Clinical Features And Significance Of Granulocyte-macrophage Colony Stimulating Factor Autoantibodies In Patients With Pulmonary Alveolar Proteinosis

Background and Objective:Pulmonary alveolar proteinosis(PAP)is a syndrome of altered surfactanthomeostasis, characterized by accumulation of periodic-acid-Schiff (PAS) positiveproteinaceous material in the alveoli, which blocked gas exchange in the lung andcan lead to life-threatening respiratory failure. The onset of clinical disease isinsidious, with a subacute indolent course that often delays the diagnosis by months toyears. The symptoms have no specificity,mainly presented progressive dyspnea.Approximately10-30%of patients are asymptomatic。 According to differentpathogenesis, PAP is classified into3types: congenital, idiopathic and secondary.Congenital PAP(CPAP) is caused by gene mutation. Secondary PAP(SPAP) relates todanger-exposure to and underlying condition. Idiopathic PAP(IPAP) has high level ofGranulocyte-macrophage colony stimulating factor auto-antibodies (GMAbs)，whichis normal in SPAP and CPAP.At present, there is no agreed guide to diagnose PAP.Analysis about domestic PAP clinical data of large sample is rare.There are few casereports about SPAP. There are no analysis on the clinical, causes, therapy andprognosis of SPAP.GMAbs from PAP patients have important significance in the clinic.(1)血清GMAbs in serum can be used to diagnose IPAP, have reliable sensitivity andspecificity.（2）Detecting GMAbs in serum is an effective method to distinguish IPAPform CPAP and SPAP.（3）GMAbs in serum can forecast the treatment effect ofGM-CSF.At present, There is no uniform standard to detect serum GMAbs and diagnose IPAP. The role of anti-GM-CSF antibodies in the aetiology andpathogenesis,monitoring disease activity, reflecting disease severity, predictingand/or monitoring treatment response, and in predicting outcome of the patientsremains unknown. The clinical research on the significance of GMAbs is rare.There isno research about GMAbs in bronchoavleolar lavage fluid(BALF) and serum beforeand after treatment.Treatment of PAP is limit. Whole lung lavage(WLL) is standard therapynow.Most patients need repeat lavage.Some patients have no improvement after WLL.There is no uniform guide about therapeutic indications. WLL is symptomatictreatment but not a radical cure.Severe complications maybe occure.Therefore,toassess the effect, complication and safety after WLL has important clinicalsignificance.Based on the study about PAP above, the research firstly takes a large sample asobject and study the clinical significance of GMAbs in serum and BALF.Then toreport5cases with SPAP and review literature and analyse163cases with SPAP. Theclinical feature,causes,therapy and prognosis.Finally to analyze the clinical feature of39cases with IPAP,investigate the effectiveness and safety after BWLL.Part1Analysis of Clinical significance of GMAbs in pulmonaryalveolar proteinosisObjective: To analyse Clinical significance of GMAbs in thediagnosis,classification, treatment effective and disease severity of PAP.Methods:Take serum from PAP group(45cases)before and after BWLL,diseasecontrol group(DC,24cases), health control group(HC,50cases),take BALF from PAPgroup(26cases) and HCgroup(20cases).To detect GMAbs in serum and BALF usingELISA,analyze data with receiver operating characteristic (ROC) curve on thediagnosis of PAP,establish cut-off (CO) value，compare the difference of GMAbsbefore and after BWLL.To compare the difference of GMAbs in BALF between PAP group and HC group and assess the relativity between GMAbs in BALF and serumand the clinical data.Results:1．The difference of GMAbs in serum from PAP、DC and HC group issignificance（F=44.19，P=0.00）. The GMAbs in serum from PAP gruop is higher thanthat from DC and HC group（P=0.00）.There is no difference between DC and HCgroup（p=0.94）。The CO value for PAP diagnosis is optical density(OD)0.049(sensitivity=87.8％，specificity=100％), both DC and HC group have no positivecases.5cases with PAP are diagnosed SPAP according to serum GMAbs negative.2．GMAbs in serum from20cases have no diffidence before(OD=0.765±0.828)and after(OD=0.646±0.592) BWLL（p=0.21）。3．GMAbs in BALF from PAP group（OD=0.402±0.496） is higher than thatfrom HC group（OD=0.012±0.006），p=0.00。GMAbs in serum have no relativitywith age, the duration of symptoms prior to diagnosis,the indicator in blood, lungfunction and arterial blood gas. GMAbs in BALF markedly have relativity withalveolar oxygen partial pressure(PaO2（)r=-0.734，p=0.007），alveolar arterial oxygendifference(P(A–a)O2)（r=0.773，p=0.001），diffusion capacity for carbonmonoxide ofthe lung (DLCO)（r=-0.712，p=0.033）.Results：Using ELISA to detect GMAbs in serum is a convenient and reliablemethod for serological diagnosis of PAP with high sensitivity (87.8%) andspecificity (100%). It have important significance for PAP classification. BWLL haveno influence on the pathogenesis of PAP. GMAbs in BALF can be used as an index toassess disease severity. Part2The clinical analysis of163cases with Secondarypulmonary alveolar proteinosisObjective:To investigate the clinical, causes, therapy and prognosis of SPAP.Methods:5cases of SPAP admitted into the First Affiliated Hospital ofGguangzhou Medical College from march2011to march2013,158cases reportedsince1958were reviewed.Results:163cases of SPAP with a male-to-female ratio of1.05:1were analyzed.The duration of symptoms prior to diagnosis is3days to5years(median3months). Amedian age at diagnosis of IPAP is39years. The complete clinical analysis of103cases shows that66cases（64.1％）presented progressive dyspnea,54cases（52.4％）cough，21cases（20.4％）expectoration，38cases（36.9％）fever。Lung physicalexamination is usually unremarkable. The complete High-resolution CT analysis of98cases shows that58case（s59.2％）presented bilateral diffuse ground glass opacitie,10cases（10.2％）a patchy geographic pattern,28cases（28.6％）“crazy-paving”appearance and28cases（28.6％）Pulmonary interstitial infiltration. The completediagnosis data analysis of114cases shows that OLB were30cases（26.3％），autopsy22cases（19.3％），transbronchial lung biopsy(TBLB)15cases（13.2％），BAL18cases（15.8％）。Among the secondary causes of161cases, there were hematopoieticdisorders in44.7％（72/161）, infections in22.3％％（36/161）, dust inhalation in14.3％（23/161）, immune disorders in9.3％（15/161）,malignant tumors excepthematopoietic disorders in5％（8/161）,drug in3.1％（5/161）,others in2cases.33cases including20（60.6％）cases secondary to hematopoietic disorders infected lungs.Among the91cases with complete therapy and prognosis data,50cases（55.0％）improved after treatment.In the40cases treated with causes and symtoms,14cases（35％）had effective；In the51cases treated with Whole lung lavage,36cases（70.6％） improved markedly. The difference is significant. The SPAP secondary tohematopoietic disorders had lower effective rate than the SPAP secondary to other causes, the effective rate was26.5％and87.5％respectively(2=32.10，P≤0.05）.Conclusions:The clinical feature and sign of SPAP is non-specific. The typicalcharacteristics of image is few. Hematopoietic disorders were the most commoncause for SPAP.SPAP had poor therapeutic effects,especially those secondary tohematopoietic disorders.Whole lung lavage improve treatment effects and prognosis. Part3Analysis of Clinical features and Bilateral whole lunglavage in the treatment of39cases with idiopathic pulmonaryalveolar proteinosisObjective：To discuss the clinical manifestations of IPAP and evaluate theefficacy and safety of BWLL in the treatment of IPAP.Methods：The clinical data of39patients with IPAP admitted into the FirstAffiliated Hospital of Gguangzhou Medical College from march2010to march2013were retrospectively analyzed, the efficacy and safety of BWLL were evaluated.Results：39cases of IPAP with a male-to-female ratio of2.25:1were analyzed.The duration of symptoms prior to diagnosis is3days–10years(median7months).Amedian age at diagnosis of IPAP is41years.32cases (82.1％) presented progressivedyspnea, isolated or in combination with cough and sputum.4cases presented coughand sputum.2cases presented chest stuffiness.1cases presented fever and chest pains.35cases were underwent CT scan,32cases （91.4％）show bilateral diffuse groundglass opacities,32cases（91.4％）showed a patchy geographic pattern and33cases（94.3％）showed “crazy-paving” appearance.According to the condition of patients,31cases were underwent48BWLL. After lavage，the symptoms were markedlyimproved． Differences on MMRC score,alveolar oxygen partialpressure(PaO2),arterial oxygen saturation (SaO2) and Diffusion Capacity for Carbon Monoxide of the Lung (DLCO)were significant before and after BWLL. Chest CT of79.6％（35/44）patients were markedly improved.Severe complications includingfever,pneumothorax and sinus bradycardia respectively occurred in three patients.17patients until now. Mean duration of clinical benefit in all patients was15.911.6months.In the next3-53months observing,75％（36/48）cases had no recurrence in4-52months(median22months）,25％（12/48） cases need BWLL in2-43months(median6months）。Conclusion：IPAP mainly presents progressive dyspnea. The characteristic ofchest image is a patchy geographic pattern and “crazy-paving” appearance.Transbronchial lung biopsy is a main diagnosis method. Bilateral whole lung lavage isan effective and safe therapeutic method in the treatment of idiopathic PAP and canimprove symptoms, the indicators of arterial blood gas analysis and lung functionand chest CT. The treatment with whole lung lavage can maintain curative effect. SummaryThe research firstly takes a large sample as object and study the clinicalsignificance of GMAbs in serum and BALF.Then to report5cases with SPAP andreview literature and analyse163cases with SPAP. The clinical feature,causes,therapyand prognosis.Finally to analyze the clinical feature of39cases with IPAP,investigatethe effectiveness and safety after BWLL.The results show that:1.Using ELISA to detect GMAbs in serum is a convenient and reliable methodfor serological diagnosis of PAP with high sensitivity (87.8%) and specificity(100%). It have important significance for PAP classification. BWLL have noinfluence on the pathogenesis of PAP. GMAbs in BALF can be used as an index toassess disease severity. 2.The clinical feature and sign of SPAP is non-specific. The typicalcharacteristics of image is few. Hematopoietic disorders were the most commoncause for SPAP.SPAP had poor therapeutic effects,especially those secondary tohematopoietic disorders.Whole lung lavage improve treatment effects and prognosis.3.IPAP mainly presents progressive dyspnea. The characteristic of chest image isa patchy geographic pattern and “crazy-paving” appearance. Transbronchial lungbiopsy is a main diagnosis method. Bilateral whole lung lavage is an effective andsafe therapeutic method in the treatment of idiopathic PAP and can improvesymptoms, the indicators of arterial blood gas analysis and lung function and chestCT. The treatment with whole lung lavage can maintain curative effect.