| BackgroundInterstitial pulmonary disease(ILD) was a kind of a variety of causes, pathogenesis remained unclear, pulmonary interstitial acute and chronic nonspecific inflammation,the onset of the disease could be manifested as alveolitis, end-stage of diffuse pulmonary interstitial fibrosis,eventually leading to respiratory failure.With poor prognosis, high mortality,it was becoming a hot spot of attention. Connective tissue disease(CTD) was one of the main etiologies of ILD. CTD involved multiple organs and tissues, lung was a common involved organs, it was characterized by interstitial lung disease(ILD). Patients with all kinds of CTD-ILD had the same imaging,pathology and clinical manifestation. Lung biopsy was diagnostic gold standard for ILD, pathological classification made sense to guide the clinical treatment, but due to traumatic examination material limitedin practice, it could’t very well developed, and the clinical diagnosis of ILD was mainly based on clinical characteristics and lung high resolution CT performance. But HRCT had limitations in the differential diagnosis of ILD complicated with pulmonary infection. So the research and discovery of ILD serological specific biomarkers had important implications for the diagnosis and differential diagnosis of ILD.Krebs von den Lungen-6 was macromolecular sialic acid glycoprotein secreted by alveolar type Ⅱ epithelial cells, it expressed in normal lung tissue and terminal bronchiole; alveolar epithelial surfaces only very small amount of expression; and in the epithelial cells of the alveolar typeⅠnot express. The levels of serum KL-6 in patients with ILD were significantly increased compared with other respiratory disease patients and healthy concentration. Related studies had shown that serum KL- 6 level more than 500 u/ml was the sign of connective tissue disease complicated with ILD. In different CTD, including RA, SLE, SSc, DM, PM, CTD patients without ILD serum KL- 6 levels in the normal range(below 500 u/ml), and a lot of CTD patients with ILD serum KL-6 level more than 500 u/ml. A high concentration of serum KL-6 level relevanted with rapid progress interstitial lung disease. In addition, for CTD-ILD, the rise of serum KL-6 was associated with FVC, DLCO and death risk.Pulmonary surfactant Protein A was sugar binding Protein,first found and rich expression in the typeⅡepithelial cells, it was an important component for alveolar surface active substances, its physiological function was involved in the formation and metabolism of the alveolar surface activity membrane. SP-A level was closely related to pulmonary fibrosis. Related studies showed that SP-A was an important biological marker to predicting the mortality of IPF, and the detection indexof pulmonary fibrosis.Pulmonary surfactant Protein Dwas protein synthesized from respiratory endings typeⅡepithelial cells. The expression and distribution of SP-D were similar to SP-A, immune function complement with each other, it was as the alveolar surface active material to reduce alveolar surface tension to prevent alveolar collapse and expansion, and participated in pulmonary congenital defense and non-antibody mediated immune responses. In recent years, the study found that SP-D was related with pulmonary function and pulmonary HRCT manifestation in CTD-ILD. Studies had shown that serum SP-A and SP-D levels were increased significantly in patients with CTD-ILD, and also associated with the severity of the SSc-ILD, it was serum biomarkers for predictive connective tissue disease related ILD.IL- 6 was a kind of small molecular peptide secreted by the activation of T cells or fibroblasts. Tzouvelekis’ study showed that IL-6 was closely related to the formation of pulmonary fibrosis, but the exact pathogenesis remained unclear, IL-6 could be used asserum indexes of predicting pulmonary interstitial fibrosis, it had certain effect onalveolar inflammation in the beginning and the formation of pulmonary fibrosis in the late of the interstitial lung disease. Kawasumi and Nara’ research showed the level of IL-6were increased significantly in rapid progressive-ILD, according the disease early IL-6 level to guide thetherapy strength of the immunosuppressive, regulation of IL- 6 levels might help in thetreatmentand prognosis of RP-ILD.So it was very significanct to explore the changes of KL-6, the SP-A, SP-D, and IL-6 in the serum of patients with CTD-ILD;and its relationship with lung HRCT,pulmonary function,clinical manifestation, and laboratory parameters; and analyzed its roles in CTD-ILD with lung infection to guid clinical treatment.Objectives Through detection of serum KL-6, SP-A, SP-D,IL-6 expression levels of patients with CTD-ILD, compared with CTD without ILD group and normal control group(NC) differences, analysised its relationship with clinical manifestations, pulmonary function, HRCT manifestations, and laboratory indexes, to explore the significance of the disease evaluation, diagnosis and differential diagnosis of CTD-ILD.Methods A case-control study from March 2014 to June 2015 hospitalized in the first affiliated hospital of Anhui medical university104 cases diagnosed with CTD-ILD. At the same time, choose 40 patients with CTD without ILD whose age, sex, disease matched with CTD-ILD, and 30 cases of healthy(normal control group) with gender, age matched.Detailed record clinical signs, laboratory index, pulmonary function and pulmonary HRCT data of all patients; At the same time,we stayed serum in all the object; serum KL- 6 levels was detected by chemiluminescence method, the levels of SP-A, SP-D, IL-6 were detected by enzyme linked immunosorbent assay(ELISA).The use of the stastical package for social science(SPSS) 19.0 software to analyze the difference and correlation between groups.Results 1. The concentration levels comparison of KL-6,SP-A,SP-D, and IL-6 among CTD-ILD group,CTD group,and normal control group: 1) CTD-ILD group compared with normal control group: CTD-ILD patients serum KL-6,SP-A,SP-D, and IL-6 levels were significantly higher than normal control group(P <0.05); 2) CTD-ILD group compared with CTD group: CTD-ILD patients KL-6,SP-A,SP-D, and IL-6 levels were significantly higher than CTD without ILD group(P <0.05); 3)CTD groupcompared withnormal control group:CTDpatients SP-A,SP-D, and IL-6 levels were significantly higher than NC group(P<0.05),there was no significant difference in the level of KL-6 between the 2 groups(P>0.05). 2. The correlation analysis of KL-6,SP-A,SP-D and IL-6 levels with clinical manifestations: The KL-6 levels were positively related with cough and expectoration, asthma, raynaud ’s phenomenon, muscle aches, pulmonary rales(P<0.05); The SP-D levels were positively related with chest tightness and limb weakness(P<0.05); The IL-6 levels were positively related with joint swelling and numbness(P<0.05);The SP-A levels were no obvious correlation with clinical manifestations(P>0.05). 3. The correlation analysis of KL-6,SP-A,SP-Dand IL-6 levels with pulmonary function: 1) Pulmonaryventilation function :The serum KL-6 levels in normal / mild ventilation dysfunction group were significantly lower than moderate / severe ventilation dysfunction group(P< 0.05); The serum SP-D levels in normal / mild ventilation dysfunction group were significantly higher than moderate / severe ventilation dysfunction group(P<0.05); The serum KL-6 and IL-6 levels between the two groups were no statistically significant difference(P>0.05); 2) Pulmonarydiffuse function :The serum SP-D levels in normal / mild diffuse dysfunction group were significantly lower than moderate / severe diffuse dysfunction group,(P<0.05); The serum KL-6,SPA,and IL-6 levels between the two groups were no statistically significant difference(P>0.05). 3) The correlation analysis : The serum KL-6 levels were negatively related with VC MAX,FVC,TLC-SB,RV-SB and positively related with FEV1/FVC,FEV1/VC MAX(P<0.05); The serum SP-A levels were negatively related with FEV1/VC MAX,MEF25,MMEF75/25(P<0.05);The serum SP-D levels were negatively related with VC MAX,TLC,and DLCO(P<0.05); the serum IL-6 levels were negatively related with DLCO(P<0.05). 4. The correlation analysis of KL-6,SP-A,SP-D, and IL-6 levels among different HRCT groups: According to the CT appearance: mainly exudative ILD groups( grinding glass, spots and patchy shadows);mainly fibrosis ILD groups(fiber cords, grid, the honeycomb,relative pathological type for unusual interstitial pneumonia).The levels of KL- 6 in mainly exudative ILD groups had a significantly higher than in mainly fibrosis ILD groups, and positively related with mainly exudative ILD(P<0.05).Between the two groups of the levels of serum SP-A, SP-D,and IL-6 had no statistical significance,no related with active ILD(P> 0.05). 5. The correlation analysis of KL-6,SP-A,SP-D, and IL-6 levels with laboratory indexs: The serum KL-6 levels were negatively related with D dimer,and positively related with white blood cell count and immunoglobulin M(P<0.05); The serum SP-A levels were negatively related with neutrophil percentage and absolute number, D dimer,CRP,and RF, positively related with lymphocytes percentage,AST(P < 0.05); The serum SP-D levels were negatively related with PLT and D dimer,and positively related with AST, ESRand RF(P<0.05); The serum IL-6 levels were negatively related with PLT and AST,and positively related with IGG, IGM,ESR, CRPand RF(P<0.05). 6. Among 104 cases diagnosed as CTD-ILD patients,the prevalence of pulmonary infection were 51.9%(54/104). SLE(58.3%),PM/DM(55%), Systemic vasculitis(54.55%) was common with pulmonary infection. 1) The concentration levels comparison of serum KL-6,SP-A,SP-D and IL-6 were no statistical difference between CTD-ILD pulmonary infection and without pulmonary infection group(P>0.05). 2) Pulmonary infection group fever, cough and expectoration, chest tightness, asthma, lower extremity edema, pulmonary rales were significantly higher than without pulmonary infection group(P<0.05), and those were positively related with pulmonary infection(P<0.05). 3) Pulmonary infection group RV/TLC-SB was significantly higher than without pulmonary infection group, and it was positively related with pulmonary infection(P<0.05); VC MAX, FVC, FEV1, FEV1*30, DLCO SB were significantly lower than without pulmonary infection group(P<0.05), and those were negatively related with pulmonary infection(P<0.05) 4) Various HRCT manifestations had no statistical difference between pulmonary infection and without pulmonary infection group(P>0.05).Accordance to the HRCT diagnostic criteria, divided into typical UIP, may UIP, does not conform to UIP. All kinds of HRCT performance were no statistical difference between two groups(P>0.05). 5) Pulmonary infection group Peripheral blood neutrophil percentage and absolute number, ESR, CRP, serum ferritin, D dimer were significantly higher than without pulmonary infection group(P<0.05), and those were positively related with pulmonary infection(P<0.05); Peripheral blood lymphocytes percentage and absolute number, PO2 and albumin were significantly lower than without pulmonary infection group(P<0.05), and those were negatively related with pulmonary infection(P<0.05); respiratory failure(PO2 less than 60 mm Hg)of pulmonary infection group was 14.8%(8/54), without pulmonary infection group was 2%(1/50)(P<0.05). 6) Etiology examination results: sputum culture positive rate of 18.9%(10/54), gram-negative bacillus in 8 cases;Fungal infection in 2 cases; Cytomegalovirus pneumonia in 5 cases; Blood culture of staphylococcus aureus in 2 cases; Bone marrow culture klebsiella bacteria in 1 case. 7) Treatment :According to the dosage of corticosteroid equivalence converted into prednisone in less than or equal to 7.5 mg/day for small-dose, medium-dose was equal to or less than 30 mg/day, high-dose more than30 mg/day. Pulmonary infection group utilization high-dose hormone rate was 47.3%, utilization rate of without pulmonary infection group was 31.4%,and positively related to the pulmonary infection(P<0.05). Immunosuppressive(cyclophosphamide, mycophenolate mofetil, cyclosporine A,etc.) used had no statistical difference between two groups(P>0.05). 8) Logistic multiple regression analysis in CTD-ILD pulmonary infection group showed: CTD-ILD complicated pulmonary infection was significantly related to cough and expectoration, lung rales increase, lymphocytes count decreased, albumin, elevated CRP(P<0.05).Conclusion 1. The CTD ILD group KL-6,SP-A,SP-Dand IL-6 levels were significantly higher than that of CTD and NC group. 2. The KL-6 levels were significantly higher in moderate / severe ventilation dysfunction group,and negatively related with FVC; The serum SP-D levelswere significantly lower in moderate / severe ventilation dysfunction group,and negatively related with DLCO; The SP-A levels were negatively related with FEV1/VC; The IL-6 levels were negatively related with DLCO. 3. The levels of KL-6 in mainly exudative ILD groups had a significantly higher than in mainly fibrosis ILD groups, and positively related with mainly exudative ILD. 4. The CTD-ILD patients with pulmonary infection rate were 51.9%. These clinical characteristics in pulmonary infection group were significantly higher than without pulmonary infection group, including the incidence of fever, expectoration; the increased of neutrophilic granulocyte, ESR, CRP, serum ferritin; and use of high doses of glucocorticoid,respiratory failure, those were positively related to pulmonary infection; Blood lymphocytes, albumin, PO2,FVC and DLCO in pulmonary infection were significantly lower than those in without pulmonary infection group, and negatively related to pulmonary infection. Pulmonary HRCT manifestations,KL-6,SP-A,SP-D, and IL-6 levelsshowed that there were no statistical difference between two groups(P>0.05). Cough and expectoration, elevated CRP, lymphocytes and albumin decreased were risk factors with CTD-ILD complicated pulmonary infection(P<0.05)... |
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