Utility of serological markers in inflammatory bowel diseases: Gadget or magic?

The panel of serologic markers for inflammatory bowel diseases （IBD） is rapidly expanding. Although antiSaccharornyces cerev/siae antibodies （ASCA） and atypical perinuclear antineutrophil cytoplasmic antibodies （P-ANCA） remain the most widely investigated, an increasing amount of experimental data is available on newly discovered antibodies directed against various microbial antigens. The role of the assessment of various antibodies in the current IBD diagnostic algorithm is often questionable due to their limited sensitivity. In contrast, the association of serologic markers with disease behavior and phenotype is becoming increasingly well-established. An increasing number of observations confirms that patients with Crohn＇s disease expressing multiple serologic markers at high titers are more likely to have complicated small bowel disease （e.g. stricture and/or perforation） and are at higher risk for surgery than those without, or with low titers of antibodies. Creating homogenous disease sub-groups based on serologic response may help develop more standardized therapeutic approaches and may help in a better understanding of the pathomechanism of IBD. Further prospective clinical studies are needed to establish the clinical role of serologic tests in IBD.

New serological markers in pediatric patients with inflammatory bowel disease

The spectrum of serological markers associated with inflammatory bowel disease (IBD) is rapidly growing. Due to frequently delayed or missed diagnoses, the application of non-invasive diagnostic tests for IBD, as well as differentiation between ulcerative colitis (UC) and Crohn’s disease (CD), would be useful in the pediatric population. In addition, the combination of pancreatic autoantibodies and antibodies against Saccharomyces cerevisiae antibodies/perinuclear cytoplasmic antibody (pANCA) improved the sensitivity of serological markers in pediatric patients with CD and UC. Some studies suggested that age-associated differences in the patterns of antibodies may be present, particularly in the youngest children. In CD, most patients develop stricturing or perforating complications, and a significant number of patients undergo surgery during the disease course. Based on recent knowledge, serum antibodies are qualitatively and quantitatively associated with complicated CD behavior and CD-related surgery. Pediatric UC is characterized by extensive colitis and a high rate of colectomy. In patients with UC, high levels of anti-CBir1 and pANCA are associated with the development of pouchitis after ileal pouch-anal anastomosis. Thus, serologic markers for IBD can be applied to stratify IBD patients into more homogeneous subgroups with respect to disease progression. In conclusion, identification of patients at an increased risk of rapid disease progression is of great interest, as the application of early and more aggressive pharmaceutical intervention could have the potential to alter the natural history of IBD, and reduce complications and hospitalizations.

Correlations of Serological Markers with Development of Systemic Involvement in Adult Immunoglobulin A Vasculitis:A Retrospective Study of 259 Patients in Central China

Objective:Although relatively rare,adult immunoglobulin A vasculitis(IgAV)can lead to severe complications and longer hospitalization,and result in poor prognosis,when compared to childhood IgAV.Hence,early identification and prevention for patients prone to develop systemic involvement are essential.The purpose of this study was to explore the correlations of common serological markers with the development of systemic involvement in adult IgAV.Methods:A retrospective analysis was performed for adult IgAV patients,who were hospitalized in Wuhan Union Hospital between January 2016 and December 2019.A total of 259 patients were enrolled,and the pre-treatment serological markers were comprehensively assessed.Results:In the present study,49.0% and 33.2% of patients developed renal and gastrointestinal(GI)involvement,respectively.Furthermore,the elevated levels of white blood cells count,D-Dimer(D-D),C-reactive protein(CRP)and neutrophil granulocyte ratio(NE%)>60% were significantly associated with GI involvement in the univariate analysis,while the decrease in high density lipoprotein level,and the elevated D-D and CRP levels were significantly associated with renal involvement(P<0.05).Moreover,a prediction model that combined multiple markers was established by performing a logistic regression analysis,and this presented a more favorable value of prediction than the individual serological markers.Conclusion:The present study suggests that common serological markers have close correlations with systemic involvement in adult IgAV,and that the establishment of a prediction model for systemic involvement may be helpful in facilitating personalized therapeutic strategies and clinical management for IgAV patients.

Positive Rate of Different Hepatitis B Virus Serological Markers in Peking Union Medical College Hospital,a General Tertiary Hospital in Beijing

Objectives To investigate the positive rate of different hepatitis B virus （HBV） serological markers, and the demographic factors related to HBV infection. Methods We enrolled all patients tested for HBV serological markers, such as HBV surface antigen （HBsAg）, HBV surface antibody （HBsAb）, hepatitis B e antigen （HBeAg）, hepatitis B e antibody （HBeAb）, HBV core antibody （HBcAb）, and HBV-DNA from July 2008 to July 2009 in Peking Union Medical College Hospital. The positive rate of each HBV serological marker was calculated according to gender, age, and department, respectively. The positive rates of HBV-DNA among patients with positive HBsAg were also analyzed. Results Among 27 409 samples included, 2681 （9.8%） were HBsAg positive. When patients were divided into 9 age groups, the age-specific positive rate of HBsAg was 1.2%, 9.6%, 12.3%, 10.9%, 10.3%, 9.7%, 8.0%, 5.8%, and 4.3%, respectively. The positive rate of HBsAg in non-surgical department, surgical department, and health examination center was 16.2%, 5.8%, and 4.7%, respectively. The positive rate of HBsAg of males （13.3%） was higher than that of females （7.3%, P=0.000）. Among the 2681 HBsAg （＋） patients, 1230 （45.9%） had HBV-DNA test, of whom 564 （45.9%） were positive. Patients with HBsAg （＋）, HBeAg （＋）, and HBcAg （＋） result usually had high positive rate of HBV-DNA results （71.8%, P=0.000）. Conclusions Among this group of patients in our hospital, the positive rate of HBsAg was relatively high. Age group of 20-29, males, and patients in non-surgical departments were factors associated with high positive rate of HBsAg.

Evaluation of Plasma Urokinase-Type Plasminogen Activator Receptor and Interleukin 34 in Patients with Chronic Hepatitis C as Serological Fibrosis Markers

Background: Hepatitis C Virus (HCV) infection is a progressive disease that may result in chronic hepatitis, fibrosis and cirrhosis. Assessment of liver fibrosis is an essential factor in the management of chronic HCV. Objective: To evaluate plasma soluble Urokinase Plasminogen Activator Receptor (sUPAR) and interleukin-34 (IL-34) as serological markers of liver fibrosis in patients with chronic HCV. Methods: This case-control study enrolled 60 chronic HCV patients who were subdivided into three groups of mild, moderate and severe hepatic fibrosis depending on Fibrosis-4 score (FIB-4). Patients were compared with 20 age and sex-matched controls. Plasma sUPAR and IL-34 levels were measured by Enzyme Linked Immunosorbent Assay (ELISA). Results: Plasma sUPAR and IL-34 were significantly increased in HCV patients when compared with controls, and their increase was positively correlated with the progression of hepatic fibrosis. Plasma sUPAR and IL-34 positively correlated with Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT), and negatively correlated with hemoglobin concentration and platelet count. The output data of Receiver Operating Characteristic (ROC) curve to differentiate patients from controls revealed that sUPAR at cut-off > 186.2 ng/L and Area Under Curve (AUC) of 0.944 had (85%) sensitivity and (100%) specificity, and IL-34 at cut off > 16.4 ng/L and AUC of 0.942 had (75%) sensitivity and (100%) specificity. The output data of ROC curve to differentiate severe from mild to moderate hepatic fibrosis patients revealed that sUPAR at cut-off > 510 ng/L and AUC of 0.837 had (80%) sensitivity and (90%) specificity. While IL-34 at cut off > 55.3 ng/L and AUC of 0.844 had (85%) sensitivity and (80%) specificity. Conclusions: Increased plasma levels of sUPAR and IL-34 in chronic HCV patients with liver fibrosis and their increase was parallel to the degree of liver fibrosis. Plasma sUPAR and IL-34 can be used as serological markers of liver fibrosis in chronic HCV patients.

Clinical value of serum pepsinogen in the diagnosis and treatment of gastric diseases

Pepsinogen,secreted from the gastric mucosa,is the precursor of pepsin.It is categorized as pepsinogen 1 and pepsinogen 2 based on its immunogenicity.The pepsinogen content that can enter the blood circulation through the capillaries of the gastric mucosa is approximately 1%and remains stable all the time.The pepsinogen content in serum will change with the pathological changes of gastric mucosa.Therefore,the level of pepsinogen in serum can play a role in serologic biopsy to reflect the function and morphology of different regions of gastric mucosa and serve as an indicator of gastric disease.This study conducts relevant research on serum pepsinogen 1,pepsinogen 2,and the ratio of pepsinogen 1 to pepsinogen 2,and reviews their important value in clinical diagnosis of Helicobacter pylori infection,gastric ulcer,and even gastric carcinoma,providing ideas for other researchers.

Prevalence of hepatitis B virus infection and associated risk factors among adult females infected with Human Immunodeficiency Virus in Ogun State,Nigeria

Background:Hepatitis B virus(HBV)infection is prevalent in sub-Saharan Africa,including Nigeria,and is frequently observed in individuals co-infected with human immunodeficiency virus(HIV).Objective:This study aims to evaluate the prevalence of serological markers for hepatitis B virus and identify the associated risk factors among women with HIV undergoing highly active antiretroviral therapy(HAART)in Ogun State,Nigeria.Methods:Ethical approval was obtained from the Babcock University Health Research Ethics Committee(BUHREC)to recruit a total of 110 adult women infected with HIV,receiving treatment at the HIV clinics of Babcock University Teaching Hospital(BUTH)in Ilishan-Remo and General Hospital in Ijebu-Ode,both located in Ogun State,Nigeria.The participants’HIV status were confirmed using three rapid diagnostic kits:Determine(Abbott Laboratories,Tokyo,Japan),Unigold HIV(Trinity Biotech Plc Bray,Co.Wicklow,Ireland),and 1/2 Stat Pak(Abbott Laboratories,Tokyo,Japan)(Chembio Diagnostic Systems,New York,USA).Additionally,an HBV 5 in 1 Panel manufactured by Innovation Biotechnology Co.,Ltd in Beijing,China,was employed to detect HBV markers qualitatively in serum samples.Results:Out of the 110 subjects that voluntarily participated in the study,4(3.6%)tested positive for HBsAg,2(1.8%)tested positive for HBsAb,81(73.6%)tested positive for HBeAg,3(2.7%)tested positive for HBeAb,and 65(59.1%)tested positive for HBcAb.There was no significant correlation between the occurrence of HBsAg and the socio-demographic characteristics of the participants(P>0.05).Various risk factors were identified,including lack of knowledge about HBV,absence of HBV vaccination history,history of blood transfusion,organ transplant,and engaging in unprotected sex,among others.Conclusion:The findings highlight the presence of HBV infection among HIV-positive women undergoing HAART in Ogun State,Nigeria,particularly within the age groups of 18–25 years and 26–30 years.These results emphasize the necessity for continuous and targeted public health interventions among this specific population.

Do we really understand what the immunological disturbances in inflammatory bowel disease mean?

The gastrointestinal tract uses a system of tolerance and controlled inflammation to limit the response to dietary or bacteria-derived antigens in the gut. When this complex system breaks down, either by a chemi- cal or pathogenic insult in a genetically predisposed individual the resulting immune response may lead to inflammatory bowel disease. Although the aetio- pathogenesis of inflammatory bowel disease remains unsolved current evidence indicates that defective T-cell apoptosis and impairment of intestinal epithelial barrier function play important roles. In inflammatory bowel disease, it has been reported that activation of macrophages seems to be as important as increased production of the macrophage-derived cytokines such as TNF-α, IL-1 and IL-6. The triggering factor for this cascade is still to be elucidated as to whether it rep- resents an auto-antigen or a hetero-antigen. It has been also demonstrated that a serologic anti-microbial response exists. This response includes antibodies against saccharomyces cerevisiae （ASCA）, E. coli outer membrane porin C （Omp-C）, flagelin （cBirl） and pseu- domonas aeroginosa （I2）. Host response to microbial pathogens includes self-defense mechanisms including defensins, pattern recognition receptors and Toll-like receptors. Neuroimmunomodulation in inflammatory bowel disease （IBD） is another interesting approach with implications on the influence of brain-gut axis on intestinal inflammation and its perpetuation. It isprobable that inflammatory bowel disease represents a heterogenic group of diseases that share similar mechanisms of tissue damage but have different ini- tiating events and immunoregulatory abnormalities. A better understanding of all these events will hope- fully provide new insights into the mechanisms of epithelial responses to microorganisms and ideas for therapies.

Current guidelines for the management of celiac disease:A systematic review with comparative analysis

BACKGROUND Wheat and other gluten-containing grains are widely consumed,providing approximately 50%of the caloric intake in both industrialised and developing countries.The widespread diffusion of gluten-containing diets has rapidly led to a sharp increase in celiac disease prevalence.This condition was thought to be very rare outside Europe and relatively ignored by health professionals and the global media.However,in recent years,the discovery of important diagnostic and pathogenic milestones has led to the emergence of celiac disease(CD)from obscurity to global prominence.These modifications have prompted experts worldwide to identify effective strategies for the diagnosis and follow-up of CD.Different scientific societies,mainly from Europe and America,have proposed guidelines based on CD's most recent evidence.AIM To identify the most recent scientific guidelines on CD,aiming to find and critically analyse the main differences.METHODS We performed a database search on PubMed selecting papers published between January 2010 and January 2021 in the English language.PubMed was lastly accessed on 1 March 2021.RESULTS We distinguished guidelines from 7 different scientific societies whose reputation is worldwide recognized and representative of the clinical practice in different geographical regions.Differences were noted in the possibility of a no-biopsy diagnosis,HLA testing,follow-up protocols,and procedures.CONCLUSION We found a relatively high concordance between the guidelines for CD.Important modifications have occurred in the last years,especially about the possibility of a no-biopsy diagnosis in children.Other modifications are expected in the next future and will probably involve the extension of the non-invasive diagnosis to the adult population and the follow-up modalities.

Non-invasive investigation in patients with inflammatory joint disease

Gut inflammation can occur in 30%-60% of patients with spondyloarthropathies.However, the presence of such gut inflammation is underestimated, only 27% of patients with histological evidence of gut inflammation have intestinal symptoms, but subclinical gut inflammation is documented in two-thirds of patients with inflammatory joint disease.There are common genetic and immunological mechanisms behind concomitant inflammation in the joints and intestinal tract.A number of blood tests, e.g.erythrocyte sedimentation rate, orosomucoid, C-reactive protein, and white cell and platelet counts, are probably the most commonly used laboratory markers of inflammatory disease, however, these tests are difficult to interpret in arthropathies associated with gut inflammation, since any increases in their blood levels might be attributable to either the joint disease or to gut inflammation.Consequently, it would be useful to have a marker capable of separately identifying gut inflammation.Fecal proteins, which are indirect markers of neutrophil migration in the gut wall, and intestinal permeability, seem to be ideal for monitoring intestinal inflammation:they are easy to measure non-invasively and are specific for intestinal disease in the absence of gastrointestinal infections.Alongside the traditional markers for characterizing intestinal inflammation, there are also antibodies, in all probability generated by the immune response to microbial antigens and auto-antigens, which have proved useful in establishing the diagnosis and assessing the severity of the condition, as well as the prognosis and the risk of complications.In short, noninvasive investigations on the gut in patients with rheumatic disease may be useful in clinical practice for a preliminary assessment of patients with suspected intestinal disease.

Clinical validation of serum immunosignatures in early diagnosis of Crohn's disease

Background:The search for biomarkers suitable for early diagnosis of Crohn's disease(CD)is challenging.This study investigated the efficacy of serological markers for the early diagnosis of CD.Methods:This was a retrospective nested cohort study.Indirect immuno-fluorescence and enzyme‐linked immunosorbent assay were used to detect ASCA IgG,ASCA IgA,AYMA IgG,AYCA IgG,FI2Y IgG,p‐ANCA IgG,GAB IgG and PAB IgG in patient serum samples.Results:The positive rates of ASCA IgG,ASCA IgA,AYMA IgG,AYCA IgG,FI2Y IgG,p‐ANCA IgG,GAB IgG and PAB IgG in patients with early CD,advanced CD and other intestinal diseases were 37.0%versus 56.8%versus 27.8%;3.7%versus 20.5%versus 19.4%;14.8%versus 2.3%versus 2.8%;25.9%versus 9.1%versus 8.3%;18.5%versus 15.9%versus 8.3%;0.0%versus 2.8%,18.5%;13.6%versus 18.2%versus 16.7%;and 7.4%versus 20.5%versus 0.0%,respectively.The positive rates of ASCA IgG,AYCA IgG and PAB IgG were significantly different among the three groups(p<0.05).In 85.2%of early CD patients,at least one antibody was detected 1 year before diagnosis.The sensitivity of the ASCA/AYMA/AYCA/FI2Y/GAB combination for early diagnosis was 85.2%.The sensitivity of the ASCA/AYMA/AYCA/FI2Y/GAB/PAB/PANCA combination for differentiating CD from other diseases was 87.3%.Conclusions:ASCA IgG and AYCA IgG have potential value in identifying the course of CD.AYCA IgG may be a potential marker for the early diagnosis of CD,and ASCA IgG indicates an advanced stage.The combination of ASCA,AYMA,AYCA,FI2Y,and GAB improves early diagnostic accuracy of CD.

Efficacy of Early Treatment on 52 Patients with Preneoplastic Hepatitis B Virus-Associated Hepatocellular Carcinoma by Compound Phyllanthus Urinaria L.

Objective:To observe the change in the number of antibodies of preneoplastic hepatocellular carcinoma(HCC) using early treatment by Compound Phyllanthus Urinaria L.(CPUL) on patients with preneoplastic hepatitis B virus(HBV)-associated HCC.Methods:A total of 102 cirrhosis patients with regenerative or dysplastic nodules whose sera were tested positive for at least one of these six proteins(five up-regulated genes URG4,URG7,URG11,URG12 and URG19,and one down-regulated gene DRG2) were assigned randomly to two groups using continual random codes by SPSS software.Fifty-two patients were in the treatment group and 50 patients were in the control group.CPUL was used in the treatment group for 3 years,while the control group did not receive any treatment.The changes in HBV-DNA level,number of antibodies,and hepatocarcinogenesis occurred were observed.Patients who did not develop HCC were followed up for another 2 years.Results:HBV-DNA levels decreased >2log in 22.2%(10/45) of patients in the treatment group in contrast to only 5.0%(2/40) of patients in the control group(P=0.0228).The number of antibodies that were tested positive in the treatment group(1.08± 1.01)was significantly lower compared with the control group(2.11 ±1.12) after 24 months of drug treatment(P<0.01).Both the positive rates of anti-URG11(33/52) and anti-URG19(31/52) were over 60%at baseline in the two groups,and were decreased to 48.1%(25/52) and 46.2%(24/52) respectively at 36 months of drug treatment,while the rates increased to 68.0%(34/50) and 66.0%(33/50) respectively(P=0.0417,P=0.0436) in the control group.The positive rate of anti-DRG2 was increased to 55.8%(29/52) at 36 months of drug treatment,while in the control group was decreased to 36.0%(18/50,P=0.0452).Among the 102 patients who developed HCC,2 were in the treatment group and 9 were in the control group,meaning that a significant difference between the two groups(P=0.0212).In11 patients who developed HCC,anti-URG11 and anti-URG19 were always positive,while anti-DRG2 was negative.Patients newly developing HCC were 6(20.0%) in the control group,and only one(2.5%) in the treatment group(P=0.0441) during 2-year follow-up after the end of the treatment.Conclusions:Anti-URG11,anti-URG19 and antiDRG2 could be used as early markers in the prediction of the therapeutic efficacy of CPUL in treating preneoplastic HCC.CPUL is useful in preventing or delaying the development of HBV-associated cirrhosis to HCC.

Evaluating seroprevalence to circumsporozoite protein to estimate exposure to three species of Plasmodium in the Brazilian Amazon

Background:Brazil has seen a great decline in malaria and the country is moving towards elimination.However,for eventual elimination,the control program needs efficient tools in order to monitor malaria exposure and transmission.In this study,we aimed to evaluate whether seroprevalence to the circumsporozoite protein(CSP)is a good tool for monitoring the exposure to and/or evaluating the burden and distribution of Plasmodium species in the Brazilian Amazon.Methods:Cross-sectional surveys were conducted in a rural area of Porto Velho,Rondônia state.Parasite infection was detected by microscopy and polymerase chain reaction.Antibodies to the sporozoite CSP repeats of Plasmodium vivax,P.falciparum,and P.malariae(PvCS,PfCS,and PmCS)were detected using the enzyme-linked immunosorbent assay technique.Human leukocyte antigen(HLA)-DRB1 and DQB1 genes were typed using Luminex®xMAP®technology.Results:The prevalence of immunoglobulin G against P.vivax CSP peptide(62%)was higher than P.falciparum(49%)and P.malariae(46%)CSP peptide.Most of the studied individuals had antibodies to at least one of the three peptides(72%),34%had antibodies to all three peptides and 28%were non-responders.Although the majority of the population was not infected at the time of the survey,74.3%of parasite-negative individuals had antibodies to at least one of the CSPs.Importantly,among individuals carrying the haplotypes DRB1*04~DQB1*03,there was a significantly higher frequency of PfCS responders,and DRB1*16~DQB1*03 haplotype for PvCS and PfCS responders.In contrast,HLA-DRB1*01 and HLA-DQB1*05 allelic groups were associated with a lack of antibodies to P.vivax and P.falciparum CSP repeats,and the haplotype DRB1*01~DQB1*05 was also associated with non-responders,including non-responders to P.malariae.Conclusions:Our results show that in low transmission settings,naturally acquired antibody responses against the CSP repeats of P.vivax,P.falciparum,and P.malariae in a single cross-sectional study may not represent a valuable marker for monitoring recent malaria exposure,especially in an area with a high prevalence of P.vivax.Furthermore,HLA class II molecules play an important role in antibody response and require further study with a larger sample size.It will be of interest to consider HLA analysis when using serosurveillance to monitor malaria exposure among genetically diverse populations.