Low skeletal muscle mass has been reported to associated with poor prognosis in patients with idiopathic pulmonary fibrosis (IPF). However, such associations have scarcely reported in idiopathic interstitial pneumonias (IIPs) other than IPF. Quantification of muscle mass obtained from chest computed tomography (CT) is used as a simple screening tool for sarcopenia in patients with respiratory diseases. However, the optimal thoracic site for muscle mass quantification is controversial. Moreover, there have been no reports investigating the association between muscle mass and acute exacerbations. This study aimed to evaluate optimal site for muscle mass quantification in chest CT to predict survival and acute exacerbation in IPF and non-IPF idiopathic interstitial pneumonias. This study included 528 patients diagnosed with IIP at 29 facilities between September 1, 2013, and April 30, 2016, following multidisciplinary discussions with prospective follow-up over a 5-year period. The cohort was divided into two groups: those with IPF and those with non-IPF IIPs. Skeletal muscle mass was quantified using the erector spinae muscle index (ESMI) and pectoralis muscle index (PMI), defined as the respective muscle area on chest computed tomography (CT) divided by height squared at the time of enrollment. Associations between these indices at baseline and both survival and acute exacerbation were analyzed. In both IPF and non-IPF cohorts, Cox regression analysis revealed that patients with low ESMI had a poorer prognosis compared to those with normal ESMI, even after adjusting for age, sex,

Anti-cancer treatments can result in various adverse effects, including infections due to immune suppression/dysregulation and drug-induced toxicity in the lung. One of the major opportunistic infections is Pneumocystis jirovecii pneumonia (PCP), which can cause severe respiratory complications and high mortality rates. Cytotoxic drugs and immune-checkpoint inhibitors (ICIs) can induce interstitial lung diseases (ILDs).Nonetheless, the differentiation of these diseases can be difficult, and the pathogenic mechanisms of such diseases are not yet fully understood. To better comprehend the immunophenotypes, we conducted an exploratory mass cytometry analysis of immune cell subsets in bronchoalveolar lavage fluid from patients with PCP, cytotoxic drug-induced ILD (DI-ILD), and ICI-associated ILD (ICI-ILD) using two panels containing 64 markers. In PCP, we observed an expansion of the CD16+ T cell population, with the highest CD16+ T proportion in a fatal case. In ICI-ILD, we found an increase in CD57+ CD8+ T cells expressing immune checkpoints (TIGIT+ LAG3+ TIM-3+ PD-1+), FCRL5+ B cells, and CCR2+ CCR5+ CD14+ monocytes. These findings uncover the diverse immunophenotypes and possible pathomechanisms of cancer treatment-related pneumonitis.

Mucin overproduction is a common feature of chronic airway diseases such as asthma and chronic obstructive pulmonary disease (COPD), and exacerbates their underlying respiratory condition. Surfactant protein D (SP-D) protects against airway diseases through modulation of immune reactions, but whether it also exerts direct effects on airway epithelial cells has remained unclear. Therefore, we sought to investigate the inhibitory role of SP-D on mucin production in airway epithelial cells. We prepared air–liquid interface (ALI) cultures of human primary bronchial epithelial cells (HBECs), which recapitulated a well-differentiated human airway epithelium. Benzo(a)pyrene (BaP), a key toxicant in cigarette smoke, induced mucin 5AC (MUC5AC) production in ALI-cultured HBECs, airway secretory cell lines, and airway epithelia of mice. Then, the protective effects of SP-D against the BaP-induced mucin overproduction were examined. BaP increased MUC5AC production in ALI cultures of HBECs, and this effect was attenuated by SP-D. SP-D also suppressed the BaP-induced phosphorylation of extracellular signal-regulated kinase (ERK) and MUC5AC expression in NCI-H292 goblet-like cells, but not in NCI-H441 club-like cells. Signal regulatory protein α (SIRPα) was found to be expressed in HBECs and NCI-H292 cells but absent in NCI-H441 cells. In NCI-H292 cells, SP-D activated SH2 domain-containing tyrosine phosphatase-1 (SHP-1), downstream of SIRPα, and knockdown of SIRPα abolished the suppressive effects of SP-D on BaP-induced ERK phosphorylation and MUC5AC production. Consistent with these in vitro findings, intratracheal instillation of SP-D prevented the BaP-induced phosphorylation of ERK and Muc5ac expression in airway epithelial cells in a mouse model. SP-D acts directly on airway epithelial cells to inhibit mucin secretion through ligation of SIRPα and SHP-1-mediated dephosphorylation of ERK. Targeting of SIRPα is therefore a potential new therapeutic approach to suppression of mucin hypersecretion in chronic airway diseases such as COPD and asthma.

Immune cells have been implicated in interstitial lung diseases (ILDs), although their phenotypes and effector mechanisms remain poorly understood. To better understand these cells, we conducted an exploratory mass cytometry analysis of immune cell subsets in bronchoalveolar lavage fluid (BALF) from patients with idiopathic pulmonary fibrosis (IPF), connective-tissue disease (CTD)-related ILD, and sarcoidosis, using two panels including 64 markers. Among myeloid cells, we observed the expansion of CD14+ CD36hi CD84hiCCR2- monocyte populations in IPF. These CD14+ CD36hi CD84hi CCR2- subsets were also increased in ILDs with a progressive phenotype, particularly in a case of acute exacerbation (AEx) of IPF. Analysis of B cells revealed the presence of cells at various stages of differentiation in BALF, with a higher percentage of IgG memory B cells in CTD-ILDs and a trend toward more FCRL5+ B cells. These FCRL5+ B cells were also present in the patient with AEx-IPF and sarcoidosis with advanced lung lesions. Among T cells, we found increased levels of IL-2R+ TIGIT+ LAG3+ CD4+ T cells in IPF, increased levels of CXCR3+ CD226+ CD4+ T cells in sarcoidosis, and increased levels of PD1+ TIGIT+ CD57+ CD8+ T cells in CTD-ILDs. Together, these findings underscore the diverse immunopathogenesis of ILDs.

Bronchiolitis obliterans syndrome (BOS) is a major complication of haematopoietic stem cell transplantation (HSCT), which affects the lungs and has limited treatment options [1]. BOS after HSCT is considered a manifestation of chronic graft-versus-host disease (GVHD). T-cells play a crucial role in its onset [2], while the contribution of myeloid cells has been largely unknown. This case study of a patient with BOS after HSCT found increased ST2+CD64+ macrophages in BALF, a potential therapeutic target for treatment-refractory BOS, and reduced CCR2+CD14+ monocytes compared to other lung disorders https://bit.ly/406Uyy9

Mass cytometry of BALF cells from a pulmonary alveolar proteinosis patient, positive for anti-GM-CSF antibodies, suggests potential impairment in human alveolar macrophage differentiation https://bit.ly/45JHUrz.

We describe two well-preserved mandibles of Stegolophodon pseudolatidens (Mammalia, Proboscidea, Stegodontidae) discovered from the lower Miocene (ca. 16.9-16.6 Ma) in Northeast Japan. The mandible of Sl. pseudolatidens is primitive within the Stegodontidae in having a short symphysis with lower tusks, tetralophodont lower molars, and a mandibular canal with the large dorsoventral diameter in the anterior segment. It is characterized by a perpendicular mandibular ramus (forming an almost right angle between the anterior margin of the mandibular ramus and the dorsal horizontal surface of the corpus), and many scratches in mesial direction on the occlusal surface of m(3), implying that Sl. pseudolatidens appears to have acquired a proal jaw movement during mastication. While the mandibular morphology of Sl. pseudolatidens is comparable to that of other species of the genus that of Stegolophodon cf. stegodontoides from the upper Miocene of Myanmar differs from that of these species in having a shorter symphysis, which is a derived condition.

Background and Aims: Lymphangioleiomyomatosis (LAM) is a rare destructive lung disease characterized by multiple thin-walled pulmonary cysts.The currently proposed diagnostic algorithm emphasizes the characteristic cystic appearance on high-resolution computed tomography (HRCT) so atypical HRCT appearances present challenges to establishing the proper LAM diagnosis.The objective of this study is to accrue atypical chest HRCT appearances, determine frequencies in both tuberous sclerosis complex (TSC)-associated LAM (TSC-LAM) and sporadic LAM (S-LAM) patients.Methods: We retrospectively evaluated radiologic findings of chest HRCT (with a section thickness of 2 mm) from 311 females, including 272 patients with S-LAM (mean age 39.2 years) and 39 patients with TSC-LAM (mean age 38.3 years) who were seen at our hospital between April 2009 and December 2016.Results: We found 2 types of radiologic findings likely to make HRCT cyst appearance atypical: characteristics of the cyst itself and atypical findings in addition to cysts.We found that approximately 80% of LAM patients, whether TSC-associated or sporadic, showed typical HRCT appearance with mild to severe cystic destruction.The remaining 20% displayed unusual profiles in cyst appearance as well as additional findings aside from cyst: the former includes large cyst, thickened walls, and irregularly shaped whereas the latter includes ground glass attenuation and diffuse noncalcified nodules.

Immune-checkpoint inhibitors (ICIs) targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed cell death-1 (PD-1), and programmed cell death-1-ligand 1 (PD-L1) have become new treatment options for various malignancies. ICIs bind to immune-checkpoint inhibitory receptors or to the foregoing ligands and block inhibitory signals to release the brakes on the immune system, thereby enhancing immune anti-tumor responses. On the other hand, unlike conventional chemotherapies, ICIs can cause specific side effects, called immune-related adverse events (irAEs). These toxicities may affect various organs, including the lungs. ICI-related pneumonitis (ICI-pneumonitis) is not the most frequent adverse event, but it is serious and can be fatal. In this review, we summarize recent findings regarding ICI-pneumonitis, with a focus on potential pathogenesis and treatment.

Sarcoidosis is a systemic, granulomatous disease caused by unknown immunological abnormalities. The organs most vulnerable to sarcoidosis are the lungs. Patients often resolve spontaneously, but the lungs can also be severely affected. Although details regarding prognostic factors in sarcoidosis patients with lung involvement remain unclear, several reports have suggested that immune checkpoint molecules are involved in the pathogenesis of sarcoidosis. In this study, we divided sarcoidosis patients into two groups based on chest computed tomography (CT) findings and compared immune checkpoint molecules expressed on T cells in bronchoalveolar lavage fluid (BALF) in the two groups, using flow cytometry. We found elevated programmed cell death 1 (PD-1) or T cell immunoglobulin- and mucin-domain-containing molecule-3 (TIM-3) expression on T cells in BALF in patients with spontaneous improvement in CT findings, compared with those in patients without improvement in CT findings. In conclusion, our study implies that PD-1 or TIM-3 expression on T cells in BALF may be a prognostic factor for pulmonary lesions in sarcoidosis.

Severe pneumonitis induced by nivolumab, an anti-programmed cell death-1 monoclonal antibody, is a rare but potentially fatal immune-related adverse event. In cases of steroid-refractory pneumonitis, an appropriate therapeutic strategy using anti-tumor necrosis factor-α (TNF-α) antibody has not been established. A 59-year-old female was diagnosed with hypopharyngeal squamous cell carcinoma. Previous therapies including chemoradiotherapy and throat laryngectomy were performed, but metastatic recurrence appeared in the intrapulmonary and mediastinal lymph nodes. The patient was administered nivolumab. On the 14th day of nivolumab administration, the patient experienced dyspnea and computed tomography of the chest showed multiple consolidations in the right lung. She was diagnosed with nivolumab-induced pneumonitis. Because the pneumonitis was refractory to steroid therapy, she was administered infliximab, and the pneumonitis improved. On the 72nd and 101st days of nivolumab administration, nivolumab-induced pneumonitis re-appeared with an elevated serum TNF-α concentration. In each occurrence of pneumonitis, repetitive administration of infliximab improved the pneumonitis. Repetitive administration of infliximab may be effective for treating recurrent nivolumab-induced pneumonitis that is associated with an increased serum TNF-α concentration.

We describe a case of fulminant onset, rapidly progressive-interstitial lung disease (RP-ILD) with anti-ARS antibodies (anti-PL-7). The patient was successfully treated with nintedanib in addition to intensive immunosuppressive therapies, including intravenous cyclophosphamide. Nintedanib has just been approved for treatment of progressive fibrosing ILD, but to date, no reports of RP-ILD treated with nintedanib have been published. This case report may advance discussions regarding the use and timing of nintedanib in treating RP-ILD.

Immune-checkpoint inhibitors (ICIs) have improved clinical outcomes and are becoming a standard treatment for many cancer types. However, these drugs also induce immune-related adverse events, among which interstitial lung disease (ILD) is potentially fatal. The underlying mechanism of ILD induction by ICIs is largely unknown. With the use of flow cytometry, we determined the expression levels of the immune-checkpoint proteins PD-1, TIM-3, TIGIT, LAG-3, and PD-L1 in T cells of bronchoalveolar lavage fluid (BALF) from patients with ICI-related ILD and compared them with those for patients with sarcoidosis or with ILD related to connective tissue disease or cytotoxic drug use. The proportions of CD8+ T cells positive for both PD-1 and TIM-3 or for TIGIT in BALF were significantly higher for ICI-related ILD patients than for those with other types of ILD. A prominent increase in the proportion of PD-1+PD-L1+ cells among CD8+ T cells was also apparent in BALF of a patient with a fatal case of ICI-related ILD, and the proportion of such cells was positively correlated with the grade of ICI-related ILD. Our data reveal the immune-checkpoint profiles of T cells in ICI-related ILD and may provide mechanistic insight into the development of this adverse event.

An asymptomatic 47-year-old woman was admitted with pleural effusion and pulmonary infiltrates 1 month after ingesting raw wild boar and deer meat. Both her blood and pleural fluid were eosinophilic. Thoracoscopy revealed multiple nodules of the pleura, and biopsy samples of the nodules showed necrosis with epithelioid cell granulomas. An enzyme-linked immunosorbent assay was positive for antibodies against Paragonimus westermani, and the patient was successfully treated with praziquantel. This is the first reported case of pulmonary or pleuropulmonary paragonimiasis where several pleural nodules were observed. The detection of pleural nodules on thoracoscopy can contribute to the prompt and accurate diagnosis of paragonimiasis.

症例は65歳女性．30年前に皮疹で発症し，20年前にサルコイドーシス（肺，皮膚）と診断され，皮膚病変に対してステロイド内服中であった．X－1年10月頃より全身倦怠感，下肢脱力を認めX年1月に入院となった．血液検査では白血球数，可溶性IL-2受容体値，アルドラーゼ値の高値を認めたが，ACE，CK値は正常，各種自己抗体は陰性であった．FDG-PETでは頸部，両肩，臀部の筋肉や，手，肘，肩，膝等の関節に高集積を認めた．下肢MRIでは臀部や骨盤部の筋にT2延長域と造影後の増強を認めたが，他疾患との鑑別は困難であった．右縫工筋より筋生検を施行し，多核巨細胞を伴った組織球とリンパ球の集簇を認め，サルコイドーシスによる筋，関節病変と考え，全身ステロイドを増量し改善を認めた．当症例は30年という長い経過中に全身の筋，関節病変をきたしたまれな1例と考えられた．

We report a case of recurrent idiopathic pulmonary hemosiderosis after a long-term remission presented with Sjögren's syndrome. The patient was diagnosed with IPH due to repeated pneumonia and blood sputum in his childhood. He was admitted to our hospital due to exertional dyspnea and dry cough with bilateral ground-glass opacity in chest computed tomography at the age of 32. Video-assisted thoracoscopic surgery was performed and the specimens showed nonspecific interstitial pneumonia pattern with diffuse, chronic alveolar hemorrhage, suggesting recurrence of IPH. He was also diagnosed with Sjögren's syndrome. Further immunological studies will reveal the pathogenesis of IPH.