Predictive potential of serum and cerebrospinal fluid biomarkers for disease activity in treated multiple sclerosis patients.

BACKGROUND: Our objective was to explore various biomarkers for predicting suboptimal responses to disease-modifying treatments (DMTs) in patients with MS (pwMS). METHODS: We conducted a longitudinal, bicentric study with pwMS stratified based on their DMTs responses. Treatment failure (TF) was defined as the onset of a second relapse, presence of two or more T2 new lesions, or disability progression independent of relapse during the follow-up period. We evaluated intrathecal synthesis (ITS) of IgG and IgM using OCB, linear indices, and Reibergrams. Free kappa light chains ITS was assessed using the linear index (FKLCi). NfL and GFAP in serum and CSF, and CHI3L1 in CSF were quantified. Quantitative variables were dichotomized based on the third quartile. Predictive efficacy was assessed through bivariate and multivariate analyses, adjusting for age, sex, EDSS, acute inflammatory activity (AI) -defined as the onset of a relapse or gadolinium-enhancing lesions within a 90-day window of lumbar puncture-, treatment modality, study center, and time from disease onset to treatment initiation. In case of collinearity, multiple models were generated or confounding variables were excluded if collinearity existed between them and the biomarker. The same methodology was used to investigate the predictive potential of various combinations of two biomarkers, based on whether any of them tested positive or exceeded the third quartile. RESULTS: A total of 137 pwMS were included. FKLCi showed no differences based on AI, no correlation with EDSS and was significantly higher in pwMS with TF (p = 0.008). FKLCi>130 was associated with TF in bivariate analysis (Log-Rank p = 0.004). Due to collinearity between age and EDSS, two different models were generated with each of them and the rest of the confounding variables, in which FKLCi>130 showed a Hazard Ratio (HR) of 2.69 (CI: 1.35-5.4) and 2.67 (CI: 1.32-5.4), respectively. The combination of either FKLC or sNfL exceeding the third quartile was also significant in bivariate (Log-Rank p = 0.04) and multivariate (HR=3.1 (CI: 1.5-6.5)) analyses. However, when analyzed independently, sNfL did not show significance, and FKLCi mirrored the pattern obtained in the previous model (HR: 3.04; CI: 1.51-6.1). Treatment with highefficacy DMTs emerged as a protective factor in all models. DISCUSSION: Our analysis and the fact that FKLCi is independent of EDSS and AI suggest that it might be a valuable parameter for discriminating aggressive phenotypes. We propose implementing high-efficacy drugs in pwMS with elevated FKLCi.

Evaluating the diagnostic performance of Liaison® chemiluminescence assay as screening tool for detection of acute Epstein-Barr infection: A comparative study.

The present investigation assessed the Liaison® diagnostic performance in detecting Epstein-Barr (EBV) IgM-VCA in a large patient cohort, considering age and symptomatology. VIDAS® were employed as a benchmark for acute EBV infection. The study also probed other coexisting conditions and potential cross-reactivity for error sources. A total of 1311 samples were analyzed, with notable associations found only among paediatric (kappa=0.75) and young adult (kappa=0.58) populations with compatible symptoms. ROC analysis revealed varying optimal cutoff values based on age and symptom categorizations. Logistic regression models identified age and patients from Oncology or Infectious Disease as significant factors for false positives. Potential interferences emerged with RF, ANCA, cytomegalovirus-IgM and VHS-IgM. Notably, Liaison® couldn´t distinguish EBV patients from Oncology, Haemathology or Internal Medicine. This study provides valuable insights, such as implementing ageand symptom-specific thresholds or reviewing test requests, for optimizing EBV serology in microbiology laboratories, leading to faster and more reliable responses.

Improving the efficiency of free kappa light chains as diagnostic biomarker of Multiple Sclerosis by using a novel algorithm.

BACKGROUND: Intrathecal immunoglobulin synthesis (ITS) plays a crucial role in the diagnosis of multiple sclerosis (MS). Traditionally, the gold standard method for detecting ITS has been through the analysis of oligoclonal bands (OCB). However, the paradigm has shifted with the introduction of the free kappa light chains (FKLC) method. In fact, a recent consensus recommends evaluating FKLC index (FKLCi) as the primary approach and reserving oligoclonal bands with borderline results. The objective of our study is to investigate the diagnostic efficiency of combining FKLC with other methods to predict ITS while minimizing the reliance on OCB. METHODS: A total of 192 patients were included in the study, consisting of 145 individuals diagnosed with multiple sclerosis (pwMS) and 46 with other neurological diseases (controls). Among the MS cases, 100 patients were assigned to the Training Cohort (TC), while an external Validation Cohort (VC) comprised of 45 MS patients was established. Diagnostic efficiency was assessed for FKLCi, OCB, Link index, and the Reiber formula for IgG and FKLC. Optimal cutoff values for Link index and FKLCi were also determined. The last procedure was developed for diverse algorithms using the parameters mentioned above, which included the optimal cutoffs previously obtained. The calculations were conducted independently for both the TC and the VC, as well as for a composite cohort formed by combining data from all patients (OC) RESULTS: One algorithm, named KRO, was developed based on the determination of FKLCi and Reiber Formula as the primary diagnostic parameters. For cases where the FKLCi result was mildly increased, OCB was utilized as a supplementary test. The KRO algorithm demonstrated superior diagnostic accuracy in the OC (89%), resulting in a reduction of OCB consumption by 91%. DISCUSSION: The KRO algorithm demonstrated superior sensitivity and accuracy although lower specificity and NPV compared to the use of FKLCi and OCB alone. The present research aligns with the new consensus recommendations regarding the diagnostic approach. Our findings indicate that employing a combined marker approach via KRO could prove to be a proficient screening tool for multiple sclerosis. This approach also holds the potential to address inherent limitations associated with each individual marker. However, to further validate and solidify the efficacy of our algorithm, additional studies involving larger cohorts are warranted.

IgG antibody response to pneumococcal-conjugated vaccine (Prevenar®13) in children with immunodeficiency disorders.

Measurement of anti-pneumococcal capsular polysaccharides (anti-PnPs) IgG titers is an important tool in the immunologic assessment of patients with suspected immunodeficiency disorders (ID) to reduce the morbi-mortality and minimize severe infections. Retrospectively, we studied the relationship among anti-PnPs IgG response to 3 doses of Prevenar®13, levels of immune system components, leukocyte populations, and clinical data in children with ID. Serum samples were collected at least 4 weeks post vaccination. Subsequently, multi-serotype enzyme-linked immunosorbent assay (ELISA) was performed. Eighty-seven children (under 12 years) were enrolled. Primary immunodeficiency disorder (PID) was the most common disorder (45) followed by possible immunodeficiency disorder (POID) (19), secondary immunodeficiency disorder (SID) (15), and mixed immunodeficiency disorder (MID) (8). The median age was 3 (1.50-5.33) years, 65% of patients were male. Deficient production of anti-PnPs IgG (titer ≤ 50 mg/L) was detected in 47 patients (54%), especially in the MID group, all of them under immunosuppressive therapy. In PCV13 responders, the mean of leukocyte population levels was higher with statistically significance differences in CD4 + /CD8 + T lymphocytes (p = 0.372, p = 0.014) and CD56 + /CD16 + NK (p = 0.016). Patients with previous bone marrow transplantation were the worst PCV13 responders. Pneumococcal IgG antibody titers (post-vaccination) along with clinical and analytical markers represented.