Utility of Anti-DSF70 Antibodies to Predict Connective Tissue Disease in Patients Originally Presenting with Idiopathic Interstitial Pneumonia.

BACKGROUND: Anti-DFS70 antibodies, corresponding to the dense fine speckled antinuclear antibody (ANA) pattern in HEp-2 substrates, have been observed in chronic inflammatory conditions, cancer and in healthy individuals but in only a small percentage of patients with connective tissue diseases (CTD). OBJECTIVES: The study was aimed to investigate the possible role of Anti-DFS70 antibodies to distinguish CTD associated interstitial lung disease (CTD-ILD) from idiopathic interstitial pneumonia (IIP) and to explore potential correlations between anti-DFS70 antibodies and clinical parameters. METHODS: Serum samples were collected from 49 healthy controls (HC), 35 scleroderma-ILD (SSc-ILD) patients as negative controls for anti-DFS70 antibody, and 260 patients with the initial diagnosis IIP including 100 nonspecific interstitial pneumonia (NSIP) and 160 idiopathic pulmonary fibrosis (IPF) patients. ANA pattern was identified by indirect immunofluorescence on HEp-2 cells and anti-DFS70 antibodies were measured in serum by ELISA. RESULTS: Serum anti-DFS70 antibodies were less frequently seen in ILD and SSc-ILD patients compared to HCs. Thirty-seven patients (34 initial idiopathic NSIP and 3 initial IPF patients) developed CTD during 24 months of follow-up, most of them combined with ANA positivity and anti-DFS70 antibody negativity. Anti-DFS70 antibody positivity was not significantly different between CTD-ILD and idiopathic ILD. CONCLUSIONS: The frequency of serum anti-DFS70 antibody is markedly decreased in patients with ILDs. Anti-DFS70 antibodies may be useful to predict CTD development in ILD patients.

Serum YKL-40 as predictor of outcome in hypersensitivity pneumonitis.

YKL-40, a chitinase-like protein mainly secreted by macrophages, neutrophils and epithelial cells, is increased in patients with idiopathic interstitial pneumonia and sarcoidosis. We aimed to investigate the role of YKL-40 as a biomarker in hypersensitivity pneumonitis (HP).72 HP patients, 100 interstitial lung disease (ILD) controls and 60 healthy controls were studied. YKL-40 was measured by ELISA in serum and bronchoalveolar lavage fluid (BALF) at baseline and follow-up. The relationship between YKL-40 levels, clinical variables and disease outcome was evaluated.Baseline serum YKL-40 levels were significantly higher in HP patients than in healthy controls (p<0.001), but lower than in patients with other ILDs. Baseline BALF YKL-40 levels in HP patients were the highest among ILD patients. In HP patients, serum YKL-40 correlated with the diffusing capacity of the lung for carbon monoxide at baseline (p<0.01) and over time (p<0.001). HP patients whose disease progressed or who died had higher baseline YKL-40 levels than those who remained stable and survived (p<0.001). At a cut-off of 119 ng·mL-1, the baseline serum YKL-40 level predicted disease progression (hazard ratio 6.567; p<0.001), and at a cut-off of 150 ng·mL-1 was associated with mortality (hazard ratio 9.989; p<0.001).Serum YKL-40 may be a useful prognostic biomarker in HP patients.

Serum YKL-40 is a reliable biomarker for pulmonary alveolar proteinosis.

BACKGROUND AND OBJECTIVE: Pulmonary alveolar proteinosis (PAP) is a rare disease characterized by alveolar filling. YKL-40, a chitinase-like protein produced by macrophages and epithelial cells, is increased in patients with interstitial lung diseases. We aimed to evaluate the role of YKL-40 as a biomarker for PAP. METHODS: A total of 34 patients with autoimmune PAP and 50 healthy controls were studied. YKL-40 was measured by ELISA in serum and bronchoalveolar lavage fluid (BALF). Chitinase coding gene polymorphisms (CHI3L1-329 and -131) were detected by PCR and pyrosequencing. Correlations between serum YKL-40 levels and disease outcome were analysed. RESULTS: Baseline serum and BALF levels of YKL-40 were higher in PAP patients than in controls (286 ± 27 ng/mL vs 42 ± 4 ng/mL, P < 0.0001; 323 ± 36 ng/mL vs 3 ± 1 ng/mL, P < 0.0001, respectively). Serum YKL-40 levels correlated with diffusing capacity of the lung for carbon monoxide (DLCO ) at baseline (P = 0.002) and over time (P < 0.0001). Patients with disease progression had higher baseline serum YKL-40 levels than those who remained stable or improved (P < 0.0001). A baseline cut-off level of 300 ng/mL was predictive of disease progression (HR (hazard ratio): 7.875, P = 0.001). The presence of the G allele was associated with higher serum and BALF levels of YKL-40. CONCLUSION: YKL-40 is elevated in serum and BALF of PAP patients, and may be of clinical utility to predict outcome in PAP.

MUC5B promoter polymorphism in Japanese patients with idiopathic pulmonary fibrosis.

BACKGROUND AND OBJECTIVE: 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. METHODS: Genomic DNA was extracted from blood samples in 384 Japanese and 137 German subjects, and rs35705950 was detected by commercially available genotyping assay. RESULTS: The genotype distributions of rs35705950 in Japanese patients with IPF, nonspecific interstitial pneumonia (NSIP) and healthy subjects (HS) were significantly different from those in the German counterparts (P < 0.001, P < 0.001 and P = 0.010, respectively). The rs35705950 T allele frequencies in patients with IPF, NSIP and HS were 3.4%, 1.7% and 0.8%, respectively in the Japanese, while they were 33.1%, 27.4% and 4.3%, respectively in the German cohort. The T allele frequencies in patients with IPF were significantly higher than those in HS both in the Japanese (P = 0.031) and German (P < 0.001) cohorts. CONCLUSIONS: The association between rs35705950 and IPF was also present in this Japanese cohort, but was not as strong as the German counterpart. To our knowledge, this is the first study to successfully validate the association between rs35705950 and IPF in a Japanese ethnicity.

Differences in serum SP-D levels between German and Japanese subjects are associated with SFTPD gene polymorphisms.

BACKGROUND: Surfactant protein A (SP-A) and SP-D are clinically established in Japan as serum biomarkers for diagnosing interstitial lung diseases (ILDs). Serum SP-D levels are affected by genetic variants. We conducted the present study to examine whether serum SP-A and/or SP-D levels in healthy subjects (HS) and patients with ILDs differ between populations with different genetic backgrounds. METHODS: German subjects (n = 303; 138 patients with idiopathic interstitial pneumonias [IIPs] and 165 HS) and Japanese subjects (n = 369; 94 patients with IIPs and 275 HS) were enrolled. Serum SP-A and SP-D levels were measured using an enzyme-linked immunosorbent assay, and four single-nucleotide polymorphisms (SNPs) in the SFTPD gene were genotyped using genomic DNA extracted from blood samples. RESULTS: In both the German and Japanese cohorts, serum SP-A and SP-D levels were significantly higher in patients with IIPs than in HS. There were no significant differences in SP-A levels between the German and Japanese cohorts; however, we found that serum SP-D levels were significantly higher in the German cohort, both in patients with IIPs and in HS (p < 0.001 and p = 0.005, respectively). Furthermore, the genotype distributions of the four SNPs in the SFTPD gene (rs721917, rs1998374, rs2243639, and rs3088308) were significantly different between German and Japanese cohorts (p < 0.001, p < 0.001, p = 0.022, and p < 0.001, respectively), and univariate linear regression analyses revealed that the genotypes of rs721917, rs1998374, and rs2243639 significantly correlated with serum SP-D levels (p < 0.001, p < 0.001, and p = 0.011, respectively). Furthermore, multivariate analyses revealed that the genotypes of these three SNPs correlated independently with serum SP-D levels (p < 0.001, p = 0.001, and p = 0.038, respectively), whereas ethnicity did not significantly correlate with serum SP-D levels. CONCLUSIONS: In patients with IIPs and HS, serum SP-D, but not SP-A, levels were significantly higher in the German than in the Japanese cohort, in part, because of the different frequencies of SFTPD gene polymorphisms.

Wash-out kinetics and efficacy of a modified lavage technique for alveolar proteinosis.

Whole lung lavage (WLL) is the standard treatment for pulmonary alveolar proteinosis (PAP). This study aimed to provide data about the kinetics of the protein wash-out, to identify factors influencing the protein concentration in the recovered fluid and to assess the efficacy of a modified lavage technique. Samples of 180 WLLs from 42 adult PAP patients were collected. 110 WLLs were performed according to the classical technique. In 70 WLLs, repeated manual ventilation was applied during the procedure. Spectrophotometry was used to measure the protein concentration in the recovered fluid. The initial protein concentration in the recovered fluid was 460 mg · dL(-1), the final concentration was 26 mg · dL(-1) and the total amount of removed proteins during a lavage was 17.5 g. A history of dust exposure was associated with a higher residual protein concentration in the recovered fluid (p=0.000013). The amount of removed proteins correlated inversely with the diffusing capacity of the lung for carbon monoxide (p=0.001) and oxygen tension (p=0.004). The modified technique removed a greater amount of proteins than the classical technique and prolonged the time to relapse (p=0.011). Exposure to dust seems to influence the kinetics of the protein wash-out. Applying manual ventilation during the procedure can enhance the efficacy of WLL.

Localization of propionibacterium acnes in granulomas supports a possible etiologic link between sarcoidosis and the bacterium.

Sarcoidosis likely results from the exposure of a genetically susceptible subject to an environmental agent, possibly an infectious one. Mycobacterial and propionibacterial organisms are the most commonly implicated potential etiologic agents. Propionibacterium acnes is the only microorganism, however, found in sarcoid lesions by bacterial culture. To evaluate the pathogenic role of this indigenous bacterium, we screened for the bacterium in sarcoid and non-sarcoid tissues using immunohistochemical methods with novel P. acnes-specific monoclonal antibodies that react with cell-membrane-bound lipoteichoic acid (PAB antibody) and ribosome-bound trigger-factor protein (TIG antibody). We examined formalin-fixed and paraffin-embedded samples of lungs and lymph nodes from 196 patients with sarcoidosis, and corresponding control samples from 275 patients with non-sarcoidosis diseases. The samples were mostly from Japanese patients, with 64 lymph node samples from German patients. Immunohistochemistry with PAB antibody revealed small round bodies within sarcoid granulomas in 20/27 (74%) video-assisted thoracic surgery lung samples, 24/50 (48%) transbronchial lung biopsy samples, 71/81 (88%) Japanese lymph node samples, and 34/38 (89%) German lymph node samples. PAB antibody did not react with non-sarcoid granulomas in any of the 45 tuberculosis samples or the 34 samples with sarcoid reaction. In nongranulomatous areas, small round bodies detected by PAB antibody were found in alveolar macrophages of lungs and paracortical macrophages of lymph nodes from many sarcoid and some non-sarcoid patients. Large-spheroidal acid-fast bodies, Hamazaki-Wesenberg bodies, which were found in 50% of sarcoid and 15% of non-sarcoid lymph node samples, reacted with both PAB and TIG antibodies. Electron microscopy revealed that these Hamazaki-Wesenberg bodies had a single bacterial structure and lacked a cell wall with occasional protrusions from the body. The high frequency and specificity of P. acnes, detected by PAB antibody within sarcoid granulomas, indicates that this indigenous bacterium might be the cause of granuloma formation in many sarcoid patients.

Immunohistochemical Detection of Potential Microbial Antigens in Granulomas in the Diagnosis of Sarcoidosis.

Sarcoidosis may have more than a single causative agent, including infectious and non-infectious agents. Among the potential infectious causes of sarcoidosis, Mycobacterium tuberculosis and Propionibacterium acnes are the most likely microorganisms. Potential latent infection by both microorganisms complicates the findings of molecular and immunologic studies. Immune responses to potential infectious agents of sarcoidosis should be considered together with the microorganisms detected in sarcoid granulomas, because immunologic reactivities to infectious agents reflect current and past infection, including latent infection unrelated to the cause of the granuloma formation. Histopathologic data more readily support P. acnes as a cause of sarcoidosis compared with M. tuberculosis, suggesting that normally symbiotic P. acnes leads to granuloma formation in some predisposed individuals with Th1 hypersensitivity against intracellular proliferation of latent P. acnes, which may be triggered by certain host or drug-induced conditions. Detection of bacterial nucleic acids in granulomas does not necessarily indicate co-localization of the bacterial proteins in the granulomas. In the histopathologic diagnosis of sarcoidosis, M. tuberculosis-associated and P. acnes-associated sarcoidosis will possibly be differentiated in some patients by immunohistochemistry with appropriate antibodies that specifically react with mycobacterial and propionibacterial antigens, respectively, for each etiology-based diagnosis and potential antimicrobial intervention against sarcoidosis.

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.

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.

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.

Hypersensitivity pneumonitis.

Hypersensitivity pneumonitis (HP) is a complex syndrome caused by the inhalation of a variety of antigens in susceptible and sensitized individuals. These antigens are found in the environment, mostly derived from bird proteins and fungi. The prevalence and incidence of HP vary widely depending on the intensity of exposure, the geographical area and the local climate. Immunopathologically, HP is characterized by an exaggerated humoral and cellular immune response affecting the small airways and lung parenchyma. A complex interplay of genetic, host and environmental factors underlies the development and progression of HP. HP can be classified into acute, chronic non-fibrotic and chronic fibrotic forms. Acute HP results from intermittent, high-level exposure to the inducing antigen, usually within a few hours of exposure, whereas chronic HP mostly originates from long-term, low-level exposure (usually to birds or moulds in the home), is not easy to define in terms of time, and may occur within weeks, months or even years of exposure. Some patients with fibrotic HP may evolve to a progressive phenotype, even with complete exposure avoidance. Diagnosis is based on an accurate exposure history, clinical presentation, characteristic high-resolution CT findings, specific IgG antibodies to the offending antigen, bronchoalveolar lavage and pathological features. Complete antigen avoidance is the mainstay of treatment. The pharmacotherapy of chronic HP consists of immunosuppressive drugs such as corticosteroids, with antifibrotic therapy being a potential therapy for patients with progressive disease.

Baseline High-Resolution CT Findings Predict Acute Exacerbation of Idiopathic Pulmonary Fibrosis: German and Japanese Cohort Study.

Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is a major cause of morbidity and death in IPF. However, sensitive predictive factors of AE-IPF have not been well-investigated. To investigate whether high-resolution computed tomographic (HRCT) abnormalities predict AE-IPF in independent ethnic cohorts, this study included 121 patients with IPF (54 German and 67 Japanese; mean age, 68.5 ± 7.6 years). Two radiologists independently visually assessed the presence and extent of lung abnormalities in each patient. Twenty-two (18.2%) patients experienced AE-IPF during the follow-up. The incidence of AE-IPF was significantly higher in the Japanese patients (n = 18, 26.9%) than in the German patients (n = 4, 7.3%, p < 0.01). In the Kaplan-Meier analysis, patients with a larger extent of ground glass opacity (GGO), fibrosis, and traction bronchiectasis experienced an earlier onset of AE-IPF (p = 0.0033, 0.0088, and 0.049, respectively). In the multivariate analysis, a larger extent of GGO and fibrosis on HRCT were independent predictors of AE-IPF (p = 0.026 and 0.037, respectively). Additionally, Japanese ethnicity was independently associated with the incidence of AE-IPF after adjustment for HRCT findings (p = 0.0074). In conclusion, a larger extent of GGO and fibrosis on HRCT and Japanese ethnicity appear to be risk factors for AE-IPF.

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-F]-alpha-methyltyrosine, which is more specific for malignancy than F-fluorodeoxyglucose positron emission tomography. The combined modality of L-[3-F]-alpha-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 Löfgren's 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 Löfgren's syndrome. SUMMARY: Recent development including novel imaging techniques, novel biopsy procedures, and genetic analyses could be of value for the diagnosis of sarcoidosis.

Systemic evaluation of a potential cutaneous sarcoidosis patient.

The diagnosis of sarcoidosis cannot be established by the presence of granuloma in a single organ, such as the skin. Therefore, the patient with potential cutaneous sarcoidosis should undergo a systemic evaluation for two reasons: to help confirm the diagnosis, and to identify other potential problems. This article reviews the recommended testing in patients with suspected or known sarcoidosis. The evaluation leads to a wide number of organs being assessed by either history, physical examination or routine laboratory investigations. The major organs routinely assessed are the lungs, the eyes, the liver and the heart.

Differential diagnosis of granulomatous lung disease: clues and pitfalls: Number 4 in the Series "Pathology for the clinician" Edited by Peter Dorfmüller and Alberto Cavazza.

Granulomatous lung diseases are a heterogeneous group of disorders that have a wide spectrum of pathologies with variable clinical manifestations and outcomes. Precise clinical evaluation, laboratory testing, pulmonary function testing, radiological imaging including high-resolution computed tomography and often histopathological assessment contribute to make a confident diagnosis of granulomatous lung diseases. Differential diagnosis is challenging, and includes both infectious (mycobacteria and fungi) and noninfectious lung diseases (sarcoidosis, necrotising sarcoid granulomatosis, hypersensitivity pneumonitis, hot tub lung, berylliosis, granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis, rheumatoid nodules, talc granulomatosis, Langerhans cell histiocytosis and bronchocentric granulomatosis). Bronchoalveolar lavage, endobronchial ultrasound-guided transbronchial needle aspiration, transbronchial cryobiopsy, positron emission tomography and genetic evaluation are potential candidates to improve the diagnostic accuracy for granulomatous lung diseases. As granuloma alone is a nonspecific histopathological finding, the multidisciplinary approach is important for a confident diagnosis.

FAM13A polymorphism as a prognostic factor in patients with idiopathic pulmonary fibrosis.

BACKGROUND: Family with sequence similarity 13, member A (FAM13A) variants have been associated with susceptibility to chronic lung diseases. A recent genome-wide association study has shown an association between a polymorphism in FAM13A rs2609255 and idiopathic interstitial pneumonias in a Caucasian population. However, the relationship between rs2609255 polymorphism and prognosis in idiopathic interstitial pneumonias has not been investigated. METHODS: Sixty-five patients with idiopathic pulmonary fibrosis (IPF) and 310 Japanese healthy volunteers were enrolled in this study. Genomic DNA was extracted from all subjects. rs2609255 was genotyped by a commercially available assay. The correlations between rs2609255 polymorphism and survival and the occurrence of acute exacerbation were evaluated. RESULTS: The frequency of the minor G allele was significantly higher in IPF patients (59.2%) than in controls (41.9%; OR = 1.78, 95% CI; 1.29-2.44, p < 0.001). The rs2609255 major T allele was associated with lower diffusing capacity of carbon monoxide values and higher composite physiologic index after adjustment for age, sex and smoking (ß = -7.20, p = 0.005 and ß = 5.59, p = 0.009, respectively). In the Kaplan-Meier analysis, the T allele carriers showed a significantly increased mortality compared to the non-carriers (p < 0.05). In the multivariate Cox-proportional hazards analysis, the T allele of rs2609255 was independently associated with poor survival (hazard ratio, 5.37; p = 0.031; 95% confidence interval, 1.16-24.82). CONCLUSIONS: FAM13A gene polymorphism showed a significant association with the susceptibility to IPF, with severity of lung function impairment and with poor prognosis.

Surfactant protein A detection in large cell carcinoma of the lung.

Large cell carcinomas of the lung are undifferentiated malignant epithelial tumors that lack cytologic features of small cell carcinoma, glandular cell carcinoma, or squamous cell differentiation. Lung surfactant protein A (SP-A) is produced by alveolar type II cells and Clara cells. Most bronchioloalveolar carcinomas of the lung react positively for SP-A. Positive SP-A staining of large cell carcinoma of the lung could indicate that at least part of these tumors have the same cellular origin or differentiation as bronchioloalveolar carcinoma. The authors determined the SP-A staining of 63 large cell carcinomas of the lung by IHC. In 20 of the 63 (32%), the tumors stained positive for SP-A. This may imply that about one third of large cell carcinomas of the lung have a similar cellular origin or differentiation as bronchioloalveolar carcinoma. The significance of this finding for prognosis and new forms of treatment remains to be determined.

MUC1 gene polymorphisms are associated with serum KL-6 levels and pulmonary dysfunction in pulmonary alveolar proteinosis.

BACKGROUND: KL-6, a human MUC1 mucin, is a sensitive biomarker for interstitial lung diseases including pulmonary alveolar proteinosis (PAP). A correlation between MUC1 gene single nucleotide polymorphism (SNP) rs4072037 genotype and serum KL-6 levels has been reported. This study was aimed at investigating the correlation between MUC1 SNP genotype, severity of disease and disease outcome in PAP. METHODS: Twenty four patients with PAP and 30 healthy volunteers were studied. MUC1 rs4072037 was detected by using a real-time polymerase chain reaction (RT-PCR). Genotyping was performed by pyrosequencing. KL-6 levels were measured in serum by Nanopia KL-6 assay (SEKISUI Diagnostics). RESULTS: The frequency of MUC1 rs4072037 alleles was significantly different between PAP patients and healthy volunteers (PAP, A/A 46%, A/G 54%, G/G 0%; healthy controls, A/A 30%, A/G 40%, G/G 30%; p = 0.013). Serum KL-6 levels were significantly higher in PAP patients than in controls (p < 0.0001), and significantly higher in PAP patients with A/A genotype than in those with A/G genotype (p = 0.007). Patients with A/A genotype had higher alveolar-arterial oxygen difference (A-aDO2) and lower DLco compared to those with A/G genotype (p = 0.027 and p = 0.012, respectively). Multivariate analysis, Kaplan-Meier analysis and C statistics showed that the rs4072037 A/A genotype was associated with higher rate of disease progression (HR: 5.557, p = 0.014). CONCLUSIONS: MUC1 rs4072037 A/A genotype is associated with more severe pulmonary dysfunction and a higher rate of disease progression in PAP patients.

Production of soluble tumor necrosis factor receptors and tumor necrosis factor-alpha by alveolar macrophages in sarcoidosis and extrinsic allergic alveolitis.

BACKGROUND: Alveolar macrophage (AM)-derived tumor necrosis factor (TNF)-alpha plays a pivotal role in the pathogenesis of sarcoidosis and extrinsic allergic alveolitis (EAA). The effects of TNF-alpha are mediated by membrane TNF receptor (mTNFR)-1 and mTNFR-2, and can be blocked by soluble TNF receptor (sTNFR)-1 and sTNFR-2. METHODS: We measured the production of the two sTNFRs and TNF-alpha in AM culture supernatants from 10 patients with active sarcoidosis, 12 patients with EAA, and 9 control subjects using an enzyme-linked immunosorbent assay method. RESULTS: Compared with control subjects, the spontaneous and lipopolysaccharide (LPS)-stimulated production of sTNFR-1, sTNFR-2, and TNF-alpha was significantly increased in patients with sarcoidosis and EAA. The concentrations of both sTNFRs, but especially of sTNFR-2, were closely related to those of TNF-alpha. The LPS-induced increase was 1.5-fold for sTNFR-1, at least fourfold for sTNFR-2, and at least 25-fold for TNF-alpha in all study populations. CONCLUSION: These results indicate that AMs can release the two sTNFRs in relation to TNF-alpha. sTNFR-2 may be more liable to shedding than sTNFR-1. Both sTNFR-1 and sTNFR-2 may be involved in the pathogenesis of sarcoidosis and EAA, possibly as counterregulators of TNF-alpha.