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Diseases caused by Mycobacterium avium complex (MAC) infection in the lungs are increasing worldwide. The recurrence rate of MAC-pulmonary disease (PD) has been reported to be as high as 25-45%. A significant percentage of recurrences occurs because of reinfection with a new genotype from the environment. A focus on reducing exposure to MAC organisms from the environment is therefore an essential component of the management of this disease as well as standard MAC-PD treatment. A macrolide-containing three-drug regimen is recommended over a two-drug regimen as a standard treatment, and azithromycin is recommended rather than clarithromycin. Both the 2007 and 2020 guidelines recommend a treatment duration of MAC-PD of at least one year after the culture conversion. Previous clinical studies have reported that ethambutol could prevent macrolide resistance. Furthermore, the concomitant use of aminoglycoside, amikacin liposomal inhalation, clofazimine, linezolid, bedaquiline, and fluoroquinolone with modification of guideline-based therapy has been studied. Long-term management of MAC-PD remains challenging because of the discontinuation of multi-drug regimens and the acquisition of macrolide resistance. Moreover, the poor compliance of guideline-based therapy for MAC-PD treatment worldwide is concerning since it causes macrolide resistance. Therefore, in this review, we focus on MAC-PD treatment and summarize various treatment options when standard treatment cannot be maintained, with reference to the latest ATS/ERS/ESCMID/IDSA clinical practice guidelines revised in 2020.

A 71-year-old man visited our hospital with dyspnea and left pleural effusion. Left pleural effusion was diagnosed as chylothorax by thoracentesis. He had no history of trauma or surgery, and there were no findings of malignant lymphoma or thrombosis. Furthermore, he was diagnosed with liver cirrhosis and hepatocellular carcinoma by computed tomography and hematological examinations, and the chylothorax was considered to be caused by liver cirrhosis. We report a review of the literature with this case since it is relatively rare for cirrhosis and hepatocellular carcinoma diagnosed from chylothorax.

現在発症原因が不明な肺疾患の特発性肺線維症（IPF）は、シリカやケイ酸塩との関連が疑われている。しかし、一般的なSEM/EDS分析ではケイ素に対する感度が不十分なため、肺葉組織内のケイ素濃度とIPF発症との相関は不明であった。そこで本研究では、SEM/EDSの100倍の感度を有する大気マイクロPIXE分析のX線エネルギースペクトルからケイ素-硫黄比を定量するプログラムを開発し、IPF組織切片とコントロール組織切片の分析に適用したところ、ケイ素-硫黄比の増加が努力肺活量低下等の肺機能悪化と相関があることが明らかとなった。

Antifibrotic agents have been widely used in patients with idiopathic pulmonary fibrosis (IPF). Long-term continuation of antifibrotic therapy is required for IPF treatment to prevent disease progression. However, antifibrotic treatment has considerable adverse events, and the continuation of treatment is uncertain in many cases. Therefore, we examined and compared the continuity of treatment between pirfenidone and nintedanib in patients with IPF. We retrospectively enrolled 261 consecutive IPF patients who received antifibrotic treatment from six core facilities in Gunma Prefecture from 2009 to 2018. Among them, 77 patients were excluded if the antifibrotic agent was switched or if the observation period was less than a year. In this study, 134 patients treated with pirfenidone and 50 treated with nintedanib were analyzed. There was no significant difference in patient background, discontinuation rate of antifibrotic treatment over time, and survival rate between the two groups. However, the discontinuation rate due to adverse events within one year of antifibrotic treatment was significantly higher in the nintedanib group than in the pirfenidone group (76% vs. 37%, p < 0.001). Furthermore, the discontinuation rate due to adverse events in nintedanib was higher than that of pirfenidone treatment throughout the observation period (70.6% vs. 31.2%, p = 0.016). The pirfenidone group tended to be discontinued due to acute exacerbation or transfer to another facility. The results of this study suggest that better management of adverse events with nintedanib leads to more continuous treatment that prevents disease progression and acute exacerbations, thus improving prognosis in patients with IPF.

Background Although the association between nontuberculous mycobacterial lung disease (NTM-LD) and malnutrition is known, there are a few reports on the association between the nutritional score and death in patients with NTM-LD. This study investigated the association between the nutrition data at the time of NTM-LD diagnosis and death. Methods A retrospective study was conducted for patients with NTM-LD who visited the Maebashi Red Cross Hospital from January 2014 to December 2018. The patients were divided into the survival and death groups and analyzed statistically. Results The diagnostic criteria for NTM-LD were met by 150 patients. The median age was 70 years (range, 20-94 years). There were 51 (34.0%) men and 99 (66.0%) women. In the death group, the body mass index was significantly low, and there were significantly more patients with asthma. Further, computed tomography at the first visit revealed significantly fewer cases of the nodular bronchiectasis type. In the hematologic examination at the time of NTM-LD diagnosis, the white blood cell, neutrophil, and platelet counts and C-reactive protein and serum calcium levels were significantly higher in the death group, while the serum albumin level was significantly lower. In the death group, the prognostic nutritional index (PNI), calculated from the hematologic findings, was significantly lower, while the Glasgow Prognostic Score (GPS) was significantly higher. A logistic regression analysis was performed on items with significant differences, and the PNI and platelet count were independent factors predicting death. Conclusions PNI might be effective as a prognostic factor for NTM-LD.

A 69-year-old woman was diagnosed with sarcoidosis, which was not treated with corticosteroid therapy. Her levels of angiotensin converting enzyme decreased significantly over 4 years and a mass lesion was detected near the lower part of her left main bronchus, and diagnosed as small cell lung cancer (SCLC). Treatment of the SCLC with a series of chemotherapeutic agents produced excellent results. The pulmonary sarcoidosis did not show any deterioration despite the frequent use of amrubicin, which is known to be a cause of interstitial pneumonia. This is a case report of SCLC complicated with sarcoidosis in a stage of spontaneous remission, possibly suggesting an association between sarcoidosis and tumor immunity, since recent reports have suggested that immune checkpoint inhibitors might be involved in the development of sarcoidosis.

Immune reconstitution inflammatory syndrome (IRIS) is an immune reaction that occurs along with the recovery of the patient's immunity. Tuberculosis-related IRIS (TB-IRIS) upon tumor necrosis factor (TNF)-&alpha, inhibitor treatment has been reported in non-human immunodeficiency virus (HIV) patients. However, the importance of biological treatment, as a risk factor of IRIS, has not yet been established. In this study, we examined TB-IRIS in non-HIV patients to explore the role of TNF-&alpha, inhibitor treatment. Out of 188 patients with pulmonary TB, seven patients had IRIS. We examined univariate logistic and multivariate analysis to elucidate risk factors of TB-IRIS. Univariate analysis indicated that usage of immunosuppressive drugs, TNF-&alpha, inhibitors, and history of food or drug allergy were significantly related with TB-IRIS. On initial treatment, the values of serological markers such as serum albumin and serum calcium were significantly related with TB-IRIS. There was a higher mortality rate in patients with TB-IRIS. Furthermore, multivariate analysis revealed that usage of TNF-&alpha, inhibitors, history of allergy, and serum hypercalcemia were related to TB-IRIS. Usage of TNF-&alpha, inhibitors, history of allergy, and serum hypercalcemia may be independent predictors of TB-IRIS in non-HIV patients. Since higher mortality has been reported for TB-IRIS, we should pay attention to TB patients with these risk factors.

Periostin, an extracellular matrix molecule, is associated with idiopathic pulmonary fibrosis (IPF). It is known that the frequency of familial IPF (FIPF) ranges from 0.5% to 2.2% among IPF cases. However, the relationship between periostin and FIPF has not been previously described. We report the first case of periostin accumulation in the lungs of a patient with an acute exacerbation of FIPF. A 72-year-old woman, diagnosed with FIPF, had been followed up for 5 years. The patient experienced increased dyspnea within a 1-month period and was referred to our hospital. The patient was hypoxic, and chest computed tomography showed rapidly expanding bilateral reticular shadows. Despite pulse-steroid and intravenous-cyclophosphamide therapy, the patient died 25 days after admission. On admission, serum periostin levels were not significantly elevated, while serum fibrotic marker levels were elevated. Immunohistochemical analysis of the lungs on autopsy showed marked accumulation of periostin in the active fibrotic lesions, whereas intact and burned-out areas did not show significant expression of periostin. This case might provide insight into the role of periostin in acute exacerbation of IPF.

A 66-year-old man had been treated with prednisolone for eosinophilic pneumonia for 8 years. His slowly progressing cough and dyspnea were accompanied by elevated levels of fibrotic serological markers and an increased reticular shadow on chest computed tomography images. The patient had recently tested positive for anti-EJ antibodies, a type of anti-aminoacyl-tRNA synthetase antibody; therefore, we diagnosed him with an exacerbation of interstitial pneumonia due to anti-synthetase syndrome (ASS). He was treated with tacrolimus and an increased prednisolone dosage. We herein present the first reported case of eosinophilic pneumonia preceding anti-EJ antibody-positive ASS.

Background and objectives: Idiopathic pulmonary fibrosis (IPF) has a particularly poor prognosis, and most IPF-related deaths are due to acute exacerbation (AE) of this condition. Few reports about biomarkers to predict prognosis of AE-IPF have been published since the release of the new AE-IPF criteria in 2016. The present study investigated relationships between serological markers and in-hospital mortality after the onset of AE-IPF. Methods: Demographic, serological, and imaging data from patients hospitalized at the Maebashi Red Cross Hospital (Gunma, Japan) between 1 January 2013, and 31 December 2017, were retrospectively reviewed. Subjects fulfilling the diagnostic criteria for AE-IPF were divided into those who survived or died, statistical analysis of risk factors was performed using data from these two groups. Results: Diagnostic criteria for AE-IPF were fulfilled by 84 patients (59 males (70.2%)), with a median age of 78 years (range, 56&ndash, 95 years). IPF was diagnosed before hospitalization in 50 (59.5%) patients and 38 (45.2%) died in hospital. Among the serological markers at hospitalization in the deceased group, C-reactive protein (CRP) was significantly higher than in the survivor group (p = 0.002), while total serum protein (p = 0.031), albumin (p = 0.047) and total cholesterol (p = 0.039) were significantly lower. Cox hazard analysis of factors predicting mortality, corrected for age, sex and BMI, revealed the following: CRP (hazard ratio (HR) 1.080 (95% confidence interval (CI) 1.022&ndash, 1.141), p = 0.006), LDH (HR 1.003 (95% CI 1.000&ndash, 1.006), p = 0.037), and total cholesterol (HR 0.985 (95% CI 0.972&ndash, 0.997), p = 0.018). Conclusions: Our data suggest that CRP, LDH, and total cholesterol may be biomarkers predicting mortality in patients with AE-IPF. However, only prospective controlled studies can confirm or not our observation as a generalizable one.

Background: Antifibrotic agents have been approved for the treatment of idiopathic pulmonary fibrosis (IPF). However, the efficacy of these drugs in the treatment of familial IPF (FIPF) has not been previously reported. Case presentation: We report the case of a 77-year-old man with FIPF, successfully treated with pirfenidone. His uncle died due to IPF, and his niece was diagnosed with the disease. He had worsening dyspnea two months prior to admission to our hospital. Upon admission, he had desaturation when exercising and broad interstitial pneumonia. Administration of pirfenidone improved his dyspnea, desaturation, and the reticular shadow on his chest radiograph. Increased fibrotic marker levels KL-6 and SP-D were also normalized in six months; treatment had no effect on his serum periostin level. Pirfenidone has been effective for over two years. Conclusion: Antifibrotic agents such as pirfenidone may be useful for the management of FIPF, as well as cases of sporadic IPF.

Background: Resolution of inflammation is an active process essential for tissue homeostasis. Resolvin E series are potent pro-resolving mediators of inflammation derived from the omega-3 fatty acid eicosapentaenoic acid (EPA). Resolvin E3 (RvE3) is a novel lipid mediator recently identified as a member of the Resolvin E series. Aims and Objects: We determined the impact of RvE3 on allergic airway inflammation using a murine model of asthma. Methods: Allergic airway inflammation was induced in BALB/c mice by House dust mite (HDM) sensitization and challenge (Day0-2,14-17). RvE3 was administrated intraperitoneally after the last HDM challenge(Day17,18). Leukocytes from the bronchoalveolar lavage fluid (BALF) were enumerated, and the lung tissue was used for pathological analysis and assessment of expression of cytokine in the lung. Lung resistance was measured and reported as the percent increase from baseline. Results: RvE3 treatment significantly reduced airway eosinophil recruitment, levels of Th2 cytokine (IL-5 and IL-13), and lung resistance to inhaled methacholine. RvE3 treatment improved airway hyper-responsiveness and airway inflammation. Conclusion: These findings provide evidence for RvE3 as a pivotal counterregulatory signal in allergic inflammation.

A 41-year-old woman treated with isoniazid (INH) for latent tuberculosis infection and an oral corticosteroid for sarcoidosis developed severe anemia two months after initiating INH. A bone marrow examination showed erythroblastopenia, and a diagnosis of INH-induced pure red cell aplasia (PRCA) was made. Her reticulocyte count and hemoglobin levels improved two weeks after discontinuation of INH. A literature review of INH-induced PRCA shows that it occurs very rarely in the context of autoimmune disorders. This report describes a case of INH-induced PRCA occurring in a patient with sarcoidosis.

Introduction: The pH of the interstitium and the bronchoalveolar space has been shown to fall in airway inflammatory disease, such as bronchial asthma. Proton-sensing T-cell death associated gene 8 (TDAG8) is mainly expressed in hematopoietic cells. We have previously reported that TDAG8 is a negative regulator for lung neutrophilic inflammation and injury, in part, through the inhibition of chemokine production in the lipopolysaccharide-induced lung injury model. In the allergic airway inflammation, such as bronchial asthma, the role of TDAG8 has not been investigated in detail. Aims: We explored the role of TDAG8 in the allergic airway inflammation with an ovalbumin (OVA)-induced asthma model. Methods: To determine the expression profile of proton-sensing GPCRs, we measured the mRNA expression in lung tissues. TDAG8-deficient (TDAG8-KO) and wild-type (WT) mice were assigned to the following two groups: OVA group, intraperitoneal sensitization and airway challenge with OVA, and control group, those with PBS. Two days after the final challenge, we measured the number of bronchoalveolar lavage (BAL) fluid cells and mRNA expression in lungs. Histological analysis of lung sections was also performed. Results: TDAG8 was expressed in lung tissues. The mRNA expression of TDAG8 and MUC5AC in lungs and eosinophil accumulation in BAL fluids were all increased in OVA group. The OVA-induced eosinophil accumulation and MUC5AC expression in lungs were lower in TDAG8-KO mice than those in WT mice. Conclusions: Our results suggest that absence of TDAG8 protects against OVA-induced allergic airway inflammation and TDAG8 plays an important role in the pathogenesis of asthma.

Idiopathic pulmonary fibrosis (IPF) is a chronic inflammatory disease with progressive destruction and dysfunction. Currently, none of therapies has great impact on long-term survival of IPF. 17(R)-ResolvinD1 (RvD1) is well known as a lipid mediator which has potent anti-inflammatory pro-resolving activity. Previous reports have shown RvD1 is efficacious on some inflammatory diseases through promotion of resolution. However, the effect of RvD1 on lung fibrosis which has been already formed remains unclear. Enhanced collagen deposition underlying IPF partly depends on matrix metalloproteinase 9 (MMP-9)/tissue inhibitor of metalloproteinase 1 (TIMP-1) imblance. Based on this knowledge, we aimed to develop potent bioactions of RvD1. We used 8 week old female C57BL/6J mice divided into 4 groups: Saline (Sal)/vehicle (veh), bleomycin (BLM)/veh, Sal/RvD1, BLM/RvD1. We administered BLM subcutaneously via micro-osmotic pump and RvD1 intraperitoneally for 5 days consecutively from day 21, during fibrotic stage. At day 28, we measured cell differentiation in bronchoaveloar fluid (BALF), histology, hydroxyproline contents, CT image and mRNA of lung tissue in each group. In BLM/RvD1 group, neutrophils and macrophages in BALF were significantly decreased. Also, histology exhibited less collagen deposition and hydroxyproline content was significantly reduced. Furthermore, the decrease in lung density, as visualized by CT image, was observed. Interestingly, RvD1 brought to normal levels of MMP-9 mRNA with declining TIMP-1 mRNA even though BLM made MMP-9 mRNA decrease markedly. Our results suggest that RvD1 provides pulmonary restoration via improving MMP-9/TIMP-1 imbalance on lung fibrosis.