Shinichiro Ohshimo

Significance of Bronchoalveolar Lavage for the Diagnosis of Idiopathic Pulmonary Fibrosis

RATIONALE According to the 2002 ATS/ERS Consensus Classification, a confident diagnosis of idiopathic pulmonary fibrosis (IPF) without surgical lung biopsy is made with consistent clinical/physiological findings and the typical features on high-resolution computed tomography (HRCT). Bronchoalveolar lavage (BAL) and/or transbronchial biopsy, one of four major criteria in the 2000 ATS/ERS IPF Statement, was no more essential in the diagnostic algorithm of 2002 ATS/ERS Consensus Classification. OBJECTIVES To evaluate the additional utility of BAL for the diagnosis of IPF. METHODS A total of 101 patients with suspected IPF on HRCT were studied. Twenty-seven patients were excluded because of lack of functional impairment (n = 20), an underlying condition causing fibrosis (n = 5), or a clinical history inconsistent with IPF (n = 2). The remaining 74 patients met all the criteria recommended in the 2002 ATS/ERS Consensus Classification for making a diagnosis in the absence of surgical biopsy. The final diagnosis was made with further examinations, including pathological analysis, in patients who showed inconsistent findings for IPF on BAL. MEASUREMENTS AND MAIN RESULTS A cut-off level of 30% for lymphocytes in BAL demonstrated a favorable discriminative power for the diagnosis of IPF. Six of the 74 patients (8%) showed a lymphocytosis of 30% or greater in BAL. Their final diagnoses were idiopathic nonspecific interstitial pneumonia (n = 3) and extrinsic allergic alveolitis (n = 3). The change in perception of the diagnosis was validated by a surgical biopsy in two cases and by subsequent outcome in four cases. CONCLUSIONS BAL lymphocytosis changed the diagnostic perception in six of 74 patients who would have been misdiagnosed as having IPF without BAL.

Diagnosis of sarcoidosis.

Purpose of review To describe the recent advances in the diagnostic procedures for sarcoidosis and explore future directions. Recent findings Novel imaging techniques have been explored in sarcoidosis, such as positron emission tomography using L-[3-18F]-α-methyltyrosine, which is more specific for malignancy than 18F-fluorodeoxyglucose positron emission tomography. The combined modality of L-[3-18F]-α-methyltyrosine–positron emission tomography with fluorodeoxyglucose–positron emission tomography could successfully discriminate sarcoidosis from malignancy. The finding of delayed enhancement in cardiac magnetic resonance imaging could identify cardiac involvement of sarcoidosis with higher sensitivity than echocardiography, thallium scintigraphy, and gallium scintigraphy. Endobronchial ultrasonograpy-guided transbronchial needle aspiration is a safe and useful tool for diagnosing sarcoidosis with a diagnostic accuracy, sensitivity and specificity of 85–93, 78–89, and 92–96%, respectively. Developments in genetics have demonstrated that 99% of the human leukocyte antigen DRB1*0301/DQB1*0201-positive patients with Löfgrens syndrome show a spontaneous remission, in contrast to only 55% of the human leukocyte antigen DRB1*0301/DQB1*0201-negative patients. These alleles could be novel promising factors for discriminating a prognosis in Löfgrens syndrome. Summary Recent development including novel imaging techniques, novel biopsy procedures, and genetic analyses could be of value for the diagnosis of sarcoidosis.

Pulmonary alveolar proteinosis: new insights from a single-center cohort of 70 patients.

BACKGROUND Pulmonary alveolar proteinosis (PAP) is a rare syndrome characterized by the intra-alveolar accumulation of surfactant lipids and proteins. The aim of the study is to describe the epidemiologic, clinical, physiologic, and laboratory features of PAP in a large single-center cohort of patients with PAP. STUDY POPULATION Over 30 years, 70 patients with PAP were managed at our institution, 64 with primary and 6 with secondary PAP. RESULTS The mean age at diagnosis was 43 years with a male to female ratio of 1.3. BAL was the most commonly applied diagnostic method, performed in 83% of cases. A history of smoking was seen in 79%, and of dust exposure in 54%, most commonly to aluminum, silica and sawdust. GM-CSF autoantibody correlated with clinical outcome and KL-6 with diffusing capacity. The number of whole lung lavages (WLL) necessary to reach remission was higher in current smokers. CONCLUSIONS This study shows that the use of BAL for the diagnosis of PAP can reduce the need of histological confirmation. A history of dust or fume inhalation is strongly associated with PAP, also with the autoimmune form. Smoking seems to influence the response to treatment, increasing the number of WLL necessary to reach remission.

Diagnostic Modalities in Sarcoidosis: BAL, EBUS, and PET

Advances have been made in minimally invasive diagnostic procedures in sarcoidosis, including bronchoalveolar lavage (BAL), endobronchial ultrasonography-guided transbronchial needle aspiration (EBUS-TBNA), and positron emission tomography (PET). Several independent groups found almost identical predictive values of the CD4:CD8 ratio in BAL for the diagnosis of sarcoidosis. A CD4:CD8 ratio greater than 3.5 shows a high specificity of 93 to 96% for sarcoidosis, but the sensitivity is low (53 to 59%). EBUS-TBNA is a safe and useful tool for diagnosing sarcoidosis stage I and II with a sensitivity of 83 to 93% and a specificity of 100%. Novel imaging techniques have been explored, such as PET using L-[3- (18)F] fluoro-alpha-methyltyrosine ( (18)F-F MT), which is more specific for malignancy than (18)F-fluorodeoxyglucose ( (18)F-FDG)-PET. The combined modality of FMT-PET with FDG-PET could successfully discriminate sarcoidosis from malignancy. These recent developments including novel biopsy procedures and novel imaging techniques could be of value to diagnosing sarcoidosis.

Circulating KL-6/MUC1 mucin carrying sialyl Lewisa oligosaccharide is an independent prognostic factor in patients with lung adenocarcinoma

MUC1 mucin is frequently observed in adenocarcinomas, and its association with metastasis has been postulated through the interaction between sialyl Lewis oligosaccharides present on this glycoprotein and selectins. Levels of soluble MUC1 recognized by anti‐KL‐6 monoclonal antibody were also frequently elevated in the sera of lung adenocarcinoma patients. The aim of this study was to demonstrate the presence of KL‐6/MUC1 carrying sialyl Lewisa oligosaccharide, designated as SLAK, and subsequently evaluate the clinical significance of circulating SLAK in patients with lung adenocarcinoma. We developed a sandwich ELISA system using anti‐sialyl Lewisa and anti‐KL‐6 antibodies to detect SLAK, and also measured circulating SLAK levels in 97 healthy controls and 103 patients with lung adenocarcinoma. Circulating SLAK levels were measured in the sera taken before treatment and then were evaluated to clarify whether such levels were related to the clinical outcomes. Levels of circulating SLAK were significantly higher in lung adenocarcinoma patients than in healthy subjects, and a higher serum SLAK level was correlated with the presence of distant metastasis. The overall survival rate for patients with high serum SLAK levels was significantly poorer than that of patients with low serum SLAK levels. The survival analysis restricted to the patients with distant metastasis also showed the same trend. In a multivariate survival analysis in lung adenocarcinoma patients, a high serum SLAK level was indicated as an independent prognostic factor. In conclusion, the circulating SLAK level at diagnosis is useful for predicting a poor prognosis in patients with lung adenocarcinoma.

MUC5B promoter polymorphism in Japanese patients with idiopathic pulmonary fibrosis

A single nucleotide polymorphism (SNP) rs35705950 in the promoter of Mucin 5B (MUC5B) has been reported to be associated with idiopathic pulmonary fibrosis (IPF) mainly in Caucasian populations. This study was conducted to confirm the association between rs35705950 and IPF in a Japanese population.

Usefulness of monitoring the circulating Krebs von den Lungen-6 levels to predict the clinical outcome of patients with advanced nonsmall cell lung cancer treated with epidermal growth factor receptor tyrosine kinase inhibitors

Krebs von den Lungen‐6 (KL‐6) is a high molecular weight glycoprotein classified in the category of human MUC1 mucin. KL‐6 has been reported to serve as a sensitive marker for interstitial pneumonia; however, recent studies have suggested that it can also be used as a tumor marker as its origin shows. To further elucidate the clinicopathological significance of circulating KL‐6 in lung cancer, we monitored the circulating KL‐6 levels in advanced nonsmall cell lung cancer (NSCLC) patients and analyzed the association between these levels and the clinical outcome of EGFR‐TKI treatment. The pretreatment levels of circulating KL‐6 were found to be significantly higher in progressive disease (PD) patients than disease‐controlled (partial response (PR) and stable disease (SD)) patients. Multivariate analyses revealed the circulating KL‐6 level to be an independent prognostic factor for overall survival as well as progression‐free survival. In addition to these observations, we found that changes in circulating KL‐6 levels at 2 weeks after the start of EGFR‐TKI treatment from the baseline could quite precisely discriminate PD cases from PR or SD patients and the clinical outcome of EGFR‐TKI in NSCLC patients. These results indicate that the monitoring of circulating KL‐6 levels in NSCLC patients is effective for both selecting patients to be treated with EGFR‐TKI and predicting the clinical outcome of EGFR‐TKI. In addition, the findings suggest that the circulating KL‐6 level could be used as a clinically relevant biomarker in patients with NSCLC, particularly those who are candidates for EGFR‐TKI treatment.

Different MUC1 gene polymorphisms in German and Japanese ethnicities affect serum KL-6 levels

BACKGROUND KL-6 is a high-molecular-weight glycoprotein classified as human Mucin-1 (MUC1). KL-6 has been reported to be a sensitive biomarker for interstitial lung diseases (ILDs) in the Japanese population. It is also known that polymorphisms in the MUC1 gene affect serum levels of KL-6. This study was conducted to evaluate serum levels of KL-6 and MUC1 polymorphisms in both German and Japanese populations. METHODS Serum levels of KL-6 were measured in 267 patients with ILDs (152 German and 115 Japanese) and 186 healthy subjects (HS) (76 German and 110 Japanese). In addition, rs4072037 single nucleotide polymorphisms (SNPs) were genotyped by polymerase chain reaction. The optimal cutoff values for discriminating patients with ILDs from HS was determined by receiver operating characteristic analysis based on ethnicity and rs4072037 genotypes. RESULTS The serum KL-6 levels in patients with ILDs were significantly higher compared with HS in both the German and the Japanese cohorts (both p<0.001). The discriminating cutoff value of serum KL-6 in the German cohort was significantly higher than the value in the Japanese cohort. The difference in the serum levels of KL-6 was significantly associated with the rs4072037 genotype distribution. CONCLUSIONS Even in the German cohort, the serum KL6 levels were significantly higher in patients with ILDs than HS. Because of differences in the genotype distribution of rs4072037, the KL-6 cutoff value for the German cohort that discriminated patients with ILDs from HS was significantly higher than the value in the Japanese cohort.

Angiogenic and Angiostatic Chemokines in Idiopathic Pulmonary Fibrosis and Granulomatous Lung Disease

Background: Angiogenesis-angiostasis balance and leukocyte recruitment are influenced by different concentrations of distinct chemokines. Objective: To investigate the relative contribution of angiogenic and angiostatic CXC chemokines to the pathogenesis of idiopathic pulmonary fibrosis (IPF) and granulomatous lung diseases, we examined the in vitro production of an angiogenic chemokine (IL-8), and 2 angiostatic chemokines (IP-10 and MIG) by alveolar macrophages. Methods: Alveolar macrophages from 16 patients with granulomatous lung diseases [8 with sarcoidosis, 8 with extrinsic allergic alveolitis (EAA)], 16 patients with IPF, and 8 control subjects were cultured for 24 h. IL-8, IL-18, IP-10 and MIG in the culture supernatants were measured by a fluorescent bead-based multiplex technique. Results: In IPF patients, IL-8 was increased and correlated with bronchoalveolar lavage (BAL) neutrophils, whereas the levels of IP-10 and MIG were normal. In sarcoidosis and EAA patients, IL-8, IP-10, and MIG were all increased and IP-10 and MIG correlated with IL-18, a Th1 cytokine, and the percentage and number of BAL lymphocytes. Conclusions: The difference in the expression of CXC chemokines and a Th1 cytokine may contribute to the different immunopathogenesis, clinical course and responsiveness to treatment of these diseases.

Serum KL-6 is a predictor of outcome in pulmonary alveolar proteinosis

BackgroundPulmonary alveolar proteinosis (PAP) is a rare disorder characterised by abundant alveolar accumulation of surfactant lipoproteins. Serum levels of KL-6, high molecular weight human MUC1 mucin, are increased in the majority of patients with PAP. The prognostic significance of KL-6 in PAP is still unknown. Aim of the study was to evaluate whether serum KL-6 levels correlate with the outcome of the disease.Patients and methodsFrom 2006 to 2012, we prospectively studied 33 patients with primary autoimmune PAP. We measured serum KL-6 levels by ELISA (Eisai, Tokyo, Japan), and evaluated the correlation between initial KL-6 levels and clinical variables. Disease progression was defined as deterioration of symptoms, and/or lung function, and/or chest imaging.Main resultsThe initial serum KL-6 levels were significantly correlated with the baseline PaO2, A-aDO2, DLCO, VC and TLC (p=0.042, 0.012, 0.012, 0.02 and 0.013, respectively). The change over time of serum KL-6 correlated with the change over time of DLCO (p=0.017). The initial serum KL-6 levels were significantly higher in patients with disease progression than in those with remission (p<0.001). At a cut-off level of 1526 U/mL, the initial serum KL-6 level predicted disease progression (Se 81%, Sp 94%). At a cut-off level of 2157 U/mL, the initial serum KL-6 predicted the necessity of repeated whole lung lavage (Se 83%, Sp 96%). In the multivariate analysis, the initial serum level of KL-6 was the strongest predictor of disease progression (HR 9.41, p=0.008).ConclusionsSerum KL-6 seems to predict outcome in PAP.