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1.
Zhonghua Jie He He Hu Xi Za Zhi ; 43(4): 362-368, 2020 Apr 12.
Artigo em Chinês | MEDLINE | ID: mdl-32294819

RESUMO

Objective: To investigate the clinical features and prognosis of interstitial lung disease patients with positive anti-neutrophil cytoplasmic antibody. Methods: The patients with interstitial lung disease who visited Peking Union Medical College Hospital from March 2006 to March 2016 were divided into three groups: interstitial lung disease with ANCA-positive(ANCA-ILD), connective tissue disease associated interstitial lung disease and interstitial pneumonia with autoimmune features (CTD-ILD/IPAF) and idiopathic interstitial pneumonia (IIP). The three groups were analyzed in terms of clinical manifestations, serology, lung function, imaging, survival and recurrence. Results: Two hundred and seventy four patients were enrolled and 38 (14%) were ANCA-positive of whom 16 were male and 22 were female. The age of 38 ANCA-positive patients was (59±10) years and the follow-up time was (52±31) months. Seven among the 38 ANCA-positive patients died and the death rate is 18.42%. The ANCA-positive patients with interstitial lung disease have higher onset age (ANCA-ILD:59±10,CTD-ILD/IPAF:52±10,IIP:53±11,H=19.29, P<0.001), lower hemoglobin (ANCA-ILD: 129±21, CTD-ILD/IPAF: 138±15, IIP: 140±19, H=8.17, P=0.017), higher erythrocyte sedimentation rate (ANCA-ILD:45±35, CTD-ILD/IPAF:26±24,IIP:19±22,H=19.73, P<0.001), lower lung function improvement rate after treatment (ANCA-ILD:31%,CTD-ILD/IPAF:59%,IIP: 39%,χ(2)=11.74,P=0.003), lower absorption rate of CT lesion (ANCA-ILD:61%,CTD-ILD/IPAF:82%,IIP:67%, χ(2)=9.23,P=0.010) and higher death rate(ANCA-ILD:18%,CTD-ILD/IPAF:6%,IIP:12%, χ(2)=7.16,P=0.028). Conclusions: There are significant differences in clinical characteristics between ANCA-positive patients and other types of pulmonary interstitial disease. And both the treatment effect and the prognosis is poor for the ANCA-positive patients.


Assuntos
Anticorpos Anticitoplasma de Neutrófilos/sangue , Doenças do Tecido Conjuntivo/diagnóstico , Pneumonias Intersticiais Idiopáticas/diagnóstico , Doenças Pulmonares Intersticiais/diagnóstico , Biomarcadores/sangue , Doenças do Tecido Conjuntivo/sangue , Doenças do Tecido Conjuntivo/imunologia , Doenças do Tecido Conjuntivo/mortalidade , Feminino , Humanos , Pneumonias Intersticiais Idiopáticas/sangue , Pneumonias Intersticiais Idiopáticas/imunologia , Pneumonias Intersticiais Idiopáticas/mortalidade , Pulmão/diagnóstico por imagem , Doenças Pulmonares Intersticiais/sangue , Doenças Pulmonares Intersticiais/imunologia , Doenças Pulmonares Intersticiais/mortalidade , Masculino , Prognóstico , Tomografia Computadorizada por Raios X
2.
Respir Med ; 146: 23-27, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30665514

RESUMO

INTRODUCTION: Idiopathic interstitial pneumonias (IIP) are diffuse lung diseases whose cause is unknown and often present with features of autoimmunity despite not meeting criteria for a connective tissue disease (CTD). Recent studies suggest that anti-RNA binding protein (anti-RBP) antibodies, which include anti-SSA, anti-SSB, anti-Sm, and anti-RNP, play a role in the loss of immune tolerance and severity of pulmonary hypertension (PH) in CTDs. We hypothesized that anti-RBP positive (RBP+) subjects would have worse measures of lung function, radiographic findings, PH, and survival than anti-RBP negative (RBP-) subjects. METHODS: Subjects with both IIP and serologies for review were identified retrospectively and stratified based on anti-RBP antibody seropositivity. Baseline cohort characteristics, pulmonary function tests (PFT), ambulatory oxygen requirement, radiographic characteristics, markers of PH, and transplant-free survival were compared between anti-RBP positive and negative groups. RESULTS: Five hundred twenty patients with IIP were identified, of which ten percent (n = 53) were anti-RBP positive. RBP+ as compared to RBP- subjects had significantly worse PFTs as indicated by FEV1 (59.6 vs. 64.9, p = 0.046) and FVC (71.6 vs. 78.8, p = 0.018). There was a higher prevalence of radiographic honeycombing (49.1% vs. 38.3%, p = 0.006) and emphysema (22.6% vs. 5.1%, p < 0.001) in the RBP+ group despite no difference in smoking history. The Pulmonary Artery-Aorta ratio was also larger in the RBP+ group (0.93 vs. 0.88, p = 0.040). There was no difference in transplant-free survival between groups (log rank = 0.912). CONCLUSION: Anti-RBP+ IIP patients may have worse lung function, increased chest radiographic abnormalities, and PH compared with those without these antibodies.


Assuntos
Proteínas de Transporte/metabolismo , Pneumonias Intersticiais Idiopáticas/sangue , Pneumonias Intersticiais Idiopáticas/epidemiologia , Pneumonias Intersticiais Idiopáticas/fisiopatologia , Idoso , Anticorpos Antinucleares/imunologia , Autoimunidade/imunologia , Proteínas de Transporte/sangue , Doenças do Tecido Conjuntivo/epidemiologia , Feminino , Humanos , Hipertensão Pulmonar/fisiopatologia , Pneumonias Intersticiais Idiopáticas/diagnóstico por imagem , Pulmão/irrigação sanguínea , Pulmão/diagnóstico por imagem , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Prevalência , Radiografia Torácica/métodos , Testes de Função Respiratória/métodos , Estudos Retrospectivos , Tomografia Computadorizada por Raios X
3.
PLoS One ; 13(6): e0199659, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29928060

RESUMO

OBJECTIVE: Although a possible association among myeloperoxidase-anti-neutrophil cytoplasmic antibody (MPO-ANCA), microscopic polyangiitis (MPA), and idiopathic pulmonary fibrosis (IPF) has been suggested, the clinical significance of MPO-ANCA in idiopathic interstitial pneumonias (IIPs), including IPF and non-IPF, remains unclear. We aimed to investigate the frequency of MPO-ANCA positivity, as well as MPA incidence and risk factors for development in patients initially diagnosed with IIP. METHODS: We retrospectively analysed 305 consecutive patients who were initially diagnosed as IIP and had MPO-ANCA results available. RESULTS: Of the 305 patients, 26 (8.5%) were MPO-ANCA-positive. Baseline characteristics were similar between the MPO-ANCA-positive and -negative patients. The cumulative 5-year MPA incidence was 24.3% in the MPO-ANCA-positive patients and 0% in the -negative patients (P < 0.0001). MPO-ANCA was positive in 15 of 133 (11.3%) patients initially diagnosed with IPF and in 11 of 172 (6.3%) patients initially diagnosed with non-IPF (P = 0.56), with cumulative 5-year MPA incidence of 6.2% and 1.0%, respectively (P = 0.10). Multivariate analysis revealed that UIP pattern on HRCT (HR = 3.20, P < 0.01) and no treatment for IIP (HR = 3.52, P < 0.01) were independently associated with MPA development in MPO-ANCA-positive patients. CONCLUSION: MPO-ANCA positivity was uncommon, but was associated with subsequent MPA development in patients initially diagnosed with IIP, including both IPF and non-IPF cases. The study suggested that attention should be paid to MPA development in MPO-ANCA-positive IIP patients with UIP pattern on HRCT and those without treatment for IIP.


Assuntos
Anticorpos Anticitoplasma de Neutrófilos/sangue , Pneumonias Intersticiais Idiopáticas/sangue , Poliangiite Microscópica/sangue , Peroxidase/sangue , Idoso , Progressão da Doença , Feminino , Seguimentos , Humanos , Pneumonias Intersticiais Idiopáticas/complicações , Pneumonias Intersticiais Idiopáticas/epidemiologia , Incidência , Masculino , Poliangiite Microscópica/complicações , Poliangiite Microscópica/epidemiologia , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco
4.
Respir Res ; 19(1): 82, 2018 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-29728109

RESUMO

BACKGROUND: Idiopathic interstitial pneumonia (IIP) is characterized by an increased rate of extracellular matrix (ECM) remodeling resulting in fibrosis. Acute exacerbations of IIP represent periods of increased disease activity, thus we hypothesized that ECM remodeling was altered during acute exacerbations and investigated this by serological neo-epitope biomarkers. METHODS: Patients who were sequentially admitted to the hospital with acute exacerbations of IIP were retrospectively analyzed for ECM remodeling at time of exacerbation (AE-IIP) and at clinical stability (S-IIP). Biomarkers released by matrix metalloproteinase-mediated degradation of collagen type I (C1M), III (C3M), IV (C4M), and VI (C6M), elastin (ELM7), versican (VCANM), biglycan (BGM), and C-reactive protein (CRPM) were assessed in serum by competitive ELISAs utilizing neo-epitope specific monoclonal antibodies. RESULTS: Sixty-eight patients at AE-IIP and 29 at S-IIP were included in this retrospective analysis. Of these, 28 and 11 patients, respectively, had idiopathic pulmonary fibrosis. At AE-IIP, serum levels of C4M (p = 0.002) and C6M (p = 0.024) were increased as compared with S-IIP, while ELM7 (p = 0.024) and VCANM (p < 0.0001) were decreased. Lower VCANM levels at AE-IIP were associated with increased risk of mortality (HR 0.64 [95% CI 0.43-0.94], p = 0.022). CONCLUSIONS: The ECM remodeling profile was significantly altered during acute exacerbations of IIP, and a biomarker of versican degradation was related to mortality outcome. These results indicate that biomarkers of ECM remodeling may be useful in the non-invasive evaluation of acute exacerbations of IIP. Especially versican degradation, as measured serologically by VCANM, may have prognostic potential and help guide treatment for acute exacerbations.


Assuntos
Pneumonias Intersticiais Idiopáticas/sangue , Pneumonias Intersticiais Idiopáticas/mortalidade , Versicanas/sangue , Idoso , Biomarcadores/sangue , Matriz Extracelular/metabolismo , Feminino , Humanos , Pneumonias Intersticiais Idiopáticas/diagnóstico , Masculino , Pessoa de Meia-Idade , Mortalidade/tendências , Estudos Retrospectivos
5.
PLoS One ; 13(5): e0196558, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29795561

RESUMO

BACKGROUND AND OBJECTIVE: High-mobility group box 1 (HMGB1) protein is important in acute lung injury. However, the role of HMGB-1 in acute exacerbation of fibrosing interstitial pneumonia (AE-FIP) has not been adequately studied. METHODS: We prospectively measured serum HMGB1 level from disease onset to day 7 in 36 patients with AE-FIP6 patients had missing data because of early death (within 7 days). We then examined the association of HMGB1 level and outcome, and the associations of rhTM with HMGB1 level and outcome in 19 patients who were treated with rhTM (rhTM group) and 11 patients who were not (control group). RESULTS: Data from 36 AE-FIP patients (mean age, 73.5±6.7years) were analyzed. Serum HMGB1 level was significantly higher in patients with AE-FIP than in those with stable idiopathic pulmonary fibrosis (16.4±13.5 vs 5.7±2.6 ng/ml, respectively; p = 0.003). HMGB1 was significantly lower on day 7 than at AE-FIP onset in survivors (6.5±4.8 vs 14.7±12.9 ng/ml, respectively; p = 0.02) but not in nonsurvivors (14.6±10.5 vs 9.2±4.8 ng/ml, respectively; p = 0.08). Although HMGB1 level at day 7 was significantly lower after rhTM treatment than at AE-FIP onset (8.4±6.1 vs 15.2±12.5 ng/ml, respectively; p = 0.02), it did not significantly decrease in patients receiving treatments other than rhTM (11.3±11.3 vs 8.3±5.3 ng/ml, respectively; p = 0.37). Three-month survival was 60.0% in the rhTM group and 36.4% in the control group (p = 0.449). In multivariate analysis, a decrease in HMGB1 was a significant independent predictor of 3-month survival (Odds ratio, 12.4; p = 0.007). CONCLUSION: rhTM lowers serum HMGB1 level and may improve survival after AE-FIP. HMGB1 may be a promising therapeutic target for AE-FIP.


Assuntos
Proteína HMGB1/sangue , Pneumonias Intersticiais Idiopáticas/sangue , Fibrose Pulmonar Idiopática/sangue , Idoso , Idoso de 80 Anos ou mais , Progressão da Doença , Feminino , Proteína HMGB1/antagonistas & inibidores , Humanos , Pneumonias Intersticiais Idiopáticas/tratamento farmacológico , Fibrose Pulmonar Idiopática/tratamento farmacológico , Estimativa de Kaplan-Meier , Masculino , Análise Multivariada , Prognóstico , Estudos Prospectivos , Proteínas Recombinantes/uso terapêutico , Valores de Referência , Trombomodulina/uso terapêutico , Resultado do Tratamento
6.
Clin Rheumatol ; 37(8): 2125-2132, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29667101

RESUMO

To investigate the clinical features, risk factors and outcomes of patients with interstitial pneumonia with autoimmune features (IPAF). A total of 1429 patients with idiopathic interstitial pneumonia (IIP) and undifferentiated connective tissue disease-associated interstitial lung disease (UCTD-ILD) were screened to identify patients who met IPAF criteria. Clinical, serological, and morphological features of patients with IPAF were characterized. Outcomes between patients with IPAF, UCTD-ILD, and IIP who were divided into idiopathic pulmonary fibrosis (IPF) and non-IPF groups were compared using survival as an endpoint. Patients with IPAF were much common in young female and had lower percentage of ever smoking and a significantly shorter survival than those with non-IPAF (P < 0.001). Subgroup analysis revealed that IPAF cohort survival was worse than that in non-IPF (P < 0.001), but better than that in IPF (P < 0.001). In IPAF cohort, the most common systemic symptom and serological abnormality were Raynaud's phenomenon (12.9%) and ANA ≥ 1:320 (49.2%); the most frequent high-resolution computed tomography (HRCT) pattern was nonspecific interstitial pneumonia (NSIP) (61.6%). Multivariate analysis indicated that several factors including age, smoking history, organizing pneumonia (OP) pattern in HRCT, and anti-RNP positivity were independently associated with significantly worse survival. IPAF had the distinct clinical features and outcomes compared with other groups of ILD. Additional studies should be needed to explore the underlying autoimmune mechanism and to determine risk stratification in future clinical research.


Assuntos
Doenças Autoimunes , Doenças Pulmonares Intersticiais , Corticosteroides/uso terapêutico , Fatores Etários , Idoso , Doenças Autoimunes/sangue , Doenças Autoimunes/complicações , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/patologia , Doenças do Tecido Conjuntivo/patologia , Feminino , Humanos , Pneumonias Intersticiais Idiopáticas/sangue , Pneumonias Intersticiais Idiopáticas/complicações , Pneumonias Intersticiais Idiopáticas/tratamento farmacológico , Pneumonias Intersticiais Idiopáticas/patologia , Imunossupressores/uso terapêutico , Doenças Pulmonares Intersticiais/sangue , Doenças Pulmonares Intersticiais/complicações , Doenças Pulmonares Intersticiais/tratamento farmacológico , Doenças Pulmonares Intersticiais/patologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Fatores Sexuais , Fumar/epidemiologia , Tomografia Computadorizada por Raios X , Resultado do Tratamento
7.
PLoS One ; 12(5): e0176789, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28467516

RESUMO

BACKGROUND: Patients with idiopathic interstitial pneumonia can experience acute respiratory worsening, also known as acute exacerbation, with a large deterioration on prognosis. The precise mechanism remains unclear; however, syndecan-4 may be involved. Syndecan-4, a transmembrane heparan sulfate proteoglycan expressed in a variety of cells (e.g., epithelial cells, macrophages, fibroblasts, etc.), performs various biological roles by binding to several proteins through its heparan sulfate glycosaminoglycan side chains. The goal of this study was to clarify the role of syndecan-4 in acute exacerbation of idiopathic interstitial pneumonia. METHODS: Patients with idiopathic interstitial pneumonia who had been sequentially admitted to our hospital due to acute exacerbation were retrospectively analyzed. First, serum syndecan-4 levels in the acute exacerbation and clinically stable phases were compared. Second, the relationship between serum syndecan-4 levels and clinical parameters was analyzed. Third, the relationship between serum syndecan-4 levels and prognosis was evaluated. RESULTS: Serum syndecan-4 levels were significantly lower in patients with acute exacerbation of idiopathic interstitial pneumonia than in patients in the clinically stable phase. Serum syndecan-4 levels also showed a significant positive correlation with white blood cell count and a weak positive tendency with KL-6 and baseline %VC. Prognosis was significantly worse in patients with idiopathic interstitial pneumonia with high baseline serum syndecan-4 levels than with low baseline levels. Multiple logistic analysis indicated baseline serum syndecan-4 level as the only prognostic predictor following acute exacerbation. CONCLUSIONS: Baseline serum syndecan-4 is a possible prognostic biomarker after the onset of acute exacerbation of idiopathic interstitial pneumonia.


Assuntos
Pneumonias Intersticiais Idiopáticas/diagnóstico , Sindecana-4/sangue , Doença Aguda , Adulto , Idoso , Biomarcadores/sangue , Estudos de Casos e Controles , Feminino , Humanos , Pneumonias Intersticiais Idiopáticas/sangue , Pneumonias Intersticiais Idiopáticas/patologia , Masculino , Prognóstico , Estudos Retrospectivos
8.
J Med Invest ; 64(1.2): 110-116, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28373606

RESUMO

OBJECTIVE: Idiopathic interstitial pneumonias (IIPs) are a group of heterogeneous diffuse parenchymal lung disorders of unknown etiology. An acute exacerbation (AE) is an acute respiratory deterioration that occurs in IIPs. The prognosis of AE of IIPs (AE-IIPs) is extremely severe; however, no established therapies exist. We aimed to evaluate the efficacy of leukocytapheresis (LCAP) to treat patients with AE-IIPs. PATIENTS AND METHODS: Six chronic IIPs patients who developed AE were enrolled in this study. We performed LCAP on days 2, 3, 9 and 10 in all six patients. All patients were also treated with high-dose corticosteroids and a continuous administration of low-molecular-weight heparin. We observed 30-day survival after the diagnosis of AE to evaluate the efficacy of LCAP. We also assessed oxygenation, high-resolution computed tomography (HRCT) findings, and certain chemical mediators in the peripheral blood. RESULTS: Five of six patients survived more than 30 days. One patient died of progressive respiratory failure. Oxygenation and HRCT findings tended to improve in all survivors. The serum levels of lactate dehydrogenase, high mobility group box-1, and interleukin-18 were significantly decreased statistically post-LCAP. No severe adverse events occurred. CONCLUSION: We suggest that LCAP is a safe and effective therapy for treating patients with AE-IIPs. J. Med. Invest. 64: 110-116, February, 2017.


Assuntos
Pneumonias Intersticiais Idiopáticas/terapia , Leucaférese , Doença Aguda , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Pneumonias Intersticiais Idiopáticas/sangue , Pneumonias Intersticiais Idiopáticas/diagnóstico por imagem , Fibrose Pulmonar Idiopática/terapia , Mediadores da Inflamação/sangue , Masculino , Projetos Piloto
9.
Sci Rep ; 6: 38949, 2016 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-27958346

RESUMO

The term "interstitial pneumonia with autoimmune features" (IPAF) has been recently proposed. We here investigate the clinical characteristics of IPAF and evaluate the clinical implications of CXCL1-CXCR2 axis in IPAF. An increased plasma level of CXCL1 was exhibited in IPAF compared to idiopathic interstitial pneumonia (IIP), chronic obstructive pulmonary disease (COPD), and healthy controls. Additionally, plasma CXCL1 levels were clinically associated with diffusing capacity of the lungs for carbon monoxide (DLCO), erythrocyte sedimentation rate (ESR), and involved parenchyma extension in IPAF. Furthermore, circulating CXCL1 levels were highest in IPAF patients with acute exacerbations. CXCR2, the chemokine receptor for CXCL1, was readily observed in inflammatory aggregates and endothelial cells in IPAF lungs, but was lower in IIP lungs and healthy lungs. Interestingly, increased CXCL1 concentrations in BALF paralleled neutrophil counts in IPAF. Overall, the plasma concentrations of CXCL1 indicated the disease activity and prognosis in IPAF. Thus, the CXCL1/CXCR2 axis appears to be involved in the progression of IPAF.


Assuntos
Doenças Autoimunes/sangue , Quimiocina CXCL1/sangue , Pneumonias Intersticiais Idiopáticas/sangue , Idoso , Sedimentação Sanguínea , Monóxido de Carbono/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/sangue , Receptores de Interleucina-8B/sangue
10.
Respir Med ; 117: 27-32, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27492510

RESUMO

BACKGROUND AND OBJECTIVE: We hypothesized that increased pulmonary vascular permeability may play a role in the pathogenesis of an acute exacerbation of the idiopathic interstitial pneumonias (AE-IIPs). Angiopoietin-2 (Ang-2) promotes endothelial activation, destabilization, and inflammation. The purpose of this study was to examine whether Ang-2 expression was associated with the pathogenesis of AE-IIPs. METHODS: Twenty-three patients with AE-IIP patients, 18 acute lung injury/acute respiratory distress syndrome (ALI/ARDS) patients, 37 idiopathic pulmonary fibrosis (IPF) patients, and 33 healthy volunteers (HVs) were enrolled. The serum level of Ang-2 was measured by an enzyme-linked immunosorbent assay. RESULTS: The serum levels of Ang-2 were higher in AE-IIPs and ALI/ARDS patients than in IPF patients and HVs; the BALF levels of Ang-2 were also higher than in IPF patients. There was a positive correlation between the serum level of Ang-2 and the CRP in patients with AE-IIP patients, whereas a significant positive correlation was found between the serum Ang-2 level and the CRP or SOFA scores of the ALI/ARDS patients. Although the baseline Ang-2 level was not related to survival, the Ang-2 levels significantly declined in survivors during treatment, while they did not change in non-survivors. CONCLUSIONS: Increased pulmonary vascular permeability and inflammation due to Ang-2 may play a role in the pathogenesis of AE-IIPs.


Assuntos
Lesão Pulmonar Aguda/sangue , Angiopoietina-2/sangue , Pneumonias Intersticiais Idiopáticas/sangue , Pulmão/metabolismo , Síndrome do Desconforto Respiratório do Adulto/sangue , Lesão Pulmonar Aguda/fisiopatologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Permeabilidade Capilar/genética , Progressão da Doença , Feminino , Humanos , Pneumonias Intersticiais Idiopáticas/diagnóstico por imagem , Pneumonias Intersticiais Idiopáticas/fisiopatologia , Fibrose Pulmonar Idiopática/diagnóstico por imagem , Fibrose Pulmonar Idiopática/patologia , Inflamação/metabolismo , Pulmão/irrigação sanguínea , Pulmão/patologia , Masculino , Pessoa de Meia-Idade , Síndrome do Desconforto Respiratório do Adulto/fisiopatologia , Estudos Retrospectivos , Análise de Sobrevida , Tomógrafos Computadorizados
11.
Am J Respir Crit Care Med ; 194(10): 1242-1251, 2016 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-27149370

RESUMO

RATIONALE: Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal interstitial lung disease (ILD) characterized by abnormal extracellular matrix (ECM) remodeling. We hypothesized that ECM remodeling might result in a plasma profile of proteins specific for IPF that could distinguish patients with IPF from other idiopathic ILDs. OBJECTIVES: To identify biomarkers that might assist in distinguishing IPF from non-IPF ILD. METHODS: We developed a panel of 35 ECM, ECM-related, and lung-specific analytes measured in plasma from 86 patients with IPF (derivation cohort) and in 63 patients with IPF (validation cohort). Comparison groups included patients with rheumatoid arthritis-associated ILD (RA-ILD; n = 33), patients with alternative idiopathic ILDs (a-ILD; n = 41), and healthy control subjects (n = 127). Univariable and multivariable logistic regression models identified biomarkers that differentiated patients with IPF from those with a-ILD. Both continuous and diagnostic threshold versions of biomarkers were considered; thresholds were chosen to maximize summed diagnostic sensitivity and specificity in univariate receiver-operating characteristic curve analysis. A diagnostic score was created from the most promising analytes. MEASUREMENTS AND MAIN RESULTS: Plasma surfactant protein (SP)-D > 31 ng/ml, matrix metalloproteinase (MMP)-7 > 1.75 ng/ml, and osteopontin > 6 ng/ml each significantly distinguished patients with IPF from patients with a-ILD, both individually and in a combined index. The odds ratio for IPF when at least one analyte in the index exceeded the threshold was 4.4 (95% confidence interval, 2.0-9.7; P = 0.0003). When at least two analytes were elevated, the odds ratio for IPF increased to 5.0 (95% confidence interval, 2.2-11.5; P = 0.0002). CONCLUSIONS: A biomarker index of SP-D, MMP-7, and osteopontin enhanced diagnostic accuracy in patients with IPF compared with those with non-IPF ILD. Our data suggest that this biomarker index may improve diagnostic confidence in IPF.


Assuntos
Fibrose Pulmonar Idiopática/sangue , Metaloproteinase 7 da Matriz/sangue , Osteopontina/sangue , Proteína D Associada a Surfactante Pulmonar/sangue , Biomarcadores/sangue , Estudos de Coortes , Diagnóstico Diferencial , Feminino , Humanos , Pneumonias Intersticiais Idiopáticas/sangue , Masculino , Pessoa de Meia-Idade , Curva ROC , Sensibilidade e Especificidade
12.
PLoS One ; 11(4): e0154285, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27115353

RESUMO

OBJECTIVE: Autoantibodies to melanoma differentiation-associated gene 5 (MDA5) are specifically expressed in patients with dermatomyositis (DM) and are associated with a subset of DM patients with rapidly progressive interstitial lung disease (RP-ILD). Here, we examined the clinical utility of a newly developed enzyme-linked immunosorbent assay (ELISA) system for detecting these antibodies. METHODS: Here we developed an improved ELISA for detecting anti-MDA5 antibodies. We then performed a multicenter clinical study involving 8 medical centers and enrolled 242 adult patients with polymyositis (PM)/DM, 190 with non-PM/DM connective tissue disease (CTD), 154 with idiopathic interstitial pneumonia (IIP), and 123 healthy controls. Anti-MDA5 antibodies in the patients' serum samples were quantified using our newly developed ELISA, and the results were compared to those obtained using the gold-standard immunoprecipitation (IP) assay. In addition, correlations between the ELISA-quantified anti-MDA5 antibodies and clinical characteristics were evaluated. RESULTS: In patients with PM/DM, the anti-MDA5 antibody measurements obtained from the ELISA and IP assay were highly concordant; the ELISA exhibited an analytical sensitivity of 98.2%, specificity of 100%, positive predictive value of 100%, and negative predictive value of 99.5% (compared to the IP assay). Anti-MDA5 antibodies were detected in 22.7% of the DM patients, but not in any of the patients with PM, non-PM/DM CTD, or IIP. Clinically amyopathic DM, RP-ILD, arthritis, and fever were more prevalent in DM patients who were anti-MDA5 antibody-positive than in those who were antibody-negative (P ≤ 0.0002 for all comparisons). In addition, anti-MDA5 antibody-positive patients with RP-ILD exhibited higher antibody levels than those without RP-ILD (P = 0.006). CONCLUSION: Our newly developed ELISA can detect anti-MDA5 antibodies as efficiently as the gold standard IP assay and has the potential to facilitate the routine clinical measurement of anti-MDA5 antibodies in patients who suspected to have DM.


Assuntos
Autoanticorpos/sangue , Doenças do Tecido Conjuntivo/diagnóstico , Dermatomiosite/diagnóstico , Ensaio de Imunoadsorção Enzimática/normas , Pneumonias Intersticiais Idiopáticas/diagnóstico , Helicase IFIH1 Induzida por Interferon/imunologia , Polimiosite/diagnóstico , Adulto , Idoso , Estudos de Casos e Controles , Doenças do Tecido Conjuntivo/sangue , Doenças do Tecido Conjuntivo/imunologia , Dermatomiosite/sangue , Dermatomiosite/imunologia , Diagnóstico Diferencial , Feminino , Expressão Gênica , Humanos , Pneumonias Intersticiais Idiopáticas/sangue , Pneumonias Intersticiais Idiopáticas/imunologia , Imunoprecipitação , Helicase IFIH1 Induzida por Interferon/antagonistas & inibidores , Helicase IFIH1 Induzida por Interferon/genética , Masculino , Pessoa de Meia-Idade , Polimiosite/sangue , Polimiosite/imunologia , Sensibilidade e Especificidade
13.
J Rheumatol ; 43(5): 887-92, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26932342

RESUMO

INTRODUCTION: Interstitial lung disease (ILD) is 1 possible manifestation of the idiopathic inflammatory myopathies (IIM). Occasionally, patients presenting with ILD are mistakenly diagnosed with idiopathic interstitial pneumonia (IIP), but after multidisciplinary evaluation, their ILD is determined to be because of antisynthetase syndrome (SynS) or myositis spectrum of disease. METHODS: We used retrospective analytic methods to identify patients with ILD evaluated at the National Jewish Health between February 2008 and August 2014 and believed initially to have IIP but ultimately diagnosed with SynS or myositis spectrum of disease. RESULTS: The cohort included 33 patients; most were white women with a mean age at presentation of 55 years. Their pulmonary physiologic impairment was moderate. In 31 cases, the ILD pattern by thoracic high-resolution computed tomography scan was nonspecific interstitial pneumonia (NSIP), organizing pneumonia (OP), or a combination of the 2. Surgical lung biopsy was performed in 21 patients; NSIP was the most common pattern. Less than one-third of the cohort had positive antinuclear antibodies. Two-thirds had positive SSA. All patients had either myositis-specific or myositis-associated autoantibody. Most had subtle extrathoracic symptoms or signs of SynS; 12 had an elevated serum creatine phosphokinase, but none had clinical evidence of myositis. None met the Peter and Bohan classification criteria for polymyositis/dermatomyositis. CONCLUSION: Among patients who present with presumed IIP, a multidisciplinary evaluation that includes the integration of clinical evaluations by rheumatologists and pulmonologists, morphologic (both histopathologic and radiographic) data, and serologic features is helpful in the detection of occult SynS or the myositis spectrum of disease.


Assuntos
Pneumonias Intersticiais Idiopáticas/diagnóstico , Pulmão/diagnóstico por imagem , Miosite/diagnóstico , Adulto , Idoso , Anticorpos Antinucleares/análise , Biópsia , Creatina Quinase/sangue , Diagnóstico Diferencial , Feminino , Humanos , Pneumonias Intersticiais Idiopáticas/sangue , Pneumonias Intersticiais Idiopáticas/etiologia , Pneumonias Intersticiais Idiopáticas/patologia , Pulmão/patologia , Masculino , Pessoa de Meia-Idade , Miosite/sangue , Miosite/complicações , Miosite/patologia , Exame Físico , Estudos Retrospectivos , Tomografia Computadorizada por Raios X
14.
Lung ; 194(2): 235-42, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26873743

RESUMO

PURPOSE: The clinical significance of proteinase-3-antineutrophil cytoplasmic antibody (PR3-ANCA) positivity is not well established in idiopathic interstitial pneumonia (IIP) patients. We aimed to determine the clinical features of PR3-ANCA-positive IIP patients. METHODS: We retrospectively reviewed 377 consecutive IIP patients; of these, 360 patients had PR3-ANCA and myeloperoxidase-antineutrophil cytoplasmic antibody test results available. The clinical features of PR3-ANCA-positive IIP patients and control ANCA-negative idiopathic pulmonary fibrosis patients (ANCA-negative IPF) were compared. RESULTS: Sixteen patients (4.4 %) were PR3-ANCA-positive IIP and 94 (26 %) were ANCA-negative IPF. The median age at diagnosis (72 vs. 70 years, P = 0.17) and proportion of males (75 vs. 89 %, P = 0.12) in PR3-ANCA-positive IIP and ANCA-negative IPF patients, respectively, were not significantly different. Radiologically, the HRCT patterns of PR3-ANCA-positive IIP patients varied (UIP, n = 3, 18.8 %; possible UIP, n = 3, 18.8 %; NSIP, n = 5, 31.3 %; unclassifiable CT pattern, n = 5, 31.3 %) more than those of ANCA-negative IPF patients (UIP, n = 69, 73.4 %; possible UIP, n = 25, 26.6 %; P < 0.001). No PR3-ANCA-positive IIP patients developed ANCA-associated vasculitis. The 5-year survival rate was 50 % in PR3-ANCA-positive IIP patients and 52 % in ANCA-negative IPF patients with no significant difference (P = 0.96 by log-rank test). CONCLUSIONS: The HRCT patterns of PR3-ANCA-positive IIP patients varied more than those of the IPF patients, but the clinical features of high IIP-onset age and male predominance were similar between the groups. Furthermore, PR3-ANCA-positive IIP patients had a poor prognosis similar to that of IPF patients.


Assuntos
Anticorpos Anticitoplasma de Neutrófilos/sangue , Pneumonias Intersticiais Idiopáticas/sangue , Mieloblastina/imunologia , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Biópsia , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Pneumonias Intersticiais Idiopáticas/diagnóstico , Pneumonias Intersticiais Idiopáticas/imunologia , Pneumonias Intersticiais Idiopáticas/mortalidade , Estimativa de Kaplan-Meier , Pulmão/diagnóstico por imagem , Pulmão/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Fatores de Tempo , Tomografia Computadorizada por Raios X
15.
Sarcoidosis Vasc Diffuse Lung Dis ; 33(4): 308-316, 2016 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-28079842

RESUMO

BACKGROUND: Hemorheological properties are important determinants of tissue oxygenation. Although hemorheological alterations in various lung diseases have been well-defined, no information is available about the effects of idiopathic interstitial pneumonia (IIP) on hemorheological parameters. OBJECTIVES: The aim of this study was to investigate hemorheological parameters (erythrocyte deformability, aggregation, and plasma viscosity -PV) and associated oxidative stress indices in patients with IIP. METHODS: The study enrolled 31 patients (9 Idiopathic pulmonary fibrosis (IPF), 10 non-specific Interstitial Pneumonia (NSIP), 12 Cryptogenic Organising Pneumonia (COP) and 33 healthy controls. Erythrocyte deformability and aggregation were measured by an ektacytometer. PV was determined by a cone-plate rotational viscometer and oxidative stress via a commercial kit. RESULTS: Erythrocyte aggregation, total oxidant status (TOS) and oxidative stress index (OSI) of IIP patients were higher than controls whereas erythrocyte deformability, PV and total antioxidant status (TAS) were unaltered. CONCLUSIONS: Increment of oxidative stress in IIP seems to depend on enhancement of oxidants, rather than alteration of antioxidants. The issue that, elevated erythrocyte aggregation may further impair tissue oxygenation by disturbing microcirculation in IIP, may be considered in the follow up and development of new treatment protocols for this disease.


Assuntos
Agregação Eritrocítica , Eritrócitos/metabolismo , Pneumonias Intersticiais Idiopáticas/sangue , Estresse Oxidativo , Idoso , Antioxidantes/análise , Biomarcadores/sangue , Viscosidade Sanguínea , Estudos de Casos e Controles , Pneumonia em Organização Criptogênica/sangue , Pneumonia em Organização Criptogênica/diagnóstico , Deformação Eritrocítica , Feminino , Humanos , Pneumonias Intersticiais Idiopáticas/diagnóstico , Fibrose Pulmonar Idiopática/sangue , Fibrose Pulmonar Idiopática/diagnóstico , Masculino , Pessoa de Meia-Idade
16.
Lung ; 192(6): 975-80, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25274153

RESUMO

INTRODUCTION: YKL-40 is a novel biomarker in diseases with inflammation, fibrosis and tissue remodelling. Previously, circulating YKL-40 was shown to be elevated in patients with idiopathic pulmonary fibrosis (IPF) and was associated with survival. OBJECTIVE: To compare YKL-40 serum levels between IPF and other interstitial pneumonias such as non-specific interstitial pneumonia (NSIP), smoking-related interstitial lung disease (SR-ILD) and cryptogenic organising pneumonia (COP). MATERIALS AND METHODS: Serum YKL-40 levels were measured in 124 healthy controls and 315 patients. Serial measurements were available in 36 patients with IPF and 6 patients with COP. RESULTS: Serum YKL-40 levels were elevated in all patient groups compared to controls (p < 0.0001), and highest levels were found in the most fibrotic diseases, which showed worst prognosis. CONCLUSION: YKL-40 is highly elevated in fibrotic interstitial pneumonias and may reflect the degree of activity of the fibrogenic process. Remarkably, levels remain high in IPF, but can decrease in other interstitial pneumonias, which appears to be related to a better prognosis.


Assuntos
Adipocinas/sangue , Pneumonias Intersticiais Idiopáticas/sangue , Pneumonias Intersticiais Idiopáticas/diagnóstico , Lectinas/sangue , Adulto , Idoso , Análise de Variância , Biomarcadores/sangue , Líquido da Lavagem Broncoalveolar , Estudos de Casos e Controles , Proteína 1 Semelhante à Quitinase-3 , Pneumonia em Organização Criptogênica/sangue , Pneumonia em Organização Criptogênica/diagnóstico , Diagnóstico Diferencial , Feminino , Humanos , Fibrose Pulmonar Idiopática/sangue , Fibrose Pulmonar Idiopática/diagnóstico , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Países Baixos , Valores de Referência , Estudos Retrospectivos
17.
Lung ; 192(5): 711-7, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24880792

RESUMO

PURPOSE: Idiopathic pleuroparenchymal fibroelastosis (IPPFE) is a recently reported rare disease entity characterized by fibrotic thickening of the pleural and subpleural parenchyma predominantly in the upper lobes in idiopathic interstitial pneumonias (IIPs). Because the clinical features of this rare disease are not fully elucidated, we examined the clinical characteristics of IPPFE, especially for serum interstitial biomarkers, surfactant protein-D (SP-D), and Krebs von den Lungen-6 (KL-6). METHODS AND RESULTS: Four consecutive cases of IPPFE who fulfilled the diagnostic criteria were studied. All cases were more than 60 years of age, and were classified as underweight by body mass index. A severe restrictive ventilatory defect was found in all cases on admission. High-resolution computed tomography showed intense pleural thickening associated with fibrosis predominant in upper lobes. Histopathological findings were also confirmed in three out of four cases. Interestingly, the serum level of SP-D was markedly elevated in all cases, while KL-6 was within normal range in three out of four cases. As compared with major IIPs such as idiopathic pulmonary fibrosis and fibrotic nonspecific interstitial pneumonia, IPPFE significantly showed higher frequency of cases with a unique pattern of serum biomarkers, which is characterized by an elevated level of SP-D with a normal range of KL-6. CONCLUSIONS: In IPPFE, SP-D might tend to be elevated, while KL-6 was within a normal range. Further study is required to determine the pathogenesis and clinical significance of the elevated SP-D in IPPFE.


Assuntos
Pneumonias Intersticiais Idiopáticas/sangue , Mucina-1/sangue , Doenças Pleurais/sangue , Proteína D Associada a Surfactante Pulmonar/sangue , Idoso , Autopsia , Biomarcadores/sangue , Biópsia , Evolução Fatal , Humanos , Pneumonias Intersticiais Idiopáticas/diagnóstico , Pneumonias Intersticiais Idiopáticas/fisiopatologia , Pneumonias Intersticiais Idiopáticas/terapia , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Doenças Pleurais/diagnóstico , Doenças Pleurais/fisiopatologia , Doenças Pleurais/terapia , Ventilação Pulmonar , Estudos Retrospectivos , Espirometria , Fatores de Tempo , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Regulação para Cima
18.
BMC Pulm Med ; 14: 48, 2014 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-24650086

RESUMO

BACKGROUND: Heat shock protein (HSP) 47, a collagen-specific molecular chaperone, is involved in the processing and/or secretion of procollagen. We hypothesized that HSP47 could be a useful marker for fibrotic lung disease. The aim of this study was to evaluate serum levels of HSP47 in patients with various idiopathic interstitial pneumonias (IIPs). METHODS: Subjects comprised 9 patients with acute interstitial pneumonia (AIP), 12 with cryptogenic organizing pneumonia (COP), 16 with nonspecific interstitial pneumonia (NSIP), 19 with idiopathic pulmonary fibrosis (IPF), and 19 healthy adult volunteers. RESULTS: Patients with AIP had serum HSP47 levels that were significantly higher than those of COP, NSIP or IPF patients and those of healthy volunteers. In contrast, serum levels of HSP47 among patients with COP, NSIP, IPF, and healthy volunteers did not differ significantly. Receiver operating characteristic curves revealed that the cut-off level for HSP47 that resulted in the highest diagnostic accuracy for discriminating between AIP and COP, NSIP, IPF, and healthy controls was 859.3 pg/mL. The sensitivity, specificity, and diagnostic accuracy were 100.0%, 98.5%, and 98.7%, respectively. CONCLUSION: The present results demonstrate that, among patients with various IIPs, serum levels of HSP47 were elevated specifically in patients with AIP.


Assuntos
Proteínas de Choque Térmico HSP47/sangue , Pneumonias Intersticiais Idiopáticas/sangue , Doença Aguda , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
19.
BMC Med Genet ; 15: 4, 2014 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-24400879

RESUMO

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.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Grupo com Ancestrais do Continente Europeu/genética , Polimorfismo de Nucleotídeo Único , Proteína D Associada a Surfactante Pulmonar/sangue , Proteína D Associada a Surfactante Pulmonar/genética , Idoso , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Alemanha , Humanos , Pneumonias Intersticiais Idiopáticas/sangue , Pneumonias Intersticiais Idiopáticas/genética , Japão , Masculino , Proteína A Associada a Surfactante Pulmonar/sangue
20.
Inflammation ; 37(1): 10-6, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23912648

RESUMO

Recent literature and our previous proteomic findings prompted us to study the coagulation system in idiopathic pulmonary fibrosis (IPF), the pathogenesis of which remains unclear. The aim of this study was to compare coagulation factors in idiopathic pulmonary fibrosis and idiopathic nonspecific interstitial pneumonia (NSIP) patients and healthy controls. Thirty-three IPF patients (23 acute exacerbation and 10 stable IPF patients), 7 NSIP patients, and 44 controls were enrolled. Concentrations of D-dimer, homocysteine, functional protein C, protein C antigen, free and total protein S antigen and activity, fibrinogen and factor VIIIc were analyzed in serum of patients and controls. The lupus anticoagulant (LAC) test was also performed. Factor VIIIc levels were significantly higher in acute exacerbation IPF patients than controls (p = 0.0001) and in stable IPF patients than controls (p = 0.002). Factor VIIIc levels were higher and PT levels were lower in acute exacerbation IPF patients who died after exacerbation than in patients who survived (p = 0.04 and p = 0.003, respectively). D-dimer, fibrinogen, and homocysteine levels were also significantly higher in IPF patients than controls (p < 0.01). Protein C activity was increased in acute exacerbation IPF patients than controls (p = 0.005). The LAC test was positive in seven IPF patients and negative in controls. Procoagulant status was demonstrated in IPF patients (mainly in acute exacerbation/IPF) than controls and NSIP patients, probably due to endothelial activation and microvascular injury. These preliminary results are of interest because of their potential implications in the pathogenesis and treatment of this disease.


Assuntos
Fatores de Coagulação Sanguínea/análise , Coagulação Sanguínea/fisiologia , Pneumonias Intersticiais Idiopáticas/sangue , Fibrose Pulmonar Idiopática/sangue , Fator VIII/análise , Feminino , Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Fibrinogênio/análise , Homocisteína/sangue , Humanos , Pneumonias Intersticiais Idiopáticas/mortalidade , Fibrose Pulmonar Idiopática/mortalidade , Inibidor de Coagulação do Lúpus/sangue , Masculino , Pessoa de Meia-Idade , Proteína C/análise , Proteína S/análise
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