Immune checkpoint inhibitors in patients with lung cancer having chronic interstitial pneumonia.

Background: In interstitial pneumonia (IP)-associated lung cancer, immune checkpoint inhibitor pneumonitis (ICIP) is common with immune checkpoint inhibitor (ICI) treatment. The purpose of the present study was to clarify the safety and efficacy of ICI treatment for patients with lung cancer with IP. Methods: This multicentre retrospective observational study was conducted from June 2016 to December 2020 in patients with primary lung cancer with IP who received ICI treatment. Results: A total of 200 patients (median age 70 years; male/female, 176/24) were enrolled from 27 institutions. ICIP occurred in 61 patients (30.5%), pneumonitis grades 3-5 in 32 patients (15.5%) and death in nine patients (4.5%). The common computed tomography pattern of ICIP was organising pneumonia in 29 patients (47.5%). Subsequently, diffuse alveolar damage (DAD) pattern was observed in 19 patients (31.1%) who had a significantly worse prognosis than those with a non-DAD pattern (median progression-free survival (PFS) 115 days versus 226 days, p=0.042; median overall survival (OS) 334 days versus 1316 days, p<0.001). Immune-related adverse events (irAEs) occurred in approximately 50% of patients. Patients with irAEs (n=100) had a better prognosis than those without irAEs (n=100) (median PFS 200 days versus 77 days, p<0.001; median OS 597 days versus 390 days p=0.0074). The objective response rate and disease control rate were 41.3% and 68.5%, respectively. Conclusions: Although ICI treatment was effective for patients with lung cancer with IP, ICIP developed in approximately 30% of patients. Patients with irAEs had a significantly better PFS and OS than those without irAEs.

Neutrophil-to-Lymphocyte Ratio in Acute Exacerbation of Idiopathic Pulmonary Fibrosis.

BACKGROUND: This study aimed to clarify the prognostic value of the neutrophil-to-lymphocyte ratio (NLR) in patients with acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF). METHODS: Eighty-six patients diagnosed with AE-IPF were included in this single-center retrospective study. The NLR was calculated by dividing the peripheral neutrophil count by the peripheral lymphocyte count. The cut-off values of the NLR for predicting 90-day survival were determined using receiver operating characteristic curve analysis. Oxygenation deterioration on days 4 and 8 relative to that on day 1 was clinically defined. The prognostic value of NLR was evaluated using Cox proportional hazard regression analysis. RESULTS: The cut-off value of day-1, day-4, and day-8 NLRs for predicting 90-day survival was 12.13, 14.90, and 10.56, respectively. A higher day-1 NLR was a significant predictor of a poor prognosis in univariate and multivariate analyses. Survival was significantly better in patients without oxygenation deterioration on days 4 and 8 than in those with deterioration. Day-4 and day-8 NLR could predict 90-day survival in patients without oxygenation deterioration. CONCLUSIONS: Day-1 NLR was a useful predictor of 90-day survival in AE-IPF. Further, monitoring day-4 and day-8 NLRs and evaluating oxygenation deterioration may be useful for managing AE-IPF.

A Case of Lymphangioleiomyomatosis Showing the Development of Mycobacterium abscessus subsp. massiliense Infection During Sirolimus Therapy.

Among nontuberculous mycobacterial pulmonary diseases (NTM-PDs), Mycobacterium abscessus species pulmonary disease (MABS-PD) is one of the most severe and intractable infections. We herein report a 45-year-old woman with advanced lymphangioleiomyomatosis (LAM) who developed MABS-PD while undergoing sirolimus therapy. MABS-PD was immediately controlled using antibiotic therapy, although the patient's lung transplant registration was significantly delayed. To our knowledge, this is the first case report on the development of NTM-PD in a patient with LAM before lung transplantation. This case suggests that the early diagnosis and optimal treatment of NTM-PD are crucial in patients with advanced LAM.

Autoimmune Pulmonary Alveolar Proteinosis Complicated by Myelodysplastic Syndrome: A Case Report.

Pulmonary alveolar proteinosis (PAP) is characterized by an abnormal surfactant accumulation in peripheral air spaces. Autoimmune PAP (APAP) results from macrophage dysfunction caused by anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibodies, and the presence of antibodies more than the cutoff value is specific for APAP. In contrast, secondary PAP (SPAP) does not require anti-GM-CSF autoantibodies and is complicated by other diseases, including myelodysplastic syndrome (MDS). A 73-year-old man with anemia and thrombocytopenia was diagnosed with APAP and MDS simultaneously. The measurement of serum anti-GM-CSF autoantibodies is important for the correct diagnosis and management of PAP, even with an established diagnosis of underlying SPAP-suggestive disease.

Vocal cord paralysis associated with pleuroparenchymal fibroelastosis: A case report and literature review.

Here, we report a case of idiopathic pleuroparenchymal fibroelastosis (PPFE) that progressed to pulmonary aspergilloma, aspiration pneumonia, and left vocal cord paralysis (VCP). To date, five cases of PPFE with VCP have been reported, including the present case. Aspiration pneumonia occurred in three cases, leading to death in two cases. Four cases had left-sided paralysis, in two of which, the paralysis occurred on side opposite to the predominant side (right side) of PPFE. Structural mechanisms underlying the recurrent laryngeal nerve could be involved. This report may further highlight the existence of hoarseness and dysphagia in PPFE.

Autoimmune Pulmonary Alveolar Proteinosis That Improved after a COVID-19 Episode.

Autoimmune pulmonary alveolar proteinosis (APAP) is caused by macrophage dysfunction owing to the presence of anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibodies. A 77-year-old man with APAP was referred to our hospital for whole-lung lavage (WLL) due to oxygenation exacerbation and pulmonary shadows. The patient had had coronavirus disease 2019 (COVID-19) during the APAP evaluation before WLL. About three months after COVID-19 resolved, his oxygenation and shadow reflecting APAP had obviously improved, thus avoiding the need for WLL. We suspected that the improvement in APAP was due to various immunological reactions induced by COVID-19.

Left Vocal Cord Paralysis in Idiopathic Pleuroparenchymal Fibroelastosis: A Case Report.

Pleuroparenchymal fibroelastosis (PPFE) is a rare interstitial lung disease that is characterized by predominant upper lobe fibrosis and pleural thickening. In this report, we present an unusual case of idiopathic PPFE with left vocal cord paralysis that developed repeated aspiration pneumonia. Vocal cord paralysis is a rare complication of PPFE, and two mechanisms can be proposed: 1) Fibrous adhesion of the recurrent laryngeal nerve to the chest wall can cause stretching of the nerve. 2) Traction or compression of the recurrent laryngeal nerve due to the distortion of the tracheobronchial tree can cause paralysis of the vocal cord. Finally, to reduce the risk of aspiration pneumonia, laryngoscopic evaluation of the vocal cord is recommended in patients with PPFE with hoarseness and dysphagia for early intervention.

Immune Checkpoint Inhibitor-Related Pneumonitis in Lung Cancer Patients with Interstitial Lung Disease: Significance of Radiological Pleuroparenchymal Fibroelastosis.

INTRODUCTION: Pleuroparenchymal fibroelastosis (PPFE) findings are associated with poor prognosis in interstitial lung disease (ILD). However, the effect of PPFE findings on the development of immune checkpoint inhibitor-related pneumonitis (ICI-pneumonitis), a life-threatening adverse event, in lung cancer patients with ILD has not been elucidated. We aimed to determine whether PPFE findings are a risk factor for ICI-pneumonitis in lung cancer patients with ILD. METHODS: We retrospectively examined 712 lung cancer patients, including 173 patients with background ILDs, who received ICI therapy in our institute between December 2015 and May 2021. Background ILDs were radiologically classified into three types: lone PPFE, other ILDs with PPFE, and other ILDs without PPFE. The cumulative ICI-pneumonitis incidence curves and median overall survival (mOS) were compared between the three radiological types, and risk factors for ICI-pneumonitis were evaluated. RESULTS: Of 173 eligible patients with ILD, 23 patients (13.3%) experienced ICI-pneumonitis. The Kaplan-Meier method and the log-rank test showed that lone PPFE patients had significantly lower incidence of ICI-pneumonitis (p = 0.024) and longer mOS (575 vs. 326 days; p = 0.0096) than other ILDs patients. ICI-pneumonitis (p = 0.35) and mOS (p = 0.29) were not significantly different between other ILDs with and without PPFE. A multivariate Cox proportional hazards regression analysis revealed that lone PPFE pattern was an independent predictive factor for ICI-pneumonitis (hazard ratio, 0.20; 95% confidence interval, 0.043-0.93; p = 0.040). CONCLUSION: ICI therapy could be safer in lone PPFE patients than in other ILDs patients with lung cancer.

Fibrotic Hypersensitivity Pneumonitis Diagnosed by a Re-evaluation with Bronchoalveolar Lavage at Disease Deterioration.

A 79-year-old man was admitted with worsening cough, dyspnea, and increased ground-glass opacity on chest computed tomography (CT). He had been diagnosed with idiopathic pulmonary fibrosis given the absence of an identifiable cause of interstitial pneumonia, chest CT findings, and absence of lymphocytosis in bronchoalveolar lavage (BAL) fluid. Meticulous history taking revealed extensive exposure to inciting antigens contained in chicken fertilizer before symptom worsening. A re-evaluation with BAL showed lymphocytosis, and clinical improvement with antigen avoidance confirmed the diagnosis of fibrotic hypersensitivity pneumonitis (fHP). A re-evaluation with BAL at disease deterioration after possible exposure to inciting antigen can facilitate a correct fHP diagnosis.

Generalized lymphatic anomaly involving the pleura and bone in an older male: A case report.

Generalized lymphatic anomaly (GLA) is a congenital malformation of the lymphatic vessels that is often diagnosed in early childhood. Owing to the rarity and heterogeneity of its clinical course, GLA is frequently misdiagnosed, especially in adults. A 67-year-old man was incidentally found to have bone and pleural lesions. Multiple bone lesions detected on magnetic resonance images were mistaken for malignancy, and pathological evaluation led to the diagnosis of GLA. GLA should be considered in the differential diagnosis of multiple bone lesions, and a proactive biopsy to confirm the diagnosis may help avoid unnecessary invasive procedures.

Concomitant Recurrent Pneumothorax and Takotsubo Cardiomyopathy in a Chronic Obstructive Pulmonary Disease Patient.

Chest pain is one of the major causes of emergency room visits. Here, we present the case of a patient with chest pain who developed recurrent pneumothorax and Takotsubo cardiomyopathy (TC). An 80-year-old man, receiving supplemental oxygen for chronic obstructive pulmonary disease (COPD), presented to the emergency room with chest pain and dyspnea. On examination, his chest pain was initially assessed to be secondary to recurrent pneumothorax. However, on further evaluation, an electrocardiogram (ECG) showed ST-segment elevation along with elevated troponin levels. Ultimately, he was diagnosed with TC. ECG, if indicated by echocardiography, should be considered to detect concomitant heart disease when dealing with pneumothorax. TC should be recognized as a cardiac disease that can be caused by pneumothorax.

Corticosteroids for pulmonary lymphangitic carcinomatosis.

Pulmonary lymphangitic carcinomatosis (PLC) is a type of lymphangitic spread of cancer cells, from a primary site to the pulmonary vasculature and lymphatics. Corticosteroids are recommended for PLC by clinical guidelines, although scientific evidence for this traditional practice is still lacking. We report a patient with lung cancer who developed clinically diagnosed PLC and was successfully treated with steroid treatment. The pulmonary shadows suggestive of PLC were remarkably improved, as well as her symptom. Corticosteroids are worth trying when PLC is clinically suspected.

Serum Biomarkers in a Radiological Pattern of Non-Fibrotic Hypersensitivity Pneumonitis: Implications for Mechanistic Difference and Differential Diagnosis.

Hypersensitivity pneumonitis (HP) is a consequence of immune-mediated reactions caused by recurrent exposure to environmental agents. Recently, clinical practice guidelines for the diagnosis of HP were published and increased interest in HP. On the other hand, novel therapies have recently emerged for various diseases, and the management of drug-related pneumonitis (DRP) has become increasingly important. Among DRP, the HP pattern (DRP-HP) shows small, poorly defined centrilobular nodules with or without widespread areas of ground-glass opacity or lobular areas of decreased attenuation and vascularity. A similar radiological pattern of non-fibrotic HP can be induced, irrespective of inhalation (non-fibrotic HP) or intravenous administration (DRP-HP). However, their difference has not been well described, although the distribution of lesions in the lungs was slightly different between these two conditions. In this review, we focus on serum biomarkers of lung epithelial cells in order to investigate the difference between DRP-HP and non-fibrotic HP (common-HP). Serum levels of Krebs von den Lungen 6 (KL-6) might be relatively lower (occasionally normal) in DRP-HP than in common-HP, implying a mechanistic difference. KL-6 could be useful in discriminating between DRP and non-fibrotic HP (common type).

Identification of CD14 and lipopolysaccharide-binding protein as novel biomarkers for sarcoidosis using proteomics of serum extracellular vesicles.

Sarcoidosis is a complex, polygenic, inflammatory granulomatous multi-organ disease of unknown cause. The granulomatous inflammation in sarcoidosis is driven by the interplay between T cells and macrophages. Extracellular vesicles (EVs) play important roles in intercellular communication. We subjected serum EVs, isolated by size exclusion chromatography, from seven patients with sarcoidosis and five control subjects to non-targeted proteomics analysis. Non-targeted, label-free proteomics analysis detected 2292 proteins in serum EVs; 42 proteins were up-regulated in patients with sarcoidosis relative to control subjects; and 324 proteins were down-regulated. The protein signature of EVs from patients with sarcoidosis reflected disease characteristics such as antigen presentation and immunological disease. Candidate biomarkers were further verified by targeted proteomics analysis (selected reaction monitoring) in 46 patients and 10 control subjects. Notably, CD14 and lipopolysaccharide-binding protein (LBP) were validated by targeted proteomics analysis. Up-regulation of these proteins was further confirmed by immunoblotting, and their expression was strongly increased in macrophages of lung granulomatous lesions. Consistent with these findings, CD14 levels were increased in lipopolysaccharide-stimulated macrophages during multinucleation, concomitant with increased levels of CD14 and LBP in EVs. The area under the curve values of CD14 and LBP were 0.81 and 0.84, respectively, and further increased to 0.98 in combination with angiotensin-converting enzyme and soluble interleukin-2 receptor. These findings suggest that CD14 and LBP in serum EVs, which are associated with granulomatous pathogenesis, can improve the diagnostic accuracy in patients with sarcoidosis.

Drug-related pneumonitis with radiographic hypersensitivity pneumonitis pattern: Three case series.

Novel therapies have recently emerged for various diseases, and the management of drug-related pneumonitis (DRP) has become increasingly important. In particular, the hypersensitivity pneumonitis (HP) pattern of DRP has been increasingly recognized due to development of new therapeutic strategies, such as immunotherapy. However, literature describing detailed clinical cases is still lacking. Herein, we report three cases of DRP with typical HP radiographic pattern. These patients were treated with different drugs, namely nano albumin-bound (nab)-paclitaxel, everolimus, or nivolumab, but had common clinical features, including a good prognosis.

Diagnostic yield and safety of bronchofiberscopy for pulmonary alveolar proteinosis.

BACKGROUND: Pulmonary alveolar proteinosis (PAP) is a diffuse lung disease characterized by the abnormal accumulation of surfactant-like material within the alveolar spaces and distal bronchioles. If high-resolution computed tomography (HRCT) indicates the presence of PAP, a definitive diagnosis of PAP is established when consistent pathological findings are obtained. Herein, we retrospectively studied the yield and safety of bronchofiberscopy in the diagnosis of PAP. METHODS: One hundred and fifty consecutive patients with PAP were prospectively registered in the PAP cohort database of the National Hospital Organization Kinki-Chuo Chest Medical Center between January 1991 and December 2018. We examined 86 patients who underwent bronchofiberscopy with bronchoalveolar lavage (BAL) and transbronchial lung forceps biopsy (TBLB). RESULTS: The patients included 56 men and 30 women, with a median age of 57 years. All patients had autoimmune PAP, and the median level of anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibodies was 42.8 µg/mL. The diagnostic yield was 90.7% (78/86) with BAL and 81.4% (70/86) with TBLB. The combination of BAL and TBLB increased the yield to 98.8%. Age, disease severity score, and frequency of traction bronchiectasis on HRCT were significantly different between the TBLB-positive and TBLB-negative groups. No patient developed serious complications due to bronchofiberscopy; TBLB-related complications included pneumothorax (3.5%) and minimal bleeding (7.0%). CONCLUSIONS: Bronchofiberscopy, in combination with BAL and TBLB, is an effective and safe method for the diagnosis of PAP, with a yield of 98.8%.

Proteomics of serum extracellular vesicles identifies a novel COPD biomarker, fibulin-3 from elastic fibres.

There is an unmet need for novel biomarkers in the diagnosis of multifactorial COPD. We applied next-generation proteomics to serum extracellular vesicles (EVs) to discover novel COPD biomarkers. EVs from 10 patients with COPD and six healthy controls were analysed by tandem mass tag-based non-targeted proteomics, and those from elastase-treated mouse models of emphysema were also analysed by non-targeted proteomics. For validation, EVs from 23 patients with COPD and 20 healthy controls were validated by targeted proteomics. Using non-targeted proteomics, we identified 406 proteins, 34 of which were significantly upregulated in patients with COPD. Of note, the EV protein signature from patients with COPD reflected inflammation and remodelling. We also identified 63 upregulated candidates from 1956 proteins by analysing EVs isolated from mouse models. Combining human and mouse biomarker candidates, we validated 45 proteins by targeted proteomics, selected reaction monitoring. Notably, levels of fibulin-3, tripeptidyl-peptidase 2, fibulin-1, and soluble scavenger receptor cysteine-rich domain-containing protein were significantly higher in patients with COPD. Moreover, six proteins; fibulin-3, tripeptidyl-peptidase 2, UTP-glucose-1-phosphate uridylyl transferase, CD81, CD177, and oncoprotein-induced transcript 3, were correlated with emphysema. Upregulation of fibulin-3 was confirmed by immunoblotting of EVs and immunohistochemistry in lungs. Strikingly, fibulin-3 knockout mice spontaneously developed emphysema with age, as evidenced by alveolar enlargement and elastin destruction. We discovered potential pathogenic biomarkers for COPD using next-generation proteomics of EVs. This is a novel strategy for biomarker discovery and precision medicine.