Effect of warm and humid days on the positivity rate of anti-Trichosporon asahii antibody test for the diagnosis of summer-type hypersensitivity pneumonitis.

BACKGROUND: Summer-type hypersensitivity pneumonitis (SHP) has been reported to occur during warm and humid summer seasons in Japan; however, the effect of weather conditions on SHP remains unknown. Anti-Trichosporon asahii antibody (TaAb) test is highly specific and useful for the diagnosing SHP. Therefore, we aimed to investigate the impact of weather conditions on SHP by examining the relationship between the positivity rate of TaAb and warm and humid days. METHODS: TaAb test data from June 2013 to June 2020 were obtained from major commercial laboratories to determine the number of samples and positivity rate of TaAb by prefecture. Using the Japan Meteorological Agency database, we counted the warm and humid days (maximum temperature ≥25 °C and average humidity ≥80 %) for each prefecture. Negative binomial regression was employed to examine the relationship between the positivity rate of TaAb and the number of warm and humid days per month. RESULTS: A total of 79,211 samples and 7626 positive samples (9.6 %) were identified. We found that the number of warm and humid days, 1 or 2 months prior to testing for TaAb, was associated with the positivity rate of the test. An increase in the positivity rate by 1.6 % and 2.9 % was observed with every 1-day increase in warm and humid days 1 month and 2 months before the test, respectively. CONCLUSIONS: Our TaAb analysis revealed a significant increase in TaAb positivity 1 or 2 months after periods of warm and humid days.

Database analysis of hypersensitivity pneumonitis in Japan.

BACKGROUND: Three epidemiological small-scale studies on hypersensitivity pneumonitis (HP) have been performed in Japan to date. Herein, we aimed to clarify the clinical characteristics of various types of HP diseases using a large nationwide database in Japan. METHODS: We used the Japanese Diagnostic Procedure Combination database that includes data from 1,031 participant hospitals. Patients with HP from 2011 to 2017 were identified using International Classification of Diseases 10th Revision codes. We analyzed patient characteristics, the yearly transition of the number of HP cases, rate per one million hospitalizations, geographical distribution, seasonality, and risk factors for in-hospital mortality. RESULTS: In total, 3,634 patients with HP were identified, including summer-type HP (SHP) (n = 490), bird fancier's lung (BFL) (n = 199), ventilation pneumonitis (n = 106), farmer's lung (n = 48), and unspecified HP (n = 2761). The length of hospital stay was significantly longer in patients with BFL (19 days) than in patients with SHP (15 days). SHP was more prevalent in the southwestern region of Japan, and hospitalization occurred mainly in summer (37.8%) and fall (37.3%). Ventilation pneumonitis was predominant in winter (28.6%) and spring (38.7%). In-hospital mortality was significantly associated with old age (p < 0.001), low body mass index (p = 0.016), severe dyspnea (p < 0.001), and BFL diagnosis on admission (p = 0.031). CONCLUSIONS: This study revealed the clinical characteristics of SHP and BFL, including the frequency of causative antigens, geographical distribution, seasonality, and risk factors for mortality, which may help in diagnosing HP and identifying causative antigens.

Mass-like Lesions Causing Compression of Large Vessels in Granulomatosis with Polyangiitis.

A 69-year-old woman with a history of otitis media with anti-neutrophil cytoplasmic antibody-associated vasculitis who had been receiving corticosteroid monotherapy presented with shortness of breath. The otitis media had been alleviated, but she had saddle nose. Chest enhanced computed tomography showed stenoses of the bronchi and large vessels surrounded by mass-like lesions in the mediastinum. These manifestations indicated an active state of granulomatosis with polyangiitis (GPA). After she was started on high-dose corticosteroids and intravenous cyclophosphamide, the mass-like lesions disappeared with improvements of the stenoses. Ameliorating mass-like lesions resulting from GPA requires therapeutic intervention using corticosteroids and immunosuppressants.

Pleurisy with pneumothorax due to CAM-resistant MAC lung disease.

A 72-year-old man received rifampicin, ethambutol and sitafloxacin to treat clarithromycin (CAM)-resistant Mycobacterium avium complex (MAC) lung disease. He was admitted because of fever. Pneumothorax and pleural effusion were present in the right lung, and a new consolidation appeared in the right upper lobe. Based on positive culture of the pleural effusion for CAM-resistant M. avium and findings on chest computed tomography, he was diagnosed with pleurisy due to M. avium, with rupture of the subpleural lung parenchymal lesion into the pleural space. Additional treatment with streptomycin (SM) improved the patient's high-grade fever. SM might be effective for pleurisy caused by CAM-resistant MAC lung disease.

Profile of metastatic lung cancer patients susceptible to development of thromboembolism during immunotherapy.

BACKGROUND: Thromboembolism (TE) is a serious complication in lung cancer patients; however, risk factors for developing TE during treatment with immuno-oncology (IO) drugs are unclear. MATERIALS AND METHODS: A retrospective study of lung cancer patients hospitalized in Tokyo Medical and Dental University was performed to clarify the association between TE and systemic therapy, especially IOs. Patients were divided into an IO cohort, a chemotherapy cohort (CT cohort), and a control cohort (patients without recurrence after surgery). Association studies of variables relevant to TE were performed. RESULTS: A total of 592 patients were enrolled (IO cohort, 120; CT cohort, 294; control cohort, 178). Eight patients (6.7%) in the IO cohort, seven (2.4%) in the CT cohort, and three (1.7%) in the control cohort developed TE. Least Absolute Shrinkage and Selection Operator (LASSO) regression analysis identified IO, a history of TE, poor performance status (PS), and prior anticoagulation therapy as being associated with TE. Subsequent multivariate logistic regression analysis identified a history of TE (odds ratio (OR), 6.03; 95% confidence interval (CI), 2.09-17.40; P = 0.01) and poor PS (OR, 3.84; 95% CI, 1.34-11.00; P < 0.001) as potential risk factors for developing TE. The incidence of TE in the IO cohort patients with both of these characteristics was significantly higher (OR, 52.82; 95% CI, 6.72-506.37; P < 0.001) than that in the control cohort. CONCLUSION: Lung cancer patients with a history of TE and poor PS are at increased risk of TE during treatment with IOs. MICRO ABSTRACT: The profiles of lung cancer patients susceptible to development of thromboembolism (TE) during immunotherapy are unclear, even though TE is associated with a worse prognosis. Here, association studies of variables relevant to TE revealed that patients with a history of TE and poor performance status are at higher risk of developing TE during immunotherapy.

Non-inferior clinical outcomes of immune checkpoint inhibitors in non-small cell lung cancer patients with interstitial lung disease.

OBJECTIVES: The efficacy of immune checkpoint inhibitors (ICIs) in non-small-cell lung cancer (NSCLC) patients with pre-existing interstitial lung disease (ILD) is unclear. MATERIALS AND METHODS: Retrospective medical data from advanced or recurrent NSCLC patients who were treated with nivolumab or pembrolizumab at ten institutions in Japan between January 2016 and September 2018 were analyzed. Eligible patients were divided into two groups according to the presence of pre-existing ILD. RESULTS: A total of 461 NSCLC patients were enrolled, 412 without ILD (Non-ILD group) and 49 with ILD (ILD group). The response rate (RR) and disease control rate (DCR) of the ILD group were not inferior to those of the Non-ILD group [RR: 49.0 % (24/49) vs. 30.1 % (124/412), P < 0.01 and DCR: 69.4 % (34/49) vs. 51.2 % (211/412), P = 0.016, respectively]. Non-inferior outcomes were also observed with respect to progression-free survival (PFS) and overall survival (OS) (median PFS: 5.9 months vs. 3.5 months, P = 0.14 and median OS: 27.8 months vs. 25.2 months, P = 0.74 in the ILD and Non-ILD groups, respectively). Among immune-related adverse effects (irAEs), checkpoint inhibitor pneumonitis (CIP) was more frequently observed among NSCLC patients in the ILD group [30.6 % (15/49) vs. 9.5 % (39/412), P < 0.01]. The frequency of irAEs other than CIP and infusion reactions was not significantly different between the ILD group and the Non-ILD group. CONCLUSION: These results suggest that the clinical outcomes of ICIs are not significantly affected by pre-existing ILD despite the increased frequency of CIP. NSCLC patients with ILD are therefore probable candidates for ICIs.

Changes in serum KL-6 levels during short-term strict antigen avoidance are associated with the prognosis of patients with fibrotic hypersensitivity pneumonitis caused by avian antigens.

BACKGROUND: Bird-related hypersensitivity pneumonitis (BRHP) is the most common type of fibrotic hypersensitivity pneumonitis (HP). Antigen avoidance (AA) is a key step in the diagnosis and management of HP, but not all fibrotic HP patients improve through AA. Because of the poor prognosis of fibrotic HP, predictive biomarkers to identify patients showing rapid progression during AA are urgently needed. METHODS: From a retrospective review of the medical records of 1941 patients with interstitial lung disease, 75 cases of fibrotic BRHP confirmed by a provocation test or surgical lung biopsy were identified. To identify potential prognostic markers obtained at or around diagnosis, physiological and serological variables at diagnosis and the relative changes in those variables during strict AA were evaluated. Cox proportional hazards models with log-rank testing were used to compare the associations between these variables and survival. RESULTS: Univariate analyses showed that gender, smoking status, and the relative change in the serum levels of Krebs von den Lungen-6 (KL-6) were associated with prognosis (P = 0.02, 0.04, and 0.02, respectively), but the presence of honeycombing and the forced vital capacity were not associated with survival. The relative change in KL-6 levels (greater than vs. less than a 10% decrease) was significantly associated with survival in a stratified analysis (73.9 vs. 34.9 months; P = 0.04). CONCLUSIONS: The relative change in KL-6 levels is associated with the prognosis of patients with fibrotic BRHP independent of previously identified prognostic biomarkers. This finding could help pulmonologists identify fibrotic BRHP patients that are likely to show rapid progression.

The utility of ground-glass attenuation score for anticancer treatment-related acute exacerbation of interstitial lung disease among lung cancer patients with interstitial lung disease.

BACKGROUND: Acute exacerbation (AE) of interstitial lung disease (ILD) is a fatal adverse event in the treatment of lung cancer patients with ILD. The value of pre-treatment radiological findings obtained by high-resolution computed tomography for the detection of anticancer treatment-related AE of ILD has not been established. METHODS: Two medical record-based retrospective studies were performed. The chemotherapy cohort included 105 lung cancer patients with ILD who received chemotherapy at Tokyo Medical and Dental University between October 2008 and December 2017. The immune checkpoint inhibitor (ICI) cohort included 48 advanced non-small cell lung cancer patients with ILD treated with ICIs at nine institutions between January 2016 and September 2018. Variables were compared between AE-positive and -negative groups. Candidate variables were analyzed by multivariate logistic regression. A P value < 0.05 was considered statistically significant. RESULTS: Anticancer treatment-related AE of ILD occurred in 12 patients (11.4%) in the chemotherapy cohort and seven patients (14.5%) in the ICI cohort. In the multivariate logistic regression analysis, ground-glass attenuation (GGA) score was the only factor significantly associated with the development of AE of ILD in both cohorts (P = 0.037 and 0.01 in the chemotherapy and ICI cohorts, respectively). CONCLUSION: Evaluation of GGA may help predict anticancer treatment-related AE of ILD.

Real world data of combined lung cancer and interstitial lung disease.

BACKGROUND: Research patients with combined lung cancer (LC) and interstitial lung disease (ILD) is insufficient. The objective of the study was to identify the frequency of such patients and treatments, including best supportive care (BSC), in the real world. METHODS: All patients with LC who were admitted to our hospital over a 5-year period from 2013 to 2017 were retrospectively analysed. RESULTS: In this study, 698 patients with LC were enrolled. A total of 148 (21.2%) suffered from LC and ILD. Seventy-one LC-ILD patients received chemotherapy, and 20 LC-ILD patients received BSC only. Eleven BSC patients whom physicians thought could receive therapy declined treatment. The median survival time of patients who received chemotherapy was 14.3 months (95% confidence interval, 8.5-19.4 months). The median survival time of BSC patients who declined treatment was 7.2 months and that was shorter than that of patients who received chemotherapy. CONCLUSIONS: This study suggests that patients with combined LC and ILD are common (21.2%) in the real world, and there is the possibility that therapy for LC-ILD patients is beneficial.

[A Case of Pulmonary Enteric Adenocarcinoma with Soleus Muscle Metastasis].

Pulmonary enteric adenocarcinoma is a unique pulmonary adenocarcinoma subtype and has histopathological findings that are similar to those of colorectal adenocarcinoma. A man in his 50s visited our hospital because of discomfort in his right lower leg for the last 9 months. Imaging studies revealed a mass in his right soleus muscle, and needle biopsy was performed. Histological findings revealed adenocarcinoma, and immunohistochemical staining showed that the tumor cells were positive for CK20 and CDX-2. The tumor was first suspected to be metastasis of gastrointestinal malignant tumors. FDG-PET/CT showed increased FDG uptake in the right soleus muscle mass and presented with increased FDG uptake in a right upper lobe mass and right mediastinum lymphadenopathy. There were no findings in other organs. Scraping cytology of a transbronchial biopsy indicated adenocarcinoma. Upper and lower gastrointestinal endoscopy showed no findings of malignancy. He was finally diagnosed with pulmonary enteric adenocarcinoma(cT3N2M1b, Stage ⅣA). Treatment with cisplatin(CDDP), pemetrexed( PEM), and bevacizumab(BEV) was initiated. After 4 courses of the regimen, the tumor was partially reduced, and the patient showed stable disease(SD).

Acute inflammatory and immunologic responses against antigen in chronic bird-related hypersensitivity pneumonitis.

BACKGROUND: Hypersensitivity pneumonitis (HP) is an immune-mediated lung disease induced by the inhalation of a wide variety of antigens and a persistent antigen exposure induces inevitably pulmonary fibrosis in chronic HP. Although neutrophils, Th1 and Th17 cells contribute to lung inflammation in acute phase of HP, there is no clear explanation as to how the immunological reaction occurs just after the inhalation of causative antigens in the chronic phase of HP. METHODS: We examined the inflammatory and immunologic profiles before and after the inhalation provocation test (IPT) in serum and bronchoalveolar lavage fluid (BALF) from patients with chronic bird-related HP (BRHP) and other interstitial lung diseases (ILDs). We analyzed BALF samples from 39 patients (19 BRHP and 20 other ILDs) and serum samples from 25 consecutive patients (20 BRHP and 5 other ILDs) who underwent the IPT. RESULTS: A significant increase of neutrophils was observed in the BALF from the BRHP patients following the IPT. Neutrophil chemoattractants, namely, granulocyte colony-stimulating factor, IL-6, IL-8, IL-17, and CXCL2 significantly increased in both the serum and BALF of the BRHP patients after the IPT. Serum IFN-γ and CXCL10, cytokines/chemokines that contributed to Th1 inflammation, were also significantly increased in BRHP following the IPT. CONCLUSIONS: This study demonstrated the exposure to the causative antigen provoked acute neutrophilic and Th1 immunologic responses similar to acute HP even in the chronic phase of HP.

[A CASE OF ACUTE EXACERBATION OF CHRONIC BIRDRELATED HYPERSENSITIVITY PNEUMONITIS WITH A REMARKABLE ELEVATION OF ENVIRONMENTAL AVIAN ANTIGEN LEVELS].

A man in his 60's with interstitial pneumonitis who was previously admitted to another hospital was transferred to our hospital for further investigations 6 years prior to an acute exacerbation. Given his history of avian contact, the presence of antibodies specific to avian antigen, and a positive result of the inhalation provocation test using pigeon dropping extracts, he was diagnosed with bird-related hypersensitivity pneumonitis (BRHP). As such, we instructed the patient to avoid exposure to avian antigen, and regularly measured the level of avian antigen in dust samples collected from his household environment. Despite avoiding the stimulus, corticosteroids and immunosuppressants were needed in view of progression of dyspnea after approximately five to six years. Four months after immunosuppressant therapy began, the patient suffered an acute exacerbation of BRHP and died. At this time, we found that the level of avian antigen was much higher than baseline. We suggest that exposure to high level of avian antigen is one cause of an acute exacerbation of BRHP.

Cyclopamine and quercetin suppress the growth of leukemia and lymphoma cells.

BACKGROUND: Hedgehog (Hh) and Wnt signaling pathways are involved in the stimulation of growth of leukemia and lymphoma cells. In the present study, whether or not the Hh inhibitor, cyclopamine, and the Wnt inhibitor, quercetin, suppress cell growth was investigated. MATERIALS AND METHODS: The effects of cyclopamine and quercetin on the in vitro growth and protein expression of ten acute leukemia and B-cell lymphoma cell lines were examined. RESULTS: Cyclopamine and quercetin suppressed cell growth and induced apoptosis in seven and eight cell lines respectively. Cyclopamine decreased the level of Gli1 protein, a target gene product of Hh signaling. Quercetin decreased the level of Notch1 protein and its active fragment in the DND-41 T-lymphoblastic leukemia cell line with constitutive Notch activation. CONCLUSION: Cyclopamine and quercetin suppress the growth of a number of leukemia and lymphoma cells. This finding suggests the potential use of these compounds in molecularly-targeted therapy for leukemia and lymphoma.