The spectrum of biochemical alterations with molecular and serological biomarkers in the diagnosis of COVID-19: searching for novel one to identify disease earlier with better prognosis and drug discovery

: Clinical and laboratory predictors of progression to serious and deadly forms are crucial in the fight against COVID-19, which has now become a worldwide pandemic. The clinical laboratory's vital role in today's crises has never been more obvious. These subjective clinical signals can be perceived more confidently during an examination with the help of biomarkers. To best combat present and future pandemics, global unity on test access is required, as well as infection prevention and diagnostic measures that are tightly linked.

Combination of Serological Biomarkers and Clinical Features To Predict Mucosal Healing in Crohn’s Disease: A Multicenter Cohort Study

Background Mucosal healing (MH) has become the treatment goal of patients with Crohn’s disease (CD). This study aims to develop a noninvasive and reliable clinical tool for individual evaluation of mucosal healing in patients with Crohn’s disease. Results The following variables were independently associated with the MH and were subsequently included into the prediction model: PLR (platelet to lymphocyte ratio), CAR (C-reactive protein to albumin ratio), ESR (erythrocyte sedimentation rate), HBI (Harvey-Bradshaw Index) score and infliximab treatment. A primary model and a simple model were established, respectively. The primary model performed better than the simple one in C-index (87.5% vs 83.0 %, p=0.004). There was no statistical significance between these two models in sensitivity (70.43% vs 62.61%, p=0.467), specificity (87.12% vs 80.69%, p=0.448), PPV (72.97% vs 61.54%, p=0.292), NPV (85.65% vs 81.39%, p=0.614), and accuracy (81.61% vs 74.71%, p=0.303). The primary model had good calibration and high levels of explained variation and discrimination in validation cohort. Conclusions This model can be used to predict MH in post-treatment CD patients. It can also be used as an indication of endoscopic surveillance to evaluate mucosal healing in patients with CD after treatment.

Precision Public Health Through Serological Biomarkers: An Integrated Surveillance Platform to Inform Public Health Interventions

The use of biomarkers to measure immune responses in serum is crucial for understanding population-level exposure and susceptibility to human pathogens. Advances in sample collection, multiplex testing, and computational modeling are transforming serosurveillance into a powerful tool for public health program design and response to infectious threats. In July 2018, 70 scientists from 20 countries met to perform a landscape analysis of approaches that support an integrated serosurveillance platform, including the consideration of issues for successful implementation. Here, we summarize the group’s insights and proposed roadmap for implementation, including objectives, technical requirements, ethical issues, logistical considerations, and monitoring and evaluation.

Carbohydrate Antigen 125 Supplements Carbohydrate Antigen 19-9 for the Prediction of Invasive Intraductal Papillary Mucinous Neoplasms of the Pancreas

BackgroundIntraductal papillary mucinous neoplasm (IPMN) is a disease with malignant potential. IPMNs of the pancreas are mainly managed according to radiographic indications, which lack accuracy in defining grades of IPMNs. Therefore, other indications such as serological biomarkers should be employed to predict the invasiveness of IPMNs.MethodsWe investigated preoperative serum levels of CA19-9, CA125 and CEA of 381 surgical patients with a definite pathological diagnosis of IPMN from July 2010 to December 2019 at Shanghai Cancer Center. We calculated the Youden indices of each point of receiver operating characteristic (ROC) curves to find the most appropriate cut-off values of CA19-9, CA125 and CEA in recognizing malignant IPMNs. Serological biomarker differences were correlated with grades and biological behaviours of IPMNs. Diagnostic indices of these serum biomarkers were calculated.ResultsMalignant group had higher serum levels of CA19-9, CA125 and CEA. According to ROC curves, the most appropriate cut-off value of CA125 were readjusted to 13.5 U/ml while the cut-off values of CA19-9 and CEA remained 37 U/ml and 5.3 ng/l as them mostly be employed. Besides, CA19-9 elevation was significantly associated with vascular invasion and perineural infiltration. We found CA125 may predict invasive IPMN in CA19-9 negative subgroup according to ROC curve. ConclusionsSerological biomarkers are useful and sensitive indications for recognizing invasive IPMNs. CA19-9 has the upmost diagnostic indices among all regularly used serum biomarkers in differentiating malignant and benign IPMNs. CA19-9 should be combined with CA125 to form a more favourable biomarker panel for IPMNs malignancy prediction.

Development of an Enzyme-Linked Immunosorbent Assay (ELISA) for Accurate and Prompt Coronavirus Disease 2019 (COVID-19) Diagnosis Using the Rational Selection of Serological Biomarkers

Prompt COVID-19 diagnosis is urgently required to support infection control measures. Currently available serological tests for measuring SARS-CoV-2 antibodies use different target antigens, although their sensitivity and specificity presents a challenge. We aimed to develop an “in-house” serological ELISA to measure antibodies against SARS-CoV-2 by combining different protein antigens. Sera (n = 44) from COVID-19-confirmed patients were evaluated against different SARS-CoV-2 protein antigens and all potential combinations using ELISA. Patients’ sera were also evaluated against commercially available ELISA diagnostic kits. The mixture containing RBD 2.5 μg/mL, S2 1 μg/mL and N 1.5 μg/mL was found to be the most potent. Plates were incubated with patients’ sera (1:100), and goat anti-human alkaline phosphatase-conjugated IgG, ΙgM and IgA antibody was added. The cut-off value for each assay was determined using the mean optical density plus two standard deviations of pre-pandemic controls. The “in-house” ELISA displayed 91% sensitivity and 97% specificity for IgG antibodies, whereas its sensitivity and specificity for IgM and IgA were 75% and 95% and 73% and 91%, respectively. The “in-house” ELISA developed here combined three SARS-CoV-2 antigens (RBD, S2 and N) as capture antigens and displayed comparable and even higher sensitivity and specificity than otherwise quite reliable commercially available ELISA diagnostic kits.

A PTX3/LDH/CRP signature correlates with lung injury CTs scan severity and disease progression in paucisymptomatic COVID-19

Background Quantitative CT (QCT) analysis is an invaluable diagnostic tool to assess lung injury and predict prognosis of patients affected by COVID-19 pneumonia. PTX3 was recently described as one of the most reliable serological predictors of clinical deterioration and short-term mortality. The present study was designed to evaluate a correlation between serological biomarkers of inflammation and lung injury measured by QCT. Methods This retrospective monocentric study analysed a cohort of patients diagnosed with COVID-19 and admitted because of respiratory failure, or significant radiological involvement on chest CT scan. All patients, males and non-pregnant females older than 18 years, underwent chest CT scan and laboratory testing at admission. Exclusion criteria were defined by concurrent acute pathological processes and ongoing specific treatments which could interfere with immune activity. The cohort was stratified based on severity in mild and severe forms. Compromised lung at QCT was then correlated to serological biomarkers representative of Sars-CoV-2. We further developed a multivariable logistic model to predict CT data and clinical deterioration based on a specific molecular signature. Internal cross-validation led to evaluate discrimination, calibration, and clinical utility of the tool that was provided by a score to simplify its application. Findings 592 patients were recruited between March 19th and December 1st, 2020. Applying exclusion criteria which consider confounders, the cohort resulted in 366 individuals characterized by 177 mild and 189 severe forms. In our predictive model, blood levels of PTX3, CRP and LDH were found to correlate with QCT values in mild COVID-19 disease. A signature of these three biomarkers had a high predictive accuracy in detecting compromised lungs as assessed by QCT. The score was elaborated and resulted representative of lung CT damage leading to clinical deterioration and oxygen need in mild disease. Interpretation The LDH, PTX3, CRP blood signature can serve as a strong correlate of compromised lung in COVID-19, possibly integrating cellular damage, systemic inflammation, myeloid and endothelial cell activation.

Detection and Evaluation of Serological Biomarkers to Predict Osteoarthritis in Anterior Cruciate Ligament Transection Combined Medial Meniscectomy Rat Model

Biomarkers are essential tools in osteoarthritis (OA) research, clinical trials, and drug development. Detecting and evaluating biomarkers in OA research can open new avenues for researching and developing new therapeutics. In the present report, we have explored the serological detection of various osteoarthritis-related biomarkers in the preclinical model of OA. In this surgical OA model, we disrupted the medial tibial cartilage’s integrity via anterior cruciate ligament transection combined with medial meniscectomy (ACLT+MMx) of a single joint of Wistar rats. The progression of OA was verified, as shown by the microscopic deterioration of cartilage and the increasing cartilage degeneration scoring from 4 to 12 weeks postsurgery. The concentration of serological biomarkers was measured at two timepoints, along with the complete blood count and bone electrolytes, with biochemical analysis further conducted. The panel evaluated inflammatory biomarkers, bone/cartilage biomarkers, and lipid metabolic pathway biomarkers. In chronic OA rats, we found a significant reduction of total vitamin D3 and C-telopeptide fragments of type II (CTX-II) levels in the serum as compared to sham-operated rats. In contrast, the serological levels of adiponectin, leptin, and matrix metallopeptidase (MMP3) were significantly enhanced in chronic OA rats. The inflammatory markers, blood cell composition, and biochemical profile remained unchanged after surgery. In conclusion, we found that a preclinical model of single-joint OA with significant deterioration of the cartilage can lead to serological changes to the cartilage and metabolic-related biomarkers without alteration of the systemic blood and biochemical profile. Thus, this biomarker profile provides a new tool for diagnostic/therapeutic assessment in OA scientific research.

Changes in serum biomarkers of inflammation in bovine besnoitiosis

Background Acute and chronic besnoitiosis in extensive natural-service herds can have relevant effects in the health of bulls and negative consequences in their productive performance. Recent progress has been made in order to elucidate the pathogenesis of this disease. In this context, the study of biomarkers of inflammation in serum would contribute to gaining knowledge about the physiopathology of bovine besnoitiosis. Serological biomarkers could help in early diagnosis and prognosis, as seropositive bulls may have mild or severe testicular lesions. Methods Herein, we have investigated the diagnostic and/or prognostic value of a panel of serum (serological) biomarkers related to inflammation, including total protein, globulin and albumin, haptoglobin (Hp), adenosine deaminase (ADA) paraoxonase-1 (PON-1) and acetylcholinesterase (AChE) in naturally and experimentally B. besnoiti-infected males classified according to different clinical phases of the disease (acute, chronic and subclinical besnoitiosis). Results Results showed a similar response pattern in these biomarkers for naturally and experimentally infected cattle, with a few relevant variations. Most significant changes occurred during the acute phase of infection, although significant changes in a few biomarkers were also observed during the chronic infection. Haptoglobin, albumin, PON-1 and ADA were identified as the biomarkers that showed changes of higher magnitude in the acute phase of the infection, whereas high total protein and globulin values were found in chronically infected cattle. We have described the changes of a panel of inflammatory biomarkers of acute and chronic bovine besnoitiosis. Conclusions In summary, several biomarkers with promising diagnostic value have been identified. The biomarkers associated with acute infection are related to previously reported molecular biomarkers in testicular parenchyma of infected bulls and could help in the diagnosis of early infections and complement results from specific immunoglobulin M (IgM) detection. Graphical abstract

Peripheral B-Cell Immunophenotyping Identifies Heterogeneity in IgG4-Related Disease

ObjectivesTo elucidate heterogeneity of IgG4-related disease (IgG4-RD) based on B cell immunophenotyping.MethodsImmunophenotyping of 4 B-cell subsets in peripheral blood from patients with active IgG4-RD (aIgG4-RD, n=105) was performed using flow cytometry to get preliminary B-cell heterogeneity spectrum. Then 10 B-cell subsets were characterized in aIgG4-RD (n = 49), remissive IgG4-RD (rIgG4-RD, n = 49), and healthy controls (HCs, n = 47), followed by principal components analysis (PCA) and cluster analysis to distinguish B-cell immunophenotypes and classify IgG4-RD patients into subgroups.ResultsCluster analysis identified two endotypes in 105 aIgG4-RD patients based on 4 B-cell subsets: Group1 with higher Breg and naive B cells (n = 48), and Group2 with higher plasmablasts and memory B cells (MBCs) (n = 57). PCA indicated that aIgG4-RD consisted of plasmablast-naive B cell and MBCs-Breg axes abnormalities. There was a negative relationship between naive B cells and disease activity. Both plasmablasts and MBCs were positively associated with serological biomarkers. Cluster analysis stratified aIgG4-RD patients into 3 subgroups based on 10 B-cell subsets: subgroup1 with low MBCs and normal Breg, subgroup2 with high MBCs and low Breg, and subgroup3 with high plasmablasts and low naive B cells. Patients in subroup2 and subgroup3 were more likely to be resistant to treatment.ConclusionPatients with aIgG4-RD can be divided into 3 subgroups based on B cell heterogeneity. The B cell immunophenotyping could help elucidate the pathogenesis of IgG4-RD, identify patients with potential refractory IgG4-RD, and provide important information for the development of new therapies.