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BackgroundSome patients with idiopathic interstitial pneumonia (IIP) show autoimmune features. Interstitial pneumonia with autoimmune features (IPAF) was recently proposed as a research concept in these patients. However, retrospective studies reported conflicting results of its prognosis. Therefore, this study was conducted to prospectively evaluate the clinical significance of autoimmune features in patients with IIP.MethodsThis nationwide multicentre study prospectively enrolled consecutive patients with IIP. At the diagnosis, we systematically evaluated 63 features suggestive of connective tissue diseases using a checklist including symptoms/signs and autoantibodies, which contained most items of the IPAF criteria and followed up with the patients. Clinical phenotypes were included in a cluster analysis.ResultsIn 376 patients with IIP enrolled, 70 patients (18.6%) met the IPAF criteria. The proportion of patients with IPAF was significantly lower in idiopathic pulmonary fibrosis (IPF) than in non-IPF (6.0% vs 24.3%, respectively). During a median observation period of 35 months, patients with IPAF more frequently developed systemic autoimmune diseases and had less frequent acute exacerbation of IIPs than patients with non-IPAF. IPAF diagnosis was significantly associated with better survival and was an independent positive prognostic factor in total and patients with non-IPF. Cluster analysis by similarity of clinical phenotypes identified a cluster in which there was a higher number of women, and patients had more autoimmune features and a better prognosis than other clusters.InterpretationThese observations suggest that some patients with IIP show autoimmune features with distinct characteristics and favourable prognosis. However, we were not able to determine the appropriate therapies for these patients.

Rationale: Acute exacerbation during the course of idiopathic pulmonary fibrosis causes a poor prognosis. Coagulation abnormalities and endothelial damage are involved in its pathogenesis. Thrombom...

Radiologic diagnosis of chronic hypersensitivity pneumonitis (CHP) presenting a usual interstitial pneumonia (UIP) pattern is challenging. The aim of this study was to identify the high-resolution CT (HRCT) findings which are useful to discriminate CHP–UIP from idiopathic pulmonary fibrosis (IPF). This study included 49 patients with well-established bird-related CHP–UIP, histologically confirmed, and 49 patients with IPF. Two groups of observers independently assessed HRCT, evaluated the extent of each abnormal HRCT finding. When their radiological diagnosis was CHP–UIP, they noted the HRCT findings inconsistent with IPF. Correct CT diagnoses were made in 79% of CHP–UIP and 53% of IPF. Although no apparent difference was seen in the extent of each HRCT finding, upper or mid-lung predominance, extensive ground-glass abnormality, and profuse micronodules were more frequently pointed out as inconsistent findings in CHP–UIP than IPF (p = 0.007, 0.010, 0.001, respectively). On regression analysis, profuse micronodules [OR 13.34 (2.85–62.37); p = 0.001] and upper or mid-lung predominance of findings [OR 2.86 (1.16–7.01); p = 0.022] remained as variables in the equation. In this cohort, some IPF cases were misdiagnosed as CHP–UIP. Profuse micronodules and upper or mid-lung predominance are important clues for the differentiation of CHP–UIP from IPF.

Objectives Pulmonary nontuberculous mycobacterial disease (pNTM) is a common pulmonary complication of rheumatoid arthritis (RA), but their association has rarely been researched. We aimed to reveal the clinical characteristics of RA with pNTM. Methods Among all the RA patients who visited Tenri hospital from April 2017 to March 2018, we enrolled those fulfilling the 2007 ATS/IDSA diagnostic criteria of pNTM, and sex- and age- matched control group at a ratio of 1:5. Demographic characteristics were compared between the two groups. Results Among 865 RA patients, 35 (4.0%) patients were complicated with pNTM. RA patients with pNTM had significantly lower BMI and higher rheumatoid factor (RF) and anti-citrullinated protein antibody (ACPA) positivity. Bronchiectasis was the most frequent lesion, followed by clusters of small nodules, patchy consolidation and cavity. Multivariable logistic regression analysis revealed bronchiectasis as a strong independent associated factor of pNTM. Treatment for pNTM was needed in 14 of the 35 (40%) RA patients with pNTM and sputum negative conversion was accomplished in 11 of the 14 cases (78.6%). Conclusions RA patients with lower BMI, RF/ACPA positivity, and bronchiectasis were associated with pNTM. Treatment for pNTM may attain sputum negative conversion and radiological improvement in patients with RA.

We report a rare case of a solitary synovial osteochondroma (SSO) in the cervical canal. A 37-year-old man presented with neck pain and the forearm dysesthesia developed immediately after a trivial motor accident. Because of aggravation he visited our hospital though he was treated conservatively for 3 months. A computed tomography (CT) scan showed an oval shaped small mass with high density rim in the cervical canal at the level of the C6/7 facet joint. This mass compressing the dural sac was visualized with a high intensity signal in T2-weighted magnetic resonance imaging (MRI) and, interestingly, with high intensity in T1-weighted images. A surgical removal was carried out. Macroscopically, it consists of a solitary, firm, juxta-articular mass associated with synobia but lacking connection with the adjacent bone. Microscopically, it is similar to conventional osteochondromas. It differs from this entity by not arising from a bone surface and by a whole coverage of synobial tissue. The final diagnosis was a SSO. There have been anecdotal case reports of a SSO in various site including knee, fingers, buttocks, wrist, and so on. To the best of our knowledge, this is the first case report of SSO arising in the spinal canal.

Background Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrotic lung disease that leads to respiratory failure and death. Although there is a greater understanding of the etiology of this disease, accurately predicting the disease course in individual patients is still not possible. This study aimed to evaluate serum cytokines/chemokines as potential biomarkers that can predict outcomes in IPF patients. Methods A multi-institutional prospective two-stage discovery and validation design using two independent cohorts was adopted. For the discovery analysis, serum samples from 100 IPF patients and 32 healthy controls were examined using an unbiased, multiplex immunoassay of 48 cytokines/chemokines. The serum cytokine/chemokine values were compared between IPF patients and controls; the association between multiplex measurements and survival time was evaluated in IPF patients. In the validation analysis, the cytokines/chemokines identified in the discovery analysis were examined in serum samples from another 81 IPF patients to verify the ability of these cytokines/chemokines to predict survival. Immunohistochemical assessment of IPF-derived lung samples was also performed to determine where this novel biomarker is expressed. Results In the discovery cohort, 18 cytokines/chemokines were significantly elevated in sera from IPF patients compared with those from controls. Interleukin-1 receptor alpha (IL-1Rα), interleukin-8 (IL-8), macrophage inflammatory protein 1 alpha (MIP-1α), and cutaneous T-cell-attracting chemokine (CTACK) were associated with survival: IL-1Rα, hazard ratio (HR) = 1.04 per 10 units, 95% confidence interval (95% CI) 1.01–1.07; IL-8, HR = 1.04, 95% CI 1.01–1.08; MIP-1α, HR = 1.19, 95% CI 1.00–1.36; and CTACK, HR = 1.12 per 100 units, 95% CI 1.02–1.21. A replication analysis was performed only for CTACK because others were previously reported to be potential biomarkers of interstitial lung diseases. In the validation cohort, CTACK was associated with survival: HR = 1.14 per 100 units, 95% CI 1.01–1.28. Immunohistochemistry revealed the expression of CTACK and CC chemokine receptor 10 (a ligand of CTACK) in airway and type II alveolar epithelial cells of IPF patients but not in those of controls. Conclusions CTACK is a novel prognostic biomarker of IPF. Trial registration None (because of no healthcare intervention)

PURPOSE The pulmonary function test (PFT) has played an essential role in diagnosing and managing interstitial lung disease (ILD) but has its contraindications and difficult conditions to perform. Therefore, the present study aimed to evaluate dynamic chest radiography (DCR) ability to predict forced vital capacity (FVC) and other PFT parameters of ILD patients. METHOD The prospective observational study included 97 patients who underwent DCR at Tenri Hospital (Tenri, Japan) between June 2019 and April 2020. Twenty-five patients with stable disease status underwent DCR twice to evaluate test-retest reliability using the intraclass correlation coefficient. From the lung field areas measured by DCR, lung volumes at maximum inspiration (V.ins) and expiration (V.exp) were estimated. Correlation coefficients between the measured values of DCR and PFT parameters were calculated. Multilinear models for predicting FVC and other PFT parameters were developed. RESULTS Intraclass correlation coefficients between first and second measurements of V.ins and V.exp were 0.94 (95% CI: 0.89-0.97, p

Few reports have highlighted the serial changes in pulmonary hypertension during respiratory management. An 18-year-old girl with severe scoliosis was referred to our hospital for worsening dyspnea on exertion. Based on chest X-ray and transthoracic echocardiography findings showing a tricuspid regurgitation pressure gradient (TRPG) of 64 mmHg, the patient was diagnosed with severe alveolar hypoventilation due to thoracic deformity and severe pulmonary hypertension. Her oxygenation improved rapidly under noninvasive positive pressure ventilation, although partial pressure of carbon dioxide remained >80 Torr. Transthoracic echocardiography on day 7 showed clinically significant and rapid improvement of pulmonary hypertension with a TRPG of 30 mmHg.

Background This study evaluated characteristics of patients treated with abemaciclib and diagnosed with interstitial lung disease (ILD), using 12-month post-marketing data from the real-world setting in Japan. Methods Spontaneous reports of adverse events in patients receiving abemaciclib were collected regularly from healthcare providers (HCPs) from November 30, 2018, to November 29, 2019. Detailed follow-up was requested on suspected ILD cases via questionnaires and/or interviews. Radiological images (when available) were reviewed by an ILD adjudication committee of specialists. The age distribution of patients prescribed abemaciclib in Japan was estimated based on insurance claims data. Results Of 4700 patients estimated to be exposed to abemaciclib, 82 cases of ILD were reported (46 serious, 13 fatal). Most (91%) had ≥ 1 symptom at diagnosis, commonly dyspnea/shortness of breath (59%), cough (44%), and/or fever (37%). The majority (68%) received steroid therapy (24 [56%] recovered/recovering; 5 [12%] not recovered; 13 [30%] deaths, 1 [2.3%] unknown). No specific imaging patterns or sites of predilection were identified, but a diffuse alveolar damage (DAD) pattern was observed at outcome in 3 of 4 evaluated fatal cases (16 in total evaluated). Features of fatal cases included advanced age, pre-existing interstitial change, and advanced Eastern Cooperative Oncology Group Performance Status. Conclusion Advanced age and a DAD pattern were identified as potential risk factors for cases with poorer outcomes, as previously reported for drug-induced ILD. HCPs should consider the benefit–risk profile when prescribing abemaciclib, informing patients of risks and regularly monitoring treated patients to ensure early detection and treatment of ILD.

Background Bird antigens are some of the most relevant antigens in hypersensitivity pneumonitis (HP). Possible sources of bird antigens are bird breeding, feather products and fertilizer with fowl droppings. For the screening and diagnosis of HP, the measurement of bird-specific antibodies should be standardized. The aim of this study was to clarify the utility of serum IgG (sIgG) and IgA (sIgA) antibodies to bird antigens in screening and diagnosing acute/chronic bird-related HP with ImmunoCAP® in multi-centre clinical research. Methods We executed a clinical performance test by conducting a multi-institutional study to measure the levels of sIgG/sIgA against pigeon, parrot and budgerigar antigens by the ImmunoCAP® system in 29 acute and 46 chronic bird-related HP patients. Results The levels of sIgG/sIgA against the bird antigens of the three species were significantly higher in subjects with acute bird-related HP and chronic bird-related HP with acute episodes (recurrent type) than in the control subjects. For sIgG, the optimal cutoff values by receiver operating characteristic (ROC) analysis were 24.6 mgA/L for pigeon, 14.0 mgA/L for parrot, and 8.7 mgA/L for budgerigar. By measuring multiple bird antigens and combining sIgG values of two species, the sensitivity and specificity for acute and recurrent-type chronic bird-related HP patients were 85–91% and 73–80%, respectively. For recurrent and insidious types of chronic bird-related HP, the sensitivity and specificity were 48–61% and 73–80%, respectively. Conclusions Measurement of the levels of sIgG/sIgA against pigeon, budgerigar and parrot antigens by ImmunoCAP® was useful for screening and diagnosis in bird-related HP.

Background Chemotherapy-induced acute exacerbation (AEx) of idiopathic interstitial pneumonias (IIPs) seriously compromises the success of treatment of Japanese lung cancer patients. Here, we conducted a nationwide surveillance to clarify the risk of AEx and compare it with the survival benefit of chemotherapy for this population. Methods Advanced nonsmall cell lung cancer (NSCLC) or small cell lung cancer (SCLC) patients with IIPs were retrospectively analysed. For the surveillance of first-line chemotherapy in 2009, we gathered clinical data from 396 patients who received chemotherapy at 19 institutions between January 1990 and July 2009. In a consecutive retrospective study in 2012, we analysed data from 278 patients from 17 institutions who received second-line chemotherapy between April 2002 and March 2012. Results Of the 396 patients analysed, 13.1% developed chemotherapy-related AEx. Combination chemotherapies of carboplatin plus paclitaxel (CP) or carboplatin plus etoposide (CE) were frequently used as first-line treatments. The lowest incidence of AEx was 3.7% in CE, followed by 8.6% in CP. In the retrospective study, 16.2% of the 278 patients developed a second-line chemotherapy-related AEx. The overall response rate by second-line chemotherapy was 7.4% in NSCLC and 25.7% in SCLC. The median overall survival from second-line and first-line chemotherapy was 8.0 and 14.3 months in NSCLC, and 8.7 and 16.0 months in SCLC, respectively. Conclusion Combination chemotherapies consisting of CP or CE are candidates for standard first-line treatments for patients with advanced lung cancer accompanied by IIP. Second-line chemotherapy should be considered for patients remaining fit enough to receive it., The Japanese are at high risk of acute exacerbation of IPF. Therefore, chemotherapy for Japanese lung cancer patients with IIPs is challenging. However, appropriate chemotherapy may give a survival benefit, despite the risk of acute deterioration of IIPs. http://bit.ly/3cROaCy

Idiopathic pulmonary fibrosis (IPF) is a disease of unknown etiology which accounts for a large proportion of cases of idiopathic interstitial pneumonia. It has a very poor prognosis with a 5-year survival rate of 30% or below, and so far there has been no guideline in Japan offering an established effective therapy based on evidence. In addition to the establishment of basic therapies, there is also an urgent need to establish therapies to deal with complications, as death occurs in many cases due to acute exacerbation or comorbid lung cancer. It was therefore decided to formulate a guideline in order to promote evidence-based clinical practice, to further improve the quality of medical treatment in the clinical setting, and to allow the benefits to be enjoyed by the public.

The authors reported a rare case of young women with neurofibromatosis type I (NF-I) who were successfully treated from the traumatic dislocation of a thoracic vertebra caused by a simple fall, and the relevant literature was reviewed. Due to various spinal dystrophic changes, the conventional posterior spinal fusion surgery was modified for the treatment. Spinal deformity is a common feature of NF-1, and a dystrophic lesion, like dural ectasia, provokes weakness in spinal structural. Unexpectedly, only seven similar cases were found. The review suggested that it is mandatory to thoroughly examine the spine in patients with NF-1, and that a good outcome can be expected even for patients with NF-1 in severe neurological condition after acute spinal cord injuries.

Background: The significance of the nutritional status in idiopathic pulmonary fibrosis (IPF) is largely unknown. Temporal body weight (BW) change, a dynamic index of nutrition status, can detect the malnutrition more accurately than the conventional single-point body mass index evaluation. Objective: To investigate how the temporal BW change influences the clinical courses of IPF. Methods: This multicenter study enrolled IPF patients from four referral hospitals of interstitial lung diseases in Japan (the Japanese cohort, the derivation cohort) and the Royal Brompton Hospital (the UK cohort, the validation cohort). The annual rate of BW change from the initial presentation was evaluated. A > 5% decrease of BW was defined as a significant BW loss. Results: Twenty-seven out of 124 patients in the Japanese cohort and 13 out of 86 patients in the UK cohort showed significant BW loss. Patients with BW loss showed significantly worse survival in both cohorts. Multivariate analyses revealed that BW loss was an independent factor for decreased survival (Japanese cohort: p = 0.047, UK cohort: p = 0.013). A 6.1% loss of BW was chosen as the optimal cutoff value to predict the 2-year mortality from the initial presentation. The stratified analysis revealed that a 6.1% or greater BW loss could predict worse survival specifically in cases without a greater than 10% decline in forced vital capacity (FVC). Conclusions: BW loss is independently associated with the survival of IPF patients, particularly when a decline in the FVC was not observed. Further studies are needed to understand the mechanisms underlying BW loss in IPF.

Background The Severe Respiratory Insufficiency (SRI) Questionnaire was originally developed in German to assess health-related quality of life (HRQL) and was validated as a multidimensional instrument with high psychometric properties in chronic hypercapnic respiratory failure (CHRF) patients receiving noninvasive ventilation (NIV). We aimed to investigate the intercultural adaptation of the Japanese SRI Questionnaire and whether it is a reliable and valid HRQL questionnaire to administer to those patients. Methods The SRI Questionnaire was adapted to Japanese using a translation and back-translation procedure, followed by equivalency assessment. It was validated in 56 stable outpatients receiving NIV for CHRF, primarily due to chronic obstructive pulmonary disease (COPD) and/or pulmonary tuberculosis sequelae. Results Examination of the frequency distribution of the Japanese SRI Questionnaire showed that the subscales and summary were approximately normally distributed and well balanced. There were no significant differences in SRI scores between patients with COPD and pulmonary tuberculosis sequelae. Cronbach׳s α values representing internal consistency of seven SRI subscales ranged from 0.56 to 0.80; attendant symptoms and sleep had the lowest values. Cronbach׳s α value was 0.92 for the SRI summary. The SRI summary score was significantly related to all eight subscales of the Medical Outcomes Study 36-item short form, with correlation coefficients of 0.41–0.66. Conclusions The Japanese SRI Questionnaire was produced using a standardized procedure and an equivalency study. It has high psychometric properties with internal consistency and concurrent validity. The Japanese SRI Questionnaire can be used to assess HRQL in patients on NIV for CHRF.

Background: The heterogeneity in IPF poses a major challenge for management of IPF. Antifibrotic drugs suppress the disease progression, and they also improve the survival in some patients. However, no biomarker has been proved to predict the response to antifibrotics. Aims and Objectives: We evaluated the significance of serum markers as predictor for response to pirfenidone in patients in phase 3 trial in Japan. Methods: We analyzed the data from 267 patients with IPF in phase 3 trial of pirfenidone in Japan. Association of baseline serum SP-D levels was examined with changes from baseline in vital capacity (VC) and progression-free survival (PFS: the progression was defined as a ≥10% decline in VC from baseline and/or death). Results: When patients were divided into high and low SP-D groups by the median level at baseline (202 ng/mL), significantly better response (changes in VC at 52 weeks and PFS) to pirfenidone was observed in low SP-D group than in high SP-D group (Figure). Serum concentration of SP-D decreased during therapeutic course in pirfenidone groups, and the decline was significant from 8 weeks after the initiation of pirfenidone. Conclusions: Serum SP-D levels has the potential for a predictor of response to pirfenidone in patients with IPF, and for a biomarker to monitor the course of treatment.

Intracranial chordomas are thought to arise from remnants of the notochord and usually occur at the parasellar region. We present a case of a primary intrasellar chondroid chordoma in a patient who was initially diagnosed with a pituitary adenoma.A 77-year-old woman had a history of two surgeries for a tumor in the sella turcica(17 months after the 1supst/supsurgery). On initial MRI, the intrasellar mass showed low signal intensity on T1WI, very high signal intensity on T2WI, and inhomogeneous enhancement. On bone reconstructive CT, the sellar floor was thin, and no abnormalities were observed at the top of the clivus. Transsphenoidal surgery was performed. The pathological diagnosis was pituitary adenoma in both cases. Seventy-two months after the 1supst/sup(31 months after the 2supnd/sup)surgery, she developed right-sided oculomotor and abducent nerve palsies again. Since recurrence occurred during the relatively short period, the surgical specimens obtained from the 1supst/supand 2supnd/supsurgeries were reexamined. Reexamination of the previously obtained specimen demonstrated areas of chondroid tissue that were embedded in a mucoid stroma and tumor cells that were composed of round or pleomorphic nuclei with vacuolated cytoplasm(physaliphorus cells)that were compatible with chondroid chordoma. The third surgery was performed. Postoperatively, her symptoms improved, and cyber knife therapy was administered for the residual part of the tumor.Although intrasellar chondroid chordomas are extremely rare, they should be considered in the differential diagnosis of tumors located in the sella turcica.

Background Diffuse panbronchiolitis (DPB) is a sinopulmonary disease mainly affecting Asian populations. Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disorder impairing ciliary structure and function. These two disorders are not easily distinguished by clinical signs and symptoms. Methods In 105 Japanese patients with recurrent sinopulmonary infection, initially diagnosed with DPB, and 37 patients with recurrent airway infection diagnosed in adulthood, the deletion allele of DRC1 or CCDC164, recently recognized as a pathogenic PCD gene variant, was searched using a multiplexed PCR‐based method, and the deletion breakpoints and other variants around the gene were determined by Sanger sequencing and targeted resequencing. Results A large homozygous deletion in DRC1 was identified in three of the 142 patients. Furthermore, heterozygous carriers of the deletion with the same breakpoint were found with the allele frequency of 0.002 in the healthy Japanese population, indicating that this loss‐of‐function variant may be acting as a common mutation causing PCD in Japanese. Conclusion PCD caused by the DRC1 defect is not readily identified by either high‐speed video‐microscopy or ciliary ultrastructure analysis, posing significant difficulties in reaching a correct diagnosis without the aid of genetic tests. Careful investigation of the causes of sinopulmonary diseases is warranted in Asian populations., A large homozygous deletion in DRC1 was identified in three patients with recurrent sinopulmonary infection. Furthermore, heterozygous carriers of the DRC1 deletion with the same break point were found with the allele frequency of 0.002 in the healthy Japanese population, indicating that this loss‐of‐function variant may be acting as a common mutation causing PCD in Japanese.

Background Few studies have examined the relationship between echocardiographic indices of right ventricular (RV) function and the severity of pulmonary disease, or their prognostic impact. We evaluated the RV function in patients with interstitial pneumonia and its prognostic impact at each stage of disease severity. Method A total of 176 patients with idiopathic interstitial pneumonias (IIPs) were retrospectively enrolled and we evaluated RV function by transthoracic echocardiography. The severity of IIPs was graded according to the Goh score. The primary outcome was all-cause death. Results There were 55 patients in mild group (31%), 66 in moderate group (38%), and 55 in severe group (31%). Regarding RV function, RV free wall longitudinal strain and tricuspid annular plane systolic excursion (TAPSE) deteriorated with increasing severity of IIPs, but fractional area change (FAC) decreased significantly only in severe group. There were 64 all-cause deaths during the follow-up period (median 908 days). In moderate group, TAPSE [hazard ratio (HR): 0.85, 95% confidence interval (CI): 0.74–0.97, p = 0.017], FAC (HR: 0.89, 95% CI: 0.83–0.96, p = 0.001), and mean pulmonary artery pressure (PAP)/cardiac output (HR: 1.50, 95% CI: 1.08–2.09, p = 0.015) were independent predictors of all-cause death, even after adjusting for age and log brain natriuretic peptide (BNP). On the other hand, not RV function or PAP but male sex and BNP level were associated with mortality in severe group. Conclusions Among patients with IIPs, RV longitudinal function deteriorated with increasing severity of IIPs. Echocardiographic indices of RV function were independently associated with mortality in moderate-stage IIPs.

Background Botrytis species are well known fungal pathogens of various plants but have not been reported as human pathogens, except as allergenic precipitants of asthma and hypersensitivity pneumonitis. Case presentation The asymptomatic patient was referred because of a nodule revealed by chest X-ray. Computed tomography (CT) showed a cavitary nodule in the right upper lobe of the lung. He underwent wedge resection of the nodule, which revealed necrotizing granulomas and a fungus ball containing Y-shaped filamentous fungi, which was confirmed histopathologically. Culture of the specimen yielded white to grayish cotton-like colonies with black sclerotia. We performed multilocus gene sequence analyses including three single-copy nuclear DNA genes encoding glyceraldehyde-3-phosphate dehydrogenase, heat-shock protein 60, and DNA-dependent RNA polymerase subunit II. The analyses revealed that the isolate was most similar to Botrytis elliptica. To date, the pulmonary Botrytis sp. infection has not recurred after lung resection and the patient did not require any additional medication. Conclusions We report the first case of an immunocompetent patient with pulmonary Botrytis sp. infection, which has not recurred after lung resection without any additional medication. Precise evaluation is necessary for the diagnosis of pulmonary Botrytis infection because it is indistinguishable from other filamentous fungi both radiologically and by histopathology. The etiology and pathophysiology of pulmonary Botrytis infection remains unclear. Further accumulation and analysis of Botrytis cases is warranted. Electronic supplementary material The online version of this article (10.1186/s12879-019-4319-2) contains supplementary material, which is available to authorized users.

OBJECTIVE Interstitial lung disease (ILD) accompanied by anti-melanoma differentiation-associated gene 5 (anti-MDA-5)-positive dermatomyositis (DM) is often rapidly progressive and associated with poor prognosis. Because there is no established treatment, we undertook this study to prospectively evaluate the efficacy and safety of a combined immunosuppressive regimen for anti-MDA-5-positive DM patients with ILD. METHODS Adult Japanese patients with new-onset anti-MDA-5-positive DM with ILD (n = 29) were enrolled at multiple study centers from 2014 to 2017. They were treated with a regimen of high-dose glucocorticoids (GCs), tacrolimus, and intravenous cyclophosphamide (IV CYC). Plasmapheresis was used if a patient's condition worsened after the regimen started. The primary end point was 6-month survival, which was compared between this group of patients and a historical control group (n = 15) consisting of anti-MDA-5-positive DM patients with ILD who received step-up treatment (high-dose GC and stepwise addition of immunosuppressant). Secondary end points were 12-month survival rate, adverse events, and changes in laboratory data. RESULTS The combined immunosuppressive regimen group showed significantly higher 6-month survival rates than the step-up treatment group (89% versus 33%; P < 0.0001). Over a period of 52 weeks, improvements in anti-MDA-5 titers, serum ferritin levels, vital capacity, and chest high-resolution computed tomography scores were observed. The combined immunosuppressive regimen group received IV CYC nearly 20 days earlier with shorter intervals and tended to receive plasmapheresis more often than patients undergoing step-up treatment. Cytomegalovirus reactivation was frequently observed over 52 weeks. CONCLUSION A combined immunosuppressive regimen is effective for anti-MDA-5-positive DM patients with ILD. Plasmapheresis can be used for additional effect in intractable disease. Patients should be carefully monitored for opportunistic infections during treatment.

Background: The prevalence of chronic kidney disease (CKD) increases with age as with idiopathic pulmonary fibrosis (IPF). Objectives: We assessed the prevalence of CKD (stages 3-5) and investigated the relationship of CKD to clinical features and outcomes in patients with IPF. Methods: This study comprised 123 patients with IPF; 61 subjects with chronic obstructive pulmonary disease (COPD), which was reportedly associated with CKD, were also enrolled as a disease control. CKD (stages 3-5) was defined as an estimated glomerular filtration rate (eGFR) 2. Results: Thirty-seven patients (30%) with IPF and 14 controls (23%) with COPD were diagnosed with CKD, and these frequencies were not significantly different. The patients with IPF and CKD were older (p < 0.01) and had a higher frequency of hypertension (p = 0.048) and ischemic heart disease (p = 0.02) than those with IPF but without CKD. Furthermore, the diffusing capacity of the lung for carbon monoxide (DLCO) and the 6-min walking distance in the patients with CKD were significantly lower (40.0 ± 13.2 vs. 45.9 ± 14.4%, p = 0.04, and 416 ± 129 vs. 474 ± 84 m, p = 0.01, respectively) than in the patients without CKD. The outcome of the patients with CKD showed significantly worse survival compared with the patients without CKD (p = 0.04). Moreover, eGFR remained an independent predictor of survival after adjusting for age and pulmonary function data. Conclusion: A substantial percentage of IPF patients have CKD. CKD with a low eGFR was associated with decreased survival in IPF.

BackgroundA randomised controlled trial in Japan showed that inhaled N-acetylcysteine monotherapy stabilised serial decline in forced vital capacity (FVC) in some patients with early idiopathic pulmonary fibrosis (IPF). However, the efficacy and tolerability of combination therapy with an antifibrotic agent and inhaled N-acetylcysteine are unknown.MethodsThis 48-week, randomised, open-label, multicentre phase 3 trial compared the efficacy and tolerability of combination therapy with pirfenidone plus inhaled N-acetylcysteine 352.4 mg twice daily with the results for pirfenidone alone in patients with IPF. The primary end-point was annual rate of decline in FVC. Exploratory efficacy measurements included serial change in diffusing capacity of the lung for carbon monoxide (DLCO) and 6-min walk distance (6MWD), progression-free survival (PFS), incidence of acute exacerbation, and tolerability.Results81 patients were randomly assigned in a 1:1 ratio to receive pirfenidone plus inhaled N-acetylcysteine (n=41) or pirfenidone (n=40). The 48-week rate of change in FVC was −300 mL and −123 mL, respectively (difference −178 mL, 95% CI −324–−31 mL; p=0.018). Serial change in DLCO, 6MWD, PFS and incidence of acute exacerbation did not significantly differ between the two groups. The incidence of adverse events (n=19 (55.9%) for pirfenidone plus N-acetylcysteine; n=18 (50%) for pirfenidone alone) was similar between groups.ConclusionsCombination treatment with inhaled N-acetylcysteine and pirfenidone is likely to result in worse outcomes for IPF.

High-resolution computed tomography (HRCT) scan is a noninvasive technique that might be valuable for evaluating bronchial wall thickening and bronchiectasis as a result of chronic inflammation in patients with severe asthma. HRCT is also useful to diagnose the complications of asthma such as pulmonary emphysema and chronic eosinophilic pneumonia. In addition, HRCT will be able to demonstrate the tracheobronchial and parenchymal abnormality dis- tinctly, with the result that it will be helpful for making differential diagnosis in the patients with wheeze, including allergic bronchopulmonary aspergillosis, eosinophilic granulomatosis with polyangiitis, bronchial tuberculosis and tracheal tumor.

Background and Objective: A randomized controlled trial in Japan showed that inhaled N-acetylcysteine (NAC) monotherapy stabilized the serial decline in FVC in some IPF patients not receiving immunosuppressive or antifibrotic agents. The effects of combination therapy with an antifibrotic agent and inhaled NAC are thus unclear. This multicenter, prospective, randomized, controlled clinical trial of Japanese patients with IPF assessed the efficacy and safety of combination therapy with pirfenidone and inhaled NAC. Methods and Main Results: Eighty-one patients (age >40 years) started on pirfenidone 1200–1800 mg /day for clinically or pathologically diagnosed IPF were randomly assigned in a 41:40 ratio to receive concomitant inhaled NAC 352.4 mg twice daily or pirfenidone alone for 48 weeks. The primary endpoint was change from baseline in FVC at 48 weeks. The exploratory efficacy measurements at 48 weeks were (1) absolute and relative change from baseline in VC, %VC, TLC, %TLC, DLco, and %DLco, (2) relative change from baseline in chest HRCT images, (3) change from baseline in 6-MWD and desaturation, (4) change from baseline in mMRC grade, (5) change from baseline in serum biomarkers (SP-D, KL-6), (6) occurrence of acute exacerbation, (7) progression-free survival (disease progression defined as a decline in FVC of 5% to 10％, worsening mMRC grade, or death), (8) mortality, and (9) adverse events. Patient enrollment started in January 2015 and was completed in June 2017. Conclusions: This trial will evaluate the efficacy and safety of combined therapy with pirfenidone and inhaled NAC in patients with IPF.

Background: Chemotherapy causes drug-induced interstitial lung disease (DILD). Information is scarce about lung cancer patients who developed DILD due to chemotherapy and then underwent next chemotherapy. Aim: To elaborate clinical characteristics of patients with lung cancer who underwent next chemotherapy after first DILD. Methods: Medical charts of 676 patients with lung cancer who underwent chemotherapy in our hospital between April 1, 2012 to March 31, 2017 were reviewed. We found 19 patients who were treated with chemotherapy again after having developed and recovered from DILD. Results: The median age of 19 patients was 72 years old (range 59-78), and 5 patients were female. Cytotoxic chemotherapy that caused first DILD were as follows: pemetrexed in 7 patients, docetaxel in 2 and paclitaxel, etoposide, and amrubicin in 1. As for epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR–TKI), gefitinib, erlotinib, afatinib, and osimertinib were responsible in 1, 1, 3 and 2 patients, respectively. Regimens that 19 patients received after first DILD revealed vinorelbine (4), pemetrexed (3), docetaxel (3), amrubicin (1), TS-1 (1), CPT-11 (1), erlotinib (2), osimertinib (1), nivolumab (1) and CAV therapy (1). Four of 19 patients developed DILD again. First and second drugs that caused DILD were found to be docetaxel-pemetrexed (1), pemetrexed-docetaxel (2), and afatinib-erlotinib (1). One patient who received two EGFR-TKIs died despite systemic steroids. Conclusions: Approximately 20% patients who had recovered from first DILD developed second DILD with retreatment. Further accumulation of data is needed to address the issue of how to treat patients after first DILD due to chemotherapy.

Objective We aimed to clarify the clinical significance of serum levels of MMPs in interstitial lung disease (ILD) complicated with PM/DM (PM/DM-ILD). Methods We retrospectively analysed serum levels of seven subsets of MMPs in 52 PM/DM-ILD patients diagnosed at Kyoto University Hospital or Tenri Hospital from January 2005 to December 2014. The patients were sub-grouped based on the presence of anti-amimoacyl-tRNA synthetase antibody (anti-ARS antibody), anti-melanoma differentiation-associated protein 5 antibody (anti-MDA5 antibody) or lack of the antibodies (ARS-ILD, MDA5-ILD and other-ILD groups, respectively) and independently analysed. Eighteen PM/DM patients without ILD and 55 healthy control were also analysed. Associations between serum levels of MMPs and clinical findings including mortality were analysed. Results Among the MMPs analysed, MMP-7 serum levels in the ARS-ILD group were significantly higher compared with those in any of the other groups of PM/DM patients or in healthy controls. On the other hand, in the MDA5-ILD group, serum MMP-7 levels >5.08 ng/ml were associated with worse overall survival both in univariate (P = 0.017; odds ratio 18.0; 95% CI 1.69, 192.00) and multivariate (P = 0.027; odds ratio 14.60; 95% CI 1.11, 192.00) analyses. Immunohistochemical analysis suggested that MMP-7 was expressed in type II alveolar epithelial cells adjacent to the fibrotic lesions. Conclusion Serum MMP-7 levels were higher in anti-ARS antibody-positive PM/DM-ILD patients, while higher serum MMP-7 levels among anti-MDA5 antibody-positive PM/DM-ILD patients were associated with a worse prognosis. Fibrotic processes may be associated with the elevation of serum MMP-7 levels.

Primary meningiomas arising outside the intracranial component are rather rare and have been termed primary extradural meningiomas(PEMs). We present a case of an intraosseous-type PEM occurring at a high convexity location and discuss the clinical characteristics of PEMs.An 80-year-old woman presented with a soft and painless subcutaneous mass of approximately 10 cm in diameter in the right parietal region, which had appeared 1 year previously. Mild cognitive dysfunction and left hemiparesis were observed upon admission. A skull radiograph and a bone window computed tomography scan revealed an osteolytic lesion at the above-mentioned site. Magnetic resonance imaging indicated that the mass was inhomogeneously enhanced and seemed to extend through the skull defect both intra- and extra-cranially. The preoperative diagnosis was a metastatic skull bone tumor due to the patient's history of breast cancer. During surgery, the tumor was found to be solid and had expanded through both the inner and outer tables of the skull, destroyed the inner table at one location, and perforated into the subdural space via the thinned, but not infiltrated, dura mater. The tumor was removed along with a wide margin of surrounding healthy bone and a cranioplasty was performed using a titanium plate. The histopathological diagnosis was atypical meningioma(World Health Organization grade II). Postoperatively, no adjuvant therapies(radiation and/or chemotherapy)were administered and the patient was reported to be well at 8 months post-surgery with no evidence of tumor recurrence.Although PEMs are rather rare, clinicians should consider the differential diagnosis of osteolytic skull vault tumors.