特发性肺泡蛋白沉积症患者血清生物标志物的临床意义

Serum markers in patients with idiopathic pulmonary alveolar proteinosis

目的 定量检测血清抗粒细胞巨噬细胞集落刺激因子（GM-CSF）抗体水平,探讨特发性肺泡蛋白沉积症（IPAP）血清生物标志物在其诊断及监测中的意义.方法 连续收集2006年3月至2013年3月北京协和医院就诊的31例IPAP患者,其中男27例,女4例,平均年龄（47±8）岁.纳入同期25名健康体检者及15例胸部CT表现与肺泡蛋白沉积症（PAP）易混淆的住院患者作为疾病对照,所有患者收集血清标本,以ELISA方法分别测定其血清抗GM-CSF抗体、肺泡表面活性物质-A（SP-A）、肺泡表面活性物质-D（SP-D）和软骨糖蛋白-39 （YKL-40）水平,分析其与LDH、癌胚抗原、肺功能和血气等指标的关系.结果 IPAP组患者血清抗GM-CSF抗体、SP-A、SP-D水平分别为29.80（13.02 ～53.86） mg/L、（47±30）和（77±57） μg/L,较健康对照组及疾病对照组升高（P＜0.05）.YKL-40和LDH水平分别为70.46（48.56 ～90.13） μg/L与（243±56） U/L,与疾病对照组比较差异无统计学意义（P＞0.05）,较健康对照组升高（P＜0.05）.癌胚抗原水平为（8 ±6） μg/L,较疾病对照组高（P＜0.05）.取2.46 mg/L为截断值,血清抗GM-CSF抗体对IPAP诊断的敏感度和特异度均达100％.IPAP组血清LDH、癌胚抗原、SP-A水平分别与P（A-a）O2呈正相关,与TLCO％、PaO2、SaO2呈负相关（P＜0.05）,SP-D水平与SaO2负相关（P＜0.05）.SP-A、SP-D水平分别与LDH、癌胚抗原正相关（P＜0.05）,LDH与癌胚抗原正相关（P＜0.05）.YKL-40水平与SP-A水平正相关（P＜0.05）,与其他血清学指标及肺功能、血气指标无线性相关关系（P＞0.05）.抗GM-CSF抗体与上述指标均无线性相关关系（P＞0.05）.结论 IPAP患者血清LDH、癌胚抗原、SP-A与SP-D水平均升高,且与疾病严重程度相关;YKL-40水平亦升高,但与疾病严重程度无关;抗GM-CSF抗体与疾病严重度无关.多数IPAP为自身免疫性,通过应用血清抗GM-CSF抗体定量检测方法,验证了其对IPAP诊断有较高的敏感度和特异度,可以用于自身免疫性PAP的诊断.

Objective Pulmonary alveolar proteinosis （PAP） is a rare lung disease characterized by PAS positive lipoproteinaceous material accumulation in the pulmonary alveoli,of which autoimmune （APAP） or idiopathic type （IPAP） accounts for about 90％.Several serum markers were reported to be valuable in IPAP diagnosis.However,data in Chinese patients was not available.Here we analyzed the diagnostic value of serum markers in Chinese IPAP patients.Methods Thirty-one IPAP patients,25 healthy volunteers and 15 patients with other lung diseases were enrolled in the study.Anti-GM-CSF antibody,SP-A,SP-D and YKL-40 levels of the serum samples were tested by ELISA method.LDH,CEA,arterial blood gas analysis and pulmonary function test results were collected and analyzed.Then the difference between the groups and the relationship between the 2 of the markers were tested.Results The level of serum anti-GM-CSF antibody,SP-A and SP-D [29.80（13.02-53.86） mg/L,（47 ± 30） and （77 ± 57） μg/L respectively] were higher in IPAP patients than in healthy volunteers and disease control patients （P ＜ 0.05）.IPAP and disease control groups had higher YKL-40 and LDH levels than the healthy control group（P ＜ 0.05）,but no statistical difference between the former 2 groups （P ＞ 0.05）.The CEA level of IPAP patients was higher than that of the disease control group （P ＜ 0.05）.The sensitivity and specificity of anti-GM-CSF antibody in IPAP diagnosis were both 100％ at the cut-off value of 2.46 μg/mL.The LDH,CEA and SP-A levels correlated positively with P（A-a） O2 and negatively with TLco％,PaO2 and SaO2 （P ＜ 0.05）.The SP-D level correlated negatively with SaO2 （P ＜ 0.05）,and positively with LDH and CEA level （P ＜ 0.05）,so did SP-A （P ＜ 0.05）.YKL-40 correlated positively with SP-A but not with other markers.Anti-GM-CSF antibody did not correlate with any of the markers.Conclusions Serum anti-GMCSF antibody testing showed high sensitivity and specificity for the diagnosis of APAP,though it did not correlate with disease severity.Serum LDH,CEA,SP-A and SP-D levels were elevated in IPAP patients and correlated well with disease severity.YKL-40 level was also higher in IPAP patients,but it could not be used as a disease severity marker.