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The prognosis of patients with connective tissue disease (CTD) has improved significantly in recent years, but interstitial lung disease (ILD) associated with connective tissue disease (CTD-ILD) remains a refractory condition, which is a leading cause of mortality. Because it is an important prognostic factor, many observational and interventional studies have been conducted to date. However, CTD is a heterogeneous group of conditions, which makes the clinical course, treatment responses, and prognosis of CTD-ILD extremely diverse. To summarize the current understanding and unsolved questions, the Japanese Respiratory Society and the Japan College of Rheumatology collaborated to publish the world's first guide focusing on CTD-ILD, based on the evidence and expert consensus of pulmonologists and rheumatologists, along with radiologists, pathologists, and dermatologists. The task force members proposed a total of 27 items, including 7 for general topics, 9 for disease-specific topics, 3 for complications, 4 for pharmacologic treatments, and 4 for non-pharmacologic therapies, with teams of 2-4 authors and reviewers for each item to prepare a consensus statement based on a systematic literature review. Subsequently, public opinions were collected from members of both societies, and a critical review was conducted by external reviewers. Finally, the task force finalized the guide upon discussion and consensus generation. This guide is expected to contribute to the standardization of CTD-ILD medical care and is also useful as a tool for promoting future research by clarifying unresolved issues.

Introduction The administration of systemic corticosteroids is a key strategy for improving COVID-19 outcomes. However, evidence is lacking on combination therapies of antiviral agents and systemic corticosteroids. The objective of this study was to investigate the efficacy and safety of the combination therapy of favipiravir and methylprednisolone in preventing respiratory failure progression in patients with COVID-19 and non-critical respiratory failure. Methods We conducted a multicenter, open-label, single-arm phase II study. The patients received favipiravir 3600 mg on the first day, followed by 1600 mg for a total of 10–14 days. Methylprednisolone was administered intravenously at 1 mg/ideal body weight (IBW)/day from days 1 to 5, followed by 0.5 mg/IBW/day from days 6 to 10 if clinically indicated. The primary endpoint was the proportion of patients requiring mechanical ventilation (MV) (including noninvasive positive pressure ventilation) or those who met the criteria for tracheal intubation within 14 days of the study treatment initiation (MVCTI-14). Results Sixty-nine patients were enrolled and underwent the study treatment. Of them, the MVCTI-14 proportion was 29.2% (90% confidence interval 20.1–39.9, p = 0.200). The proportion of patients who required MV or who died within 30 days was 26.2%, and 30-day mortality was 4.9%. The most significant risk factor for MVCTI-14 was a smoking history (odds ratio 4.1, 95% confidence interval 1.2–14.2). The most common grade 3–4 treatment-related adverse event was hyperglycemia, which was observed in 21.7%. Conclusion The MVCTI-14 proportion did not reach a favorable level in the clinical trial setting with the threshold of 35%. However, the proportion of MV or death within 30 days was 26.6%, which might be close to the findings (28.1%) of the RECOVERY trial, which showed the efficacy of dexamethasone for patients with COVID-19 and non-critical respiratory failure. Further evaluation of this combination therapy is needed. Clinical Trial Registration Japan Registry of Clinical Trials (jRCT) identifier jRCTs041200025. Supplementary Information The online version contains supplementary material available at 10.1007/s40121-021-00512-9.

Introduction Numerous severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) serological tests exists commercially; however, their performance using clinical samples is limited. Although insufficient to detect SARS-CoV-2 in the early phase of infection, antibody assays can be of great use for surveillance studies or for some coronavirus disease 2019 (COVID-19) patients presenting late to the hospital. Methods This study evaluated the sensitivity and specificity of four commercial SARS-CoV-2 lateral flow antibody tests using 213 serum specimens from 90 PCR-positive confirmed COVID-19 patients. Of 59 negative control sera, 50 were obtained from patients with other respiratory infectious diseases before COVID-19 pandemic began while nine were from patients infected with other respiratory viruses, including two seasonal coronaviruses. Results The varied sensitivities for the four commercial kits were 70.9%, 65.3%, 45.1%, and 65.7% for BioMedomics, Autobio Diagnostics, Genbody, and KURABO, respectively, between sick days 1 and 155 in COVID-19 patients. The sensitivities of the four tests gradually increased over time after infection before sick day 5 (15.0%, 12.5%, 15.0%, and 20.0%); from sick day 11–15 (95.7%, 87.2%, 53.2%, and 89.4%); and after sick day 20 (100%, 100%, 68.6%, and 96.1%), respectively. For severe illness, the sensitivities were quite high in the late phase after sick day 15. The specificities were over 96% for all four tests. No cross-reaction due to other pathogens, including seasonal coronaviruses, was observed. Conclusions Our results demonstrated the large differences in the antibody test performances. This ought to be considered when performing surveillance analysis.

The differentiation between major histological types of lung cancer, such as adenocarcinoma (ADC), squamous cell carcinoma (SCC), and small-cell lung cancer (SCLC) is of crucial importance for determining optimum cancer treatment. Hematoxylin and Eosin (H&E)-stained slides of small transbronchial lung biopsy (TBLB) are one of the primary sources for making a diagnosis; however, a subset of cases present a challenge for pathologists to diagnose from H&E-stained slides alone, and these either require further immunohistochemistry or are deferred to surgical resection for definitive diagnosis. We trained a deep learning model to classify H&E-stained Whole Slide Images of TBLB specimens into ADC, SCC, SCLC, and non-neoplastic using a training set of 579 WSIs. The trained model was capable of classifying an independent test set of 83 challenging indeterminate cases with a receiver operator curve area under the curve (AUC) of 0.99. We further evaluated the model on four independent test sets—one TBLB and three surgical, with combined total of 2407 WSIs—demonstrating highly promising results with AUCs ranging from 0.94 to 0.99.

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...

A 52-year-old woman was diagnosed as having anti-centromere antibody (ACA)-positive primary Sjögren syndrome (pSS). Eight years later, she visited our hospital because she had developed dyspnoea. She was diagnosed as having pulmonary arterial hypertension (PAH) with pulmonary veno-occlusive disease on the basis of the results of right heart catheterisation, a severe decrease in diffusing capacity of the lung for carbon monoxide (D

Background: The concept of progressive fibrosing interstitial lung diseases (PF-ILD) has been recently proposed to describe a progressive phenotype in fibrosing ILDs, separate from the classical differential diagnosis of ILDs. However, we still do not know enough about how we can differentiate PF-ILD patients from non–PF-ILD patients in advance or how we can predict decline of lung function in PF-ILD patients. Periostin is a matricellular protein playing a critical role in the pathogenesis of pulmonary fibrosis significantly high in idiopathic pulmonary fibrosis patients. Methods: In this study, we applied three periostin ELISA systems—an original ELISA system recognizing total periostin, an ELISA system recognizing only the monomeric periostin, and a modified ELISA system that can measure periostin independently of the IgA complex established in this study—to serum from idiopathic interstitial pneumonia (IIP) patients to address whether periostin can differentiate PF-ILD from non–PF-ILD patients in advance, whether periostin can predict the decline of lung function in PF-ILD patients, and which ELISA system for periostin is the most suitable for these purposes.Results: We established the modified ELISA system using SS16A recognizing the R3 domain instead of SS18A recognizing the R1 domain as the primary mAb that can measure periostin independently of the IgA complex. All periostin values found by the three systems were significantly higher in PF-ILD patients than in healthy subjects in addition to SP-D and KL-6, whereas all the periostin values, but not SP-D or KL-6, could differentiate PF-ILD patients from patients with IIP other than PF-ILD, in the order of the monomer system, the modified system, and the original system. Moreover, the periostin values by all three systems, but not SP-D or KL-6, showed significant correlations with decline of either %VC or DL, CO, in order of the monomer system, the modified system, and the original system.Conclusions: Serum periostin, but not SP-D and KL-6, differentiates PF-ILD from non–PF-ILD and predicts decline of lung function in PF-ILD patients. The monomer periostin ELISA system is the best at doing so. These results demonstrate that periostin, particularly the monomeric form, is useful in treating PF-ILD patients.

Patients with fibrosing interstitial lung disease (FILD) have poor health-related quality of life (HRQOL). We analyzed predictors of short-term improvement of HRQOL after starting pulmonary rehabilitation (PR) in moderate to severe FILD patients. This study involved 28 consecutive patients with FILD (20 males, median age of 77.5 years), who participated in PR program of our hospital for &gt, 6 weeks. The St. George’s Respiratory Questionnaire (SGRQ) score and the 6-min walk distance (6MWD) were evaluated before and after PR, and the predictors of efficacy of PR were analyzed. The duration from diagnosis of FILD to start of PR showed a positive correlation with the increase in the SGRQ score, and the baseline SGRQ score showed a negative correlation with increase in the 6MWD. The FILD subtype, modified Medical Research Council score, and treatment history were not associated with the endpoints. According to the receiver operating characteristic curve (ROC) analyses, starting PR within 514 days after diagnosis of FILD was a significant favorable predictor of improvement in the SGRQ total score more than a minimal clinically important difference of 4. In this study, early intervention of PR and lower SGRQ score were associated with the favorable response to PR. PR for FILD should be initiated early before the disease becomes severe.

This study examined the changes in physical function and quality of life (QOL) of postoperative patients with pancreatic cancer for 3 months after surgery and examined the factors affecting the QOL at the 3 months after surgery. Methods: This study comprised 32 pancreatic cancer patients who underwent surgery at our hospital. Among these patients, 20 patients for whom data was measured before surgery to 3 months after surgery were selected for statistical analyses: 8 males and 12 females, 69.8 ± 7.4 years. The preoperative and postoperative rehabilitation was given to patients under the guidance of a physiotherapist. Nutritional status, body composition, physical function, gait assessments, and QOL were investigated. Results: Body weight, body fat mass, body fat percentage, body mass index (BMI), and muscle mass significantly decreased 3 months after surgery compared with their respective preoperative values. The mean grip strength at the time of 3 months after the surgery had decreased significantly from 27.3 kg to 24.5 kg. The mean skeletal muscle mass index (SMI) had decreased significantly from 6.3 kg before surgery to 5.9 kg after the surgery. The QOL scores for global health status, physical, and role showed significant decreases 2 weeks after surgery compared with the respective preoperative scores. Significant improvements in these scores were observed 3 months after surgery compared with the respective scores 2 weeks after surgery. Physical function assessments after surgery were associated with QOL 3 months after surgery. Conclusion: Recovery of patients after pancreatic cancer surgery in body weight, BMI, body fat percentage, body fat percentage, muscle mass, SMI, and grip strength was not sufficient at the time of 3 months after surgery. It has been observed that physical function of patients has affected the improvement of QOL.

Cancer immunotherapy including immune checkpoint inhibitors (ICI) has revolutionized non-small cell lung cancer (NSCLC) therapy. Recently, the microbiome status before initiation of ICI therapy has been emphasized as a predictive biomarker in patients undergoing ICI therapy. However, the microbiome diversity and composition during ICI therapy is unknown. This multicenter, prospective observational study analyzed both saliva and feces from 28 patients with NSCLC. We performed 16S ribosomal RNA gene sequencing, then analyzed associations of oral and gut microbiome diversity or composition with ICI response. Seventeen patients (responders) had a partial ICI response, and the remaining 11 patients (non-responders) had stable or progressive disease. At the genus level, the alpha diversity of the gut microbiome was significantly greater in ICI responders than in non-responders (Chao 1, p = 0.0174; PD whole tree, p = 0.0219; observed species, p = 0.0238; Shannon, p = 0.0362), while the beta diversity of the gut microbiome was significantly lower in ICI responders (principal coordinates analysis, p = 0.035). Compositional differences in the gut microbiome were observed between the two groups; in particular, Blautia was enriched in ICI responders, whereas RF32 unclassified was enriched in ICI non-responders. There were no significant differences between groups in the oral microbiome. This study revealed a strong association between gut microbiome diversity and ICI response in Japanese NSCLC patients. Moreover, specific gut microbiome compositions may influence the ICI response. These findings might be useful in identifying biomarkers to predict ICI response, as well as in developing biotic therapies to enhance the ICI response.

Background: M2-like/repair macrophages are thought to contribute to fibrotic process of idiopathic pulmonary fibrosis (IPF). We analyzed the association between pulmonary accumulation of M2-like macrophages and survival in IPF patients. Methods: Lung tissues were obtained by surgical lung biopsy from patients with IPF (n=16), nonspecific interstitial pneumonia (NSIP, n=8) and control subjects (n=14). Samples were also obtained at autopsy from 9 patients who died of acute exacerbation (AE) of IPF. Lung specimens and/or human peripheral blood mononuclear cells-derived macrophages were evaluated by immunohistochemistry for expression of CD68 (pan-macrophage marker), CD163, and CD204 (M2-like macrophage markers), and by in situ mRNA hybridization and ELISA for production of transforming growth factor-β1 (TGF-β1). Results: CD68 + , CD163 + , and CD204 + cell counts and CD163 + /CD68 + and CD204 + /CD68 + cell ratios were comparable in IPF and NSIP lung tissues and significantly higher than in control tissues. IPF-AE lung samples contained significantly elevated CD68 + and CD163 + cell counts and CD163 + /CD68 + cell ratio compared with IPF samples, whereas CD204 + cell counts and CD204 + /CD68 + cells ratio did not differ. High CD163 + /CD68 + and CD204 + /CD68 + cell ratios were significantly associated with shorter overall survival and time-to-AE in IPF patients. In vitro -differentiated human CD163 + and CD204 + macrophages both secreted TGF-β1; however, the novel IPF drug pentraxin 2/serum amyloid protein could suppress secretion only by CD204 + macrophages. Conclusions: Pulmonary accumulation of CD163 + and CD204 + macrophages is associated with worse clinical course in IPF patients. Suppression of macrophage activation and TGF-β1 secretion may be a potential therapeutic target for IPF.

We present a pulmonary sarcoidosis patient with specific elevation of serum Krebs von den lungen-6 (KL-6) levels, who was successfully treated with inhaled corticosteroids. Pulmonary sarcoidosis was initially identified as a chest radiograph abnormality during a routine medical examination, and subsequently confirmed by a high serum level of soluble interleukin 2 receptor. The patient was started on high-dose inhaled budesonide because of high serum levels of angiotensin-converting enzyme (ACE) and KL-6. Following treatment, radiographic findings improved, ACE levels normalized, and serum KL-6 levels markedly decreased. No recurrence was detected at 100 months with a budesonide dosage of 800 μg/day. This case demonstrates the efficacy of highdose inhaled corticosteroids for the initial treatment of pulmonary sarcoidosis.

A 78-year-old man who had worked in the building industry visited our hospital because of groundglass opacity with smoothly thickened, intralobular interstitial lines and interlobular septal lines on chest high-resolution computed tomography (HRCT). HRCT image also showed a focal area of reticulation and pleural thickening. Lung specimens obtained by surgical lung biopsy showed accumulations of intra-alveolar periodic acid-Schiffpositive materials, usual interstitial pneumonia (UIP)-like subpleural lung fibrosis and asbestos bodies (1 body/cm2 in high-power field, ×400). Serum granulocyte-macrophage colony stimulating factor autoantibody was positive. The patient was diagnosed as having autoimmune pulmonary alveolar proteinosis (PAP) and needed differential diagnosis from secondary PAP caused from pulmonary asbestosis and UIP. Careful observation of the manifestations of pulmonary asbestosis and the progression of fibrosis using HRCT will be necessary in this patient.

To elucidate the host genetic loci affecting severity of SARS-CoV-2 infection, or Coronavirus disease 2019 (COVID-19), is an emerging issue in the face of the current devastating pandemic. Here, we report a genome-wide association study (GWAS) of COVID-19 in a Japanese population led by the Japan COVID-19 Task Force, as one of the initial discovery GWAS studies performed on a non-European population. Enrolling a total of 2,393 cases and 3,289 controls, we not only replicated previously reported COVID-19 risk variants (e.g., LZTFL1, FOXP4, ABO, and IFNAR2), but also found a variant on 5p35 (rs60200309-A at DOCK2) that was significantly associated with severe COVID-19 in younger (-8 (odds ratio = 2.01, 95% confidence interval = 1.58-2.55). This risk allele was prevalent in East Asians, including Japanese (minor allele frequency [MAF] = 0.097), but rarely found in Europeans. Cross-population Mendelian randomization analysis made a causal inference of a number of complex human traits on COVID-19. In particular, obesity had a significant impact on severe COVID-19. The presence of the population-specific risk allele underscores the need of non-European studies of COVID-19 host genetics.

BACKGROUND: The associations of serum monomeric periostin (M-PN) level and serial change in M-PN with acute exacerbation of chronic fibrosing interstitial pneumonia (AE-FIP) are unclear. METHODS: We prospectively measured serum M-PN level from onset of AE to day 14 in 37 patients with AE-FIP and evaluated its association with outcome. To determine localization of periostin expression, immunohistochemical staining of pathological lung tissue from autopsy cases of AE-IPF was evaluated. RESULTS: Data from 37 AE-FIP patients (28 men; age 73.9±7.8 years) were analyzed. With healthy controls as reference, serum M-PN level was significantly higher in patients with AE-FIP (P=0.02) but not in those with stable idiopathic pulmonary fibrosis (P=1.00). M-PN was significantly lower on day 7 than at AE-FIP onset in survivors [14.6±5.8 vs. 9.3±2.8 ng/mL (onset to day 7: P

Background: 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.Methods: 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.Results: 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 < 0.001), regardless of baseline clinical status. The duration of invasive mechanical ventilation was shorter in corticosteroid versus non-corticosteroid group (HR, 1.466; 95% CI, 0.841–2.554; p = 0.177). Of the 106 patients who received methylprednisolone, the duration of invasive mechanical ventilation was significantly shorter in the pulse/semi-pulse versus standard dose group (HR, 2.831; 95% CI, 1.347–5.950; p = 0.006).Conclusions: Corticosteroids for hospitalized patients with COVID-19 did not improve clinical status on Day 15, but reduced the time to improvement in radiological findings for all patients regardless of disease severity and also reduced the duration of invasive mechanical ventilation in patients who required intubation.Trial registration: This study was registered in the University hospital Medical Information Network Clinical Trials Registry on April 21, 2020 (ID: UMIN000040211).

Background and objective In the SENSCIS trial in patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD), nintedanib reduced the rate of decline in forced vital capacity (FVC) (mL/year) over 52 weeks by 44% in comparison with placebo, with manageable adverse events in most patients. We analyzed the efficacy and safety of nintedanib in patients of Asian race. Methods Patients with SSc-ILD were randomized to receive nintedanib or placebo. The outcomes over 52 weeks were analyzed in Asian versus non-Asian patients. Results Of the 288 patients in each treatment group, 62 (21.5%) in the nintedanib group and 81 (28.1%) in the placebo group were Asian; 90.2% of the Asian patients were enrolled in Asian countries. In the placebo group, the rate of FVC decline over 52 weeks was consistent between Asian and non-Asian patients (−99.9 and −90.6 mL/year, respectively). The effect of nintedanib on reducing the rate of FVC decline over 52 weeks was consistent between Asian (difference, 44.3 mL/year [95% CI: −32.8, 121.4]) and non-Asian patients (difference, 39.0 mL/year [95% CI: −5.1, 83.1]) (treatment-by-time-by-subgroup interaction, p = 0.91). Diarrhea was the most frequent adverse event and was reported in similar proportions of Asian and non-Asian patients in the nintedanib group (80.6% and 74.3%, respectively) and placebo group (28.4% and 32.9%, respectively). Conclusions In patients with SSc-ILD, nintedanib had a consistent benefit on slowing the progression of SSc-ILD in Asian and non-Asian patients, with a similar adverse event profile. Trial registration ClinicalTrials.gov NCT02597933 .

A 69-year-old man was admitted to our hospital under diagnosis of pneumonia due to severe acute respiratory syndrome-corona virus 2 (SARS-CoV-2) (Day 0). He underwent endotracheal intubation from Day 3. Although his respiratory condition improved and anesthetic drugs were discontinued, no cough reflex was observed despite intubation having been performed until Day 17. His tendon reflexes were also diminished. We suspected that he had developed Guillain-Barre syndrome (GBS), and administered intravenous immunoglobulin from Day 18. The absence of cough reflex improved and extubation was successfully performed on Day 23. Neurological disorders including GBS should be considered when intubated SARS-CoV-2 patients present with a loss of cough reflex during the treatment period.

To evaluate computed tomography (CT) findings of nonspecific interstitial pneumonia (NSIP) based on the current classification of idiopathic interstitial pneumonias (IIPs) and elucidate a characteristic of previously diagnosed NSIP excluded from the current classification. The study included 74 patients with biopsy-proven NSIP (idiopathic NSIP [I-NSIP], 39 patients; NSIP associated with connective tissue disease [CTD-NSIP], 35 patients). Among patients who were compatible with the current classification of IIPs, 29 and 21 were categorized as having current I-NSIP and current CTD-NSIP, respectively. The remaining 24 patients were categorized as having previous I-NSIP or previous CTD-NSIP due to the primary pathologic diagnosis of cellular NSIP or associated findings of acute inflammatory changes. CT findings were evaluated and compared among the four groups. Current I-NSIP was indicated by ground-glass attenuation and reticulation with traction bronchiectasis/bronchiolectasis in predominantly peribronchovascular areas of the lower lung zone. The previous I-NSIP group tended to show broader airspace consolidation than the current I-NSIP group (p = 0.068). The previous CTD-NSIP group showed significantly broader airspace consolidation than the current I-NSIP group (p = 0.035). Broad airspace consolidation is a characteristic of previously diagnosed CTD-NSIP excluded from the current classification of IIPs.

Background: Lung cancer coexisting with idiopathic pulmonary fibrosis (IPF) or chronic obstructive pulmonary disease (COPD) can lead to poor prognosis. Telomere-related polymorphisms may be implicated in the pathogenesis of these three lung diseases. As to elucidate the mechanism of lung cancer via IPF or COPD may enable early detection and early treatment of the disease, we firstly examined the association between telomere-related polymorphisms and the risk of IPF and COPD in a case-control study. Materials and Methods: A total of 572 patients with IPF (n = 155) or COPD (n = 417), who were derived from our on-going cohort study, and controls (n = 379), who were derived from our previous case-control study, were included in this study. Telomerase reverse transcriptase (TERT) rs2736100, telomere RNA component (TERC) rs1881984, and oligonucleotide/oligosaccharide-binding fold containing1 (OBFC1) rs11191865 were genotyped with real-time PCR using TaqMan fluorescent probes. Unconditional logistic regression was used to assess the adjusted odds ratios and 95% confidence intervals. Results: TERT rs2736100 was significantly associated with the risk of IPF; increases in the number of this risk allele increased the risk of IPF (Ptrend = 0.008). Similarly, TERT rs2736100 was associated with the risk of COPD. In regard to the combined action of the three loci, increasing numbers of “at-risk” genotypes increased the risk of IPF in a dose-dependent manner (P trend=0.003). Conclusions: TERT rs2736100 was associated with the risks of both IPF and COPD in a Japanese population. A combination of the “at-risk” genotypes might be important to identify the population at risk for IPF more clearly.

Anti-melanoma differentiation-associated gene 5 antibody (anti-MDA5-Ab) is associated with fatal rapidly progressive interstitial lung disease (RP-ILD) in patients with dermatomyositis (DM). We attempted to clarify whether anti-MDA5-Ab is associated with long-term outcomes in patients with DM-ILD.Thirty-six patients with DM-ILD were retrospectively analyzed for their serum anti-MDA5-Ab by using an enzyme-linked immunosorbent assay. We analyzed the association between clinical parameters, including the serum levels of anti-MDA5-Ab and ferritin.Fourteen patients (39%) were positive for anti-MDA5-Ab. The serum levels of anti-MDA5-Ab and ferritin in 7 patients with acute death were higher than those in the surviving patients. An "unclassifiable pattern" on chest computed tomography and the development of RP-ILD were also prognostic markers. The serum levels of anti-MDA5-Ab and ferritin (cut-off levels, 100 IU/mL and 899 ng/mL, respectively) were markers predictive of acute death, showing good sensitivity (86% and 83%) and specificity (97% and 100%). All 7 patients with acute death developed RP-ILD and were positive for anti-MDA5-Ab, including 6 patients with a high titer (≥100 IU/mL), whereas only 2 patients (29%) developed RP-ILD among the 7 survivors with a low titer of anti-MDA5-Ab (100 IU/mL). In contrast, a low positive titer of anti-MDA5-Ab was not associated with changes in pulmonary function for 2 years.Although a high serum titer of anti-MDA5-Ab (≥100 IU/mL) is associated with acute death via the development of RP-ILD, outcomes in the chronic phase for patients with a low titer of anti-MDA5-Ab (100 IU/mL) were similar to those of patients without anti-MDA5-Ab.

BACKGROUND The role of IL-38, a new member of the IL-1 family, in airway eosinophilic inflammatory conditions such as asthma is unclear. To investigate the role of IL-38 in airway eosinophilic inflammation, an IL-38-gene deficient (KO) murine asthma model was analyzed. METHODS The numbers of eosinophils and neutrophils, and levels of IL-5, IL-13 and IL-17A protein and mRNA in bronchoalveolar lavage fluid (BALF) and lung tissue were compared between wild-type (WT) and IL-38-KO mice after OVA sensitization and challenge. The effects of additional purified recombinant mouse (rm) IL-38 protein were investigated in the IL-38-KO murine asthma model. RESULTS The IL-38 and IL-5 mRNA in WT mice was significantly higher after OVA challenge than after saline challenge (p

OBJECTIVES Relapsing polychondritis (RP) is a very rare autoimmune disorder characterized by recurrent episodes of inflammation and destruction of cartilaginous tissues. We examined the clinical characteristics, management, and outcomes of Japanese RP patients. METHODS We identified 8 RP cases in our department between 2003 and 2017. Detailed clinical features, testing, treatment, and outcomes were recorded. RESULTS The mean time from symptom onset to diagnosis was 9 months. Four cases presented with auricular chondritis and laryngotracheal involvement and 3 cases presented with a saddle nose deformity. Anti-type II collagen antibody was positive in 5 of 6 cases. Of 3 cases with associated diseases (rheumatoid arthritis, ulcerative colitis, and Sjogren's syndrome), 2 died of respiratory failure. CONCLUSIONS When RP is diagnosed, early computed tomography or pulmonary function testing is essential to enable early treatment. Undiagnosed airway involvement can cause tracheobronchial wall fibrosis, leading to fixed stenosis.

We describe a case of a woman who presented with a persistent cough, general fatigue, and a fever. Interstitial lung disease was rapidly progressive and resistant to high-dose steroid therapy. She tested positive for the presence of anti-melanoma differentiation-associated gene 5 (MDA-5) antibody, although she had no skin manifestations of dermatomyositis. She was eventually diagnosed with unclassifiable idiopathic interstitial pneumonia and was successfully treated with intensive immunosuppressive therapy including intravenous cyclophosphamide. To our knowledge, this is the first report of anti-MDA-5 antibody in a patient with idiopathic interstitial pneumonia.

IntroductionThe rapid spread of COVID-19 posed a global burden. Substantial number of people died of the disease in the acute phase of infection. In addition, a significant proportion of patients have been reported to suffer from post-acute phase symptoms, sequelae of COVID-19, which may negatively influence the quality of daily living and/or socioeconomic circumstances of the patients. However, no previous study has comprehensively and objectively assessed the quality of life of patients by using existing international scales. Further, evidence of socioeconomic consequences among patients with COVID-19 is scarce. To address the multidimensional issues from sequelae of COVID-19, evidence from comprehensive surveys beyond clinical perspectives is critical that investigates health, and social determinants of disease progression as well as socioeconomic consequences at a large scale.Methods and analysisIn this study, we plan to conduct a nationwide and comprehensive survey for the sequelae of COVID-19 in a total of 1000 patients diagnosed at 27 hospitals throughout Japan. This study will evaluate not only the health-related status of patients from clinical perspectives but also the Health-related Quality of Life (HRQoL) scores, socioeconomic status and consequences to discuss the sequelae of the disease and the related risk factors. The primary endpoint is the frequency of long-term complications of COVID-19 infection. The secondary endpoints are risk factors for progression to sequelae of COVID-19 infection. The study will provide robust and important evidence as a resource to tackle the issues from the sequelae of COVID-19 from the multi-dimensional perspectives.Ethics and disseminationThis trial was approved by the Keio University School of Medicine Ethics Committee (20200243, UMIN000042299). The results of this study will be reported at a society meeting or published in a peer-reviewed journal.

Background The efficacy of nintedanib in progressive fibrosing interstitial lung diseases (ILDs) was demonstrated in the randomised, double-blind, placebo-controlled INBUILD trial. This subgroup analysis evaluated the efficacy and safety of nintedanib in the Japanese population. Methods Patients with progressive fibrosing ILDs (evaluated by physicians within 24 months of screening) were randomised (1:1) to twice-daily 150-mg nintedanib or placebo; treatment continued until the last patient completed 52 weeks. The primary endpoint was the annual rate of decline in forced vital capacity (FVC) over 52 weeks. Time-to-first acute ILD exacerbation or death and time-to-death up until the last patient had completed the week 52 visit were evaluated. This subgroup analysis included 108 Japanese patients. Results The adjusted annual rates of FVC decline (mL/year) over 52 weeks for Japanese patients were −148.31 (nintedanib) and −240.36 (placebo), adjusted difference: 92.05 (95% CI: −10.69–194.80) and for non-Japanese patients were −67.41 (nintedanib) and −177.65 (placebo), adjusted difference: 110.24 (95% CI: 64.97–155.52). No heterogeneity in treatment effect between Japanese and non-Japanese subgroups was observed (treatment-by-subgroup interaction, p = 0.75). The risks of “acute exacerbation or death” (hazard ratio, 0.30 [95% CI: 0.10–0.91]) and mortality (hazard ratio, 0.54 [95% CI: 0.14–2.11]) in Japanese patients were numerically lower for nintedanib than placebo. There were no new or unexpected safety findings. Conclusions In Japanese patients, nintedanib slowed ILD progression, evidenced by a reduction in the annual rate of decline in FVC vs placebo. The efficacy and safety of nintedanib in Japanese patients were consistent with the overall INBUILD population. Clinicaltrials.gov NCT02999178 (21-Dec-2016).

Background: The purpose of this study was to investigate the factors related to patient’s participation in leisure activity in breast cancer patients with axillary lymph node dissection at 3 months after surgery. Methods: In total, 160 women who were employed before their surgery were evaluated. Age, body mass index (BMI), employment, level of lymph node dissection, marital status, children, coresident household members, preoperative chemotherapy, postoperative chemotherapy, postoperative hormonal therapy, postoperative radiotherapy, shoulder range of motion test, upper limb function, quality of life, and patient’s participation in leisure activity were evaluated. Results: Patients who undertook leisure activities constituted the leisure activity group, and patients who did not constituted the non-leisure activity group. Global health status, emotional function, social function, and dyspnea were significantly different between the leisure activity group and the non-leisure activity group at 3 months after surgery (p &lt, 0.05). Regarding factors that affected participation in leisure activities, logistic regression analysis showed that only participation in leisure activities before surgery was significantly associated with participation in leisure activities at 3 months after surgery (p &lt, 0.05). Conclusion: Patients who did not participate in leisure activities prior to surgery were unlikely to participate 3 months after surgery and thus require intervention to encourage their involvement.

The main target of anti-inflammatory drug therapies for coronavirus disease 2019 (COVID-19) is reducing the risk of acute respiratory distress syndrome (ARDS), an important risk factor for acute death. In the RECOVERY trial, 6 mg/day of dexamethasone for up to 10 days improved 28-day mortality compared with those who received usual care alone. Here, we present three COVID-19 cases who improved after treatment with methylprednisolone (MPSL) and/or following prednisolone (PSL) for acute progression of respiratory failure. Three male COVID-19 patients, aged 56, 84, and 49 years old, developed acute respiratory failure after admission. MPSL therapy (500 mg/day for 3 days) was started for these patients at 4, 4, and, 2 days after admission, respectively, when oxygen administration was required. Following this therapy, two of the three present cases received 30 or 40 mg/day of PSL for an additional 6 and 8 days, respectively. The remaining case discontinued corticosteroid after MPSL therapy. All three cases survived, had fever reduction at 6, 2, and 1 days after start of MPSL therapy, could discontinue oxygen therapy at 6, 6, and 11 days after start of MPSL therapy, and showed negative results for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) polymerase chain reaction at 8, 6, and 22 days after start of MPSL therapy, respectively. No serious side effects due to drug discontinuation of treatment for COVID-19 were observed. MPSL is a candidate drug for corticosteroid therapy for COVID-19. Corticosteroid therapy should be started in the early stage of respiratory failure. Optimal drug selection, timing of intervention, dose, and duration of corticosteroid therapy for COVID-19 should be analyzed in the further studies. © Journal of Xiangya Medicine. All rights reserved.

Introduction: Idiopathic pulmonary fibrosis (IPF) is a fibrotic disease of unknown aetiology with a poor prognosis. Several clinical trials of nintedanib in patients with IPF have reported its inhibitory effect on reduced lung function, incidence of acute exacerbation of IPF and worsened health-related quality of life. Although nintedanib has a manageable safety and tolerability profile over long-term use, it was discontinued in over 20% of patients because of adverse events such as diarrhoea and liver dysfunction. This might explain why nintedanib use in patients with IPF is not widespread, especially among patients with early-stage IPF. In the present study, we aimed to clarify the efficacy, safety and tolerability of nintedanib in patients with stage I/II IPF, based on the Japanese IPF disease severity staging classification system. Methods and analysis: This is an ongoing, prospective, multicentre observational cohort study of patients with stage I/II IPF who will start receiving nintedanib. Totally, 215 patients at 35 sites in Kyushu and Okinawa, Japan will be enrolled and followed up for 3 years. Nintedanib therapy would be initiated at the discretion of the investigator. The primary endpoint, change in forced vital capacity (FVC) at 156 weeks, will be shown as the mean change in FVC from baseline to week 156 with 95% CIs estimated using the Wald method. The safety endpoint—occurrence of adverse events—will be assessed in each system organ class/preferred term. Ethics and dissemination: The study protocol and informed consent documents were approved by the Institutional Review Board at Nagasaki University Hospital (approval number 19102146) and each participating site. Written informed consent was obtained from all participants. Patient recruitment has begun. The results will be disseminated through scientific peer-reviewed publications and national and international conferences. Trial registration number: UMIN000038192., BMJ open, 11(6), art. no. e047249; 2021

Rett syndrome (RTT) is a neurodevelopmental disorder mainly caused by mutations in the gene encoding the transcriptional regulator Methyl-CpG-binding protein 2 (MeCP2), located on the X chromosome. Many RTT patients have breathing abnormalities, such as apnea and breathing irregularity, and respiratory infection is the most common cause of death in these individuals. Previous studies showed that MeCP2 is highly expressed in the lung, but its role in pulmonary function remains unknown. In this study, we found that MeCP2 deficiency affects pulmonary gene expression and structures. We also found that Mecp2-null mice, which also have breathing problems, often exhibit inflammatory lung injury. These injuries occurred in specific sites in the lung lobes. In addition, polarizable foreign materials were identified in the injured lungs of Mecp2-null mice. These results indicated that aspiration might be a cause of inflammatory lung injury in Mecp2-null mice. On the other hand, MeCP2 deficiency affected the expression of several neuromodulator genes in the lower brainstem. Among them, neuropeptide substance P (SP) immunostaining was reduced in Mecp2-null brainstem. These findings suggest that alteration of SP expression in brainstem may be involved in autonomic dysregulation, and may be one of the causes of aspiration in Mecp2-null mice.

Background Interleukin (IL)-38, a member of the IL-1 family, shows high homology to IL-1 receptor antagonist (IL-1Ra) and IL-36 receptor antagonist (IL-36Ra). Its function in interstitial lung disease (ILD) is still unknown. Methods To determine the expression pattern of IL-38 mRNA, a panel of cDNAs derived from various tissues was analyzed by quantitative real-time PCR. Immunohistochemical reactivity with anti-human IL-38 monoclonal antibody (clone H127C) was evaluated semi-quantitatively in lung tissue samples from 12 patients with idiopathic pulmonary fibrosis/usual interstitial pneumonia (IPF/UIP), 5 with acute exacerbation of IPF, and 10 with anticancer drug-induced ILD (bleomycin in 5 and epidermal growth factor receptor-tyrosine kinase inhibitor in 5). Control lung tissues were obtained from areas of normal lung in 22 lung cancer patients who underwent extirpation surgery. Results IL-38 transcripts were strongly expressed in the lung, spleen, synoviocytes, and peripheral blood mononuclear cells, and at a lower level in pancreas and muscle. IL-38 protein was not strongly expressed in normal pulmonary alveolar tissues in all 22 control lungs. In contrast, IL-38 was overexpressed in the lungs of 4 of 5 (80%) patients with acute IPF exacerbation and 100% (10/10) of the patients with drug-induced ILD. IL-38 overexpression was limited to hyperplastic type II pneumocytes, which are considered to reflect regenerative change following diffuse alveolar damage in ILD. Conclusions IL-38 may play an important role in acute and/or chronic inflammation in anticancer drug-induced lung injury and acute exacerbation of IPF.

Objective The utility of detecting Mycobacterium tuberculosis in urine samples from patients with pulmonary tuberculous with diffuse small nodular shadows (suspected miliary tuberculosis (MTB)) is still unclear in Japan. A retrospective cross-sectional study was conducted to investigate the detection rates of M. tuberculosis in urine of patients with suspected MTB. Methods Among 687 hospitalized patients with tuberculosis, 45 with culture-confirmed suspected MTB and the data of culture and polymerase chain reaction (PCR) for M. tuberculosis in urine and sputum samples were investigated. The detection rates of M. tuberculosis in urine using cultures and PCR were calculated. The detection rate of urine was then compared with that of bone marrow aspiration. Results Fourteen patients with suspected MTB were ultimately analyzed. A diagnosis of miliary tuberculosis was suspected in all patients before anti-tuberculosis chemotherapy. Positive results by PCR (11 [78.6%] cases) and culture (8 [57.1%]) were obtained from urine samples. In patients with suspected MTB, there was no significant difference in the detection rates between M. tuberculosis in urine using a combination of PCR and culture (85.6% [12/14 cases]) and bone marrow aspiration (66.7% [8/12 cases]) (p>0.05). Conclusion Using PCR and culture, we demonstrated high detection rates of M. tuberculosis in the urine of patients with suspected MTB. A combination of PCR and culture compared favorably with the detection rates achieved with bone marrow aspiration. We believe that detection of M. tuberculosis from urine and sputum samples may be easy and safe for patients with disseminated tuberculosis infections such as definitive MTB.

A 40-year-old female dental technician visited our hospital for the investigation of a chest X-ray abnormality. Chest computed tomography demonstrated centrilobular nodules and lung volume reduction, and her serum KL-6 level was elevated. A histological analysis of the specimens obtained on a surgical lung biopsy showed peribronchiolar fibrosis with pigmented macrophages and cholesterol clefts. An energy-dispersive X-ray analysis showed that these lung tissues contained some metals, including indium. The serum indium level was also elevated. We diagnosed this patient with pneumoconiosis caused by exposure to sandblasting certain dental metals. This is the first reported case of pneumoconiosis in a dental technician associated with exposure to indium.

The aim of this study was to identify factors in the working environment associated with regular dental attendance. Thirty-three general practitioners provided data on 488 patients who underwent dental maintenance between 2003 and 2015. The age of the patients ranged from 40 to 65 years. Appointment adherence, employment format, overtime work, night work, and subjective evaluation of work were investigated. Multiple logistic regression analysis was performed to identify factors associated with regular dental attendance. Among all participants, 296 (60.7%) were female, 320 (65.6%) worked full-time, 193 (39.5%) worked overtime, and 34 (7.0%) worked nights. The results of the analysis revealed that only night work was a significant factor after adjusting for sex, age, and employment format (odds ratio, 0.220; 95% confidence interval, 0.088-0.550). The results of this study suggest that night work disturbs regular dental attendance.

Background We attempted to clarify whether the presence of anti-aminoacyl-transfer RNA synthetase antibody (anti-ARS Ab) or anti-melanoma differentiation-associated gene 5 antibody (anti-MDA5 Ab) is associated with the therapeutic response of polymyositis/dermatomyositis-associated interstitial lung disease (PM/DM-ILD). Methods We retrospectively investigated 22 patients with PM/DM-ILD (10 positive for anti-ARS Ab and nine positive for anti-MDA5 Ab) for whom antibody analysis of conserved serum was possible. We assessed mortality in the first three months as the therapeutic response in the acute phase and compared changes in clinical data for up to one year considered as the chronic phase. We classified the clinical changes over the year into three groups: Improvement (increased % vital capacity [%VC] or diffusing capacity of the lung for carbon monoxide [%D LCO ]≥10 or 15%), deterioration (decreased %VC or %D LCO ≥10 or 15%), and no change (remainder of the changes). The extent of abnormality demonstrated by high-resolution computed tomography (HRCT) was scored. Results Positivity for anti-MDA5 Ab, but not for anti-ARS Ab, was associated with mortality in the first 3 months. Evaluation of the therapeutic response in the first year showed that positivity for the anti-ARS Ab, but not for the anti-MDA5 Ab, was associated with an improvement in %D LCO and a decline in the serum KL-6 levels. Positivity for the anti-ARS Ab or negativity for anti-MDA5 Ab was associated with a greater decrease in bronchial dilatation as seen by HRCT. Conclusions Anti-ARS and anti-MDA5 Abs are associated with the therapeutic response of PM/DM-ILD.

Whether poorer pulmonary function accelerates progression of arterial stiffness remains unknown as prior observational studies have not examined longitudinal changes in arterial stiffness in relation to earlier pulmonary function. Data (N=5342, 26% female) were drawn from the Whitehall II cohort study. Participants completed repeated assessments of forced expiratory volume in 1 second (FEV 1 , L) and carotid-femoral pulse wave velocity (cf-PWV, m/s) over 5 years. The effect of FEV 1 on later cf-PWV and its progression was estimated using linear mixed-effects modeling. Possible explanatory mechanisms, such as mediation by low-grade systemic inflammation, common-cause explanation by preexisting cardiometabolic risk factors, and reverse-causation bias, were assessed. Poorer pulmonary function was associated with later higher cf-PWV and its subsequent progression (cf-PWV 5-year change 0.09, 95% CI 0.03–0.17 per SD lower FEV 1 ) after adjustment for age, sex, ethnicity, heart rate, and mean arterial pressure. Decrease in pulmonary function was associated with later higher cf-PWV (0.17, 95% CI 0.04–0.30 in the top compared to bottom quartile of decline in FEV 1 ). There was no evidence to support mediation by circulating CRP (C-reactive protein) or IL (interleukin)-6. Furthermore, arterial stiffness was not associated with later FEV 1 after accounting for cardiometabolic status. In conclusion, poorer pulmonary function predicted future arterial stiffness. These findings support pulmonary function as a clinically important risk factor for arterial stiffness and provide justification for future intervention studies for pulmonary function based on its relationship with arterial stiffness.