Tomohiro Handa

Significance of Pulmonary Arterial Pressure and Diffusion Capacity of the Lung as Prognosticator in Patients With Idiopathic Pulmonary Fibrosis

STUDY OBJECTIVES To evaluate the long-term clinical course of patients with idiopathic pulmonary fibrosis (IPF) complicated with pulmonary arterial hypertension. DESIGN Prospective analysis of consecutive IPF patients undergoing initial workup with right-heart catheterization (RHC) and pulmonary function testing (PFT). Pulmonary arterial pressure (PAP) and diffusion capacity of the lung for carbon monoxide (Dlco) were focused on. SETTING University hospital. PATIENTS Seventy-eight patients with IPF (67 men, 11 women; diagnosis by pathology, n = 59; clinical diagnosis, n = 19) had been followed up after initial workup for a maximum of 14 years. MEASUREMENTS AND RESULTS RHC data on 61 patients and PFT data on 52 patients were available. Five-year survival rates were 62.2% in the normal-PAP group (mean PAP < 17 mm Hg, n = 37) and 16.7% in the high-PAP group (mean PAP > 17 mm Hg, n = 24) [p < 0.001]; 70.4% in the preserved-Dlco group (percentage of predicted > 40%, n = 27) and 20.0% in the low-Dlco group (percentage of predicted < 40%, n = 25) [p < 0.001]; and 82.6% in group 1 (normal PAP and preserved Dlco, n = 23) and 15.6% in group 2 (high PAP, low Dlco, or both, n = 32) [p < 0.0001]. The relative risks of mortality within 5 years after RHC were 2.20 (95% confidence interval [CI], 1.40 to 3.45) in the high-PAP group, 2.70 (95% CI, 1.46 to 4.99) in the low-Dlco group, and 4.85 (95% CI, 1.97 to 11.97) in group 2. CONCLUSION Dlco was a critical factor for evaluating disease status and prognosis, and PAP status provided feasible information in the initial workup of IPF patients.

Detection of antisynthetase syndrome in patients with idiopathic interstitial pneumonias

OBJECTIVES Antisynthetase syndrome (ASS) is characterized by autoantibodies to aminoacyl-tRNA synthetases (anti-synthetase) and it is frequently associated with interstitial lung disease. The purpose of this study was to elucidate the prevalence and characteristics of the anti-synthetase positive subpopulation among idiopathic interstitial pneumonias (IIPs) and to clarify the importance of screening for these antibodies. METHODS A retrospective study was performed in 198 consecutive cases with IIPs. Screening for six anti-synthetase antibodies was performed in all cases. Clinical profiles of all cases were compared with reference to the presence of anti-synthetase. High-resolution computed tomography (HRCT) findings of anti-synthetase positive cases were also analyzed. RESULTS 13 cases (6.6%) were positive for anti-synthetase. Anti-EJ was most prevalent, followed by anti-PL-12. Onset ages of anti-synthetase positive cases were younger than those of anti-synthetase negative cases. Extrapulmonary features of ASS were absent in 6 anti-synthetase positive cases (46.2%). Histologically, among 5 UIP with lymphoid follicles and 11 NSIP cases, the prevalence of anti-synthetase positive cases was 8/16 (50%). On HRCT, ground glass opacity and traction bronchiectasis were the major findings in anti-synthetase positive cases, while honeycombing was absent. CONCLUSIONS Anti-synthetase positive cases were not rare among IIPs. Anti-synthetase should be screened for in IIPs, especially in pathological NSIP or UIP with lymphoid follicles. These patients should be screened for anti-synthetase even if no suggestive extrapulmonary manifestation exists.

HRCT features of interstitial lung disease in dermatomyositis with anti-CADM-140 antibody

BACKGROUND Anti-CADM-140 antibody (anti-CADM-140), also referred to as anti-melanoma differentiation-associated gene 5 (MDA5) antibody, is a myositis-specific antibody identified in the sera of patients with clinically amyopathic dermatomyositis (C-ADM) and is associated with a worse prognosis in dermatomyositis-associated interstitial lung disease (DM-ILD). We sought to determine high-resolution computed tomography (HRCT) features of DM-ILD with anti-CADM-140. METHODS Twenty-five patients newly diagnosed with DM-ILD at Kyoto University Hospital between 2005 and 2009 were retrospectively reviewed. Serum anti-CADM-140 was measured in all patients at their first visit. Chest HRCT images taken prior to treatment were classified based on the dominant findings and their distribution, and compared between patients with and without the antibody. RESULTS Of 25 DM-ILD patients, 12 were positive and 13 were negative for anti-CADM-140. HRCT patterns differed significantly between anti-CADM-140-positive and negative patients (P = 0.002). Lower consolidation or ground-glass attenuation (GGA) pattern (50.0%) and random GGA pattern (33.3%) were the predominant patterns in anti-CADM-140-positive cases, while lower reticulation pattern (69.2%) was frequently seen in anti-CADM-140-negative cases. Anti-CADM-140-positive cases were also significantly characterized by the absence of intralobular reticular opacities (0% in anti-CADM-140 (+) vs. 84.6% in anti-CADM-140 (-), P < 0.0001). CONCLUSIONS Anti-CADM-140-positive DM-ILD was characterized by lower consolidation or GGA pattern, random GGA pattern, and the absence of intralobular reticular opacities.

The Multicenter Study of a New Assay for Simultaneous Detection of Multiple Anti-Aminoacyl-tRNA Synthetases in Myositis and Interstitial Pneumonia

Objective Autoantibodies to aminoacyl-tRNA synthetases (ARSs) are useful in the diagnosis of idiopathic inflammatory myopathy (IIM) with interstitial pneumonia (IP). We developed an enzyme-linked immunosorbent assay (ELISA) system using a mixture of recombinant ARS antigens and tested its utility in a multicenter study. Methods: We prepared six recombinant ARSs: GST-Jo-1, His-PL-12, His-EJ and GST-KS expressed in Escherichia coli, and His-PL-7 and His-OJ expressed in Hi-5 cells. After confirming their antigenic activity, with the exception of His-OJ, we developed our ELISA system in which the five recombinant ARSs (without His-OJ) were mixed. Efficiency was confirmed using the sera from 526 Japanese patients with connective tissue disease (CTD) (IIM n = 250, systemic lupus erythematosus n = 91, systemic sclerosis n = 70, rheumatoid arthritis n = 75, Sjögren’s syndrome n = 27 and other diseases n = 13), 168 with idiopathic interstitial pneumonia (IIP) and 30 healthy controls collected from eight institutes. IIPs were classified into two groups; idiopathic pulmonary fibrosis (IPF) (n = 38) and non-IPF (n = 130). Results were compared with those of RNA immunoprecipitation. Results: Sensitivity and specificity of the ELISA were 97.1% and 99.8%, respectively when compared with the RNA immunoprecipitation assay. Anti-ARS antibodies were detected in 30.8% of IIM, 2.5% of non-myositis CTD, and 10.7% of IIP (5.3% of IPF and 12.3% of non-IPF). Anti-ARS-positive non-IPF patients were younger and more frequently treated with glucocorticoids and/or immunosuppressants than anti-ARS-negative patients. Conclusion: A newly established ELISA detected anti-ARS antibodies as efficiently as RNA immunoprecipitation. This system will enable easier and wider use in the detection of anti-ARS antibodies in patients with IIM and IIP.

Analysis of systemic and airway inflammation in obstructive sleep apnea

PurposeThe presence of both systemic and airway inflammation has been suggested in obstructive sleep apnea (OSA) by increased levels of inflammatory biomarkers in the circulation and respiratory specimens. We aimed to investigate the relationship between systemic and airway inflammation in OSA.MethodsThis study was conducted by simultaneously measuring various biomarkers both in serum and induced sputum of 43 patients. We compared the relationships of these biomarker levels with polysomnographic data and obesity measurements and also investigated their interrelationships between systemic and local compartments. We also assessed the relation of inflammatory markers with proximal airway resistance measured by impulse oscillometry.ResultsIn multiple regression analyses, each measured serum biomarker [leptin, interleukin-6 (IL-6), IL-8, tumor necrosis factor-α (TNF-α), and vascular endothelial growth factor (VEGF)] significantly correlated with waist circumference or fat area determined by computed tomography. In contrast, regarding airway inflammation, sputum IL-6, IL-8, TNF-α, and VEGF significantly correlated with OSA severity as indicated by the respiratory disturbance index or oxygen desaturation indices. Sputum IL-6, IL-8, TNF-α, and VEGF were significantly related to sputum neutrophil number, and sputum IL-8 and TNF-α were related to proximal airway resistance independently of body mass index. There were no significant interrelationships between the same biomarkers in serum and induced sputum.ConclusionsSystemic and airway inflammation in OSA might be differently regulated by OSA itself and comorbid obesity, depending on the type of cytokine. Although we did not find apparent interrelationships between systemic and local compartments, further studies are needed to clarify this concept.

Outcome of Sarcoidosis

Sarcoidosis is a chronic granulomatous inflammatory disease of unknown etiology with heterogeneous outcome. Based on the natural history or clinical treatment course, the outcomes of cases can be divided into two wings: spontaneous regression (self-limited disease) or progression of extensive fibrotic lesions as a postgranulomatous fibrosis. In addition to examining these outcomes, this article focuses on several related concepts, including chronicity (persistence of the lesions), relapse/recurrence, deterioration, and mortality. It also reviews the outcomes from the point of view of relevant clinical phenotypes, the natural disease course, the effects of treatment, and the effects of lung transplantation. Finally, it considers the effects of pulmonary hypertension, various genetic factors on the outcomes, and the efficacy of several novel therapeutic drugs in treating sarcoidosis.

Cell profiles of bronchoalveolar lavage fluid as prognosticators of idiopathic pulmonary fibrosis/usual interstitial pneumonia among Japanese patients

Background: The role of bronchoalveolar lavage fluid (BALF) cell profiles in predicting the clinical outcome of idiopathic pulmonary fibrosis (IPF)/usual interstitial pneumonia (UIP) is still under discussion. Objective: To determine whether BALF cell profiles affect the survival of patients with UIP diagnosed by surgical lung biopsy/autopsy at the early stage of IPF. Methods: This hospital-based retrospective cohort study used 81 Japanese patients with histologically proven IPF/UIP who underwent BAL examination. The BALF samples were obtained from non-current smokers: NCS (n = 41) and current smokers: CS (n = 40). The Kaplan-Meier and Cox’s proportional hazard methods were used to estimate the survival and evaluate the risk ratio for death in the two groups. To detect the multicollinearity, a stepwise regression was employed. Results: A slight increase in the absolute numbers of BALF neutrophils tended to relate to a decrease in the relative risk for death in NCS patients and CS patients in the univariate analysis. In stepwise regression, the increase in percent vital capacity and the increase in the BALF CD4/CD8 ratio in NCS was detected as a favorable predictor, while increased BALF cells affected the results due to chronic smoking in CS. Conclusions: Based on the study bias of the biopsy-proven IPF/UIP patients at stable stages, an independent variable indicating a favorable outcome was an increased BALF CD4/CD8 ratio in NCS patients, while it was difficult to identify definite prognosticators in CS patients.

Glomerulonephritis induced by methicillin-sensitive Staphylococcus aureus infection.

A 57-year-old woman developed exacerbation of atopic dermatitis, fever, and nephrotic syndrome with microscopic hematuria. By bacteriological study, methicillin-sensitive Staphylococcus aureus (MSSA) was detected from each culture of pharyngeal mucus, stool, and blood samples. Renal biopsy specimens showed endocapillary proliferative glomerulonephritis with massive IgA deposition in the mesangium and along the capillary loops. After antistaphylococcal therapy with antibiotics, MSSA was negative for each culture and urinary protein decreased. Nine months after the first renal biopsy, a re-biopsy was performed, which revealed apparent disappearance of both endocapillary cell proliferation and IgA deposition. It is known that methicillin-resistant S. aureus (MRSA) infection causes glomerulonephritis through T-cell stimulation by superantigen presented by MRSA. The present results suggest that not only MRSA but also MSSA can cause this type of glomerulonephritis.

Living-donor lobar lung transplantation provides similar survival to cadaveric lung transplantation even for very ill patients †

OBJECTIVES Living-donor lobar lung transplantation (LDLLT) has been performed as a life-saving procedure for critically ill patients who are unlikely to survive the long wait for cadaveric lungs. The purpose of this study was to compare the preoperative condition and outcome of LDLLT patients with those of conventional cadaveric lung transplantation (CLT) patients. METHODS A new lung transplant programme was established in 2008 at Kyoto University. Between June 2008 and January 2014, we performed 79 lung transplants, including 42 LDLLTs (10 single, 32 bilateral) and 37 CLTs (22 single, 15 bilateral). Data collected included pre- and perioperative variables and mid-term survival. All data were analysed retrospectively as of January 2014. RESULTS The majority of patients were female (57.1%) in the LDLLT group and male (64.9%) in the CLT group. The average age was similar (36.6 ± 20.7 vs 39.7 ± 12.6 years, P = 0.42) between the two groups. Preoperatively, interstitial lung disease was more common in LDLLT patients than in CLT patients (47.6 vs 24.3%, P = 0.048); prior haematopoietic stem cell transplantation was performed more often in LDLLT patients than in CLT patients (33.3 vs 13.5%, P = 0.040) and there were more steroid-dependent LDLLT patients than CLT patients (64.3 vs 29.7%, P = 0.0022). Based on preoperative criteria of lower body mass index (17.2 ± 4.0 vs 19.3 ± 3.3 kg/m(2), P = 0.013), less ambulatory ability (42.9 vs 86.5%, P = 0.0001) and more ventilator dependence (11.9 vs 2.7%, P = 0.12), LDLLT patients were more debilitated than CLT patients. LDLLT patients required longer postoperative mechanical ventilation than CLT patients (15.6 ± 16.2 vs 8.5 ± 8.1 days, P = 0.025). However, 1- and 3-year survival rates were similar between the two groups (89.7 and 86.1% vs 88.3 and 83.1%, P = 0.55). All living donors returned to their previous lifestyles without restriction. CONCLUSIONS Although LDLLT patients were in a worse preoperative condition than CLT patients, LDLLT patients demonstrated survival rates similar to CLT patients. LDLLT is a viable option for patients too ill to survive a long waiting time for cadaveric donors.

Treatment with Methotrexate and Low-dose Corticosteroids in Sarcoidosis Patients with Cardiac Lesions

The Authors Reply There are several weaknesses of the study in respect to the examined number of patients. However, regarding the diagnosis of sarcoidosis, we carefully checked the involved lesions (including the sites and severity) according to the 2006 Japanese guidelines (1). The patients cannot be diagnosed with any other disease, even if sarcoidosis is removed from the differential diagnosis. Based on our experience with more than 2,000 sarcoidosis patients, we selected typical cases that have a substantial amount of clinical evidence of sarcoidosis lesions. All cases satisfied the major criteria according to the 2006 Japanese guidelines (1). This guideline is approved by another reviewer (2). In addition, basal thinning of the interventricular septum was detected in 15 patients; two patients without basal thinning had other positive findings that satisfied the diagnostic criteria. Positron emission tomography negative cases also showed abnormalities related to the presence of the cardiac lesions due to sarcoidosis. Ischemic heart diseases were actively differentiated during their time courses. We explained the specific treatment for all patients with cardiac sarcoidosis. The importance of the new treatment was to reduce the adverse effects of standard corticosteroid therapy. However, some patients showed a hesitation to receive the novel therapy using methotrexate and therefore were treated with corticosteroid therapy only. Other patients were treated with the two drugs. We selected age-matched patients between two groups. Therefore, after removing the age-mismatched patients (younger patients), the number of the cases became smaller. In the comparison between the two groups, there were no statistically significant differences in the forced expiratory volume one second (FEV1) or any other parameters. Regarding the FEV1, the smallest value in our patients was 1.39 L and this patient showed mild airflow limitation with mild fibrotic lesions. Therefore, it was difficult to relate the airflow lesion to heart dysfunction. We analyzed differences in the outcome indices (including the left ventricular ejection fraction) between the groups at various time points and found statistical significance after 3 years. There were no clear results that stabilized the cardiac function two years after treatment with either the standard dose or a high dose of corticosteroid therapy (3). There was also a slight increase in the cardio-thoracic ratio associated with an increase of the N-terminal fragment pro-brain natriuretic peptide. These findings may be attributed directly to the treatment method, as there was no apparent ischemic heart disease or hypertension.