tiotropium responders. CONCLUSION: Tiotropium may alleviate chronic cough in asthma refractory to ICS/LABA by modulating C-CRS. Heightened C-CRS may predict responsiveness to tiotropium for refractory cough in asthma. TRIAL REGISTRATION: Clinical Trials Registry ID: UMIN000021064 (https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000024253).

Targeting the interleukin-5 pathway improves cough hypersensitivity in patients with severe uncontrolled asthma.

BACKGROUND: Capsaicin cough sensitivity (C-CS) reflects airway neuronal dysfunction and may be a significant biomarker of asthma. Although mepolizumab reduces cough in patients with severe uncontrolled asthma, it is unclear whether the cough reduction is associated with improved C-CS. OBJECTIVE: To clarify the effect of biologics on C-CS and cough-specific quality of life (QoL) in patients with severe uncontrolled asthma using our previous study cohort. METHODS: Overall, 52 consecutive patients who visited our hospital for severe uncontrolled asthma were included in the original study cohort, and 30 patients were eligible for this study. Changes in C-CS and cough-specific QoL were compared between patients treated with the anti-interleukin-5 (IL-5) pathway (n = 16) and those treated with other biologics (n = 14). The C-CS was measured as the concentration of capsaicin required to induce at least 5 coughs. RESULTS: Biologics significantly improved C-CS (P = .03). Anti-IL-5 pathway therapies significantly improved C-CS, whereas other biologics did not (P < .01 and P = .89, respectively). The C-CS improved significantly more in the anti-IL-5 pathway group than in the group treated with other biologics (P = .02). Changes in C-CS significantly correlated with improvements in cough-specific QoL in the anti-IL-5 pathway group (r = 0.58, P = .01) but not in the group treated with other biologics (r = 0.35, P = .22). CONCLUSION: Anti-IL-5 pathway therapies improve C-CS and cough-specific QoL, and targeting the IL-5 pathway may be a therapeutic strategy for cough hypersensitivity in patients with severe uncontrolled asthma.

Specific IgE Response and Omalizumab Responsiveness in Severe Allergic Asthma.

Objective: Omalizumab has demonstrated clinical efficacy in patients with severe allergic asthma sensitized to perennial allergens and/or severe pollinosis through inhibition of IgE-dependent allergic response. When considering the "one airway, one disease" concept, sensitization to pollen could predict responsiveness to omalizumab. This study aimed to assess whether the pretreatment specific IgE response could be a predictor of responsiveness to omalizumab in severe allergic asthma sensitized to perennial allergens. Methods: In this retrospective study, 41 adult patients with severe allergic asthma sensitized to perennial allergens (27 females; mean age 59 years) who had completed 52-week omalizumab treatment were enrolled. The Global Evaluation of Treatment Effectiveness was performed, and demographic characteristics and the positive ratios of specific IgE responses classified into five subgroups (pollen, dust mite, house dust, mold, and animal dander) were compared between responders and non-responders. Multivariate logistic regression analyses were performed to identify predictors of responsiveness to omalizumab. Results: Thirty-one patients (76%) were identified as responders. The number of sensitized aeroallergen subgroups and sensitization to pollens were significantly higher in responders than in non-responders (both p<0.05). Multivariate logistic regression analysis showed that sensitization to pollen (OR = 8.41, p = 0.02) was independently associated with the effectiveness of omalizumab. Conclusion: Pretreatment serum pollen-specific IgE could be a predictor of responsiveness to omalizumab.

Decreased capsaicin cough reflex sensitivity predicts hospitalisation due to COPD.

INTRODUCTION: Patients with chronic obstructive pulmonary disease (COPD) are often hospitalised due to severe acute exacerbation (AE) or community-acquired pneumonia (CAP). Previous studies revealed the association of cough reflex sensitivity with the pathophysiology of COPD and pneumonia. We hypothesised that cough reflex sensitivity may be associated with severe AE or CAP requiring hospitalisation in patients with COPD. METHODS: We prospectively recruited 68 patients with COPD between June 2018 and January 2020. Patient characteristics, lung and cardiac functions, and biomarkers, including capsaicin cough reflex sensitivity and blood eosinophil count, were evaluated at enrolment. All participants were monitored for AE or CAP requiring hospitalisation for 12 months. We determined the risk factors and ORs for hospitalisation in patients with COPD using a multivariate analysis. RESULTS: Eight patients experienced AE (n=3) or CAP (n=5) and required hospitalisation during follow-up. Patients in the hospitalisation+ group had higher modified Medical Research Council scores and blood eosinophil counts (≥300 µL) than those in the hospitalisation- group. Capsaicin cough reflex sensitivity tended to decrease in the hospitalisation+ group compared with that in the hospitalisation- group. Multivariate analysis revealed that a decreased capsaicin cough reflex and high eosinophil count (≥300 µL) were predictive risk factors for future hospitalisation due to AE-COPD or CAP. CONCLUSION: In addition to eosinophils, decreased capsaicin cough reflex sensitivity was associated with hospitalisation due to AE-COPD or CAP. Capsaicin cough reflex sensitivity in patients with COPD may play a role in the prevention of severe AE or pneumonia requiring hospitalisation. TRIAL REGISTRATION NUMBER: UMIN000032497.

Tracheal Glomus Tumor Complicated with Asthma Exacerbation in a Pregnant Woman.

A 34-year-old pregnant woman in the 34th week of gestation with uncontrolled asthma was admitted because of asthma exacerbation. Although she received bronchodilators and systemic corticosteroids, respiratory failure rapidly progressed. Chest computed tomography revealed a mass occluding approximately 80% of the tracheal lumen. After urgent Caesarean section, endobronchial resection was performed. The pathological findings of the resected tumor were compatible with tracheal glomus tumor. Tracheal tumors are often misdiagnosed as asthma, but its complication with asthma is rare. Even if the diagnosis of asthma is definitive, clinicians should consider coexisting diseases, including tracheal tumors, when asthma control is poor.

Functional gastrointestinal disorders are associated with capsaicin cough sensitivity in severe asthma.

BACKGROUND: Although sensory nerve dysfunction is related to the pathology of severe uncontrolled asthma and functional gastrointestinal disorders (FGIDs), the impact of comorbid FGIDs on the pathophysiology of severe uncontrolled asthma remains poorly understood. The aim was to clarify the physiological relationships between severe uncontrolled asthma and FGIDs. METHODS: Fifty-two patients with severe uncontrolled asthma who visited our hospital between September 2016 and August 2019 were retrospectively analyzed. Clinical characteristics, other comorbidities including gastroesophageal reflux disease (GERD), and biomarkers such as fractional nitric oxide (FeNO) and capsaicin cough sensitivity (C-CS) before the beginning of biologics or bronchial thermoplasty, were compared between patients with and without comorbid FGIDs. C-CS was evaluated by C5 (concentration of inhaled capsaicin that induced five or more coughs), and C5 ≤2.44 µM was defined as heightened C-CS. RESULTS: Seventeen patients had comorbid FGIDs. These patients had a lower FeNO level (21.9 ± 1.7 ppb vs. 33.9 ± 2.8 ppb, P = 0.04), a lower C5 threshold (2.24 ± 2.88 µM vs. 8.91 ± 5.5 µM, P < 0.001), a higher prevalence of comorbid GERD (64.7% vs. 31.7%, P = 0.03), and a higher prevalence of heightened C-CS (70.6% vs. 28.6%, P = 0.007) than those without FGIDs. Analysis of covariance showed a significant effect of FGIDs on C-CS in severe uncontrolled asthma without being affected by GERD. CONCLUSIONS: Comorbid FGIDs are associated with heightened C-CS in patients with severe uncontrolled asthma, and they may be an important extra-respiratory manifestation of the airway neuronal dysfunction phenotype of severe uncontrolled asthma.

SARC-F scores can predict health status and daily activity in patients with idiopathic pulmonary fibrosis.

Background: The strength, assistance in walking, rising from a chair, climbing stairs, and falls questionnaire (SARC-F) is widely used for screening sarcopenia. We aimed to examine the association of SARC-F scores with the measurements of quality of life and activity in patients with idiopathic pulmonary fibrosis (IPF). Methods: This cross-sectional pilot study prospectively enrolled 54 patients with IPF who completed pulmonary function tests, the 6-min walk test, the chronic obstructive pulmonary disease assessment test (CAT), St. George's Respiratory Questionnaire (SGRQ), the Hospital Anxiety and Depression Scale, and a daily step count. The daily step count was measured continuously for 7 consecutive days using a tri-axis accelerometer device. Results: The mean age was 73.6±7.9 years and the mean percent predicted forced vital capacity was 80.4%±15.6%. The median [interquartile range] SARC-F score, SGRQ total scores, and CAT scores were 2 [1-3.25], 28.8 [14.4-46.9], and 13 [7-22], respectively. SARC-F scores were correlated with the percent predicted forced vital capacity (r=-0.51, P<0.001), CAT score (r=0.57, P<0.001), SGRQ total score (r=0.77, P<0.001), Hospital Anxiety and Depression Scale anxiety score (r=0.31, P=0.025), and Hospital Anxiety and Depression Scale depression score (r=0.28, P=0.041). Linear regression analyses revealed that the 6-minute walk test (6MWT) (standardized ß=0.33, P=0.011) and SARC-F score (standardized ß=-0.39, P=0.005), but not the CAT score and SGRQ total score, were significant predictors for daily step count. Conclusions: SARC-F scores were correlated with health status and daily activity in patients with IPF. Further studies are warranted to validate the utility of the SARC-F in patients with IPF.

Erratum: Change original to "Characteristics of the European Thoracic Society/American Thoracic Society severe asthma definition as a determinant of future use of biologics/bronchial thermoplasty".

[This corrects the article e13 in vol. 12, PMID: 35571548.].

Residual Dyspnea May Predict Small Airways Dysfunction and Poor Responsiveness to Single-Inhaler Triple Therapy in Asthmatic Patients.

Purpose: Recently, single-inhaler triple therapy (SITT) has demonstrated efficacy in patients with uncontrolled asthma who were symptomatic despite treatment with inhaled corticosteroids/long-acting ß2 agonists. However, the characteristics of patients who benefit from SITT remain unclear in the real-world. The aim of this study was to examine the predictors of responsiveness to SITT in patients with asthma. Patients and Methods: A total of 45 patients with asthma who had regularly visited our respiratory clinic and were started on SITT from March 2019 to March 2021 were retrospectively analyzed. Patients' demographic characteristics, residual respiratory symptoms, type 2 biomarkers, and lung function before SITT were assessed from the patients' medical records. Predictors of responsiveness to four-week SITT were evaluated in these patients. The definition of responders was based on the physician-assessed global evaluation of treatment effectiveness. Results: Thirty-four (75%) of 45 patients were identified as responders to SITT. Non-responders showed significantly lower forced vital capacity (FVC) (%predicted) values, and complained of dyspnea more frequently than responders before SITT (p = 0.01 and p = 0.02, respectively). There were no significant differences in demographic characteristics and type 2 biomarkers between responders and non-responders. Clinical predictors of poor response to SITT were residual dyspnea (OR = 0.14, p = 0.02), low FVC (%predicted) values (OR = 1.05, p = 0.01), and FVC (%predicted) <80% (OR = 0.11, p = 0.02). Multivariate analysis showed that poor response to SITT was associated with residual dyspnea before SITT (OR = 0.14, p = 0.02). On the other hand, patients with residual dyspnea had significantly lower FEF25-75 (%predicted) values than patients without residual dyspnea before SITT (p = 0.04). Conclusion: Residual dyspnea, reflecting small airways dysfunction, may predict poor responsiveness to short-term SITT in patients with asthma.

Pathophysiological conditions induced by SARS-CoV-2 infection reduce ACE2 expression in the lung.

SARS-CoV-2 infection causes a variety of physiological responses in the lung, and understanding how the expression of SARS-CoV-2 receptor, angiotensin-converting enzyme 2 (ACE2), and its proteolytic activator, transmembrane serine protease 2 (TMPRSS2), are affected in patients with underlying disease such as interstitial pneumonia will be important in considering COVID-19 progression. We examined the expression of ACE2 and TMPRSS2 in an induced usual interstitial pneumonia (iUIP) mouse model and patients with IPF as well as the changes in whole-lung ACE2 and TMPRSS2 expression under physiological conditions caused by viral infection. Histopathological and biochemical characteristics were analyzed using human specimens from patients with IPF and precision-cut lung slices (PCLS) from iUIP mouse model showing UIP with honeycombing and severe fibrosis after non-specific interstitial pneumonia. ACE2 expression decreased with acute lung inflammation and increased in the abnormal lung epithelium of the iUIP mouse model. ACE2 is also expressed in metaplastic epithelial cells. Poly(I:C), interferons, and cytokines associated with fibrosis decreased ACE2 expression in PCLS in the iUIP model. Hypoxia also decreases ACE2 via HIF1α in PCLS. Antifibrotic agent, nintedanib attenuates ACE2 expression in invasive epithelial cells. Patients with IPF are at a higher risk of SARS-CoV-2 infection due to the high expression of ACE2. However, ACE2 and TMPRSS2 expression is decreased by immune intermediaries, including interferons and cytokines that are associated with viral infection and upon administration of antifibrotic agents, suggesting that most of the viral infection-induced pathophysiological responses aid the development of resistance against SARS-CoV-2 infection.

An autopsy case of immune-related severe colitis due to long-term use of nivolumab in a patient with non-small cell lung cancer.

Immune checkpoint inhibitors (ICIs) have been developed as cornerstones of cancer therapy, but the growing use of ICIs has induced immune-related adverse effects (irAEs). Immune-related colitis, which is one of the most common irAEs, generally occurs 2-4 months after ICI treatment initiation and can be life threatening. Therefore, early diagnosis and appropriate management are required. A rare autopsy case of nivolumab-related severe colitis that occurred 34 months after the start of treatment and recurred despite temporal remission with corticosteroids and infliximab is presented. Physicians should be aware of the possibility of late-onset irAEs in patients on receiving long-term ICI treatment.

Frequency and impact on clinical outcomes of sarcopenia in patients with idiopathic pulmonary fibrosis.

OBJECTIVES: Sarcopenia is a syndrome characterized by reduced muscle mass and function. It is well-recognized as a complication in chronic diseases such as chronic obstructive pulmonary disease. However, little is known about sarcopenia in patients with idiopathic pulmonary fibrosis (IPF). This study aimed to investigate the clinical characteristics of sarcopenia and the association between quality of life and sarcopenia in patients with IPF. METHODS: In this pilot cross-sectional study, 56 Japanese outpatients with IPF (49 men) were enrolled prospectively. Sarcopenia was diagnosed according to the criteria of the Asian Working Group for Sarcopenia 2019. Its associations with clinical parameters including age, pulmonary functions, physical performance, and patient-reported outcomes (PROs) were examined. RESULTS: The frequency of sarcopenia was 39.3% (n = 22) in this cohort. There were significant differences in St George's Respiratory Questionnaire (p = .005), modified Medical Research Council score (p = .004), and Hospital and Anxiety Depression Scale depression score (p = .030) between the sarcopenic and non-sarcopenic groups. On multivariate regression analysis, 6-min walk distance (6MWD) was an independent factor associated with sarcopenia (odds ratio 1.241, 95% confidence interval 1.016-1.515, p = .034). CONCLUSION: Sarcopenia was associated with PROs and physical performance in patients with IPF.