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Abstract 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.

ABSTRACT Background Although transbronchial lung cryobiopsy (TBLC) is widely used in diagnostic algorithms for various interstitial lung diseases (ILDs), its real‐world utility in the therapeutic decision‐making strategy for ILD patients remains unclear, in particular, when judging the time to start antifibrotic agents. Methods We analyzed medical records of 40 consecutive patients with idiopathic or fibrotic hypersensitivity pneumonitis who underwent TBLC. A TBLC‐based usual interstitial pneumonia (UIP) score was used to assess three morphologic descriptors: patchy fibrosis, fibroblastic foci, and honeycombing. Results In our 40 patients with ILD, the most frequent radiological feature was indeterminate for UIP (45.0%). Final diagnosis included idiopathic pulmonary fibrosis (22.5%), fibrotic nonspecific interstitial pneumonia (5.0%), fibrotic hypersensitivity pneumonitis (35.0%), and unclassifiable ILD (37.5%). Linear mixed‐effects analysis showed that declines in the slopes of %FVC and %DLCO in patients with TBLC‐based UIP “Score ≥ 2” were significantly steeper than those of patients with “Score ≤ 1.” During follow‐up of patients with Score ≥ 2 (n = 24), more than half of them (n = 17) received an antifibrotic agent, with most patients (n = 13) receiving early administration of the antifibrotic agent within 6 months after the TBLC procedure. Conclusions TBLC‐based UIP Score ≥ 2 indicated the increased possibility of a progressive fibrosis course that may prove helpful in predicting progressive pulmonary fibrosis/progressive fibrosing ILD even if disease is temporarily stabilized due to anti‐inflammatory agents. Patients may benefit from early introduction of antifibrotic agents by treating clinicians.

Abstract Background Para‐tracheal or para‐carinal air cysts (PACs) are often asymptomatic and usually detected incidentally by methods such as computed tomography. Their clinical significance is unclear in patients with pleuroparenchymal fibroelastosis (PPFE). Methods We evaluated the clinical significance of PACs in PPFE and their relationship with pneumomediastinum or pneumothorax. Results In total, 50 patients had PPFE and 34 (68%) had PACs. Most PACs were para‐carinal (n = 30). A para‐tracheal air cyst was detected in only nine patients, which included five patients having both para‐carinal and para‐tracheal air cysts. Overall median survival was 24.7 months. Survival was not significantly different between the patients with [PACs(+)] and without PACs (P = 0.268). A high frequency (64%) of the complication of pneumomediastinum or pneumothorax occurred in the overall population during follow‐up. Pneumomediastinum/pneumothorax occurred significantly more frequently in patients with PACs(+) than in those without (76.5% vs. 37.5%; P = 0.012). PACs(+) was the only significant risk factor for pneumomediastinum/pneumothorax. Conclusions Our data showed that PACs commonly occur in patients with PPFE, and most PACs were para‐carinal air cysts. Additionally, PACs(+) was a significant risk factor for pneumomediastinum/pneumothorax; therefore, clinicians should be more aware of these complications during follow‐up examination, particular in PACs(+) patients with PPFE.

Abstract Background The diagnostic accuracy and safety of transbronchial lung cryobiopsy (TBLC) via a flexible bronchoscope under sedation compared with that of surgical lung biopsy (SLB) in the same patients is unknown. Methods Retrospectively the data of fifty-two patients with interstitial lung diseases (median age: 63.5 years; 21 auto-antibody positive) who underwent TBLC followed by SLB (median time from TBLC to SLB: 57 days) was collected. The samples from TBLC and SLB were randomly labelled to mask the relationship between the two samples. Diagnosis was made independently by pathologists, radiologists, and pulmonary physicians in a stepwise manner, and a final diagnosis was made at multidisciplinary discussion (MDD). In each diagnostic step the specific diagnosis, the diagnostic confidence level, idiopathic pulmonary fibrosis (IPF) diagnostic guideline criteria, and treatment strategy were recorded. Results Without clinical and radiological information, the agreement between the histological diagnoses by TBLC and SLB was 42.3% (kappa [κ] = 0.23, 95% confidence interval [CI]: 0.08–0.39). However, the agreement between the TBLC-MDD and SLB-MDD diagnoses and IPF/non-IPF diagnosis using the two biopsy methods was 65.4% (κ = 0.57, 95% CI: 0.42–0.73) and 90.4% (47/52), respectively. Out of 38 (73.1%) cases diagnosed with high or definite confidence at TBLC-MDD, 29 had concordant SLB-MDD diagnoses (agreement: 76.3%, κ = 0.71, 95% CI: 0.55–0.87), and the agreement for IPF/non-IPF diagnoses was 97.4% (37/38). By adding the pathological diagnosis, the inter-observer agreement of clinical diagnosis improved from κ = 0.22 to κ = 0.42 for TBLC and from κ = 0.27 to κ = 0.38 for SLB, and the prevalence of high or definite diagnostic confidence improved from 23.0% to 73.0% and from 17.3% to 73.0%, respectively. Of all 383 TBLC performed during the same period, pneumothorax occurred in 5.0% of cases, and no severe bleeding, acute exacerbation of interstitial lung disease, or fatal event was observed. Conclusions TBLC via a flexible bronchoscope under deep sedation is safely performed, and the TBLC-MDD diagnosis with a high or definite confidence level is concordant with the SLB-MDD diagnosis in the same patients.

Abstract Background Some patients with connective tissue disease (CTD)-associated interstitial lung disease (ILD) progress to pulmonary fibrosis over their disease course despite initial improvement, potentially indicating a poor prognosis. Transbronchial lung cryobiopsy (TBLC) is a new bioptic approach used in diffuse parenchymal lung diseases. This study of CTD-ILD assessed the utility of TBLC in determining therapeutic decision-making strategies. Methods We analyzed medical records of 31 consecutive CTD-ILD patients who underwent TBLC focusing on radio-pathological correlation and disease course. A TBLC-based usual interstitial pneumonia (UIP) score was used that assessed three morphologic descriptors: i) patchy fibrosis, ii) fibroblastic foci, and iii) honeycombing. Results Among the patients with CTD-ILD, 3 had rheumatoid arthritis, 2 systemic sclerosis, 5 polymyositis/dermatomyositis, 8 anti-synthetase syndrome, 6 Sjögren’s syndrome, and 5 had microscopic polyangiitis. Pulmonary function test results showed a mean %FVC of 82.4% and %DLCO of 67.7%. Among the 10 CTD patients and TBLC-proven pathological UIP, 3 patients had prominent inflammatory cells in addition to a framework of UIP, and pulmonary function of most patients improved with anti-inflammatory agents. Six (40%) of 15 patients with TBLC-based UIP score ≥ 1 had a progressive disease course during follow-up, of whom 4 patients received anti-fibrotic agents. Conclusions TBLC in patients with CTD-ILD can help determine an appropriate medication strategy, particularly when UIP-like lesions are present. TBLC may be useful when judging which agents to prioritize, anti-inflammatory or anti-fibrotic, is difficult. Moreover, additional information from TBLC may be beneficial when considering early intervention with anti-fibrotic agents in clinical practice.

Abstract Background Myeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA) is often positive in patients with interstitial lung disease (ILD), which is also often present in patients with microscopic polyangiitis (MPA). A possible association between MPO-ANCA, MPA, and idiopathic ILD remains unclear. The objective of this study was to determine whether high-resolution computed tomography (HRCT) classification based on recent idiopathic pulmonary fibrosis guideline and specific CT findings can obtain new knowledge of prognostic factors in all MPO-ANCA-positive patients with ILD including both idiopathic ILD and MPA-ILD. Methods We analyzed 101 consecutive MPO-ANCA-positive patients with respiratory disease. We assessed the diagnostic accuracy of CT findings, HRCT pattern, and specific radiological signs. Prognostic predictors were determined using Cox regression models. Results Subjects with chronic ILD included 22 patients with MPA-ILD and 39 patients with ILD but without MPA. A quarter of the patients were radiological indeterminate for usual interstitial pneumonia (UIP) pattern, which resulted in a better prognosis than that for UIP pattern. “Increased attenuation around honeycomb and traction bronchiectasis” and “anterior upper lobe honeycomb-like lesion” were found to be highly frequent radiological findings (39% and 30%, respectively). In addition, the latter finding was a significant negative prognostic factor. Conclusions Radiological indeterminate for UIP was a useful HRCT classification in MPO-ANCA-positive patients with ILD. In addition, anterior upper lobe honeycomb-like lesion was found to be specific radiological finding that was a significant prognostic factor. The present results might aid in the assessment of appropriate strategies of diagnosis in these patients.

Abstract. Introduction:. A subgroup analysis of the CAPACITY and ASCEND trials showed that pirfenidone use beyond disease progression reduced the risk of subsequent forced vital capacity (FVC) decline and death. Our study aimed to compare the efficacy and safety of nintedanib with or without pirfenidone for patients with idiopathic pulmonary fibrosis (IPF) who experienced disease progression during previous pirfenidone therapy. Methods:. In this randomized, open-label, selection design phase II trial, patients with IPF and a ≥5% relative decline in FVC within 6 months of the pirfenidone administration period were randomly assigned to nintedanib (switch group) or nintedanib plus pirfenidone (combination group). The primary endpoint was the incidence of a ≥5% relative decline in FVC or death during the first 6 months. Results:. Only 7 patients were enrolled (4 in the switch group and 3 in the combination group). Although the switch group continued with nintedanib for 1 year or more, 2 patients (66.7%) in the combination group discontinued nintedanib within 6 months due to severe adverse events. Given the slow case registration and safety concerns in the combination group, the trial was terminated without extending the registration. The incidence of a ≥5% relative decline in FVC during the first 6 months was 50.0% in the switch group and 66.7% in the combination group. There were no deaths during the observation period. Conclusions:. Clinical trials verifying the use of pirfenidone after disease progression in IPF may be difficult to enroll patients. Definitive conclusions on both safety and efficacy cannot be drawn from the results of this study alone. Trial registration:. UMIN Clinical Trial Registry; registration number, UMIN000019436; date of first registration, 21/10/2015; https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000022471.

Abstract Background Interstitial lung disease (ILD) is the most common and important pulmonary manifestation of rheumatoid arthritis (RA). A radiological honeycomb pattern has been described in diverse forms of ILD that can impact survival. However, the clinical course and sequential radiological changes in the formation of the honeycomb pattern in patients with RA-ILD is not fully understood. Methods We evaluated the sequential changes in computed tomography findings in 40 patients with chronic forms of RA-ILD without the honeycomb pattern at initial diagnosis. We classified the patients into the Non-honeycomb group and Honeycomb group, and then analyzed the characteristics and prognosis of the two groups. The term “honeycomb formation” indicated a positive finding of honeycombing on any available follow-up CT. Results Our RA-ILD cohort included patients with probable usual interstitial pneumonia (UIP) (35%), nonspecific interstitial pneumonia (NSIP) (20%), and mixed NSIP/UIP (45%). Among all RA-ILD patients, 16 (40%) showed honeycomb formation on follow-up CT (median time between initial and last follow-up CT was 4.7 years). Patient characteristics and prognosis were not significantly different between the Non-honeycomb and Honeycomb groups. However, Kaplan-Meier survival curve for the time from the date of honeycomb formation to death showed a poor median survival time of 3.2 years. Conclusions A certain number of patients with RA-ILD developed a honeycomb pattern during long-term follow-up, regardless of whether they had UIP or NSIP. Prognosis in the patients with characteristics of both progressive ILD and honeycomb formation could be poor. Although radiological findings over the disease course and clinical disease behavior in RA-ILD are heterogenous, clinicians should be alert to the possibility of progressive disease and poor prognosis in patients with RA-ILD who form a honeycomb pattern during follow-up observation.

Epithelioid hemangioendothelioma (EHE) affects many organs, particularly lung and liver, and typically presents as multiple lesions. Treatment for EHE is not yet standardized, but surgery is appropriate when lesions are resectable. In our patient, radiography revealed multiple bilateral pulmonary nodules, and CT showed several liver tumors. The liver masses and those in the right lung were removed during the initial surgery; pathology of hepatic specimens confirmed the diagnosis of EHE. During the second operation, the left lung nodules were excised, and all were EHEs. Surgical removal of multiorgan multinodular EHE is a viable treatment option, especially for young patients.

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

Abstract Lung or head and neck cancer have been indicated as solid cancers associated with invasive pulmonary aspergillosis (IPA), but the relationship with hepatocellular carcinoma (HCC) is unknown. We report a case of HCC in which the presence of cirrhosis and corticosteroid administration may have caused the development of IPA.

Abstract Background Nintedanib is a tyrosine kinase inhibitor that efficiently slows the progression of idiopathic pulmonary fibrosis (IPF) and has an acceptable tolerability profile. In contrast, immune checkpoint inhibitors (ICIs) such as programmed death 1 and programmed death ligand 1 inhibitors have shown clinical activity and marked efficacy in the treatment of non-small cell lung cancer. However, it is unclear whether nintedanib reduces the risk of ICI-induced pneumonitis in IPF. Case presentation A 78-year-old man with squamous cell lung carcinoma in IPF underwent second-line treatment with pembrolizumab. He was diagnosed as having pembrolizumab-induced pneumonitis after two cycles. He was administered prednisolone (PSL) and then improved immediately. Thereafter, his lung cancer lesion enlarged despite treatment with TS-1. Atezolizumab was then administered as 4th-line chemotherapy, but he immediately developed atezolizumab-induced pneumonitis after 1 cycle. The re-escalated dosage of PSL improved the pneumonitis, and then nintedanib was started as additional therapy. Under careful observation with nintedanib, atezolizumab was re-administered on day 1 of an every-21-day cycle. After three cycles, it remained stable without exacerbation of drug-induced pneumonitis. Conclusion This case indicates the possibility that the addition of nintedanib to ICI therapy might prevent drug-induced pneumonitis or acute exacerbation of IPF. However, whether anti-fibrotic agents such as nintedanib are actually effective in preventing ICI-induced pneumonitis in ILD remains unknown and additional research is greatly needed to identify effective therapies for ILD combined with lung cancer.

Abstract Background Current clinical practice guidelines for idiopathic pulmonary fibrosis (IPF) conditionally recommend use of pirfenidone and nintedanib. However, an optimal treatment sequence has not been established, and the data of treatment sequence from pirfenidone to nintedanib are limited. This study aimed to evaluate safety, tolerability and efficacy of nintedanib switched from pirfenidone in patients with IPF. Methods Thirty consecutive IPF cases, which discontinued pirfenidone because of a decline in forced vital capacity (FVC) or intolerable adverse event (AE), and newly started nintedanib (150 mg twice daily) from September 2015 to August 2017 (switch-group) were retrospectively reviewed. Subsequently, we compared the characteristics, treatment status, and AEs between the switch-group and other 64 IPF patients newly started nintedanib during the same period without any prior anti-fibrotic treatment (pirfenidone-naïve group). Results In the switch group, median age, body weight, body mass index (BMI), and %FVC were 72 years old, 54.9 kg, 21.0 kg/m2, and 52.9%, respectively. Most common AE of nintedanib was aspartate aminotransferase/alanine aminotransferase elevation (71.9%), followed by anorexia (46.7%) and diarrhea (46.7%); whereas, anorexia (63.3%) and ≥ 5% weight loss from baseline (56.7%) were common during pirfenidone administration. Sixteen patients (53.3%) discontinued nintedanib within 6 months (early termination). Multivariate logistic regression analysis revealed a significant association between low BMI and early nintedanib termination in the switch-group (p = 0.0239). Nintedanib suppressed FVC decline as compared with that during administration period of pirfenidone in 70% of the patients who could undergo lung function before and after switching to nintedanib. The incidence of early termination of nintedanib was higher in the switch-group than in the pirfenidone-naïve group, whereas body-weight, BMI, absolute FVC values, and %FVC were significantly lower in the switch-group (just before nintedanib initiation) than in the pirfenidone-naïve group. Nintedanib-induced anorexia was more frequent and severer in the switch-group than in the pirfenidone-naïve group, but no significant differences were observed in terms of other AEs. Conclusions A high incidence of early termination of nintedanib was noted when patients were switched from pirfenidone. Anorexia and weight loss during prior pirfenidone administration may increase the rate of the early termination of subsequent nintedanib treatment.

Tracheobronchial lesions are rare extramuscular complications for idiopathic inflammatory myopathies including dermatomyositis. We herein report a 65-year-old woman with tracheal ulcer during the progression of dermatomyositis-associated interstitial lung disease. Treatment with corticosteroids combined with immunosuppressive agents resulted in improvement of the tracheal ulcer and pulmonary involvement. We believe that the tracheal ulceration might reflect the disease behaviour of dermatomyositis and dermatomyositis-associated interstitial pneumonia.

A 72-year-old Japanese man was admitted to our hospital for treatment of severe COVID-19 pneumonia and was started on favipiravir, heparin calcium, and methylprednisolone pulse therapy. He recovered from respiratory failure about one month later. However, he soon developed purpura in his lower limbs and thrombocytopenia, and immune thrombocytopenia was subsequently diagnosed. Although immune thrombocytopenia is one of the early complications of COVID-19, the use of corticosteroids for COVID-19 is thought to be a factor in the late onset of immune thrombocytopenia. In cases of severe COVID-19 for which corticosteroids were used for treatment, autoimmune diseases such as immune thrombocytopenia may manifest themselves late in the disease course.

Background Ante mortem diagnosis of amyloidosis of the respiratory system is rare. Few data are available regarding clinical presentation, precursor proteins, diagnostic procedures, comorbidities, complications, and outcome. We assessed clinical features of a series of patients with amyloidosis of the respiratory system in two Japanese centres. Methods Medical records of 16 patients with amyloidosis of the respiratory system were retrospectively analysed. Amyloid was diagnosed by polarisation microscopy using Congo red-stained tissue specimens and classified immunohistochemically. Results Median patient age was 71 years, and median follow-up period was 5 years. Immunoglobulin light-chain (AL)-λ amyloidosis was found in eight and AL-κ in five patients. Two patients harboured wild-type transthyretin and one harboured serum amyloid A-derived amyloid. Five different forms of amyloidosis of the respiratory system were observed: nodular pulmonary amyloidosis (seven patients), diffuse alveolar-septal amyloidosis (five), mediastinal lymph node amyloidosis (three), tracheobronchial amyloidosis (one), and pleural amyloidosis (one). One patient had diffuse alveolar-septal amyloidosis and mediastinal lymph node amyloidosis. Three of five patients with diffuse alveolar-septal amyloidosis were diagnosed by transbronchial lung biopsy as having concurrent diffuse alveolar haemorrhage or pneumocystis pneumonia. Two of three patients with mediastinal lymph node amyloidosis were diagnosed by endobronchial ultrasound-guided transbronchial needle aspiration. Conclusions Not only nodular pulmonary amyloidosis, diffuse alveolar-septal amyloidosis, and tracheobronchial amyloidosis but also mediastinal lymph node amyloidosis and pleural amyloidosis should be considered in the differential diagnosis of amyloidosis of the respiratory system. Useful diagnostic methods include transbronchial lung biopsy for diffuse alveolar-septal amyloidosis and endobronchial ultrasound-guided transbronchial needle aspiration for mediastinal lymph node amyloidosis.

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

An 85-year-old woman with antibiotics-resistant pneumonia after surgery for metastatic brain tumor from lung cancer was consulted to our department. Chest CT showed diffuse GGO bilaterally. BALF showed elevated ratios of lymphocytes and CD4/CD8. Tests for bacteria, mycobacteria, and fungi were negative. She improved following levetiracetam discontinuance and systemic corticosteroid administration, and we diagnosed levetiracetam-induced lung injury. Although levetiracetam is widely used, few reports of levetiracetam-induced pneumonia exist. Changes in chest images may occur after levetiracetam administration if patients have multiple risk factors for development of drug-induced interstitial lung disease. Bronchoscopy is useful for differential diagnosis if new lung lesions appear after starting levetiracetam.

An 85-year-old man was being treated for advanced squamous cell lung carcinoma with nivolumab as a second-line treatment. From the beginning of the third course, erythema appeared on his trunk and gradually progressed. Around the start of the fifth course, erythema spread to the proximal part of all limbs in addition to the trunk and was accompanied by a strong itching sensation. He was diagnosed as having contact dermatitis by a dermatologist because his rash was observed only where the moisture-absorbing fiber material of his underwear made contact with the skin surface. After suspending treatment of nivolumab, changing his underwear to a cotton material, and using moisturizers and steroid ointments, his rash disappeared in about a month and the size of his lung tumors remained reduced. The patient developed contact dermatitis despite the use of similar underwear without any skin problems for several years. We speculated that nivolumab-induced T-cell activation may have occurred in his skin, making him more likely to develop contact dermatitis, whose onset is thought to involve T-cell activation. No cases of contact dermatitis have been reported previously although the frequency of eruption as an immune-related adverse event is relatively high. When using immune checkpoint inhibitors including nivolumab, clinicians need to pay attention to the occurrence of skin disorders related to T-cell activation.

Abstract Background Pulmonary emphysema combined with systemic sclerosis (SSc)-associated interstitial lung disease (ILD) occurs more often in smokers but also in never-smokers. This study aimed to describe a new finding characterized by peculiar emphysematous change with SSc-associated ILD (SSc-ILD). Methods We conducted a retrospective review of 21 consecutive patients with SSc-ILD diagnosed by surgical lung biopsy and focused on the radio-pathological correlation of the emphysematous change. Results Pathological pulmonary emphysema (p-PE) with SSc-ILD was the predominant complication in 16 patients (76.2%) with/without a smoking history, of whom 62.5% were never-smokers. A low attenuation area (LAA) within interstitial abnormality on high-resolution computed tomography (HRCT) was present in 31.3%. Diffusing capacity of the lung for carbon monoxide (DLCO) was lower, disease extent on HRCT higher, and intimal/medial thickening in muscular pulmonary arteries more common in the patients with p-PE with SSc-ILD. However, forced vital capacity (FVC) was well preserved regardless of whether p-PE was observed. Most SSc-ILD patients had pulmonary microvasculature changes in arterioles (90.5%), venules (85.7%), and interlobular veins (81.0%). Conclusions Pulmonary emphysematous changes (LAA within interstitial abnormalities on HRCT and destruction of fibrously thickened alveolar walls) are specific and novel radio-pathological features of SSc-ILD. Peripheral vasculopathy may help to destroy the fibrously thickened alveolar walls, resulting in emphysematous change in SSc-ILD.

A 66-year-old man, an ex-smoker, was referred to our hospital for slightly progressive respiratory symptoms of cough and dyspnea on exertion and chest abnormal shadow. Chest high-resolution computed tomography showed wide-ranging ground-glass attenuation and reticulation with lower lobe predominance. Bronchoalveolar lavage (BAL) fluid revealed a marked increase in lymphocytes (53.0%), and a surgical lung biopsy revealed a pattern of desquamative interstitial pneumonia (DIP) with hyperplasia of the lymphoid follicles. His serum was positive for anti-Ku and anti-SS-A antibodies, and he had signs (such as Raynaud's phenomenon, joint pain, and mechanic's hand) suspicious of connective tissue disease (CTD) although a definitive diagnosis of CTD had not been established. On the basis of the findings in our patient obtained from the serologic domain, BAL, and pathological examination, clinicians should consider the important correlation of DIP with CTD as well as with smoking. Keywords: Desquamative interstitial pneumonia, Anti-Ku antibody, Connective tissue disease

We report a rare case of lung abscess due to Eubacterium brachy. In this case, an analysis of the aspirate from frank pus revealed Gram-positive coccobacilli. We initially strongly suspected lung abscess associated with actinomycosis because of the chronic/recurrent clinical course and radio-pathological findings such as a granuloma lesion. Although a biochemical analysis revealed Actinomyces sp., 16S rRNA gene sequencing and a phylogenetic tree analysis of the isolated strain confirmed the presence of E. brachy. Some cases previously diagnosed as actinomycosis might be correctly diagnosed as E. brachy infection. Clinicians should be aware that additional studies using 16S rRNA gene sequencing are needed to clarify whether pulmonary infection associated with E. brachy is a similar entity to that of chronic granulomatous infection disease in pulmonary actinomycosis.

We herein report the first case, to our knowledge, of tracheobronchial ulcer with anti-melanoma differentiation-associated gene 5 (anti-MDA 5) antibody-positive interstitial lung disease (ILD). A 53-year-old man complained of shoulder and wrist pain and was suspected of having polymyalgia rheumatica at another hospital. Thereafter, treatment with prednisolone was started. Although his arthralgia improved, he suffered from progressive dyspnea on exertion and an abnormal shadow was noted on chest X-ray, so he was transferred to our hospital. Chest computed tomography scan revealed ground-glass opacities and intralobular septal thickening. We diagnosed him as having clinically amyopathic dermatomyositis associated with ILD based on the specific skin findings and elevated anti-MDA 5 antibody titer. Fiberoptic bronchoscopy showed ulcerations of the trachea and bronchus. Treatment with dose increments of prednisolone combined with other immunosuppressive drugs resulted in improvement of his respiratory condition and tracheobronchial lesions. Clinicians should be aware that tracheobronchial ulcers can be associated with anti-MDA 5 antibody-positive interstitial lung disease. Keywords: Tracheo-bronchial ulcer, Anti-melanoma differentiation-associated gene 5, Interstitial lung disease

Pulmonary tumor thrombotic microangiopathy (PTTM) is rare but should be considered as a possible diagnosis in patients with cancer. In this case, PTTM induced by lung cancer was more accurately diagnosed using cell block immunohistochemistry of pulmonary microvascular cytology (PMC) because we could confirm that lung adenocarcinoma was the origin of PTTM by the positive result of TTF-1 for atypical cells in PMC. The PMC procedure was minimally invasive and safer than lung biopsy. We believe that the cell block technique of PMC should be considered as one diagnostic option in PTTM. Keywords: Pulmonary tumor thrombotic microangiopathy, Pulmonary microvascular cytology, Cell block technique

We report a case of pathological emphysema formation in a never-smoker with scleroderma-related interstitial pneumonia. We realized the importance of pulmonary vasculopathy causing the coexistence of emphysema and fibrosis in scleroderma. Our discovery provides novel information that emphysema can occur in patients with scleroderma-related interstitial pneumonia who have never smoked. Keywords: Emphysema, Systemic sclerosis, Vasculopathy, Interstitial lung disease

Patients with idiopathic interstitial pneumonias sometimes have a few features of connective tissue disease (CTD) and yet do not fulfil the diagnostic criteria for any specific CTD.This study was conducted to elucidate the characteristics, prognosis, and disease behavior in patients with interstitial lung disease (ILD) associated with systemic sclerosis (SSc)-related autoantibodies.We retrospectively analyzed medical records of 72 ILD patients: 40 patients with SSc (SSc-ILD) and 32 patients with SSc-related autoantibody-positive ILD but not with CTD (ScAb-ILD), indicating lung-dominant CTD with SSc-related autoantibody.Patients with SSc-ILD were predominantly females and non-smokers, and most had nonspecific interstitial pneumonia confirmed by high-resolution computed tomography (HRCT) and pathological analysis. However, about half of the patients with ScAb-ILD were male and current or ex-smokers. On HRCT analysis, honeycombing was more predominant in patients with ScAb-ILD than with SSc-ILD. Pathological analysis showed the severity of vascular intimal or medial thickening in the SSc-ILD patients to be significantly higher than that in the ScAb-ILD patients. Survival curves showed that the patients with ScAb-ILD had a significantly poorer outcome than those with SSc-ILD.Data from this study suggest that lung-dominant CTD with SSc-related autoantibody is a different disease entity from SSc-ILD.

Objective. The aim of this study was to review HIV-negative patients with pulmonary cryptococcosis to analyze the correlations between clinical characteristics and chest computed tomography (CT) findings. Methods. We retrospectively analyzed medical records of 16 HIV-negative patients with pulmonary cryptococcosis diagnosed at our institution, and clinical characteristics of the patients with nodules or masses without ground-glass attenuation (GGA)/consolidation type were compared with those of patients with inclusive GGA or consolidation type. Results. Host status was immunocompromised (81.2%) in most of the patients, and 6 (37.5%) were asymptomatic. The most frequent radiologic abnormalities on chest CT scans were one or more nodules (87.5%), GGA (37.5%), and consolidations (18.8%). Most lesions were located in the lower lung. Levels of hemoglobin and platelets were significantly lower in patients with inclusive GGA or consolidation type. Although the differences were not significant, patients with inclusive GGA or consolidation type tended to have a C-reactive protein level of ≥1.0 mg/dL. Conclusion. If a patient with anemia and thrombocytopenia shows GGA or consolidation in the lung, pulmonary cryptococcosis should be given careful consideration.

A 39-year-old man was admitted for spontaneous pneumothorax. He underwent pulmonary resection to correct the lesion causing the air leakage, and a pathological diagnosis of pulmonary pleomorphic carcinoma was made because we thought that the pneumothorax developed due to the direct rupture of necrotic neoplastic tissue into the pleural cavity. After the operation, the patient received chemotherapy, during which multiple cystic metastases gradually developed in the lung that caused repeated occurrences of pneumothorax. Clinicians must be careful to recognize that pneumothorax can also be a complication of primary and various metastatic pulmonary malignancies.