Efficacy and safety of lascufloxacin for nursing- and healthcare-associated pneumonia: A single-arm, open-label clinical trial.

BACKGROUND: Nursing- and healthcare-associated pneumonia (NHCAP) constitutes most of the pneumonia in elderly patients including aspiration pneumonia in Japan. Lascufloxacin (LSFX) possesses broad antibacterial activity against respiratory pathogens, such as Streptococcus spp. And anaerobes inside the oral cavity. However, the efficacy and safety of LSFX in NHCAP treatment remains unknown. We aimed to evaluate the efficacy and safety of LSFX tablets in the treatment of patients with NHCAP. METHODS: In this single-arm, open-label, uncontrolled study, LSFX was administered to patients with NHCAP at 24 facilities. The study participants were orally administered 75 mg LSFX once daily for 7 days. The primary endpoint was the clinical efficacy at the time of test of cure (TOC). The secondary endpoints included clinical efficacy at the time of end of treatment (EOT), early clinical efficacy, microbiological efficacy, and safety analysis. RESULT: During the study period, 75 patients provided written informed consent to participate and were included. Finally, 56 and 71 patients were eligible for clinical efficacy and safety analyses, respectively. The median age of the patients was significantly high at 86 years. All patients were classified as having moderate disease severity using the A-DROP scoring system. LSFX tablets demonstrated high efficacy rates of 78.6 % at TOC and 89.3 % at EOT. The risk factors for resistant bacteria or aspiration pneumonia did not affect clinical efficacy. No severe adverse events associated with the study drugs were observed. CONCLUSION: Oral LSFX is an acceptable treatment option for moderate NHCAP in elderly patients who can take oral medications.

A comparative study of the sarcopenia screening in older patients with interstitial lung disease.

BACKGROUND: The Asian Working Group for Sarcopenia 2019 (AWGS 2019) is the gold standard diagnostic criteria for sarcopenia in Asian populations. The calf circumference (CalF), the strength, assistance in walking, rising from a chair, climbing stairs, and falls (SARC-F) and the SARC-CalF questionnaires for sarcopenia screening have been used by AWGS 2019. The aim of this study was to assess accuracy of these three sarcopenia screening tools in patients with interstitial lung disease. METHODS: In this cross-sectional study, stable patients with interstitial lung disease were enrolled. The SARC-F, SARC-CalF, and CalF, used in patients with interstitial lung disease, were compared to the diagnostic criteria proposed by AWGS 2019. The accuracy of screening tools was compared using sensitivity and specificity. Moreover, areas under the receiver operating characteristic curves (AUC) were computed. RESULTS: Seventy eight patients were analyzed, and sarcopenia was identified in 25 (32.1%) patients with interstitial lung disease by the AWGS 2019 criteria. The sensitivity of the CalF was highest (96%) of the three screening tools, while the specificity was 60%. The sensitivity of SARC-F and SARC-CalF were 24% and 68%, while the specificity were 92% and 66%, respectively. The AUCs of CalF, SARC-F, and SARC-CalF in all patients were 0.78, 0.58, and 0.67, respectively. CONCLUSIONS: The CalF is most suitable for screening sarcopenia in patients with interstitial lung disease, while SARC-F and SARC-CalF are not.

A proposed prognostic prediction score for pleuroparenchymal fibroelastosis.

BACKGROUND: Clinical course of pleuroparenchymal fibroelastosis (PPFE) shows considerable variation among patients, but there is no established prognostic prediction model for PPFE. METHODS: The prediction model was developed using retrospective data from two cohorts: our single-center cohort and a nationwide multicenter cohort involving 21 institutions. Cox regression analyses were used to identify prognostic factors. The total score was defined as the weighted sum of values for the selected variables. The performance of the prediction models was evaluated by Harrell's concordance index (C-index). We also examined the usefulness of the gender-age-physiology (GAP) model for predicting the prognosis of PPFE patients. RESULTS: We examined 104 patients with PPFE (52 cases from each cohort). In a multivariate Cox analysis, a lower forced vital capacity (FVC [defined as FVC < 65%]; hazard ratio [HR], 2.23), a history of pneumothorax (HR, 3.27), the presence of a lower lobe interstitial lung disease (ILD) (HR, 2.31), and higher serum Krebs von den Lungen-6 (KL-6) levels (> 550 U/mL, HR, 2.56) were significantly associated with a poor prognosis. The total score was calculated as 1 × (FVC, < 65%) + 1 × (history of pneumothorax) + 1 × (presence of lower lobe ILD) + 1 × (KL-6, > 550 U/mL). PPFE patients were divided into three groups based on the prognostic score: stage I (0-1 points), stage II (2 points), and stage III (3-4 points). The survival rates were significantly different in each stage. The GAP stage was significantly associated with the prognosis of PPFE, but no difference was found between moderate (stage II) and severe (stage III) disease. Our new model for PPFE patients (PPFE Prognosis Score) showed better performance in the prediction of mortality in comparison to the GAP model (C-index of 0.713 vs. 0.649). CONCLUSIONS: Our new model for PPFE patients could be useful for predicting their prognosis.

Small molecule inhibitor of HSP47 prevents pro-fibrotic mechanisms of fibroblasts in vitro.

Excessive extracellular matrix deposition, in particular collagen, is an important cause of lung fibrosis. Heat shock protein 47 (HSP47), a collagen-binding protein, plays an important role in the intracellular processing of procollagen. A small molecule that blocks the collagen chaperone function of HSP47 has been reported as an HSP47 inhibitor. The aim of this study was to assess the effect of the HSP47 inhibitor on collagen synthesis and other fibrotic process in vitro. We evaluated collagen expression by western blot, and determined cell viability and migration by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and scratch test, respectively, in human and mouse lung fibroblasts. Treatment of lung fibroblasts with HSP47 siRNA decreased collagen type I expression. Similarly, the HSP47 inhibitor decreased collagen type I expression in transforming growth factor beta 1 (TGF-ß1)-treated lung fibroblasts in a dose-dependent manner. The inhibitor also decreased the viability and cell migration ability of TGF-ß1-treated lung fibroblasts. Overall, we demonstrated that HSP47 is a potential therapeutic target for pulmonary fibrosis. The small molecule HSP47 inhibitor may mediate antifibrotic effects by suppressing the overexpression of collagen, and inhibiting the viability and migration of fibroblasts. Further research is needed to clarify the therapeutic potential of this HSP47 inhibitor for pulmonary fibrosis.

Presence of heat shock protein 47-positive fibroblasts in cancer stroma is associated with increased risk of postoperative recurrence in patients with lung cancer.

BACKGROUND: Heat shock protein 47 (HSP47), a collagen-binding protein, has a specific role in the intracellular processing of procollagen production. HSP47 expression is associated with cancer growth and metastasis in several types of cancers. However, none of the studies have assessed whether HSP47 expression is associated with the risk of postoperative recurrence of lung cancer until now. Therefore, we aimed to assess this association. METHODS: The study population consisted of a cohort of consecutive patients who underwent surgery for lung cancer at Nagasaki University Hospital, Nagasaki, Japan, from January 2009 to December 2010. Patient characteristics, survival and disease-free survival (DFS), and laboratory findings were compared between patients who tested positive and negative for HSP47 expression in lung cancer cells and between those who showed high and low numbers of HSP47-positive fibroblasts in cancer stroma. RESULTS: A total of 133 patients underwent surgery for lung cancer. Sixty-seven patients (50.4%) had HSP47-positive cancer cells, and 91 patients (68.4%) had a higher number of HSP47-positive fibroblasts. The patients with a high number of HSP47-positive fibroblasts had a shorter DFS than those with a low number of HSP47-positive fibroblasts. Multivariate analysis identified only the presence of a high number of HSP47-positive fibroblasts as an independent risk factor for recurrence of lung cancer after surgery (odds ratio, 4.371; 95% confidence interval, 1.054-29.83; P = 0.042). CONCLUSION: The present study demonstrated that the presence of a high number of HSP47-positive fibroblasts in the cancer stroma was a risk factor for recurrence of lung cancer after surgery.

Postoperative acute exacerbation of interstitial pneumonia in pulmonary and non-pulmonary surgery: a retrospective study.

BACKGROUND: Acute exacerbation of interstitial pneumonia (AE-IP) is a serious complication of pulmonary surgery in patients with IP. However, little is known about AE-IP after non-pulmonary surgery. The aim of this study was to determine the frequency of AE-IP after non-pulmonary surgery and identify its risk factors. METHODS: One hundred and fifty-one patients with IP who underwent pulmonary surgery and 291 who underwent non-pulmonary surgery were retrospectively investigated. RESULTS: AE-IP developed in 5 (3.3%) of the 151 patients in the pulmonary surgery group and 4 (1.4%) of the 291 in the non-pulmonary surgery group; the difference was not statistically significant. A logistic regression model showed that serum C-reactive protein (CRP) was a predictor of AE-IP in the non-pulmonary surgery group (odds ratio 1.187, 95% confidence interval 1.073-1.344, P = 0.002). CONCLUSIONS: This is the first study to compare the frequency of AE-IP after pulmonary surgery with that after non-pulmonary surgery performed under the same conditions. The results suggest that the frequency of AE-IP after non-pulmonary surgery is similar to that after pulmonary surgery. A high preoperative C-reactive protein level is a potential risk factor for AE-IP after non-pulmonary surgery.

Serum Soluble Interleukin-2 Receptor Is a Biomarker for Pneumocystis jirovecii Pneumonia among Patients with Rheumatoid Arthritis under Methotrexate Therapy.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by systemic joint inflammation and may manifest as interstitial pneumonia (IP). Methotrexate (MTX) is one of the main therapeutic drugs used for RA, but MTX could cause severe side effects, including Pneumocystis jirovecii pneumonia (PCP) and IP. Owing to similar symptoms, it is sometimes difficult to discriminate MTX therapy-associated PCP (MTX-PCP) and MTX therapy-associated IP (MTX-IP). Soluble interleukin-2 receptor (sIL-2R) is considered a marker of T-cell activation, and serum sIL-2R levels are elevated in RA and PCP. This led us to hypothesize that serum sIL-2R is a potential biomarker for discriminating MTX-PCP and MTX-IP. Accordingly, we carried out a retrospective analysis of 20 MITX-PCP cases, 30 MTX-IP cases, and as controls, 16 patients with RA-associated IP (RA-IP) and 13 patients with PCP without MTX treatment (PCP group). C-reactive protein and alveolar-arterial oxygen differences were higher in the MTX-PCP group than those in the RA-IP and MTX-IP groups. Importantly, serum levels of sIL-2R in MTX-PCP were significantly higher than those in other three groups. Based on the receiver operating characteristic curve, the cut-off level of sIL-2R resulting in the highest diagnostic accuracy for MTX-PCP was 1,311.5 U/mL, discriminating between MTX-PCP and other groups with 91.7% sensitivity and 78.6% specificity. Thus, patients with MTX-PCP show a higher degree of systemic inflammation, severe hypoxemia, and increased sIL-2R levels compared with those in MTX-IP cases. In conclusion, serum sIL-2R could be a biomarker for PCP diagnosis among patients with RA under MTX therapy.

Elevated α-defensin levels in plasma and bronchoalveolar lavage fluid from patients with myositis-associated interstitial lung disease.

BACKGROUND: Interstitial lung disease (ILD) is a prognostic indicator of poor outcome in myositis. Although the pathogenesis of myositis-associated ILD is not well understood, neutrophils are thought to play a pivotal role. Neutrophils store azurophil granules that contain defensins, which are antimicrobial peptides that regulate the inflammatory response. Here, we evaluated levels of the human neutrophil peptides (HNPs) α-defensin 1 through 3 in patients with myositis-associated ILD to determine whether HNPs represent disease markers and play a role in the pathogenesis of myositis-associated ILD. METHODS: HNP levels were measured in the plasma and bronchoalveolar lavage fluid (BALF) of 56 patients with myositis-associated ILD and 24 healthy controls by enzyme-linked immunosorbent assay. RESULTS: Analysis revealed significantly higher HNP levels in plasma and BALF samples from patients with myositis-associated ILD as compared to those of healthy controls; however, plasma HNPs were significantly correlated with total cell counts in BALF. Additionally, BALF HNP levels were positively correlated with serum surfactant protein-A and the percentage of neutrophils in BALF, and BALF HNP levels correlated with the percentage of reticular opacities in high-resolution computed tomography results for patients with anti-aminoacyl-tRNA synthetase (ARS) antibody positive myositis-associated ILD. Survival did not differ between patients with higher and lower levels of plasma and BALF HNPs. CONCLUSIONS: Plasma and BALF HNPs might reflect the disease activities of myositis-associated ILD, especially in patients with anti-ARS antibody positive myositis-associated ILD. However further studies are necessary to clarify whether HNPs represent disease markers and play roles in disease pathogenesis.

Pulmonary Nodular Lymphoid Hyperplasia Evaluated with Bronchoalveolar Lavage Fluid Findings: A Case Report and Review of the Literature on Japanese Patients.

Pulmonary nodular lymphoid hyperplasia (PNLH) is a very rare disease, and it is difficult to diagnose PNLH and distinguish it from mucosa-associated lymphoid tissue (MALT) lymphoma. In addition, information on bronchoalveolar lavage fluid (BALF) analyses is lacking. We herein report a 36-year-old Japanese woman diagnosed with PLNH by a surgical biopsy and analysis of BALF. The BALF showed an increase in B-cell marker-positive lymphocytes, normal patterns of B-cell clonality, mucosa-associated lymphoid tissue 1 gene, and immunoglobulin heavy chain at 14q32 translocations. We also reviewed Japanese cases of PNLH described in Japanese or English to explore the characteristics of such cases.

Pulmonary and Intestinal Involvement in a Patient with Myeloperoxidase-specific Antineutrophil Cytoplasmic Antibody-positive Hermansky-Pudlak Syndrome.

A 26-year-old Japanese woman was admitted with a 1-month history of diarrhea, a high fever for a few days, and exacerbation of dyspnea. She was treated with an antifibrotic drug and long-term oxygen therapy for Hermansky-Pudlak syndrome-related pulmonary fibrosis. New ground-glass attenuation appeared on chest computed tomography (CT), and a colon biopsy showed an inflammatory cell accumulation with a high titer of myeloperoxidase (MPO)-specific anti-neutrophil cytoplasmic antibodies (ANCA). Systemic inflammation related to MPO-ANCA titer elevation was suspected. Steroid pulse therapy and intravenous cyclophosphamide improved chest CT findings and diarrhea. Therefore, immunosuppressant treatment should be considered for systemic inflammation related to MPO-ANCA.

Lung involvement during the prediagnostic phase of idiopathic pleuroparenchymal fibroelastosis.

Patients with PPFE sometimes have lung involvement at the lung apex long before the diagnosis. The prediagnostic phase with apical fibrosis is much longer than the postdiagnostic phase in patients with PPFE. https://bit.ly/32X1iXi.

Limited efficacy of nintedanib for idiopathic pleuroparenchymal fibroelastosis.

BACKGROUND: The antifibrotic agent nintedanib has been reported to effectively prevent the decline in forced vital capacity (FVC) in a broad range of interstitial lung diseases. However, the efficacy of nintedanib against idiopathic pleuroparenchymal fibroelastosis (iPPFE) remains unclear. METHODS: We retrospectively examined patients with idiopathic PPFE or idiopathic pulmonary fibrosis (IPF) who received nintedanib for more than 6 months. We evaluated annual changes in %FVC, radiological PPFE lesions, and body weight before and during nintedanib treatment. To investigate radiological PPFE lesions, we examined the fibrosis score, which was defined as the mean percentage of the high attenuation area in the whole lung parenchyma using three axial computed tomography images. RESULTS: Overall, 15 patients with iPPFE and 27 patients with IPF were included in the present study. In patients with IPF, the annual rate of decline in %FVC was significantly lower during nintedanib treatment than that before treatment (-2.01%/year [-7.64 to 3.21] versus -7.64%/year [-10.8 to -4.44], p = 0.031). Meanwhile, in patients with iPPFE, the annual rate of decline in %FVC during nintedanib treatment was higher than that before treatment (-18.0%/year [-21.6 to -12.7] versus -9.40%/year [-12.3 to -8.23], p = 0.109). In addition, nintedanib treatment failed to inhibit the annual rate of increase in fibrosis score in patients with iPPFE (6.53/year [1.18-15.3] during treatment versus 2.70/year [0.27-12.2] before treatment, p = 0.175). CONCLUSIONS: Nintedanib efficacy may be limited in patients with iPPFE.

Platythorax progresses with lung involvement in pleuroparenchymal fibroelastosis.

BACKGROUND: Patients diagnosed with pleuroparenchymal fibroelastosis (PPFE) exhibit unique clinical features, including upper lobe-dominant lung involvement and platythorax (or flattened thoracic cage). Although platythorax have been shown to be a sign of disease progression, the temporal relationship between the progression of platythorax and the extent of lung involvement has not been closely investigated. METHODS: We retrospectively investigated patients diagnosed with PPFE, who did not exhibit fibrotic lesions other than PPFE in the lower lobes. We estimated the fibrosis score, which is a visual score indicating the percentage of lung parenchyma occupied by the disease on computed tomography images selected every 2 cm from the lung apex to the lung base, and the flat chest index (the ratio of the anteroposterior diameter of the thoracic cage to the transverse diameter of the thoracic cage). Additionally, we investigated serial changes in the flat chest index and fibrosis score. RESULTS: A total of 29 patients were included in this study. The fibrosis score was found to be weakly and inversely correlated with forced vital capacity %predicted at the diagnosis (r = -0.40, p = 0.038). Furthermore, the annual changes in the flat chest index and fibrosis score was found to be moderately and inversely correlated (r = -0.663, p = 0.0037). CONCLUSIONS: These results indicate that there is a causal relationship between the progression of fibroelastosis and that of platythorax in patients with PPFE.

Nodular Pulmonary Amyloidosis Associated with Sjögren's Syndrome.

Amyloidosis is a rare disease characterized by the deposition of abnormal proteins in extracellular tissues. We herein report a case with instructive radiologic features of nodular pulmonary amyloidosis associated with Sjögren's syndrome. A 67-year-old woman was referred to our department because of an abnormal chest radiograph. Chest computed tomography revealed multiple round cysts accompanied by calcified nodules. The patient was clinically diagnosed with primary Sjögren's syndrome and pathologically diagnosed with nodular pulmonary amyloidosis (light chain, kappa). Although multiple lung cysts have many etiologies, the presence of calcified nodules associated with multiple lung cysts is useful for narrowing down the differential diagnosis.

Unusual lung adenocarcinoma spread along with pulmonary emphysema.

Lung adenocarcinoma can rarely present with imaging findings that mimic fibrotic lesions of interstitial pneumonia. Asymmetric lung involvement and symptoms of haemoptysis may be the clinical clues to the suspicion of lung neoplasm rather than fibrotic lung disease.

Screening of Inhibitors Targeting Heat Shock Protein 47 Involved in the Development of Idiopathic Pulmonary Fibrosis.

Heat shock protein 47 (HSP47), a collagen-specific molecular chaperone, is causally related to fibrotic diseases, including idiopathic pulmonary fibrosis. The identification of Compounds that interfere with the HSP47-collagen interaction is essential for the development of relevant therapeutics. Herein, we prepared human HSP47 as a soluble fusion protein expressed in E. coli and established an assay system for HSP47 inhibitor screening. We screened a natural and synthetic Compound library established at Nagasaki University. Among 1023 Compounds, 13 exhibited inhibitory activity against human HSP47, of which three inhibited its function in a dose-dependent manner. Epigallocatechin-3-O-gallate, one of these three Compounds, is a typical polyphenol Compound derived from tea leaves. Structurally related Compounds were synthesized and examined for their activity, revealing a hydroxyl group at A-ring position 5 as important for its activity. The present findings provide valuable insight for the development of natural product-derived therapeutics for fibrotic diseases, including idiopathic pulmonary fibrosis.

HLA-B54 is an independent risk factor for pneumonia in Japanese patients with interstitial lung disease: A multicenter retrospective cohort study.

PURPOSE: Pneumonia is a major cause of respiratory-related hospitalization and an important prognostic factor in patients with chronic interstitial lung disease (ILD). However, the relationship between the incidence of pneumonia and human leukocyte antigen (HLA) serotype has not been fully elucidated. Therefore, this study aimed to determine if there is a relationship between HLA serotype and the incidence of pneumonia in Japanese patients with ILD. METHODS: The medical records of patients with ILD treated at any of three centers in Japan were reviewed to determine their HLA-A and HLA-B serotypes. The characteristics of patients with and without pneumonia were compared. Cox regression analysis was performed to identify risk factors for pneumonia and death in these patients. RESULTS: One hundred and forty-four patients with ILD (pneumonia group, n = 27; non-pneumonia group, n = 117) and complete HLA serology data available were included. HLA-B54 positivity was significantly more common in the pneumonia group than in the non-pneumonia group (37.0% vs. 15.4%, p = 0.010). HLA-B54 positivity was also a significant risk factor for pneumonia (hazard ratio [HR] 4.166, 95% confidence interval [CI] 1.862-9.320, p = 0.001) and death (HR 4.050, 95% CI 1.581-10.374, p = 0.004) in patients with ILD. Furthermore, HLA-B54 positivity was a significant risk factor for pneumonia (HR 3.964, 95% CI 1.392-11.090, p = 0.010) and death (HR 8.131, 95% CI 1.763-37.494, p = 0.007) in patients with idiopathic pulmonary fibrosis. CONCLUSION: HLA-B54 positivity was a significant risk factor for pneumonia and death in patients with ILD, including those with idiopathic pulmonary fibrosis.

Impact of Corticosteroid Administration within 7 Days of the Hospitalization for Influenza Pneumonia with Respiratory Failure: A Propensity Score Analysis Using a Nationwide Administrative Database.

Influenza pneumonia, which causes acute respiratory distress syndrome and multiple organ failure, has no established management protocol. Recently, corticosteroid therapy was used to treat coronavirus disease 2019 with respiratory failure; however, its effectiveness as a treatment for influenza pneumonia remains controversial. To investigate the impact of corticosteroid therapy for the early phase of severe influenza pneumonia, we compared influenza pneumonia patients with respiratory failure treated with or without corticosteroids within 7 days after hospital admission using a Japanese nationwide administrative database. The primary endpoint was the mortality rate. The secondary endpoints were duration of intensive-care unit management, invasive mechanical ventilation, and hospital stay. The inverse probability weighting method with estimated propensity scores was used to minimize the data collection bias. We included 3519 patients with influenza pneumonia with respiratory failure. Of these, 875 were treated with corticosteroids. There was no significant difference between the groups regarding 30-day and 90-day mortality, duration of intensive-care unit management, invasive mechanical ventilation, and hospital stay. However, the in-hospital mortality rate was higher in the corticosteroid group. The use of systematic corticosteroid therapy in patients with influenza pneumonia was associated with a higher in-hospital mortality rate.

Clinical Features of Anti-MDA5 Antibody-positive Rapidly Progressive Interstitial Lung Disease without Signs of Dermatomyositis.

Anti-melanoma differentiation-associated gene 5 (anti-MDA5) antibody is associated with rapidly progressive interstitial lung disease (RP-ILD) in patients with clinically amyopathic dermatomyositis (CADM) or dermatomyositis (DM). We herein report three Japanese cases of anti-MDA5 antibody-positive RP-ILD without signs of CADM or DM. High-resolution computed tomography revealed patchy or subpleural distribution of consolidations and/or ground-glass opacities accompanied by traction bronchiectasis. All patients succumbed to respiratory failure within two months. Anti-MDA5 antibody-positive RP-ILD without signs of CADM or DM should be included in the differential diagnosis of acute/subacute ILD. Measurement of anti-MDA5 antibody and an intensive immunosuppressive regimen might rescue these patients from RP-ILD.

Pulmonary Alveolar Proteinosis with Ulcerative Colitis.

A 65-year-old Japanese man was referred to our hospital for the further assessment of cough and dyspnea. He had a history of ulcerative colitis for which he was receiving treatment. Chest computed tomography showed a crazy-paving pattern. His bronchoalveolar lavage fluid had a milky appearance, and a transbronchial lung biopsy specimen revealed acellular periodic acid-Schiff stain-positive bodies. The serum anti-granulocyte macrophage-colony stimulating factor (GM-CSF) antibody titer was elevated. The diagnosis was autoimmune pulmonary alveolar proteinosis (PAP). There are few reports of autoimmune PAP in patients with ulcerative colitis. Some reports suggest that PAP and inflammatory bowel disease might have a common pathogenesis involving the anti-GM-CSF antibody.