A case of autoimmune pulmonary alveolar proteinosis during the course of treatment of rapidly progressive interstitial pneumonia associated with anti-MDA5 antibody-positive dermatomyositis.

BACKGROUND: Autoimmune pulmonary alveolar proteinosis (APAP) is a diffuse lung disease that causes abnormal accumulation of lipoproteins in the alveoli; however, its pathogenesis remains unclear. Recently, APAP cases have been reported during the course of dermatomyositis. The combination of these two diseases may be coincidental; however, it may have been overlooked because differentiating APAP from a flare-up of interstitial pneumonia associated with dermatomyositis is challenging. This didactic case demonstrates the need for early APAP scrutiny. CASE PRESENTATION: A 50-year-old woman was diagnosed with anti-melanoma differentiation-associated gene 5 (anti-MDA5) antibody-positive dermatitis and interstitial pneumonia in April 2021. The patient was treated with corticosteroids, tacrolimus, and cyclophosphamide pulse therapy for interstitial pneumonia complicated by MDA5 antibody-positive dermatitis, which improved the symptoms and interstitial pneumonia. Eight months after the start of treatment, a new interstitial shadow appeared that worsened. Therefore, three additional courses of cyclophosphamide pulse therapy were administered; however, the respiratory symptoms and interstitial shadows did not improve. Respiratory failure progressed, and 14 months after treatment initiation, bronchoscopy revealed turbid alveolar lavage fluid, numerous foamy macrophages, and numerous periodic acid-Schiff-positive unstructured materials. Blood test results revealed high anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) antibody levels, leading to a diagnosis of APAP. The patient underwent whole-lung lavage, and the respiratory disturbance promptly improved. Anti-GM-CSF antibodies were measured from the cryopreserved serum samples collected at the time of diagnosis of anti-MDA5 antibody-positive dermatitis, and 10 months later, both values were significantly higher than normal. CONCLUSIONS: This is the first report of anti-MDA5 antibody-positive dermatomyositis complicated by interstitial pneumonia with APAP, which may develop during immunosuppressive therapy and be misdiagnosed as a re-exacerbation of interstitial pneumonia. In anti-MDA5 antibody-positive dermatomyositis, APAP comorbidity may have been overlooked, and early evaluation with bronchoalveolar lavage fluid and anti-GM-CSF antibody measurements should be considered, keeping the development of APAP in mind.

Prevalence and risk factors for medication-refractory reflux esophagitis in patients with systemic sclerosis in Japan.

BACKGROUNDS: Patients with systemic sclerosis (SSc) often have esophageal motility abnormalities and weak esophago-gastric junction (EGJ) barrier function, which causes proton pump inhibitor (PPI)-refractory reflux esophagitis (RE). The aims of this study were to clarify the current management of RE and prevalence and risk factors of medication-refractory RE in patients with SSc in Japan. METHODS: A total of 188 consecutive patients with SSc who underwent both esophageal high-resolution manometry (HRM) and esophagogastroduodenoscopy (EGD) were reviewed. The presence of RE and grades of the gastroesophageal flap valve (GEFV) were assessed. Esophageal motility was assessed retrospectively according to the Chicago classification v3.0. When RE was seen on a standard dose of PPI or any dose of vonoprazan (VPZ), it was defined as medication-refractory RE. RESULTS: Approximately 80% of patients received maintenance therapy with acid secretion inhibitors regardless of esophageal motility abnormalities. Approximately 50% of patients received maintenance therapy with PPI, and approximately 30% of patients received VPZ. Medication-refractory RE was observed in 30 patients (16.0%). In multivariable analyses, the number of EGD and absent contractility were significant risk factors for medication-refractory RE. Furthermore, combined absent contractility and GEFV grade III or IV had higher odds ratios than did absent contractility alone. CONCLUSIONS: Patients with persistent reflux symptoms and those with absent contractility and GEFV grade III or IV should receive maintenance therapy with strong acid inhibition to prevent medication-refractory RE.

Effective treatment with mepolizumab in a patient with severe eosinophilic granulomatosis with polyangiitis complicated with small intestine perforation.

Eosinophilic granulomatosis with polyangiitis (EGPA) is systemic vasculitis caused by eosinophilia affecting small to medium-sized blood vessels, which damages the organs. Antineutrophil cytoplasmic antibody-associated vasculitis EGPA treatment guidelines added anti-interleukin-5 antibody mepolizumab to the standard treatment protocol for active-non-severe EGPA based on the MIRRA study. Nevertheless, the role of mepolizumab in treating patients with active severe EGPA has not been established. We treated a patient with EGPA complicated with small intestine perforation using steroid pulse intravenous, high-dose glucocorticoids, intravenous high-dose immunoglobulin therapy, and mepolizumab without immunosuppression agents; the patient went into remission, suggesting that mepolizumab is an effective therapeutic agent that could lead to remission in severe EGPA.

Clinical differences among patients with myeloperoxidase-antineutrophil cytoplasmic antibody-positive interstitial lung disease.

INTRODUCTION: Patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis and idiopathic interstitial lung diseases (IIPs) are positive for myeloperoxidase (MPO)-ANCA. MPO-ANCA-positive vasculitis mainly comprises microscopic polyangiitis (MPA) and unclassifiable vasculitis. These diseases are frequently complicated by interstitial lung disease (ILD). Few studies have reported the clinical differences between the subtypes of MPO-ANCA-positive ILD. Therefore, this study aimed to examine the clinical findings and courses of MPO-ANCA-positive ILD. METHOD: This retrospective study enrolled 100 patients with MPO-ANCA-positive ILD who were categorized into three groups: MPA (n = 44), unclassifiable vasculitis (n = 29), and IIP (n = 27). Our study compared the clinical findings and prognosis of these patients and analyzed the poor prognostic factors. Furthermore, we assessed the association between the patients with and without acute exacerbation of ILD (AE-ILD). RESULTS: Our study found clinical differences in serum markers, clinical symptoms, and treatment regimens among the three groups. ILD complications, as the main cause of death, differed among the three groups (P = 0.04). Patients with unclassifiable vasculitis showed higher survival rates than those with IIP (P = 0.046). Patients with AE-ILD showed fewer general symptoms (P = 0.02) and lower survival rates (P < 0.01) than those without AE-ILD. In multivariate analysis, AE-ILD development was a strong poor prognostic factor for MPO-ANCA-positive ILD. CONCLUSIONS: The subtypes of MPO-ANCA-positive ILD have different clinical features and prognoses. Patients who develop AE-ILD require careful evaluation of clinical courses. Key Points • In myeloperoxidase (MPO)-antineutrophil cytoplasmic antibody (ANCA)-positive interstitial lung disease (ILD), patients with unclassifiable vasculitis showed a better prognosis than those with idiopathic ILD.. • Development of acute exacerbation in ILD was a strong poor prognostic factor in patients with MPO-ANCA-positive ILD..

A pregnant woman with severe dyspnoea.

Preterm delivery is a feasible option in the third trimester of pregnancy in the treatment of pregnant women with acute respiratory distress syndrome due to miliary tuberculosis with respiratory failure https://bit.ly/3stKOzj.

Durable response to afatinib rechallenge in a long-term survivor of non-small cell lung cancer harboring EGFR L858R and L747V mutations.

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors are standard therapeutic agents for non-small cell lung cancer (NSCLC) patients with major EGFR mutations such as exon 19 deletions and a L858R mutation, whereas treatment strategies for cases with uncommon EGFR mutations remain to be fully established. Here, we report a long-term (≥20 years from initial diagnosis) NSCLC survivor carrying EGFR L858R and L747V mutations. The patient received gefitinib monotherapy, systemic chemotherapy/chemoimmunotherapy, and local consolidative therapies for oligometastatic lesions, and responded to afatinib rechallenge with a progression-free survival of 12 months. The current case suggests that afatinib is effective in NSCLC patients with EGFR L858R and L747V mutations and that a therapeutic approach combining appropriately timed systemic therapies with local consolidative therapies for oligometastatic lesions improves long-term survival.

Quantitative CT analysis of interstitial pneumonia in anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis: a single center, retrospective study.

INTRODUCTION: This study aimed to assess the utility of quantitative high-resolution computed tomography (HRCT) for determining the clinical course of anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis-associated interstitial lung disease (MDA5+ ILD). METHOD: This study retrospectively analyzed the data of 34 patients with MDA5+ ILD to determine the association between the clinical findings and extent of ILD via quantitative CT analysis at baseline and short-term follow-up. Quantified HRCT scores were evaluated as the lung severity score (LSS), percentage of opacity, and percentage of high opacity. RESULTS: Thirty-four patients underwent follow-up CT scans 35 (range: 14-78) days after diagnosis. Patients who died of rapidly progressive ILD had higher LSS (p < 0.01), percentage of opacity (p < 0.01), percentage of high opacity (p = 0.01), total ground-glass opacity score (p = 0.01), serum C-reactive protein (CRP) (p = 0.03), and alveolar-arterial oxygen difference (Aa-DO2) (p = 0.01) at follow-up than those who survived. Quantified HRCT scores correlated with serum CRP and Aa-DO2 levels at follow-up. LSS at follow-up (AUC = 0.844, p < 0.01) was the best predictor of death in MDA5+ ILD patients. Patients with an LSS of > 6.5 at follow-up had higher mortality than those with an LSS of ≤ 6.5, especially when receiving triple therapy. In multivariate analysis, an LSS of > 6.5 at follow-up was significantly associated with a poor outcome. CONCLUSIONS: Quantitative CT analysis of MDA5+ ILD is useful for the objective assessment of respiratory status and disease activity. Short-term HRCT evaluation, particularly LSS, is most important in predicting its clinical course during triple therapy. Key Points • Quantitative CT analysis plays an important role in evaluating the clinical course of anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis-associated interstitial lung disease (MDA5+ ILD). • Quantified HRCT scores, particularly lung severity score, at short-term intervals from diagnosis can help to predict prognosis after triple therapy in MDA5+ ILD.

Influence of obesity in interstitial lung disease associated with anti-aminoacyl-tRNA synthetase antibodies.

BACKGROUND: Obesity is a major risk factor for developing various respiratory diseases. Patients with anti-aminoacyl tRNA synthetase (ARS) antibodies often have interstitial lung disease (ILD). The present study was conducted to evaluate the association between obesity and outcomes of anti-ARS antibody-related ILD (ARS-ILD). METHODS: We retrospectively investigated 58 patients with ARS-ILD and compared the clinical characteristics, treatment, and prognoses between obese (body mass index [BMI] ≥25 kg/m2) and nonobese (BMI <25 kg/m2) patients. Chest fat was quantified via computed tomography (CT). Thoracic subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) were measured at diagnosis and first relapse of ILD. RESULTS: Sixteen patients were obese. Obese patients had lower percentages of predicted diffusing capacity of the lungs for carbon monoxide and higher high-resolution CT scores and SAT and VAT indexes than did nonobese patients. The ILD relapse rate was higher in obese patients (P < 0.01), especially among those with high SAT indexes (P < 0.01). The SAT and VAT indexes increased significantly from diagnosis until first relapse. Among clinical parameters at first relapse, SAT and VAT indexes were correlated with serum Krebs von den Lungen-6 levels (r = 0.720, P = 0.008) and total ground-glass attenuation scores (r = 0.620, P = 0.024), respectively. CONCLUSIONS: Obesity and high SAT indexes are risk factors for ILD relapse in patients positive for anti-ARS antibodies. Evaluating and quantifying patients' chest fat on CT is important for predicting ILD relapse.

A case of a patient with neurofibromatosis type I who developed pneumothorax and eosinophilic pleural effusion after suffering from COVID-19 pneumonia.

Coronavirus disease 2019 (COVID-19) has become a global pandemic since its discovery in December 2019, and as the disease continues to evolve, varying complications associated with it continue to arise. In this regard, computed tomography has played an extremely important role in the diagnosis and evaluation of COVID-19 pneumonia and its complications. We encountered a case of a male patient with neurofibromatosis (type I) who developed concurrent pneumothorax and pleural effusion during his recovery period from severe COVID-19 pneumonia. Pulmonary fibrosis and emphysema were also confirmed. Furthermore, an eosinophil pleural effusion appeared and was prolonged during the healing process of COVID-19. This clinical presentation suggests that fibrosis and emphysema formation due to neurofibromatosis may have caused pneumothorax and pleural effusion.

Interstitial lung disease with myeloperoxidase-antineutrophil cytoplasmic antibody-associated vasculitis in elderly patients.

Anti-neutrophil cytoplasmic antibodies-associated vasculitis (AAV) occurs in elderly people, and patients with anti-myeloperoxidase autoantibodies (MPO-ANCA)-positive AAV are often complicated with interstitial lung disease (ILD). This study aimed to evaluate the age-related clinical features of elderly patients with MPO-ANCA-positive AAV-ILD. This study retrospectively investigated 63 patients with MPO-ANCA-positive AAV-ILD, all of whom were 65 years or older at diagnosis. Clinical characteristics, causes of death and survival rates among three groups stratified by age (65-74 years, n = 29; 75-79 years, n = 18; over 80 years, n = 16) were compared. This study also examined the association with severe infections in these patients. Among the three age groups, there were significant differences in sex (P = 0.032), serum Krebs von den Lungen-6 (P < 0.01), and total ground-glass opacity score (P = 0.011). The causes of death were mainly severe infections and complications of ILD. Kaplan-Meier curve analysis showed a significantly lower 5-year survival rate in the oldest group (P < 0.01). Regarding severe infections in these patients, the 5-year cumulative incidence of severe infections was higher in the patients receiving steroid pulse therapy (P = 0.034). The clinical characteristics of MPO-ANCA-positive AAV-ILD differ with age in elderly patients, with age being an important poor prognostic factor in these patients. The administration of steroid pulse therapy is a significant risk factor of severe infection in MPO-ANCA-positive elderly patients with AAV-ILD.

Clinical features of dermatomyositis associated with anti-MDA5 antibodies by age.

OBJECTIVES: Anti-melanoma differentiation-associated gene 5 (MDA5) autoantibody-positive and age at onset ≥60 years are poor prognosis factors in polymyositis (PM) and dermatomyositis (DM) associated with interstitial lung disease (ILD) among Japanese patients. However, the influence of age on the clinical features of anti-MDA5 autoantibody-positive patients with DM remains unclear. METHODS: We retrospectively examined 40 patients with DM and anti-MDA5 autoantibodies according to age. We compared patients aged <60 and ≥60 years with respect to clinical features including laboratory test findings, high-resolution lung computed tomography data, treatment content, and complications such as infections and prognosis. We also examined clinical features between surviving and deceased patients in the older patient group. RESULTS: Of 40 enrolled patients, 13 were classified as old and 27 as young. Older patients had significantly fewer clinical symptoms including arthralgia/arthritis (p < .01), skin ulceration (p = .02), and higher mortality than younger patients (p = .02) complicated with rapidly progressive ILD (RP-ILD), combination immunosuppressive therapy, and strictly controlled infections. CONCLUSION: Clinical features and mortality of anti-MDA5 autoantibody-positive DM patients were influenced by age. Patients aged ≥60 years had a worse prognosis, and combination immunosuppressive therapy was often ineffective for RP-ILD in older patients.

Successful afatinib rechallenge in a patient with non-small cell lung cancer harboring EGFR G719C and S768I mutations.

Recent studies have indicated that afatinib is beneficial for patients with non-small cell lung cancer (NSCLC) harboring uncommon epidermal growth factor receptor (EGFR) mutations, while the effectiveness of afatinib rechallenge has not been fully defined. Here, we report a long-term survival case of NSCLC harboring concomitant EGFR G719C and S768I mutations who received afatinib rechallenge followed by chemotherapy. The present case suggests that combined therapeutic strategies such as afatinib plus sequential chemotherapy would be beneficial based on appropriately timed rebiopsies from recurrent lesions. KEY POINTS: SIGNIFICANT FINDINGS OF THE STUDY AND WHAT THIS STUDY ADDS: A NSCLC patient carrying EGFR G719X/S768I mutations survived for a long period of time with afatinib rechallenge followed by chemotherapy. Combined therapeutic strategies should be considered based on rebiopsies in appropriate timing in NSCLC with uncommon EGFR mutations.

Rare metastatic pancreatic tumors from lung cancer with cystic changes resembling intraductal papillary mucinous neoplasm: a case report.

BACKGROUND: Metastatic pancreatic tumors from lung cancer (MPTLC) constitute 3% of all metastatic pancreatic tumors. We present an extremely rare case of cystic MPTLC that was difficult to distinguish from intraductal papillary mucinous neoplasm (IPMN). CASE PRESENTATION: The patient was a 74-year-old woman who underwent lobectomy of lung cancer 2 years before presentation to our hospital. She was referred to our department for resection of cystic pancreatic tumors, which were diagnosed as IPMN with high-risk stigmata. Abdominal computed tomography (CT) showed a 37-mm-wide cystic tumor with a contrasted solid nodule in the pancreatic head and a 17-mm-wide cystic tumor in the pancreatic tail. We performed a total pancreatectomy for these lesions. According to histopathological and immunohistochemical findings, the tumors were diagnosed as metastatic pancreatic tumors from lung cancer. CONCLUSION: In this case, the cystic morphology was formed by eosinophilic secretions from tumor cells, and it was difficult to distinguish from IPMN with high-risk stigmata. We consider this case, based on the variable clinical findings, an extremely rare variant of MPTLC.

Prevalence and clinical characteristics of earlobe crease in systemic sclerosis: Possible association with vascular dysfunction.

Patients with systemic sclerosis (SSc) develop various vasculopathy-induced vascular disorders such as Raynaud's phenomenon, abnormal nail-fold capillaries, persistent digital ischemia, digital ulcers (DU), and sometimes develop renal crisis and pulmonary artery hypertension (PAH), affecting prognosis. Earlobe crease (ELC), also known as Frank's sign, is a wrinkle extending from the tragus to the outer border of the earlobe and is generally recognized as the sign of cardiovascular events. However, no previous study analyzed the association between ELC and SSc. In this study, we examined the prevalence and clinical characteristics of ELC in SSc patients. We analyzed 145 Japanese SSc patients and found that the prevalence of ELC in SSc patients was 23.4% (43/145), similar to that previously reported in the general population without SSc. Using univariate analysis, we found that SSc patients with ELC were characterized by old age, high incidence of DU, ILD and PAH, and high complication of coronary artery diseases (CAD) compared with SSc patients without ELC. In multivariate analysis, ELC was significantly associated with old age and incidence of DU. PAH tended to correlate with ELC without statistical significance. These results suggest that ELC may be associated with vascular disorders in SSc patients. This is the first report concerning the prevalence and clinical characteristics of ELC in patients with SSc. ELC is very easy to detect in clinical practice and helps physicians to identify SSc patients at risk of developing vascular disorders such as DU and PAH.

Administration of docetaxel plus ramucirumab with primary prophylactic pegylated-granulocyte colony-stimulating factor for pretreated non-small cell lung cancer: a phase II study.

PURPOSE: Although docetaxel plus ramucirumab has shown superior treatment efficacy over docetaxel monotherapy for patients with non-small cell lung cancer (NSCLC), the high rate of febrile neutropenia (FN) presents a clinical problem. This study aimed to validate the primary prophylactic use of pegfilgrastim with docetaxel and ramucirumab treatment in Japanese patients with NSCLC. METHODS: Patients with NSCLC with progression after at least one round of chemotherapy were enrolled and administered docetaxel (60 mg/m2) plus ramucirumab (10 mg/kg) intravenously on day 1, followed by pegylated-granulocyte colony-stimulating factor (3.6 mg) on day 2 of a 21-day treatment cycle. The primary study endpoint was the percentage of patients who developed FN. Secondary endpoints included overall survival, progression-free survival, overall response rate, and safety. RESULTS: Overall, 20 patients (15 men and 5 women) were enrolled, of whom one developed FN, resulting in an overall FN rate of 5%. The response and disease control rates were 40% and 85%, respectively. The median progression-free survival was 6.6 (95% confidence interval [CI], 0.5-NR) months. The median overall survival was 18.4 (95% CI, 2.2-11.0) months. Six patients aged over 75 years were included in this study, and although most adverse events were durable, ramucirumab-associated adverse events occurred more frequently in these patients. CONCLUSIONS: We observed a 5% FN rate using primary prophylactic pegylated-granulocyte colony-stimulating factor with docetaxel plus ramucirumab in Japanese patients with NSCLC. While most adverse events were durable, elderly patients should be closely monitored.

Clinical features and poor prognostic factors of anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis with rapid progressive interstitial lung disease.

Anti-melanoma differentiation-associated gene 5 (MDA5) antibody has been recognized to be significantly associated with a subset of dermatomyositis patients with rapidly progressive interstitial lung disease (RP-ILD). To elucidate the clinical characteristics and poor prognostic factors in Japanese dermatomyositis patients with anti-MDA5 antibody. Clinical features of anti-MDA5 antibody-positive dermatomyositis patients and risk factors, potentially associated with a poor prognosis, were retrospectively analysed. A total of 37.3% (28/75) dermatomyositis patients were positive for anti-MDA5 antibody. The frequency of Gottron's papules, palmar violaceous macules, antihelix/helix violaceous macules, and clinically amyopathic dermatomyositis (CADM) was significantly higher in patients with anti-MDA5 antibody. Of anti-MDA5 antibody-positive dermatomyositis patients, 57.1% developed RP-ILD, and in those with RP-ILD, serum ferritin level was markedly high and partial pressure of arterial oxygen (PaO2) was significantly low at first visit. Among patients with anti-MDA5 antibody with RP-ILD, non-survivors were older and revealed lower PaO2 at first visit relative to survivors. Furthermore, patients who did not take triple therapy (prednisolone, calcineurin inhibitor and cyclophosphamide) as initial treatment resulted in poor outcome. Anti-MDA5 antibody may be associated with CADM, the progression to RP-ILD, high serum ferritin level, and characteristic skin manifestations. High serum ferritin level in patients with anti-MDA5 antibody may be associated with the development of RP-ILD and poor prognosis. Early treatment with triple therapy, including intravenous cyclophosphamide, may improve the prognosis of RP-ILD.

A versatile platform technology for recombinant vaccines using non-propagative human parainfluenza virus type 2 vector.

Ectopic protein with proper steric structure was efficiently loaded onto the envelope of the F gene-defective BC-PIV vector derived from human parainfluenza virus type 2 (hPIV2) by a reverse genetics method of recombinant virus production. Further, ectopic antigenic peptide was successfully loaded either outside, inside, or at both sides of the envelope of the vector. The BC-PIV vector harboring the Ebola virus GP gene was able to elicit neutralizing antibodies in mice. In addition, BC-PIV with antigenic epitopes of both melanoma gp100 and WT1 tumor antigen induced a CD8+ T-cell-mediated response in tumor-transplanted syngeneic mice. Considering the low pathogenicity and recurrent infections of parental hPIV2, BC-PIV can be used as a versatile vector with high safety for recombinant vaccine development, addressing unmet medical needs.