Search

Abstract This study investigated the utility of periostin, a matricellular protein, as a prognostic biomarker in patients with idiopathic pulmonary fibrosis (IPF) who received nintedanib. Monomeric and total periostin levels were measured by enzyme-linked immunosorbent assay in 87 eligible patients who participated in a multicenter prospective study. Forty-three antifibrotic drug-naive patients with IPF described in previous studies were set as historical controls. Monomeric and total periostin levels were not significantly associated with the change in forced vital capacity (FVC) or diffusing capacity of the lungs for carbon monoxide (DLCO) during any follow-up period. Higher monomeric and total periostin levels were independent risk factors for overall survival in the Cox proportional hazard model. In the analysis of nintedanib effectiveness, higher binarized monomeric periostin levels were associated with more favorable suppressive effects on decreased vital capacity (VC) and DLCO in the treatment group compared with historical controls. Higher binarized levels of total periostin were associated with more favorable suppressive effects on decreased DLCO but not VC. In conclusion, higher periostin levels were independently associated with survival and better therapeutic effectiveness in patients with IPF treated with nintedanib. Periostin assessments may contribute to determining therapeutic strategies for patients with IPF.

Abstract Background The prognosis for acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is poor, and there is no established treatment. Hence, we aimed to investigate the effectiveness of a polymyxin B-immobilised fibre column (PMX) for the treatment of AE-IPF. Methods Data were retrospectively collected from the Japanese Diagnosis Procedure Combination database from 1 July 2010 to 31 March 2018. We identified adult patients with idiopathic pulmonary fibrosis who received high-dose methylprednisolone (mPSL) therapy and mechanical ventilation upon admission. Eligible patients (n = 5616) were divided into those receiving PMX treatment combined with high-dose mPSL (PMX group, n = 199) and high-dose mPSL alone (mPSL alone group, n = 5417). To compare outcomes between the two groups, we applied a stabilised inverse probability of treatment weighting (IPTW) using propensity scores. The primary outcome was in-hospital mortality, and the secondary outcomes were 14- and 28-day mortality and length of hospital stay. Results The in-hospital mortality rates of the PMX and mPSL alone groups were 79.9% and 76.4%, respectively. The results did not significantly differ between the two groups after performing a stabilised IPTW. The odds ratio of the PMX group compared with the mPSL alone group was 1.56 (95% confidence interval 0.80–3.06; p = 0.19). The 14- and 28-day mortality and length of hospital stay (secondary outcomes) also did not significantly differ between the two groups. Conclusions In AE-IPF patients using mechanical ventilation, the treatment outcome was not significantly better for PMX combined with high-dose mPSL than for high-dose mPSL alone.

A 45-year-old male was diagnosed with arrhythmia during a routine health examination. Findings from different modalities, such as echocardiography and radiography, were consistent with cardiac involvement in sarcoidosis. There was no ocular involvement or superficial lymph node enlargement. A chest computed tomography scan did not reveal any pulmonary lesions or bilateral hilar lymphadenopathy. To pathologically diagnose systemic sarcoidosis, transbronchial lung cryobiopsy was performed. Results showed pathological evidence of noncaseating epithelioid granulomas. Herein, we present a case in which sarcoidosis diagnosis was confirmed via transbronchial lung cryobiopsy despite the absence of respiratory lesions on computed tomography scan.

Airway-centered fibroelastosis is characterized by peribronchovascular fibroelastosis, predominantly in the upper lobes, with little-to-no pleural involvement. In this study, we describe two cases of airway-centered fibroelastosis diagnosed based on radiological and pathological findings. The first case comprised a 44-year-old man whose forced vital capacity improved over three months following treatment with nintedanib. The second case involved a 50-year-old woman who was treated with oral corticosteroids but yielded an unfavorable outcome. An effective treatment for airway-centered fibroelastosis has not yet been identified; therefore, this study may help contribute to a more thorough discussion regarding treatment strategies for this disease.

Abstract Background Although corticosteroid therapy with dose tapering is the most commonly used treatment for acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF), there is no consensus on the tapering regimen. This study aimed to investigate the association between early corticosteroid dose tapering and in-hospital mortality in patients with AE-IPF. Methods In this retrospective cohort study, we analyzed the data of a cohort from eight Japanese tertiary care hospitals and routinely collected administrative data from a cohort from 185 Japanese hospitals. Patients with AE-IPF were classified into the early and non-early tapering groups depending on whether the maintenance dose of corticosteroids was reduced within two weeks of admission. Propensity score analysis with inverse probability weighting (IPW) was performed to estimate the effect of early corticosteroid dose tapering. Results The multi-center cohort included 153 eligible patients, of whom 47 (31%) died, whereas the administrative cohort included 229 patients, of whom 51 (22%) died. Patients with early tapering tended to have a better prognosis than those without it (unadjusted hazard ratio [95% confidence interval] 0.41 [0.22–0.76] and 0.65 [0.36–1.18] in the multi-center and administrative cohorts, respectively). After IPW, the early tapering group had a better prognosis than the non-early tapering group (IPW-adjusted hazard ratio [95% confidence interval] 0.37 [0.14–0.99] and 0.27 [0.094–0.83] in the multi-center and administrative cohorts, respectively). Conclusion Early corticosteroid dose tapering was associated with a favorable prognosis in patients with AE-IPF. Further studies are warranted to confirm the effects of early corticosteroid dose tapering in patients with AE-IPF.

Genetic mechanisms influencing COVID-19 susceptibility are not well understood. Here, the authors analyzed whole blood RNA-seq data of 465 Japanese individuals with COVID-19, highlighting thousands of fine-mapped variants affecting expression and splicing of genes, as well as the presence of COVID-19 severity-interaction eQTLs.

Abstract Background Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is the leading cause of death among patients with IPF. However, there is no established treatment for this condition. Hence, we aimed to investigate the effectiveness and safety of recombinant human soluble thrombomodulin (rTM) for the treatment of AE-IPF. Methods Data were retrospectively collected from the Japanese Diagnosis Procedure Combination database from 1 January 2014 to 31 March 2018. We identified adult patients with IPF who received high-dose methylprednisolone (mPSL) therapy and mechanical ventilation upon admission. Eligible patients (n = 2814) were divided into those receiving high-dose mPSL alone (mPSL alone group, n = 2602) and rTM combined with high-dose mPSL (rTM group, n = 212). A stabilised inverse probability of treatment weighting (IPTW) using propensity scores was performed to compare outcomes between the two groups. The primary outcome was in-hospital mortality, and the secondary outcomes were 14- and 28-day mortality, bleeding events and length of hospital stay. Results The in-hospital mortality rates of the mPSL alone and rTM groups were 75.9% and 76.9%, respectively. The results did not significantly differ between the two groups after performing a stabilised IPTW. The odds ratio of the rTM group compared to the mPSL alone group was 1.15 (95% confidence interval: 0.71–1.84; p = 0.57). Moreover, the secondary outcomes did not differ significantly between the two groups. Conclusions In patients with AE-IPF who developed severe respiratory failure, rTM in addition to high-dose mPSL was not associated with a better outcome.

Adult T-cell leukemia/lymphoma (ATLL) is a human T-cell leukemia virus type 1-inducing unevenly-distributed T-cell malignancy, which is often complicated by opportunistic infections. Here, we discuss the case of a 75-year-old woman presenting with Pneumocystis pneumonia (PCP) who was subsequently diagnosed with ATLL in Tokyo, a non-endemic area of ATLL. In addition to the elevated soluble interleukin-2 receptor and the detection of flower cells in the screening blood test, the high-resolution computed tomography findings, atypical of PCP, were clues to the diagnosis of ATLL. ATLL should be considered as an underlying disease when patients present with PCP, even in non-endemic areas.

Abstract Background Drug-induced hypersensitivity syndrome (DIHS)/drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is an important adverse reaction caused by a few drugs. Reactivation of human herpesvirus 6 (HHV-6) is known to be associated with its pathogenesis. DIHS occasionally manifests as pulmonary lesions with a variety of imaging findings. Case presentation An 83-year-old woman started taking minodronic acid hydrate 5 years before admission. She noticed a generalized skin rash 44 days before admission and started oral betamethasone-d-chlorpheniramine maleate combination tablets for allergic dermatitis. She developed a fever and cough in addition to the rash, and was referred to our hospital. Laboratory data showed a high level of eosinophils and liver and biliary enzymes. Computed tomography (CT) studies revealed bilateral diffuse ground-glass opacities with ill-defined centrilobular nodules from the central to peripheral regions of the lungs. Transbronchial lung cryobiopsy specimens showed that lymphocyte infiltration was observed in the alveolar walls and fibrinous exudates and floating macrophages in the alveolar lumina. Immunohistochemistry of biopsy specimens showed more CD4+ lymphocytes than CD8+ lymphocytes, while few Foxp3+ lymphocytes were recognized. The serum anti-HHV-6 immunoglobulin G titer increased at 3 weeks after the first test. Based on these findings, we diagnosed her with DIHS. We continued care without using corticosteroids since there was no worsening of breathing or skin condition. Eventually, her clinical symptoms chest CT had improved. Minodronic acid hydrate was identified as the culprit drug based on the positive results of the patch test and drug-induced lymphocyte stimulation test. Conclusions We described the first case of DIHS caused by minodronic acid hydrate. Lung lesions in DIHS can present with bilateral diffuse ground-glass opacities and ill-defined centrilobular nodules on a CT scan during the recovery phase. Clinicians should be aware of DIHS, even if patients are not involved with typical DIHS/DRESS-causing drugs.

Abstract Corticosteroids use in coronavirus disease 2019 (COVID-19) is controversial, especially in mild to severe patients who do not require invasive/noninvasive ventilation. Moreover, many factors remain unclear regarding the appropriate use of corticosteroids for COVID-19. In this context, this multicenter, retrospective, propensity score–matched study was launched to evaluate the efficacy of systemic corticosteroid administration for hospitalized patients with COVID-19 ranging in the degree of severity from mild to critically-ill disease. This multicenter, retrospective study enrolled consecutive hospitalized COVID-19 patients diagnosed January–April 2020 across 30 institutions in Japan. Clinical outcomes were compared for COVID-19 patients who received or did not receive corticosteroids, after adjusting for propensity scores. The primary endpoint was the odds ratio (OR) for improvement on a 7-point ordinal score on Day 15. Of 1092 COVID-19 patients analyzed, 118 patients were assigned to either the corticosteroid and non-corticosteroid group, after propensity score matching. At baseline, most patients did not require invasive/noninvasive ventilation (85.6% corticosteroid group vs. 89.8% non-corticosteroid group). The odds of improvement in a 7-point ordinal score on Day 15 was significantly lower for the corticosteroid versus non-corticosteroid group (OR, 0.611; 95% confidence interval [CI], 0.388–0.962; p = 0.034). The time to improvement in radiological findings was significantly shorter in the corticosteroid versus non-corticosteroid group (hazard ratio [HR], 1.758; 95% CI, 1.323–2.337; p

Herein, we report an autopsy case of idiopathic pulmonary fibrosis (IPF) in which remarkable honeycomb cyst expansion appeared in the clinical course. Radiological findings initially showed subpleural predominant reticulation that had progressed to usual interstitial pneumonia with honeycomb cysts, along with a restrictive pattern in the pulmonary function tests. The diameter of honeycomb cysts had gradually increased, and some cysts had abruptly expanded at the end stage. Based on pathological findings of autopsy specimens, bronchiectasis, alveolar collapse due to inflammation, and check-valve mechanism caused by a slit-like orifice of the cysts could have contributed to honeycomb cyst expansion.

Pulmonary amyloidosis is a rare disease characterized by abnormal extracellular deposition of amyloid fibril in the lung tissue, and the identification of amyloid deposits is essential for its diagnosis. Surgical lung biopsy (SLB) is a standard diagnostic method for pulmonary amyloidosis. However, it has a relatively high post-procedural mortality rate. Recently, transbronchial lung cryobiopsy (TBLC) has been gradually used for diagnosing interstitial lung disease. However, its diagnostic efficacy for pulmonary amyloidosis has not yet been validated. Here, we describe two cases of pulmonary amyloidosis with deposition of amyloid light chain detected via TBLC. Since SLB is a high-risk procedure for the patients due to age and complications, TBLC was performed. Both patients presented with Congo red-positive amyloid deposits. One patient with localized pulmonary amyloidosis had a good clinical course without therapeutic intervention and was followed up. The other with systemic amyloidosis received chemotherapy and presented with a stable clinical course. TBLC can collect a larger pulmonary specimen for pulmonary amyloidosis than forceps biopsy and has fewer complications and a lower mortality rate than SLB. Thus, it can be a diagnostic method for pulmonary amyloidosis.

Background Radial endobronchial ultrasonography (R-EBUS) has been used in conjunction with transbronchial lung cryobiopsy (TBLC) to diagnose diffuse parenchymal lung disease (DPLD) and to decrease the risk of bleeding complications. The diagnostic utility of different R-EBUS signs, however, remains unknown.Objectives This study aimed to determine whether different R-EBUS signs could be used to more accurately diagnose DPLD and whether bronchial bleeding could be prevented with use of R-EBUS during TBLC.Method Eighty-seven patients with DPLD were included in this multicentre prospective study, with 49 patients undergoing R-EBUS. R-EBUS signals were characterised as displaying either dense or blizzard signs. Pathological confidence of specimens obtained from TBLC was compared between patients with dense versus blizzard signs, and severity of bronchial bleeding was determined based on whether R-EBUS was performed or not.Results All patients with dense signs on R-EBUS showed consolidation on high-resolution CT (HRCT) imaging. Pathological confidence of lung specimens was significantly higher in patients with dense signs versus those with blizzard signs (p

Background Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease characterised by chronic fibrosis, and acute exacerbation of IPF (AE-IPF) is the leading cause of death in patients with IPF. Data on the association between the body mass index (BMI) and prognosis of AE-IPF are lacking. This study was performed to evaluate the association between BMI and in-hospital mortality in patients who developed AE-IPF using a national inpatient database. Methods Using the Japanese Diagnosis Procedure Combination database, we retrospectively collected data of inpatients with AE-IPF from 1 July, 2010 to 31 March, 2018. We performed a multivariable logistic regression analysis to evaluate the association between all-cause in-hospital mortality and BMI, categorised as underweight (

Background The treatment efficacy of immune checkpoint inhibitor (ICI) and clinical outcomes in patients with non‐small cell lung cancer (NSCLC) who develop severe grade checkpoint inhibitor pneumonitis (CIP) are unclear. Here, we report on the treatment efficacy of ICI and prognosis in NSCLC patients with severe grade CIP. Methods In this retrospective cohort study, CIP severity, CIP‐related mortality, and ICI efficacy in 71 patients with advanced NSCLC treated with ICIs were evaluated. Data was obtained from the patients’ medical charts. Results All grade and severe grade CIP were observed in 22 and 11 patients, respectively. The CIP‐related mortality rate was 22.7% (N = 5). An Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score of ≥2 and pre‐existing interstitial lung disease (ILD) were significantly associated with the development of severe grade CIP (P = 0.001 and P = 0.035, respectively). The median progression‐free survival (PFS) and overall survival (OS) were significantly shorter in patients with severe grade CIP than in those without severe grade CIP (PFS 1.0 month, 95% confidence interval [CI] 0.5–2.0 vs. 3.5 months, 95% CI 2.0–5.0 months, P = 0.003; OS 3.0 months, 95% CI 0.5–13 vs. 12.7 months, 95% CI 8.0–21.0 months, P = 0.011). Conclusion CIP is a serious complication with a poor prognosis associated with high mortality. The efficacy of ICI is significantly worse in patients with severe grade CIP than in those without severe grade CIP. Whether ICIs should be administered to patients with CIP risk factors, such as an ECOG PS score of ≥2 or pre‐existing ILD, should be carefully assessed.

Severe bronchial asthma is a chronic disorder of the airways that may be accompanied by comorbid diseases. Invasive treatment, including surgery, in patients with severe asthma has limitations depending on the degree of control of the asthma. A 71-year-old woman was diagnosed with squamous cell carcinoma with high programmed death-ligand 1 (PD-L1) expression and cT3N0M1a. After 13 cycles of pembrolizumab every 3 weeks, chest computed tomography (CT) revealed a dramatic decrease in the lesion size in the left upper lobe, but the size of the lesion in the right lower lobe was significantly increased. The pathological findings of the right residual tumor by CT-guided transthoracic needle biopsy (CTNB) revealed squamous cell carcinoma with no PD-L1 expression, and right lower lobectomy was recommended. However, because the patient had frequent asthma attacks and cough, surgery was considered risky. Increased blood eosinophil count was observed, and benralizumab was administered for asthma control. The symptoms disappeared 2 days after benralizumab administration, and peak flow increased. Surgery was performed 5 days after benralizumab administration. There was a marked reduction in the eosinophil count of the surgical tissue compared with the preoperative CTNB tissue. No asthma attacks were observed during and after surgery, and the control of asthma and lung cancer was stable. Benralizumab is considered promising for the treatment of eosinophilic severe uncontrolled asthma. Keywords: Interleukin-5 receptor α monoclonal antibody, Immune checkpoint inhibitor, Lung cancer, Severe uncontrolled asthma, Video-assisted thoracic surgery

Background: The preoperative diagnosis of pulmonary sclerosing pneumocytoma (PSP) is complicated since PSP has several histological structural patterns in the same neoplasm; hence, it is sometimes pathologically misdiagnosed as adenocarcinoma or carcinoid. In recent years, with the prevalence of transbronchial cryobiopsy (TBLC), we are able to obtain larger specimens than previously. However, to date, there have been no reports describing PSP diagnosed using TBLC. Case reports: A 43-year-old man was referred to our hospital for an abnormal lesion in the left lung discovered on routine health examination. A computed tomography scan of the chest revealed a 14-mm heterogeneous round nodule with surrounding ground-glass opacity in the left lower lobe. The tumor size increased to 18 mm in three weeks, and he developed bloody sputum. TBLC was performed using radial endobronchial ultrasonography and fluoroscopy. An occlusion balloon and prophylactic epinephrine were used to prevent severe bleeding. Histologically, epithelioid cells with solid proliferation, various papillary lesions, and hemosiderin-laden histiocytes were observed. Immunohistochemical staining revealed the histiocytes positive for thyroid transcription factor-1 and vimentin, and the type II pneumocyte-like-cells positive for cytokeratin 7. The tumor was preoperatively diagnosed as a PSP; the patient underwent left basal segmentectomy and consequently, a final diagnosed of PSP was formulated. Conclusion: We report the first case of PSP preoperatively diagnosed using TBLC. Therefore, cryobiopsy could be beneficial in the preoperative diagnosis of PSP.

Transbronchial lung cryobiopsy (TBLC) has been increasingly utilised to diagnose diffuse parenchymal lung diseases (DPLDs) and lung cancers; however, TBLC protocols have not yet been standardised and the rate of complications associated with this procedure vary widely. Therefore, this prospective multicentre observational study investigated the safety and utility of the TBLC technique in patients with diffuse and localised respiratory diseases. This study was conducted at multiple medical centres in Japan between July 2018 and April 2019. The study's primary end-point was the rate of severe or serious adverse events associated with TBLC. Adverse events included bronchial bleeding, pneumothorax, pneumonia, respiratory failure, and an acute exacerbation of interstitial pneumonia. Adverse events were graded according to severity. During the TBLC procedure, an endobronchial balloon catheter for bronchial blockade was used in all patients. Pathological confidence and quality of specimens were categorised into three groups. A total of 112 patients were included. Neither severe nor serious adverse events were identified; therefore, the primary end-point was met. Nineteen patients (17%) experienced no bronchial bleeding. Mild or moderate bronchial bleeding was identified in 67% and 16% of patients, respectively. Mild pneumothoraces were identified in four patients (3.6%). The safety profile in patients aged ≥75 years was not significantly different from younger patients. Definite or probable pathological diagnoses were made in 84.9% of patients. This TBLC protocol with routine use of an endobronchial balloon had an acceptable safety profile and diagnostic yield in patients, including elderly ones, with diffuse and localised respiratory diseases.

Objective: In 2014, an autochthonous dengue fever outbreak occurred around the Yoyogi Park in Japan for the first time in 70 years. Despite no local cases reported since then, the risk of another outbreak remains high. This study reviews the autochthonous dengue fever cases of the outbreak, investigates its causes, and delineates preventive measures against autochthonous dengue epidemics. Methods: We conducted a case series study of 15 patients who visited our institution during the 2014 outbreak. We collected and evaluated data on the surveillance of vector mosquitoes, weather, pest control, travelers’ origins and destinations, and imported dengue fever cases using reports made by public institutions. Results: All patients recovered with supportive treatments and none met the diagnostic criteria for severe dengue infection. Twelve patients with positive real-time polymerase chain reactions were confirmed as having dengue virus-1 infections. We found no obvious associations between the number of mosquitoes and the weather, or between the number of imported dengue fever cases and that of travelers. Insect growth regulator (IGR) against vector mosquitoes has been used since 2014 for pest control, but the number of larvae has not declined in the Yoyogi Park, although that of imagoes has been relatively suppressed. Conclusion: The 2014 outbreak emerged without particularly favorable climate conditions for vector mosquitoes. We found no obvious associations between the number of travelers or the imported dengue fever cases and the outbreak, but the increasing number of travelers may contribute to another outbreak. Pest control, including IGR, remains essential for infection control.

Chronic eosinophilic pneumonia (CEP) is an eosinophilic inflammatory disease of unknown etiology, and oral corticosteroid (OCS) is commonly used for its treatment. Approximately half of CEP cases relapse secondary to reduction or termination of OCS. A 43-year-old woman visited our hospital because of a chronic cough and abnormal chest X-ray findings. She was diagnosed with CEP because of marked eosinophilia, as well as eosinophilic infiltrates in cryobiopsy samples. After initiation of OCS treatment, her symptoms disappeared with a decrease in peripheral blood eosinophil counts and the amelioration of abnormal infiltrative shadows on chest X-ray. However, symptoms reappeared after OCS termination, including a recurrence of eosinophilia and appearance of fresh abnormal shadows on chest X-ray. Because she refused readministration of OCS because of side effects such as appetite enhancement and moon face in last treatment course, we administered her a single dose of benralizumab. Her symptoms and peripheral eosinophil counts were markedly ameliorated 1 week after benralizumab administration. The marked amelioration in abnormal shadows on chest X-ray were maintained 2 weeks after benralizumab administration. She had no relapse of CEP for almost 6 months after benralizumab administration. Our experience with this case suggests that a single dose of benralizumab may be a treatment option for relapsed CEP cases or those with side effects of long-term OCS therapy.

Background: Thoracoscopic pleural biopsy is an efficient procedure in patients with undiagnosed exudative pleurisy. Rigid or flexible forceps have been widely used for this procedure. Recently, the use of cryo-techniques was reported in pleural biopsy during semi-rigid thoracoscopy; however, the feasibility and safety of pleural cryobiopsy in elderly patients have not yet been fully elucidated. Case reports: We describe two elderly patients who safely underwent semi-rigid thoracoscopic cryobiopsy and were diagnosed with tuberculous pleurisy. Both were >85 years of age, and chest auscultation revealed reduced breath sounds in the right lower zones. Laboratory investigations revealed an elevated level of C-reactive protein without leukocytosis in both patients. Computed tomography scan of the chest revealed right pleural effusion in both patients. Pleural fluid biochemical analysis results were indicative of an exudate. Sputum cultures demonstrated no bacterial growth and smears were negative for the presence of acid-fast bacilli. For definitive diagnosis, pleural biopsy was performed via thoracoscopic cryobiopsy. Specimens obtained from the cryoprobe demonstrated 200-300-μm caseating and non-caseating epitheloid cell granulomas with Langerhans type giant cells. Based on the above results, both patients were diagnosed with TB pleurisy. Anti-tuberculosis treatment resulted in good clinical outcome in both patients. Conclusion: Cryobiopsy is easier and more efficient than biopsy with conventional forceps. Our findings in these patients suggest that semi-rigid thoracoscopic cryobiopsy might be a useful alternative diagnostic method for undiagnosed pleural effusion in elderly patients. Keywords: Semi-rigid pleuroscopy, Cryobiopsy, Tuberculous pleurisy, Elderly

Abstract Background Idiopathic pulmonary fibrosis (IPF) is a progressive disease with high mortality, and the pathogenesis of the disease is still incompletely understood. Although lymphocytes, especially CD4+CD25+FoxP3+ regulatory T cells (Tregs), have been implicated in the development of IPF, contradictory results have been reported regarding the contribution of Tregs to fibrosis both in animals and humans. The aim of this study was to investigate whether a specific T cell subset has therapeutic potential in inhibiting bleomycin (BLM)-induced murine pulmonary fibrosis. Methods C57BL/6 mice received BLM (100 mg/kg body weight) with osmotic pumps (day 0), and pulmonary fibrosis was induced. Then, splenocytes or Tregs were adoptively transferred via the tail vein. The lungs were removed and subjected to histological and biochemical examinations to study the effects of these cells on pulmonary fibrosis, and blood samples were collected by cardiac punctures to measure relevant cytokines by enzyme-linked immunosorbent assay. Tregs isolated from an interleukin (IL)-10 knock-out mice were used to assess the effect of this mediator. To determine the roles of the spleen in this model, spleen vessels were carefully cauterized and the spleen was removed either on day 0 or 14 after BLM challenge. Results Splenocytes significantly ameliorated BLM-induced pulmonary fibrosis when they were administered on day 14. This effect was abrogated by depleting Tregs with an anti-CD25 monoclonal antibody. Adoptive transfer of Tregs on day 14 after a BLM challenge significantly attenuated pulmonary fibrosis, and this was accompanied by decreased production of fibroblast growth factor (FGF) 9-positive cells bearing the morphology of alveolar epithelial cells. In addition, BLM-induced plasma IL-10 expression reverted to basal levels after adoptive transfer of Tregs. Moreover, BLM-induced fibrocyte chemoattractant chemokine (CC motif) ligand-2 production was significantly ameliorated by Treg adoptive transfer in lung homogenates, accompanied by reduced accumulation of bone-marrow derived fibrocytes. Genetic ablation of IL-10 abrogated the ameliorating effect of Tregs on pulmonary fibrosis. Finally, splenectomy on day 0 after a BLM challenge significantly ameliorated lung fibrosis, whereas splenectomy on day 14 had no effect. Conclusions These findings warrant further investigations to develop a cell-based therapy using Tregs for treating IPF.

Correct staging of lung cancer is important for the selection of the best therapy, but discriminating between lymphadenopathy from lung cancer and from sarcoidosis by imaging examinations is difficult. Additionally, distinguishing lymphadenopathy of sarcoidosis from sarcoid reactions which are sometimes caused by lung cancer is difficult on imaging and pathological findings. A 73-year-old woman was diagnosed as lung cancer clinical T1bN3M0 stage ШB based on false-positive 18F-fluoro-2-deoxyglucose positron emission tomography uptake. Because the effects of chemotherapy were different between the lymphadenopathy and the primary lesion, endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) was performed and revealed sarcoidosis as the cause of the lymphadenopathy with using a specific monoclonal antibody against Propionibacterium acnes (PAB antibody). Accordingly, the stage was changed to clinical T1bN0M0 stage ІA, for which radical operation was performed. EBUS-TBNA should be performed aggressively when the effect of chemotherapy is different between lymphadenopathies and other lesions, and the PAB antibody can help to discriminate between sarcoidosis and sarcoid reactions caused by lung cancer. The combination of EBUS-TBNA and the PAB antibody is expected to be valuable in the definitive diagnosis of a lymphadenopathy for the staging of lung cancer. Keywords: Endobronchial ultrasound-guided transbronchial needle aspiration, 18F-fluoro-2-deoxyglucose positron emission tomography, Propionibacterium acnes, A specific monoclonal antibody against Propionibacterium acnes