Clinical Significance Of Systemic Immune-inflammation Index And Platelet-to-Lymphocyte Ratio In Patients With HBV Induced Liver Fibrosis And Their Reference Intervals Defining In Healthy Population

Backgrounds and Aims The systemic immune-inflammation index(SII),platelet-to-lymphocyte ratio(PLR),neutrophil-to-lymphocyte ratio(NLR),neutrophil-to-lymphocyte ratio The lymphocyte-to-monocyte ratio(LMR)and the monocyte-to-lymphocyte ratio(MLR)are systemic inflammatory biomarkers based on neutrophils,lymphocytes,monocytes and platelets.It is biological indicator related to the body's immune response closely.More and more research have shown that these indicators are connected with infection,cancer,autoimmune diseases.In the past two years,SII has been paid more attention by researchers,and it has been shown to be a prognostic factor for postoperative prognosis of hepatocellular carcinoma,Metastatic prostate cancer,small cell lung cancer,esophageal squamous cell carcinoma and other diseases.Hepatitis B is one of the most common infectious diseases in the world.With the widespread use of antiviral drugs such as entecavir,the popularity of hepatitis B vaccine and the blockage of mother-to-child transmission have made control of its infection,but there is still no effective methods to achieve complete cure,still cause great harm to infected people.Hepatitis,liver cirrhosis,liver cancer is known as hepatitis infection "three steps".In all stages there are different degrees of fibrosis.Timely monitoring of liver fibrosis,timely use of anti-fibrosis drugs,can effectively slow the disease progression.At present,the gold standard of liver fibrosis is still the pathologic examination of liver puncture,and it is urgent to seek more reliable diagnostic index.SII,PLR,NLR,LMR,MLR have been shown to be closely related to the progression and treatment of many diseases,but there is no research to explore the diagnostic value of these indicators for the degree of hepatitis B fibrosis.This study was to analyze the changes of SII,PLR,NLR,LMR and MLR in patients with different degrees of liver fibrosis,and to explore the diagnostic value of these indexes in the diagnosis of hepatic B fibrosis.In this study,we developed the results of an indirect method based on the Clinical and Laboratory Standards Institute(CLSI)document C28-A3-Defining,Establishing,and Verifying Reference Intervals in the Clinical Laboratory;Approved Guideline-To establish a reference interval for SII,PLR,NLR,LMR,MLR in healthy populations.And provide reference interval for the clinical design of the related experimental design and the clinical application of these inflammatory markers.Methods 1.The first part: collecting the result of Fibro Scan of HBV infection Patients,including 192 cases and 40 healthy controls;the second part: Collected from our hospital physical examination records of adult(not less than 18 years of age)individual blood test results,a total of 26796 cases,and collected blood samples of healthy individuals 450 cases 2.According to their respective inclusion criteria strictly selected subjects.The first part was divided into three groups according to the degree of liver fibrosis: 33 patients with fibrous fibrosis(F0F1),43 patients with mild fibrosis(F2),25 patients with moderate fibrosis(F2F3),severe fibrosis group(F3F4)28 cases,liver cirrhosis group(F4)63 cases;the second part in accordance with the clinical and laboratory standards Association(Clinical and Laboratory Standards Institute,CLSI)document C28-A3 excluded outliers,a total of 24029 cases meet the inclusion criteria.3.The blood samples were collected by EDTA-K2 anticoagulated blood vessel.The liver specimens were collected by vacuum separation and vacuum tube.The specimens were detected by COULTER LH 755 automatic blood analyzer and Roche Cobas E702 automatic biochemical analyzer.The degree of hepatic fibrosis was determined by Fibro Scan liver fibrosis noninvasive instrument.4.Calculate SII,PLR,NLR,LMR,MLR,APRI,FIB-4 values using the corresponding formula.5.ROC analysis of SII,PLR,APRI,FIB-4 on HBV infection in the degree of liver fibrosis.6.Establish and verify the reference intervals for SII,PLR,NLR,LMR,MLR as specified in C28-A3.Results Part One: SII,PLR and other inflammatory indicators in patients with hepatitis B fibrosis in the clinical significance 1.There were 192 cases of HBV infection and 40 healthy controls.The mean age of the infected group was 43.14 ± 13.29 years old,and the average age of the healthy control group was 45.63 ± 12.93 years.The differences of PLR,LMR,MLR,SII,APRI and FIB-4 between the HBV infection group and the HC group were statistically significant(p <0.05).2.Contrast the data of SII,PLR,NLR and other inflammatory indexes between different levels of fibrosis in HBV infection.(P <0.05).The expression of PLR in F0F1 group and F4 group was significantly different from that in F0F1 group and F4 group(P <0.05).The expression of PLR in F0F1 group and F4 group was significantly different(P <0.05)F2 group and F4 group,F2F3 group and F4 group were statistically significant(p <0.05);FIB-4 in F0F1 group and F4 group,F2 group and F4 group,F2F3 group and F4 group,F3F4 and F4 group difference Statistically significant(p <0.05).3.The levels of hepatic fibrosis in patients with HBV infection were F012 mild to moderate and F34 severe and hardened.Contrast SII,PLR,APRI,FIB-4 were different between the two groups(p <0.05).4.The diagnostic effect of SII,PLR,APRI and FIB-4 on hepatic fibrosis in HBV infection was analyzed by receiver operating characteristic curve(ROC).ROC analysis showed that the AUC of SII was 0.637(95% CI: 0.559-0.715),the cutoff value was 241.75,the sensitivity was 53%,the specificity was 73%;the AUC of PLR was 0.615(95% CI: 0.534-0.700),the Cutoff value 47.89,the sensitivity was 95%,the specificity was 27%;the AUC of APRI was 0.733(95% CI: 0.663-0.804),the Cutoff value was 0.89,the sensitivity was 56%,the specificity was 83%;the AUC of FIB-95% CI: 0.710-0.843),Cutoff value 1.55,sensitivity 74%,specificity 70%.5.The SII,PLR and APRI,FIB-4 joint ROC.The AUC of APRI and PLR combined with ROC was 0.741(95% CI: 0.671-0.81),the sensitivity was 59% and the specificity was 81%.The AUC of APRI and RII was 0.743(95% CI: 0.673-0.813)The sensitivity and specificity of FIB-4 and SII were 0.778(95% CI: 0.712-0.844),the sensitivity was 69% and the specificity was 76%.FIB-4 and SII,PLR were combined with ROC The AUC was 0.782(95% CI: 0.716-0.847),with a sensitivity of 75% and a specificity of 74%.Part Two: the establishment of reference interval of SII,PLR and other inflammatory indicators in healthy population 1.A total of 24029 subjects were included in the study,including 12660 males and 11,369 females.The average age was 44.23 ± 14.21 years.2.The results showed that NLR,LMR and MLR were significantly different in male and female groups(p <0.05).The results showed that PLR,NLR,LMR and MLR were different in age.There were significant differences in age group(p <0.05).3.According to the stratified situation,95% confidence intervals for each index were calculated,the reference interval for SII is [161,701];the reference interval for PLR in the adult is [61,179],in the elderly is [55,179];the reference interval for NLR in adult male is[0.90,2.94],in adult women is[0.85,3.06],in older men is[0.95,3.57],in older women is [0.83,3.30];the reference interval for LMR in adult male is [2.50,7.50],[2.75,8.50] for adult women,[2.16,7.41] for older men,[2.40,8.33] for older women;the reference interval for MLR in adult male is [0.12,0.35],in adult women is [0.10,0.32],in older men is [0.12,0.41],in older women is [0.11,0.33].4.Based on the Clinical and Laboratory Standards Association(CLSI)document C28-A3,verify the established reference interval.According to the stratification requirements,a certain amount of reference individuals was randomly selected from the local reference population,and the hematological parameters were determined after the outliers were excluded,and compared with the established reference interval.Verify that the established reference interval is available.Conclusions 1.SII and PLR have different diagnostic significance for different degree of hepatic fibrosis in HBV infection.SII,PLR and APRI,FIB-4 combined diagnosis can improve the diagnostic value of the latter.2.Reference intervals established for PLR,NLR,SII,LMR and MLR according to the Clinical and Laboratory Standards Association(CLSI)document C28-A3 can be used for the study of relevant inflammatory indicators and clinical application.