Automated computed tomography quantification of fibrosis predicts prognosis in combined pulmonary fibrosis and emphysema in a real-world setting: a single-centre, retrospective study.

BACKGROUND: Combined pulmonary fibrosis and emphysema (CPFE) is a heterogeneous clinico-radiological syndrome without a consensus definition. There are limited data on the relation between the amount of parenchymal fibrosis and prognosis. In this study, we assessed the prognostic implications of the extent of fibrosis assessed by an automated quantitative computed tomography (CT) technique and the radiological and functional change over time in patients with a broad spectrum of fibrotic interstitial lung diseases (ILDs) encountered in a real-world setting. METHODS: We conducted a single-centre, retrospective study of 228 consecutive patients with CPFE, encountered from 2007 to 2015 at Kameda Medical Center, Chiba, Japan. We investigated the prognostic value of automated CT fibrosis quantification and the subsequent course of CPFE. RESULTS: Among 228 patients with CPFE, 89 had fibrosis affecting < 5% of their lungs, 54 had 5 to < 10% fibrosis, and 85 had ≥ 10% fibrosis at the time of diagnosis. Lower volume of fibrosis correlated with lower rates of mortality and acute exacerbation (p < 0.001). In particular, among those with < 5% fibrosis, only 4.5% died and none experienced acute exacerbation during follow-up, whereas 57.6% and 29.4% of those with ≥ 10% fibrosis experienced death and acute exacerbation, respectively. Although, the ≥ 10% fibrosis group had the poorest overall survival as well as the highest incidence of acute exacerbation, the incidence of decline in pulmonary function tests, change per year in total lung volume, and progression of fibrosis on chest CT was highest in the 5 to < 10% fibrosis group. The Cox proportional hazard model for CPFE progression (defined by composite criteria of death, acute exacerbation, and decline in forced vital capacity or diffusing capacity) showed fibrosis proportion was a risk factor independent of age, sex, smoking pack-years, the Charlson Comorbidity Index, lung cancer, connective tissue disease, and idiopathic pulmonary fibrosis. CONCLUSIONS: Less severe (< 5%) fibrosis at baseline was associated with disease stability and better prognosis compared to more severe fibrosis in CPFE occurring with fibrotic ILDs. Further studies including a validation cohort will be needed. Trial Registration Retrospectively registered.

GATA-1 regulates the generation and function of basophils.

Developmental processes of hematopoietic cells are orchestrated by transcriptional networks. GATA-1, the founding member of the GATA family of transcription factors, has been demonstrated to play crucial roles in the differentiation of erythroid cells, magakaryocytes, eosinophils, and mast cells. However, the role of GATA-1 in basophils remains elusive. Here we show that basophils abundantly express Gata1 mRNAs, and that siRNA-mediated knockdown of Gata1 resulted in impaired production of IL-4 by basophils in response to the stimulation with IgE plus antigens. ΔdblGATA mice that carry the mutated Gata1 promoter and are widely used for functional analysis of eosinophils owing to their selective loss of eosinophils showed a decreased number of basophils with reduced expression of Gata1 mRNAs. The number of basophil progenitors in bone marrow was reduced in these mice, and the generation of basophils from their bone marrow cells in culture with IL-3 or thymic stromal lymphopoietin was impaired. ΔdblGATA basophils responded poorly ex vivo to stimulation with IgE plus antigens compared with wild-type basophils as assessed by degranulation and production of IL-4 and IL-6. Moreover, ΔdblGATA mice showed impaired responses in basophil-mediated protective immunity against intestinal helminth infection. Thus, ΔdblGATA mice showed numerical and functional aberrancy in basophils in addition to the known deficiency of eosinophils. Our findings demonstrate that GATA-1 plays a key role in the generation and function of basophils and underscore the need for careful distinction of the cell lineage responsible for each phenotype observed in ΔdblGATA mice.

Recurrent Optic Perineuritis With Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease Complicated With Granulomatous Polyangiitis.

Optic perineuritis (OPN) is an intraorbital inflammatory disease that targets the optic nerve sheath, which can cause severe vision loss. OPN has been recently reported to be sometimes caused by myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD). MOGAD is rarely reported to be complicated with other autoimmune diseases. We report the first rare case of MOG-associated OPN complicated with granulomatous with polyangiitis (GPA). The vision loss, in this case, was initially considered to be caused by cavernous sinusitis in GPA. However, she was diagnosed with MOGAD with serial MRI findings and positive MOG antibody and had been successfully treated with glucocorticoid and tocilizumab for one and half years. This case emphasized the importance of evaluating the MOG antibody in a patient with recurrent OPN, complicated with vasculitis.

[Siblings with familial interstitial pneumonia].

The index case was a 71-year-old man with no smoking history. He was given a diagnosis of idiopathic interstitial pneumonia at the age of 65. He was admitted to our hospital because of persistent cough and dyspnea on exertion. Two months after initiation of corticosteroid treatment he died of acute exacerbations of interstitial pneumonia. Among his family, four of seven brothers had interstitial pneumonia and all three sons of his were also found to have interstitial pneumonia, and of these seven patients six had a history of smoking. The average age at diagnosis of his generation was 66.5 and that of his son's generation was 45.3. In proband generation chest CT showed traction bronchiectasis or honeycombing in subpleural lesions. In addition, it revealed centrilobular micronodules and interlobular reticular shadow in the second generation. We found 2 single nucleotide polymorphisms of surfactant protein C gene in all children of the proband.

Predictors of acute exacerbation in biopsy-proven idiopathic pulmonary fibrosis.

BACKGROUND: Acute exacerbation (AE) is a major cause of death in patients with idiopathic pulmonary fibrosis (IPF). Current evidence on AE-IPF has been largely based on clinical, rather than pathological, analyses. METHODS: We investigated AE incidence and its predictors using clinical, radiological, and pathological data of patients diagnosed with IPF by multi-disciplinary discussion. This study, a secondary analysis of previous research, included 155 patients with IPF who underwent surgical lung biopsy (SLB). Cumulative AE incidence was evaluated by the Kaplan-Meier method. Predictors of AE-IPF were analyzed with a Fine-Gray sub-distribution hazard model. Sub-analysis was performed using propensity score-matching analysis. RESULTS: In this cohort, the median age of the patients was 66 years and the median percent-predicted forced vital capacity was 82.8%. The cumulative AE incidence rates at 30 days and one year post SLB were 1.9% and 7.6%, respectively. On multivariable analysis, a lower percent-predicted diffusing capacity of the lung for carbon monoxide (%DLCO) (hazard ratio 0.98 per 1% increase, P = 0.02) and fibroblastic foci (FF)-present (vs. absent; hazard ratio 3.01, P = 0.04) were independently associated with a higher incidence of AE. The propensity score-matching analysis with adjustment for age, gender, and %DLCO revealed that the cumulative AE incidence rate was significantly higher in the FF-present subgroup than in the FF-absent subgroup (1-year incidence rate, 10.5% vs. 0%, respectively; P = 0.04 by Gray's test). CONCLUSIONS: FF and %DLCO were independent predictors of AE in patients with biopsy-proven IPF. FF may be associated with the pathogenesis of AE-IPF.

Clinical Characteristics Based on the New Criteria of Acute Exacerbation in Patients with Idiopathic Pulmonary Fibrosis.

OBJECTIVE: Idiopathic pulmonary fibrosis (IPF) is the most common parenchymal lung disease. Patients with IPF sometimes develop acute exacerbation (AE), which predicts a poor prognosis. To evaluate the predictors of 90-day mortality of AE in patients with IPF based on the new 2016 criteria. MATERIALS AND METHODS: Sixty-five patients with AE were studied retrospectively between January 2001 and December 2016 at Okinawa Chubu Hospital. RESULTS: The mean age of the patients was 74 years, with 40 (61.5%) men and 25 (38.5%) women. Among our cohort, 37 were current or ex-smokers, with a mean exposure of 32.4 pack-years. The mean grade of the modified Medical Research Council breathlessness scale was 2.8, and the mean duration of dyspnea prior to admission was 6.5 days. Clubbed fingernails were present in 29% of patients. Triggered AE occurred in 12 (18%) of patients. Patients with triggered AE had more extensive ground-glass opacity and higher consolidation scores than the idiopathic AE group (7.3 vs. 4.2, p=0.01). The triggered group had shorter survival than the idiopathic group (1.4 vs. 11.4 months, p=0.094). Serum lactate dehydrogenase (LDH), ΔLDH, and the ratio of partial pressure of oxygen to the fraction of inspiratory oxygen ratio were strong predictors of 90-day mortality. Hazard ratios were 1.003 (p=0.004), 1.004 (p=0.02), and 0.994 (p=0.010), respectively. CONCLUSION: Compared with idiopathic AE, triggered AE in patients with IPF had more extensive infiltration and tended toward shorter survival. Serial trends of serum LDH >2 weeks can help predict prognosis of AE in patients with IPF.

Clinical characteristics of dermatomyosits/polymyositis associated interstitial lung disease according to the autoantibody.

BACKGROUND: Dermatomyositis (DM) and polymyositis (PM) often have association with interstitial lung disease (ILD) which have disease specific autoantibody. METHODOLOGY: We reviewed medical records of DM/PM associated ILD from January 2000 to December 2017 according to the autoantibody. RESULT: We identified 52 patients, of whom 30 were antibody negative, 18 had anti aminoacyl-tRNA synthetases (ARS) antibodies and 4 had anti melanoma differentiation-associated gene (MDA)-5 antibody. In high resolution computed tomography (HRCT) of the chest, area of ground glass opacity (GGO), consolidation, and lung tip consolidation were more extensive in anti MDA-5 antibody positive patients (p=0.051, p=0.026, and p=0.027, respectively). Among laboratory findings, GOT had strong correlations with CPK (r=0.889, p < 0.001), and LDH (r=0.910, p < 0.001). Among roentgenographic findings, there were moderate correlations between GGO and consolidation (r=0.668, p < 0.001), and between reticular shadow and traction bronchiectasis (p=0.633, p < 0.001). ILD patients with anti MDA-5 antibodies had decreased survival (1.00 vs 84.3, 22.9 months, p < 0.001). CONCLUSION: ILD patients with anti ARS antibody had intense inflammation, but reversible fibrosis and good prognosis. On the other hand, anti MDA-5 antibody positive ILD patients had shorter survival. Extent of parenchymal shadow and serum GOT were useful indicator of disease activity of PM/DM associated ILD patients in our cohort. J. Med. Invest. 65:251-257, August, 2018.

Causative species of nontuberculous mycobacterial lung disease and comparative investigation on clinical features of Mycobacterium abscessus complex disease: A retrospective analysis for two major hospitals in a subtropical region of Japan.

Nontuberculous mycobacteria (NTM) lung disease is increasing globally. Although the etiological epidemiology of NTM is different across regions, Mycobacterium avium complex (MAC) is the leading cause of NTM lung disease in most countries, including mainland Japan. Okinawa is located in the southernmost region of Japan and is the only prefecture categorized as a subtropical region in Japan, it is therefore likely the etiological epidemiology of NTM lung disease is different from mainland Japan. From 2009 to 2015, the medical records of patients, with respiratory specimens positive for NTMs, visiting or admitted to two Okinawan hospitals, were retrospectively analyzed. NTM lung disease cases were defined according to the American Thoracic Society criteria and patient epidemiology and clinical information were evaluated. Results indicate four hundred sixteen patients had bacterial cultures positive for NTM. The most common NTM was M. abscessus complex (MABC) (n = 127; 30.5%), followed by M. intracellulare (n = 85; 20.4%). NTM lung disease was diagnosed in 114 patients. Of these cases, MABC was most common (n = 41; 36.0%), followed by M. intracellulare (n = 31; 27.2%). Chronic obstructive pulmonary disease (COPD) and tracheostomy patients were more likely to develop MABC than MAC lung disease. Multivariate analysis showed a probable association between COPD and MABC lung disease. Chest computed tomography (CT) evaluation revealed bronchiectasis, nodules, and consolidation were less frequently observed in MABC patients compared with MAC patients. Our data suggests Okinawa may be one of the few places where MABC is the predominant pathogen causing NTM lung disease and our results add new insight to MABC lung disease, which is not yet well understood.

Clinical characteristics of idiopathic pulmonary fibrosis patients according to their smoking status.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is the most common form of idiopathic interstitial pneumonias (IIPs) of unknown etiology that often affects male, elderly smokers. However, it is sometimes observed in never smokers. This study aimed to clarify the clinical characteristics of IPF in never-smoking patients compared with those in smoking patients. METHODS: We retrospectively reviewed medical records, pulmonary function tests, and chest high-resolution computed tomography (HRCT) scan of never-smoking and smoking IPF patients from July 1, 2008 to June 30, 2013 at our hospital. RESULTS: We identified 32 never-smoking IPF patients and 66 smoking IPF patients. Never-smoking IPF patients developed more acute exacerbation (AE) than smoking IPF patients (50% vs. 18.2%, P<0.0001). The strongest predictor of AE in never-smoking IPF was modified Medical Research Council (mMRC) breathlessness scale [Hazards ratio (HR), 2.84, P=0.006]. The median survival time of never-smoking and smoking were 18.5 (0.1-138) and 26.3 (0.1-98.4) months, P<0.0001, respectively. The Cox proportional hazard model showed that 1-year mMRC breathlessness scale (HR, 3.24, P=0.001) and gender, age, and physiology (GAP) score (HR, 1.59, P=0.029) were strong predictors of mortality in never-smoking IPF patients at our hospital. CONCLUSIONS: In conclusion, never-smoking IPF patients developed AE more often and showed poor prognosis compared with smoking IPF patients. The 1-year mMRC breathlessness scale was an important predictor of mortality at our hospital.

Body mass index-percent forced vital capacity-respiratory hospitalization: new staging for idiopathic pulmonary fibrosis patients.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is relentless progressive interstitial lung disease. Evaluating predictor of mortality for IPF patients is crucial. The aim of this study was to evaluate the serial trend of important indicators of prognosis and create a useful staging method for IPF patients. METHODS: We retrospectively searched medical records, pulmonary function tests (PFTs), and chest high resolution computed tomography (HRCT) scans from January 1, 2008 through June 30, 2015 at our hospital. We also evaluated the same parameters 1-year later. RESULTS: We identified 65 IPF patients. The mean age was 71.9±1.8 years (range, 22-85 years). In terms of PFTs, mean percent predicted forced vital capacity (%FVC) was 69.8±2.7. Baseline mean body mass index (BMI) was 24.3±0.6 kg/mm2. Mean survival was 39.2 months (range, 0.9-158.9 months). Cox proportional hazard ratios (HRs) showed the following to be predictors of mortality in IPF patients: 1-year BMI (HR: 0.899; 95% CI: 0.825-0.979; P=0.021); 1-year %FVC (HR: 0.932; 95% CI: 0.887-0.979; P=0.005) and 1-year respiratory hospitalization (HR: 3.307; 95% CI: 2.149-5.090; P<0.001). On the basis of these date, we created a new staging method for predicting mortality for IPF patients, consisting of delta BMI, delta %FVC and respiratory hospitalization within a year following diagnosis of IPF (BFR staging). We stratified patients into one of three groups according to the composite points. Mean survival of stages 1, 2, and 3 was 77.9 (30.8-158.9), 43.9 (0.9-145.2) and 14.8 (3.5-32) months (P<0.001), respectively. CONCLUSIONS: In our cohort of IPF patients, this new staging method, including delta BMI and delta %FVC and respiratory hospitalization within 1-year showed a clear survival difference.

Clinical characteristics of idiopathic pulmonary fibrosis patients with gender, age, and physiology staging at Okinawa Chubu Hospital.

BACKGROUND: Gender, age, and physiology (GAP) staging was recently advocated for idiopathic pulmonary fibrosis (IPF). However, clinical findings of GAP staging for IPF are limited. We aimed to investigate the clinical characteristics of IPF patients according to GAP staging in our hospital. METHODS: We retrospectively reviewed patient medical records and chest high-resolution computed tomography (HRCT) images from June 1, 2002, to December 31, 2012. RESULTS: We identified 54 IPF patients with [36 men; mean age: 71 years (range, 53-85 years)]. Mean fibrosis and ground glass opacity (GGO) scores were 1.9 (0-4) and 1.6 (1-3.3), respectively. Mean percent predicted forced vital capacity (% FVC), percent predicted diffusing capacity of the lung for carbon monoxide (% DLco) were 70.6 (6.4-114.3), 49.2 (15-105.9), respectively. Cox proportional hazards model showed that gender, percent predicted diffusing capacity of the lung for carbon monoxide (% DLco), and composite physiologic index (CPI) were strong predictors of mortality. Stage III patients had more pulmonary hypertension (50% vs. 23%, 0%) and progressive modified Medical Research Council (mMRC) changes at 1 year (1.3 vs. 0.6, 1.1; P=0.07) compared with other stages. CONCLUSIONS: In our cohort, GAP staging was useful for evaluating IPF severity. Stage III patients might had more pulmonary hypertension and progressive dyspnea. Multicenter analyses are warranted to confirm these findings.

The skin is an important bulwark of acquired immunity against intestinal helminths.

Once animals have experienced a helminthic infection, they often show stronger protective immunity against subsequent infections. Although helminthic infections are well known to elicit Th2-type immune responses, it remains ill-defined where and how acquired protection is executed. Here we show that skin-invading larvae of the intestinal helminth Nippostrongylus brasiliensis are surrounded by skin-infiltrating cells and are prevented from migrating out of infected skin during the second but not the first infection. B cell- or IgE receptor FcεRI-deficient mice showed impaired larval trapping in the skin. Selective ablation of basophils, but not mast cells, abolished the larval trapping, leading to increased worm burden in the lung and hence severe lung injury. Skin-infiltrating basophils produced IL-4 that in turn promoted the generation of M2-type macrophages, leading to the larval trapping in the skin through arginase-1 production. Basophils had no apparent contribution to worm expulsion from the intestine. This study thus reveals a novel mode of acquired antihelminth immunity, in which IgE-armed basophils mediate skin trapping of larvae, thereby limiting lung injury caused by larval migration.