Radiological and histopathological features and treatment response by subtypes of interstitial pneumonia with autoimmune features: A prospective, multicentre cohort study.

BACKGROUND: Patients with idiopathic interstitial pneumonia (IIP) have a favourable prognosis when they have interstitial pneumonia with autoimmune features (IPAF). However, precise IPAF-related findings from high-resolution computed tomography (HRCT) and lung histopathological specimens and the treatment response have not been fully determined. Therefore, this study was conducted to evaluate the relationship between findings on HRCT or lung histopathological specimens and the progression of interstitial pneumonia in patients with IPAF. METHODS: This multicentre cohort study prospectively enrolled consecutive patients with IIP. At the diagnosis of IIP, we systematically evaluated 74 features suggestive of connective tissue diseases and followed them up. HRCT, lung specimens, serum antibodies, and the clinical course were also evaluated. RESULTS: Among 222 patients with IIP, 26 (11.7%) fulfilled the IPAF criteria. During a median observation period of 36 months, patients with IPAF showed better survival than those without IPAF (p = 0.034). While histopathological findings were not related to IPAF, nonspecific interstitial pneumonia (NSIP) with organizing pneumonia (OP) overlap was the most prevalent HRCT pattern (p < 0.001) and the consolidation opacity was the most common radiological finding in IPAF (p = 0.017). Furthermore, in patients with IPAF, the diagnosis of COP or NSIP with OP overlap was associated with a higher increase in %FVC in 1 year than in those with idiopathic pulmonary fibrosis, NSIP, or unclassifiable IIP (p = 0.002). CONCLUSIONS: This study shows the presence of consolidation opacity on HRCT and the diagnosis of COP or NSIP with OP overlap are associated with IPAF and its favourable treatment response in patients with IPAF.

Prognostic Role of Interferon-λ3 in Anti-Melanoma Differentiation-Associated Gene 5-Positive Dermatomyositis-Associated Interstitial Lung Disease.

OBJECTIVE: Interferon-λ3 (IFNλ3) is a cytokine with antiviral functions on barrier surfaces, and it is associated with disease activity in autoimmune diseases. This study assessed the clinical significance of serum IFNλ3 levels in polymyositis/dermatomyositis (PM/DM)-associated interstitial lung disease (ILD). METHODS: We measured serum IFNλ3 levels in 221 patients with PM/DM-ILD (155 in the derivation cohort, 66 in the validation cohort) and 38 controls. We evaluated factors associated with mortality risk among 79 patients with anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive DM-ILD. RESULTS: Serum IFNλ3 levels at diagnosis were significantly higher in patients with PM/DM-ILD than in healthy controls. Remarkably, serum IFNλ3 levels were specifically increased in patients with anti-MDA5 antibody-positive DM-ILD in both the derivation and validation cohorts. In anti-MDA5 antibody-positive DM-ILD, patients with high IFNλ3 levels (>120 pg/mL) had significantly lower survival rates than those with low IFNλ3 levels (≤120 pg/mL). A multivariate analysis revealed that high IFNλ3 levels, as well as old age and low Pao2, were significantly associated with poor prognoses in patients with anti-MDA5 antibody-positive DM-ILD. In a classification analysis of patients with anti-MDA5 antibody-positive DM-ILD based on age, IFNλ3 level, and Pao2, patients with old age (>53 years), high IFNλ3 levels (>120 pg/mL), and low Pao2 (<75 mm Hg) had the worst survival. In lung pathologic analyses, IFNλ3-positive staining was observed in macrophages, airway epithelial cells, the pleural region, and intrapulmonary veins in patients with anti-MDA5 antibody-positive DM-ILD. CONCLUSION: Serum IFNλ3 is a promising biomarker for identifying patients at high risk of poor outcomes in anti-MDA5 antibody-positive DM-ILD.

Assessment of malnutrition-related risk in patients with idiopathic pleuroparenchymal fibroelastosis.

Background: Idiopathic pleuroparenchymal fibroelastosis (IPPFE) is characterised by upper lobe-dominant fibrosis involving the pleura and subpleural lung parenchyma, with advanced cases often complicated by progressive weight loss. Therefore, we hypothesised that nutritional status is associated with mortality in IPPFE. Methods: This retrospective study assesses nutritional status at the time of diagnosis and 1 year after diagnosis in 131 patients with IPPFE. Malnutrition-related risk was evaluated using the Geriatric Nutritional Risk Index (GNRI). Results: Of the 131 patients, 96 (73.8%) were at malnutrition-related risk at the time of diagnosis according to the GNRI. Of these, 21 patients (16.0%) were classified as at major malnutrition-related risk (GNRI <82). Patients at major malnutrition-related risk were significantly older and had worse pulmonary function than patients at low (GNRI 92- <98) and moderate (GNRI 82- <92) malnutrition-related risk. GNRI scores decreased significantly from the time of diagnosis to 1 year after diagnosis. Patients with a lower GNRI (<91.8) had significantly shorter survival than patients with a median GNRI or higher (≥91.8). Patients with declines in annual GNRI scores of ≥5 had significantly shorter survival than patients with declines in annual GNRI scores of <5. In multivariate analysis, major malnutrition-related risk was significantly associated with increased mortality after adjustment for age, sex and forced vital capacity (hazard ratio 1.957). A composite scoring model including age, sex and major malnutrition-related risk was able to separate mortality risk in IPPFE. Conclusion: Assessment of nutritional status by the GNRI provides useful information for managing patients with IPPFE by predicting mortality risk.

Frequency, proportion of PF-ILD, and prognostic factors in patients with acute exacerbation of ILD related to systemic autoimmune diseases.

BACKGROUND: Acute exacerbation (AE) of systemic autoimmune disease-related interstitial lung diseases (SAID-ILD) is less common than AE of idiopathic pulmonary fibrosis (IPF) and the details of AE-SAID-ILD have not been elucidated, but the prognosis is similarly devastating. This study was undertaken to determine the incidences of AE-ILD in each SAID and to elucidate the proportion of progressive fibrosing (PF)-ILD in AE-SAID-ILD. METHODS: We retrospectively analysed data for patients with SAID-ILD who were diagnosed and observed at our hospital between 1999 and 2020. RESULTS: Two hundred and thirty-two patients with SAID-ILD were enrolled, with a mean observation period of 100.2 months. AE-SAID-ILD was found in 25 patients (10.78%), mainly in patients with RA (17 patients, 68%) and elderly male patients with a smoking history. The overall incidence of AE-SAID-ILD was 1.29%/person-year, and the incidence for each SAID was as follows: RA 2.193, microscopic polyarteritis (MPA) 3.203, systemic sclerosis (SSc) 2.277, primary Sjögren syndrome 0.426, and polymyositis/dermatomyositis 0.222. The incidence of AE of RA/MPA/SSc-ILD was significantly higher than that of other AE-SAID-ILD (p < 0.001). Five of 25 patients (20%) fulfilled the criteria for PF-ILD. The 90-day survival rate was 48.0%, and a higher neutrophil count at AE (HR 13.27, 95%CI 2.447-246, p = 0.001) and early commencement of long-duration direct haemoperfusion with a polymyxin B-immobilised fibre column (HR 0.105, 95%CI 0.005-0.858, p = 0.035) were significant prognostic factors. CONCLUSIONS: The incidence of AE-SAID-ILD was significantly higher in patients with RA, MPA, or SSc than in patients with other SAID. Furthermore, even in patients with AE-SAID-ILD, the proportion of PF-ILD just before AE was not high (20%).

Idiopathic pleuroparenchymal fibroelastosis: three-dimensional computed tomography assessment of upper-lobe lung volume.

BACKGROUND: Idiopathic pleuroparenchymal fibroelastosis (iPPFE) is a rare interstitial lung disease characterised by predominant upper-lobe fibrosis involving the pleura and subpleural lung parenchyma. Despite its poor prognosis, there is no consensus on prognostic determinants of iPPFE to date. Because volume loss in the upper lobe is a distinct feature of iPPFE, we hypothesised that the lung volume of the bilateral upper lobes (upper-lobe volume) accurately indicates disease severity and mortality risk in iPPFE patients. METHODS: This retrospective study assessed two cohorts of 132 patients with iPPFE (69 in Hamamatsu cohort; 63 in Seirei cohort) and 45 controls. Each lobe volume was quantitatively measured using three-dimensional computed tomography at the time of iPPFE diagnosis and standardised using predicted forced vital capacity. RESULTS: The standardised upper-lobe volume in iPPFE patients was less than half that of controls, whereas the lower-lobe volume did not decrease. iPPFE patients with lower standardised upper-lobe volume had significantly shorter survival rates than those with higher volume (median survival: 6.08 versus 2.48 years, p<0.001). In multivariate analysis, the lower standardised upper-lobe volume was significantly associated with increased mortality adjusting for age, sex and forced vital capacity (HR 0.939). A composite scoring model, including age, sex and standardised upper-lobe volume, better predicted risk of death than the gender-age-physiology model. CONCLUSION: Assessment of upper-lobe volume provides useful information for managing iPPFE by evaluating disease severity and mortality risk in clinical practice.

Standardised 3D-CT lung volumes for patients with idiopathic pulmonary fibrosis.

BACKGROUND: The assessment of lung physiology via pulmonary function tests (PFTs) is essential for patients with idiopathic pulmonary fibrosis (IPF). However, PFTs require active participation, which can be challenging for patients with severe respiratory failure, such as during moments of acute exacerbation (AE) of IPF. Recent advances have enabled the re-construction of 3-dimensional computed-tomography (3D-CT) images. This study established a standardisation method and quantitative analysis of lung volume (LV) based on anthropometry using 3D-CT images. METHODS: This is a retrospective multi-center cohort study. The standardised 3D-CT LV in patients with IPF at diagnosis (n = 140) and during AE (cohort1; n = 61 and cohort2; n = 50) and those of controls (n = 53) were assessed. RESULTS: The standardised 3D-CT LVs at IPF diagnosis were less than those of control patients, especially in the lower lung lobes. The standardised 3D-CT LVs were correlated with forced vital capacity (FVC) and validated using the modified Gender-Age-Physiology (GAP) index. The standardised 3D-CT LVs at IPF diagnosis were independently associated with prognosis. During AE, PFTs were difficult to perform, 3D-CT analyses revealed reduced lung capacity in both the upper and lower lobes compared to those obtained at diagnosis. Lower standardised 3D-CT LVs during AE were independently associated with worse outcomes in the two independent cohorts. In particular, volume loss in the upper lobe at AE had prognostic values. CONCLUSIONS: A novel image quantification method for assessing pulmonary physiology using standardised 3D-CT-derived LVs was developed. This method successfully predicts mortality in patients with IPF and AE of IPF, and may be a useful alternative when PFTs cannot be performed.

Transient leukocytopenia following combination therapy for COVID-19.

BACKGROUND: Combination therapy with dexamethasone, remdesivir, and baricitinib has become a promising treatment for moderate or severe COVID-19; however, we have observed transient leukocytopenia in COVID-19 patients who received combination therapy. METHODS: Twelve consecutive COVID-19 patients treated with combination therapy were included in this retrospective analysis. Blood cell counts collected at the following three time points were analyzed: before the start of therapy (period 1), within 24 h of starting therapy (period 2), and within 48 h of period 2 (period 3). RESULTS: The leukocyte count significantly decreased in period 2 compared to period 1 and then significantly increased in period 3 without withdrawal of baricitinib. The neutrophil count transiently decreased in period 2 and recovered in period 3. CONCLUSIONS: Clinicians should be aware of transient leukocytopenia in patients with COVID-19 during the early phase of combination therapy.

Metformin reduces pleural fibroelastosis by inhibition of extracellular matrix production induced by CD90-positive myofibroblasts.

Metformin, an AMP-activated protein kinase activator used to treat diabetes mellitus, has recently attracted attention as a promising anti-fibrotic agent. However, its anti-fibrotic effects on pleural fibroelastosis remain unknown. We induced mouse pleural fibroelastosis by intra-pleural coadministration of bleomycin and carbon and evaluated its validity as a preclinical model for human pleural fibrosis. We assessed the expression of the myofibroblast surface marker CD90 in the fibrotic pleura and the effects of metformin in vivo and in vitro. Finally, we evaluated the effects of metformin on human pleural mesothelial cells stimulated by transforming growth factor ß1 (TGFß1). The fibrotic pleura in mice had collagen and elastin fiber deposition similar to that seen in human fibrotic pleura. Moreover, CD90-positive myofibroblasts were detected in and successfully isolated from the fibrotic pleura. Metformin significantly suppressed the deposition of collagen and elastic fibers in the fibrotic pleura and decreased the expression of extracellular matrix (ECM)-related genes, including Col1a1, Col3a1, Fn1, and Eln, in pleural CD90-positive myofibroblasts. In human pleural mesothelial cells, metformin decreased TGFß1-induced upregulation of ECM-related genes and SNAI1. Overall, metformin suppresses pleural fibroelastosis by inhibition of ECM production by pleural myofibroblasts, suggesting that this drug has therapeutic potential against human pleural fibrosis, including pleuroparenchymal fibroelastosis.

CD8-positive peripheral T cell lymphoma in a patient following long-term nivolumab for advanced lung adenocarcinoma: A case report.

A 54-year-old male smoker presented with hemoptysis. Advanced lung adenocarcinoma, cT1cN3M1b, stage IVB, was diagnosed. Enlargement of multiple intraperitoneal and inguinal lymph nodes and peripheral atypical lymphocytosis appeared after 33 cycles of second-line treatment with nivolumab, and a specimen obtained by left inguinal lymph node biopsy showed peripheral T cell lymphoma (PTCL), not otherwise specified. Lymphoma cells expressed CD3+, CD8+, and CD56+, but not CD4+ or PD-1. Despite systemic chemotherapy with cyclophosphamide, hydroxydaunorubicin, oncovin, and prednisolone, the patient died of PTCL 864 days after the initial visit. The possible relationship between treatment with immune checkpoint inhibitors (ICIs) and PTCL development is discussed here.

Anti-Jo-1 Antibody-positive Interstitial Pneumonia in an Elderly Patient with Congenital Rubella Syndrome.

A 71-year-old woman with congenital rubella syndrome (CRS) presented with prolonged cough. No physical findings suggested the presence of any connective tissue diseases. Chest computed tomography showed ground-glass opacities and consolidations in the bilateral lower lobes. She had elevated serum Krebs von den Lungen-6, hypoxemia and positive serum anti-Jo-1 antibody. Bronchoalveolar lavage fluid revealed lymphocytosis with a decreased CD4/CD8 ratio. A transbronchial lung biopsy specimen revealed organizing pneumonia. Based on a diagnosis of interstitial pneumonia with autoimmune features (IPAF), systemic corticosteroids were administered, and a good outcome was obtained. A possible relationship between CRS and IPAF is herein discussed.

Bucillamine-induced Pneumonitis in a Patient with Rheumatoid Arthritis-associated Interstitial Pneumonia: A Case Report and Review of the Literature.

An 81-year-old woman with rheumatoid arthritis (RA) who had been treated with bucillamine presented with dyspnea. Computed tomography of the chest showed ground-glass opacities and consolidations in both lungs and honeycombing in both basal lung areas. An elevation of the serum Krebs von den Lungen-6 level and hypoxemia were seen. Lymphocytosis with a decreased CD4/CD8 ratio was seen in the bronchoalveolar lavage fluid. A transbronchial lung biopsy specimen showed organizing pneumonia. Based on a diagnosis of bucillamine-induced pneumonitis (BIP) with RA-associated pre-existing interstitial pneumonia, she was successfully treated with the cessation of bucillamine and systemic corticosteroid therapy. The risk factors and prognosis of BIP are discussed.

Direct pulmonary infiltrates as an initial manifestation of chronic lymphocytic leukemia.

An 85-year-old man who did not have any hematological or respiratory disorders was transferred to our hospital because of progressive dyspnea. Computed tomography (CT) findings showed ground-glass opacities with a centrilobular distribution and centrilobular micronodules with a "tree-in-bud" pattern. A biopsy of the lungs showed lymphocytic infiltrations in the parenchyma and these were positive for B cell markers. A diagnosis of chronic lymphocytic leukemia (CLL) was made and direct pulmonary involvement of CLL was confirmed simultaneously. One month after initiation of chemotherapy, his symptoms improved and a chest CT scan showed marked resolution. Pulmonary infiltrates of CLL should be included in the differential diagnosis when these signs are encountered on CT.

Lupus Pleuritis with Silicotic Nodules in the Parietal Pleura.

A 63-year-old man with occupational exposure to silica presented with cutaneous ulcer, pleuritic pain, and a fever. Laboratory data showed lymphopenia and positive serum antinuclear and anti-DNA antibodies. Computed tomography of the chest showed egg shell-like calcification of the hilar and mediastinal lymph nodes without pulmonary parenchymal involvement of silicosis. A surgical biopsy showed silicotic nodules with surrounding infiltration of lymphocytes and plasma cells in the parietal pleura. With a diagnosis of systemic lupus erythematosus (SLE), systemic corticosteroid therapy was given, which led to the resolution of symptoms and laboratory abnormalities. We discuss the relationship between silica exposure and the development of SLE.