Effects of Anti-Fibrotic Drugs on Transcriptome of Peripheral Blood Mononuclear Cells in Idiopathic Pulmonary Fibrosis.

Two anti-fibrotic drugs, pirfenidone (PFD) and nintedanib (NTD), are currently used to treat idiopathic pulmonary fibrosis (IPF). Peripheral blood mononuclear cells (PBMCs) are immunocompetent cells that could orchestrate cell-cell interactions associated with IPF pathogenesis. We employed RNA sequencing to examine the transcriptome signature in the bulk PBMCs of patients with IPF and the effects of anti-fibrotic drugs on these signatures. Differentially expressed genes (DEGs) between "patients with IPF and healthy controls" and "before and after anti-fibrotic treatment" were analyzed. Enrichment analysis suggested that fatty acid elongation interferes with TGF-ß/Smad signaling and the production of oxidative stress since treatment with NTD upregulates the fatty acid elongation enzymes ELOVL6. Treatment with PFD downregulates COL1A1, which produces wound-healing collagens because activated monocyte-derived macrophages participate in the production of collagen, type I, and alpha 1 during tissue damage. Plasminogen activator inhibitor-1 (PAI-1) regulates wound healing by inhibiting plasmin-mediated matrix metalloproteinase activation, and the inhibition of PAI-1 activity attenuates lung fibrosis. DEG analysis suggested that both the PFD and NTD upregulate SERPINE1, which regulates PAI-1 activity. This study embraces a novel approach by using RNA sequencing to examine PBMCs in IPF, potentially revealing systemic biomarkers or pathways that could be targeted for therapy.

Different Transcriptome Features of Peripheral Blood Mononuclear Cells in Non-Emphysematous Chronic Obstructive Pulmonary Disease.

Non-emphysematous chronic obstructive pulmonary disease (COPD), which is defined based on chest computed tomography findings, presented different transcriptome features of peripheral blood mononuclear cells (PBMCs) compared with emphysematous COPD. Enrichment analysis of transcriptomic data in COPD demonstrated that the "Hematopoietic cell lineage" pathway in Kyoto Encyclopedia of Genes and Genomes pathway analysis was highly upregulated, suggesting that cellular dynamic dysregulation in COPD lungs is affected by pathologically modified PBMCs. The differentially expressed genes (DEGs) upregulated in PBMCs reflected the disease state of non-emphysematous COPD. Upregulated DEGs such as XCL1, PRKCZ, TMEM102, CD200R1, and AQP1 activate T lymphocytes and eosinophils. Upregulating keratan sulfate biosynthesis and metabolic processes is associated with protection against the destruction of the distal airways. ITGA3 upregulation augments interactions with extracellular matrix proteins, and COL6A1 augments the profibrotic mast cell phenotype during alveolar collagen VI deposition. Upregulating HSPG2, PDGFRB, and PAK4 contributes to the thickening of the airway wall, and upregulating SERPINF1 expression explains the better-preserved vascular bed. Therefore, gene expression and pathway analysis in PBMCs in patients with non-emphysematous COPD represented type 2 immune responses and airway remodeling features. Therefore, these patients have asthmatic potential despite no clinical signs of asthma, in contrast to those with emphysematous COPD.

Clinical Characteristics and Risk Factors of Lung Injury Induced by Nab-Paclitaxel.

Background/Aim: Nab-paclitaxel (Nab-PTX) has been widely used to treat several advanced cancers. Nab-PTX can cause drug-induced lung injury (DILI); however, its clinical and radiographic features have not been clarified. We aimed to assess the clinical characteristics of Nab-PTX-induced lung injury and identify its associated risk factors. Patients and Methods: We retrospectively investigated 304 patients who received Nab-PTX at Chiba University Hospital between November 2010 and November 2017. We obtained information regarding the clinical course, laboratory findings, and chest computed tomography findings from their medical records. Results: Forty-one patients (13%) developed DILI. Grade 1 lung injury occurred in 27 patients (8.8%), grade 2, 8 patients (2.6%); grade 3, 3 patients (0.9%); grade 4, 1 (0.3%); and grade 5, 2 (0.6%). Multivariate analysis revealed that age >56 years (odds ratio [OR]: 3.0), pre-existing interstitial lung changes (OR: 3.2), and combined drugs with gemcitabine (OR: 2.7) were independent risk factors for DILI owing to Nab-PTX administration. Conclusion: Nab-PTX-induced lung injury is not rare; however, most cases are asymptomatic (grade 1). Older age, pre-existing interstitial lung changes, and combined drugs with gemcitabine could increase the incidence of Nab-PTX-induced lung injury; such patients should be treated with greater care.

Transcriptome Analysis of Peripheral Blood Mononuclear Cells in Pulmonary Sarcoidosis.

BACKGROUND: Sarcoidosis is a granulomatous systemic disease of unknown etiology. Mononuclear cells such as macrophages or lymphocytes in lung tissue and hilar or mediastinal lymph nodes have been recognized to play an essential role in granuloma formation in pulmonary sarcoidosis. Peripheral blood mononuclear cells (PBMCs) consist of several immunocompetent cells and have been shown to play a mechanistic role in the pathogenesis of sarcoidosis. However, the genetic modifications that occur in bulk PBMCs of sarcoidosis remain to be elucidated. PURPOSE: This study aimed to explore the pathobiological markers of sarcoidosis in PBMCs by comparing the transcriptional signature of PBMCs from patients with pulmonary sarcoidosis with those of healthy controls by RNA sequencing. METHODS: PBMC samples were collected from subjects with pulmonary sarcoidosis with no steroid/immunosuppressant drugs (n = 8) and healthy controls (n = 11) from August 2020 to April 2021, and RNA sequencing was performed with the PBMC samples. RESULTS: Principal component analysis using RNA sequencing datasets comparing pulmonary sarcoidosis with healthy controls revealed that the two groups appeared to be differentiated, in which 270 differentially expressed genes were found in PBMCs between sarcoidosis and healthy controls. Enrichment analysis for gene ontology suggested that some biological processes related to the pathobiology of sarcoidosis, such as cellular response to interleukin (IL)-1 and IFN-γ, regulation of IL-6 production, IL-8 secretion, regulation of mononuclear cell migration, and response to lipopolysaccharide, were involved. Enrichment analysis of the KEGG pathway indicated the involvement of tumor necrosis factor (TNF), toll-like receptor signaling, IL-17 signaling pathways, phagosomes, and ribosomes. Most of the genes involved in TNF and IL-17 signaling pathways and phagosomes were upregulated, while most of the ribosome-related genes were downregulated. CONCLUSION: The present study demonstrated that bulk gene expression patterns in PBMCs were different between patients with pulmonary sarcoidosis and healthy controls. The changes in the gene expression pattern of PBMCs could reflect the existence of sarcoidosis lesions and influence granuloma formation in sarcoidosis. These new findings are important to strengthen our understanding of the etiology and pathobiology of sarcoidosis and indicate a potential therapeutic target for sarcoidosis.

What are the factors affecting the recovery rate of bronchoalveolar lavage fluid?

BACKGROUND: Bronchoalveolar lavage (BAL) is a useful examination for the evaluation of interstitial lung disease. A high BAL fluid (BALF) recovery rate is desirable because low recovery rates lead to inaccurate diagnoses and increased adverse events. Few studies have explored whether BALF recovery rates are influenced by clinical factors. OBJECTIVES: This study aimed to identify the clinical parameters affecting the recovery rates of BALF and the extent of their effects. METHOD: Data from patients who underwent BAL at the Chiba University Hospital between 2013 and 2019 were retrospectively reviewed. BAL was performed with three aliquots of 50-ml physiological saline. The potential association of the BALF recovery rate with clinical parameters such as age, sex, smoking status, underlying disease, bronchus used for the procedure and pulmonary function, was analysed. RESULTS: Eight hundred twenty-six patients had undergone BAL. The average recovery rate was 52.4%. Factors affecting BALF recovery rates included male sex (odds ratio [OR]: 0.32, 95% confidence interval [CI]: 0.20-0.53, p < 0.001); age ≥ 65 years (OR: 0.50, 95% CI: 0.33-0.76, p < 0.001); use of the left bronchus (OR: 0.46, 95% CI: 0.30-0.71, p = 0.001) and bronchi other than the middle lobe bronchus or lingula (OR: 0.41, 95% CI: 0.25-0.65, p < 0.001); and forced expiratory volume in 1 s divided by forced vital capacity <80% (OR: 0.42, 95% CI: 0.40-1.00, p < 0.001). CONCLUSION: Sex, age, bronchus used for the procedure and pulmonary function may be useful as pre-procedural predictors of BALF recovery rates.

Exacerbation of autoimmune pulmonary alveolar proteinosis that improved with lone treatment of complicating nontuberculous mycobacterial infection: A case report.

Herein, we present the case of a 63-year-old man with autoimmune pulmonary alveolar proteinosis (APAP) complicated by Mycobacterium avium complex (MAC) infection. APAP was diagnosed based on serum anti-granulocyte-macrophage colony-stimulating factor antibody, bronchoalveolar lavage fluid (BALF) findings, and transbronchial lung biopsy. Nodular shadows with cavities were visible on chest CT images, and Mycobacterium intracellulare was identified by BALF culture. Rifampicin, ethambutol, and clarithromycin were administered, and 4 months later, the nodular shadows of MAC had disappeared, and APAP was remarkably improved. Thus, in cases of APAP exacerbation complicated with infections, such as MAC, control of the infections may improve APAP.

Risk factors for acute exacerbation following bronchoalveolar lavage in patients with suspected idiopathic pulmonary fibrosis: A retrospective cohort study.

INTRODUCTION: Bronchoalveolar lavage (BAL) is useful for diagnosing diffuse lung disease and excluding other conditions. However, acute exacerbations (AEs) are recognized as important complications of BAL in patients with idiopathic pulmonary fibrosis (IPF). This study aimed to identify risk factors for BAL-induced AEs in patients with IPF. MATERIAL AND METHODS: We retrospectively analyzed the data of 155 patients with suspected IPF who had undergone BAL between January 2013 and December 2018. BAL-related AE was defined as the development of AE within 30 days after the procedure. We compared clinical features and parameters between patients with AE (AE group) and without AE (non-AE group). We also reviewed the relevant reported literature. RESULTS: Among the 155 patients, 5 (3.2%) developed AE within 30 days after BAL. The average duration from BAL to AE onset was 7.8 days (2-16 days). Results from the univariate analysis revealed PaO2 < 75 mm Hg (p = 0.036), neutrophil content in BAL ≥ 7% (p = 0.0061), %DLCO < 50% (p = 0.019), Gender-Age-Physiology (GAP) stage III (p = 0.034), and BAL recovery rates < 30% (p < 0.001) as significant risk factors for post-BAL AE. All five patients who developed AE recovered and were discharged. CONCLUSIONS: Disease severity, high neutrophil levels in BAL, and poor BAL recovery rates may be risk factors for BAL-induced AEs.

Prognostic value of lymphocyte counts in bronchoalveolar lavage fluid in patients with acute respiratory failure: a retrospective cohort study.

BACKGROUND: Cellular patterns in bronchoalveolar lavage fluid (BALF) are used to distinguish or rule out particular diseases in patients with acute respiratory failure (ARF). However, whether BALF cellular patterns can predict mortality or not is unknown. We test the hypothesis that BALF cellular patterns have predictive value for mortality in patients with ARF. METHODS: This was a retrospective single-center observational study conducted in a Japanese University Hospital. Consecutive patients (n = 78) with both pulmonary infiltrates and ARF who were examined by bronchoalveolar lavage (BAL) between April 2015 and May 2018 with at least 1 year of follow-up were analyzed. Primary analysis was receiver operating characteristic curve-area under the curve (ROC-AUC) analysis for 1-year mortality. RESULTS: Among the final sample size of 78 patients, survivors (n = 56) had significantly increased lymphocyte and eosinophil counts and decreased neutrophil counts in BALF compared with non-survivors (n = 22). Among the fractions, lymphocyte count was the most significantly different (30 [12-50] vs. 7.0 [2.9-13]%, P <0.0001). In the ROC curve analysis of the association of BALF lymphocytes with 1-year mortality, the AUC was 0.787 (P <0.0001, cut-off value [Youden index] 19.0%). Furthermore, ≥20% BALF lymphocytes were significantly associated with increased survival with adjustment for baseline imbalances (1-year adjusted hazard ratio, 0.0929; 95% confidence interval, 0.0147-0.323, P <0.0001; 90-day P =0.0012). Increased survival was significantly associated with ≥20% BALF lymphocytes in both interstitial lung disease (ILD) and non-ILD subgroups (P =0.0052 and P =0.0033, respectively). In secondary outcome analysis, patients with ≥20% BALF lymphocytes had significantly increased ventilator-free days, which represents less respiratory dysfunction than those with <20% BALF lymphocytes. CONCLUSIONS: In the patients with ARF, ≥20% lymphocytes in BALF was associated with significantly less ventilatory support, lower mortality at both 90-day and 1-year follow-ups.

Presence of concurrent sarcoid-like granulomas indicates better survival in cancer patients: a retrospective cohort study.

INTRODUCTION: An increased risk of sarcoidosis and sarcoid-like reactions in subjects with a history of malignancy has been suggested. We assessed the incidence and clinical characteristics of cancer patients with biopsies containing sarcoid-like granulomas on cancer metastasis and patient survival. METHODS: This is a retrospective, multicentre, observational study involving endobronchial ultrasound transbronchial needle aspiration and a melanoma patient dataset at the University of Miami, USA, and a sarcoidosis patient database at Chiba University, Japan. Subjects with a confirmed diagnosis of cancer and who subsequently developed granulomas in different organs were enrolled. The study was registered at Clinicaltrials.gov (NCT03844698). RESULTS: 133 patients met the study's criteria. The most common primary cancer sites were the skin (22.5%), breast (20.3%) and lymph node (12.8%). 24 (18%) patients developed sarcoid-like granulomas within 1 year of cancer diagnosis, 54 (40.6%) between 1 and 5 years and 49 (36.8%) after 5 years. Imaging showed possible sarcoid-like granulomas in lymph nodes in 51 cases (38.3%) and lung tissue and mediastinal lymph nodes in 73 cases (54.9%); some parenchymal reticular opacity and fibrosis was found in 5 (3.7%) and significant parenchymal fibrosis in 2 (1.5%) subjects. According to logistic regression analysis, the frequency of metastatic cancer was significantly lower in patients with sarcoid-like granulomas than in controls. Moreover, multivariate Cox proportional hazard analysis showed a significant survival advantage in those with sarcoid-like granuloma. CONCLUSION: Sarcoid-like granulomas are uncommon pathology findings in cancer patients. There is a significant association between the presence of granulomas and reduced metastasis and increased survival. Further study is warranted to understand the protective mechanism involved.

The Gender-Age-Physiology system as a prognostic model in patients with idiopathic pulmonary fibrosis treated with nintedanib: a longitudinal cohort study.

INTRODUCTION: The Gender-Age-Physiology (GAP) system is a tool for predicting prognosis in patients with idiopathic pulmonary fibrosis (IPF). Yet, to date, the GAP system has not been evaluated in patients with IPF who received nintedanib. MATERIAL AND METHODS: This single-center retrospective study included 89 patients with IPF who received Nintedanib for at least 3 months. All-cause mortality was set as the end point. Clinical parameters, including the GAP stage, were statistically analyzed for risk factors leading to mortality using the Cox proportional hazard model. RESULTS: The median follow-up was 16.4 months (range 3.7-37.4 months), during which 23 patients died. Univariate analysis revealed that the GAP stage (hazard ratio [HR] 3.00, 95% confidence interval [CI] 1.52-5.92, p = 0.0014) and PaO2 (HR 0.95, 95% CI 0.92-0.98, p = 0.0063) were significant prognostic factors. Multivariate analysis revealed that the GAP stage was a significant prognostic factor (HR 2.26, 95% CI 1.07-4.78, p = 0.031). Log-rank analysis revealed that there were no significant differences in "Gender" (p = 0.47) and "Age" (p = 0.18) factors. However, there were significant differences in "Physiology" factors (% of forced vital capacity, p = 0.018; % of diffusing capacity of lung carbon monoxide, p < 0.001). The cumulative incidences of mortality at 1 and 2 years were as follows: GAP I: 5.1% and 6.8%; GAP II: 9.5% and 29.3%; and GAP III: 18.9% and 84.2%. CONCLUSIONS: The GAP system is useful as a prognostic tool in patients with IPF who have been treated with nintedanib.

Clinical characteristics and risk factors of drug-induced lung injury by ALK tyrosine kinase inhibitors: A single center retrospective analysis.

BACKGROUND: If anaplastic lymphoma kinase (ALK) gene rearrangement in lung cancer is identified, ALK-tyrosine kinase inhibitors (ALK-TKIs) can be an effective treatment. However, the details of drug-induced lung injury (DILI) caused by ALK-TKI, which can be a serious side effect of ALK-TKIs, remains unclear. This study aimed to investigate the clinical features and the onset risk factors of DILI by ALK-TKIs in clinical practice. METHODS: The clinical features of 56 consecutive patients who received crizotinib, alectinib, and/or ceritinib at our hospital from 2012 to 2018 were retrospectively examined. Among these, patients diagnosed with DILI due to ALK-TKIs were evaluated in terms of clinical features and parameters. Each clinical parameter before the administration of ALK-TKIs was compared between the DILI onset group and the non-onset group. RESULTS: A total of seven cases were diagnosed with DILI due to ALK-TKIs; no DILI-related deaths were observed. Chest computed tomography (CT) scan findings identified six patients with the organizing pneumonia (OP) pattern and one with the hypersensitivity pneumonia pattern. The onset of DILI was significantly different in patients age ≥ 64 years and with a creatinine clearance <80 mL/minute. CONCLUSIONS: Extra caution for DILI due to ALK-TKIs may be needed when recommending ALK-TKIs for patients over 64 years of age, or with decreased renal function. CT images of the majority of patients with DILI by ALK-TKIs show an OP pattern. KEY POINTS: Significant findings of the study: Extra caution is needed when recommending ALK-TKIs for patients over 64 years of age or those with decreased renal function. Computed tomography images of the majority of patients with DILI by ALK-TKIs show an OP pattern. WHAT THIS STUDY ADDS: The same or a different ALK-TKI may be considered as a treatment option after the onset of DILI, based on careful judgment.

Tolerability of nintedanib-related diarrhea in patients with idiopathic pulmonary fibrosis.

BACKGROUND: Nintedanib is an important drug for the treatment of idiopathic pulmonary fibrosis (IPF). However, the drug is discontinued in some patients who present with diarrhea. In this study, we aimed to assess the drug continuation rate in patients who developed diarrhea during nintedanib therapy and to evaluate if antidiarrheal drugs or nintedanib dose reductions improved clinical tolerability and efficacy. METHODS: Eighty-six patients with IPF were treated in our institution between December 2015 and March 2018. Among them, 50 patients who experienced nintedanib-related diarrhea were analyzed regarding tolerability and persistence rate. RESULTS: In 50 patients who experienced nintedanib-related diarrhea, 26 (n = 11, without reduction and n = 15, with reduction) continuously received nintedanib. Meanwhile, the drug was discontinued in 24 patients (n = 13, without reduction and n = 11, with reduction). In 9 of 24 patients, the drug was discontinued due to diarrhea. The annual rate of decline in forced vital capacity and the duration of nintedanib administration were not significantly different between groups with and without dosage reduction. Moreover, 23, 13, 8, and 2 patients received 1, 2, 3, and 4 agents, respectively. Clostridium butyricum is a probiotic bacterium most commonly used as an antidiarrheal agent. In this study, it was used in 28 of 46 patients. The total durations of nintedanib administration differed significantly according to the number of antidiarrheal drugs taken: 853 ± 221 days, more than three agents; 424 ± 365 days, without an agent (p = 0.043); and 460 ± 142, one agent (p = 0.0003). CONCLUSIONS: When diarrhea occurs within a year after using nintedanib, the dose reduction may be acceptable without affecting pulmonary function. Moreover, treatment with multiple antidiarrheals may be a practical option to maintain the use of nintedanib therapy compared with monotherapy and no therapy.

Differences in tolerability of pirfenidone between elderly and younger patients with idiopathic pulmonary fibrosis.

PURPOSE: Although pirfenidone (PFD) is a key drug for the treatment of idiopathic pulmonary fibrosis (IPF), differences in tolerability between elderly and young patients remain unclear. This study aimed to investigate age-related differences in adverse drug reactions to PFD and to evaluate whether patient age influences the safety and tolerability of PFD in clinical practice. PATIENTS AND METHOD: One hundred fifty-four patients with IPF were treated with PFD in our institution between May 2009 and April 2017; these patients were classified into 2 groups on the basis of age: ≥75 years of age (elderly patients) and <75 years of age (younger patients). In each group, the clinical course, laboratory data, radiographic findings, adverse events, and tolerability of PFD at 6 months and 1 year after administration were retrospectively analyzed. RESULTS: Among the 120 patients examined in this study, 31 patients (26%) were ≥75 years of age. The continuation rate of PFD at 1 year in the elderly patient group was significantly lower (n=11 [35%] vs 57 [64%], p=0.007) than in the younger patient group. Regarding adverse drug reactions to PFD, the incidence of gastrointestinal disorders including anorexia (n=24 [77%] vs 40 [45%], p=0.002) and the discontinuation caused by gastrointestinal disorders (n=11 [35%] vs 13 [15%], p=0.019) were significantly higher in elderly patients than those in younger patients. However, with the exception of gastrointestinal disorders, other adverse drug reactions did not significantly differ between elderly and younger patients. CONCLUSIONS: Compared with younger patients, elderly patients with IPF had a higher incidence of gastrointestinal disorders, along with an increased discontinuation rate of PFD. More careful management of gastrointestinal disorders may be required to ensure continuation of PFD in elderly patients.