INTRODUCTION AND OBJECTIVES:Early diagnosis of primary biliary cholangitis (PBC) is fundamental, as treatment with ursodeoxycholic acid (UDCA) prevents its progression. The aim of our study is to investigate undiagnosed patients in our region and to treat retrieved patients. PATIENTS AND METHODS:Analysis of databases (immunology, biochemistry and other data from their medical records) was performed between January 2019 and December 2021. PBC was diagnosed if anti-mitochondrial antibodies were positive (>1:80) and alkaline phosphatase (AP) was chronically elevated in the absence of other liver disease. Identified patients were contacted. RESULTS:A total of 306 patients were identified and 221 had previously been diagnosed with PBC and were undergoing treatment. Fifty-one patients did not meet the current criteria for diagnosis and treatment at their last blood test. Six patients had died by the time the study started. Finally, we found 28 patients with a probable diagnosis of PBC who could benefit from treatment (9.6%). We contacted all 28 patients and 16 (57.14%) of them agreed to come to our hospital for diagnosis confirmation, ultrasound and fibroscan. All of them were women, aged between 46 and 74 years (mean 61.18, SD 9.19). Laboratory analysis showed a mean AP of 144.25 (SD 71.03) and mean GGPT of 115.62 (SD 98.42). Mean bilirubin was 0.55 (SD 0.22). Fibroscan showed a mean value of 6.05 kPa. UDCA was initiated in 14 patients; two patients refused treatment. CONCLUSIONS:The use of hospital databases enabled us to diagnose and treat 16 (57.14%) of the 28 detected patients.

Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease in which immune dysregulation plays a central role. As the life expectancy of people with MS (pwMS) increases, understanding how aging affects their immune system-collectively referred to as immunosenescence-has become crucial. In this study, we characterized immunosenescence in pwMS by analyzing age-related changes in the immune system. To fulfill this, blood samples were collected from pwMS and healthy controls (HCs) of independent cohorts: i) immune cell populations were assessed in PBMCs (n= 110), ii) thymic involution and telomere attrition were measured in DNA samples (n=150), and iii) inflammatory and neurodegeneration markers were evaluated in plasma (n=146).Our results revealed distinct age-associated alterations in immune cell subsets between pwMS and HCs, including B and NK cells. Notably, pwMS showed an age-related increase in CD28-CD57+ and CD28+CD57+ cells in CD4+ and CD8+ T cells. Thymic involution was reported with age in both groups and, importantly, we found a more pronounced thymic involution in younger pwMS. A positive correlation was found between age and the levels of IL-6, TNF-α, and CRP in pwMS, results consistent with the inflammaging phenomenon. Similarly, NFL levels were elevated in pwMS and correlated positively with age in both groups., Remarkably, we found a positive correlation between NFL levels and IL-6, and between NFL levels and TNF-α only in pwMS. Telomere shortening occurred with age in both groups, without significant differences. Notably, our study provides an integrative and multi-biomarker characterization of immune aging process in pwMS, revealing new insights into this complex relationship. These findings highlight specific age-related immune alterations in MS and underscore the importance of incorporating age and immunosenescence monitoring into MS clinical management and therapeutic strategies.

Multiple Sclerosis (MS) is a chronic, immune-mediated disease characterized by demyelination, axonal damage, and cognitive impairment. Emerging evidence suggests that disruptions in cholesterol metabolism contribute to MS progression, as cholesterol and related sterols play a crucial role in immune regulation and myelin composition.This study analyzed cholesterol, non cholesterol sterols (NCS), and oxysterols in serum and cerebrospinal fluid (CSF) from 127 individuals with clinically isolated syndrome, relapsing-remitting MS or primary progressive MS as well as 49 individuals wirh other neurological disorders (OND). Additionally, serum Neurofilament light chain (NfL), a marker of axonal damage, was measured.Results revealed significant alterations in cholesterol metabolism in MS. Serum cholesterol and cholesterol synthesis markers were elevated, while CSF cholesterol levels were reduced, indicating a contrasting pattern between peripheral and central cholesterol metabolism. Cholesterol absorption was notably decreased in individuals with MS. NfL levels mirrored the pattern observed in serum cholesterol but were inversely related to CSF cholesterol, suggesting a potential link between axonal damage and disease progression. Importantly, serum-CSF correlation varied by MS type and gender.The observed gender-specific differences in cholesterol metabolism may contribute to our understanding of the distinct disease manifestations in men and women and should be taken into account in both the diagnosis and treatment of MS. The findings also suggest that impaired cholesterol synthesis in the brain may play a role in MS pathology, with reduced CSF cholesterol levels potentially serving as a marker of demyelination. Furthermore, specific serum (oxy)sterols emerged as promising biomarkers for MS diagnosis and progression. Together, these insights improve our understanding of MS and may support the identification of novel diagnostic markers and therapeutic targets.

BACKGROUND:Common variable immunodeficiency (CVID) includes a heterogeneous group of disorders of predominantly antibody deficiencies featuring infectious and noninfectious complications that might lead to severe organ damage and shortened survival. Appropriate clinical management of CVID has been hampered by the lack of robust biomarkers to predict the development of clinical complications and patient outcome. OBJECTIVE:We investigated the association of individual serologic, cellular, and molecular biomarkers with disease behavior and outcome in CVID. METHODS:A multicenter cohort of 209 CVID patients was studied using age-matched reference values from 334 healthy donors to better define TCD4+-naive cell defects (late-onset combined immunodeficiency [LOCID]) and classify CVID-associated B-cell/plasma cell (PC) and natural killer (NK) cell defects. RESULTS:Globally, susceptibility to respiratory infections was strongly associated with low serum immunoglobulin (sIg), particularly sIgA, whereas noninfectious complications and disease severity mostly depended on TCD4+-naive cell, NK cell, and B-cell/PC defects. LOCID was independently associated with splenomegaly, lymphadenopathy, interstitial lung disease, cytopenia, and lymphoma. Milder B-cell/PC defects (MBC+/PC+/Ab-) protected from noninfectious complications, whereas a marked defect of classical CD27+ memory B cells (27MBC-) (with decreased NK cell and sIgM) was associated with enteropathy and (with LOCID and sIgA) liver disease. Together, lower sIgG, LOCID, and particularly 27MBC-, were strongly associated with shorter survival and early death in CVID. Conversely, CVID-associated pathogenic/risk alleles did not emerge as independent factors associated with disease behavior and outcome. CONCLUSION:Our results provide a new set of biomarkers closely associated with infectious and noninfectious complications of CVID, which together predict survival and might contribute to guide patient monitoring and clinical management.

Emerging evidence suggests that the severe-acute-respiratory-syndrome-related coronavirus (SARS- CoV-2) infection and anti-SARS-CoV-2 vaccines may trigger autoimmune responses in genetically predisposed individuals. Idiopathic inflammatory myopathies (IIMs) are a group of diseases with a broad spectrum of clinical manifestations featured by the presence of myositis autoantibodies (MAs). The diagnosis of IIM is challenging due to the limitations of current classification criteria and diagnostic assays. We conducted a multicenter observational study, whose main goal was to describe the incidence of IIM following exposure to SARS-CoV-2 infection and/or its specific vaccination, and to compare the rates of both. A total of 788 patients belonging to 11 different Spanish referral centers were analyzed, with a cumulative count of 1,209 MAs measured by line blot immunoassays (LIA). The study identified distinct patterns in the frequency of aminoacyl-tRNA synthetase (ARS) antibodies compared to pre-pandemic periods. Notably, the most prevalent ARS antibody identified associated to IIM was anti-PL-7 (14.85%), whereas anti-Jo1, traditionally the most frequent antibody documented, had a frequency of 7.23% in our cohort. Anti- MDA5, the most commonly described antibody in the literature associated with the SARS-CoV-2 infection, was identified in 11.68% of our patients. Our cohort displayed positive antinuclear antibodies (ANA) result in 61% of patients, which suggests an underlying autoimmune background. The most prevalent final diagnoses were anti- synthetase syndrome (ASSD) or IIM-non-ASSD (21.31% of total cases) and other systemic autoimmune diseases (SAID) with 13.57% of cases. 91.13% of patients received at least one dose of a messenger RNA (mRNA) coronavirus disease 2019 (COVID-19) vaccine, with a median of three doses per patient. It is noteworthy that patients with prior SARS-CoV-2 infection or heterologous vaccination demonstrated a higher frequency of multiple autoantibody positivity (p<0.05), which could reflect different humoral and cellular immune signatures. This collaborative work enhances our understanding of IIM and may facilitate the optimization of care through the implementation of standardized approaches. Further investigation is required to fully characterize the autoimmune risks and phenotypes following a diagnosis of SARS-CoV-2 infection or vaccination.Emerging evidence suggests that the severe-acute-respiratory-syndrome-related coronavirus (SARS- CoV-2) infection and anti-SARS-CoV-2 vaccines may trigger autoimmune responses in genetically predisposed individuals. Idiopathic inflammatory myopathies (IIMs) are a group of diseases with a broad spectrum of clinical manifestations featured by the presence of myositis autoantibodies (MAs). The diagnosis of IIM is challenging due to the limitations of current classification criteria and diagnostic assays. We conducted a multicenter observational study, whose main goal was to describe the incidence of IIM following exposure to SARS-CoV-2 infection and/or its specific vaccination, and to compare the rates of both. A total of 788 patients belonging to 11 different Spanish referral centers were analyzed, with a cumulative count of 1,209 MAs measured by line blot immunoassays (LIA). The study identified distinct patterns in the frequency of aminoacyl-tRNA synthetase (ARS) antibodies compared to pre-pandemic periods. Notably, the most prevalent ARS antibody identified associated to IIM was anti-PL-7 (14.85%), whereas anti-Jo1, traditionally the most frequent antibody documented, had a frequency of 7.23% in our cohort. Anti- MDA5, the most commonly described antibody in the literature associated with the SARS-CoV-2 infection, was identified in 11.68% of our patients. Our cohort displayed positive antinuclear antibodies (ANA) result in 61% of patients, which suggests an underlying autoimmune background. The most prevalent final diagnoses were anti- synthetase syndrome (ASSD) or IIM-non-ASSD (21.31% of total cases) and other systemic autoimmune diseases (SAID) with 13.57% of cases. 91.13% of patients received at least one dose of a messenger RNA (mRNA) coronavirus disease 2019 (COVID-19) vaccine, with a median of three doses per patient. It is noteworthy that patients with prior SARS-CoV-2 infection or heterologous vaccination demonstrated a higher frequency of multiple autoantibody positivity (p<0.05), which could reflect different humoral and cellular immune signatures. This collaborative work enhances our understanding of IIM and may facilitate the optimization of care through the implementation of standardized approaches. Further investigation is required to fully characterize the autoimmune risks and phenotypes following a diagnosis of SARS-CoV-2 infection or vaccination.

Objective: This study aimed to unravel the single tetraspanin pattern of extracellular vesicles (EVs), L1CAM+ and GLAST+ EV levels as diagnostic biomarkers to stratify people with multiple sclerosis (pwMS), specifically relapsing–remitting (RRMS) and primary progressive (PPMS). Methods: The ExoView platform was used to directly track single EVs using a clinically feasible volume of cerebrospinal fluid (CSF) and serum samples. This technology allowed us to examine the patterns of classical tetraspanin and quantify the levels of L1CAM and GLAST proteins, commonly used to immunoisolate putative neuron- and astrocyte-derived EVs. Results: The tetraspanin EV pattern does not allow us to differentiate RRMS, PPMS and non-MS donors neither in CSF nor serum, but this was associated with the type of biofluid. L1CAM+ and GLAST+ EVs showed a very low presence of tetraspanin proteins. Additionally, a significant decrease in the particle count of L1CAM+ EVs was detected in L1CAM-captured spots, and L1CAM+ and GLAST+ EVs decreased in GLAST-captured spots in the CSF from PPMS subjects compared to RRMS. Interestingly, only GLAST+ EVs exhibited a lower quantity in the CSF from PPMS compared to both MS and non-MS samples. Finally, GLAST+ EVs demonstrated a medium negative and significative correlation with GFAP levels—a biomarker of MS progression, astrocyte damage and neurodegenerative processes. Conclusions: ExoView technology could track neural EV biomarkers and be potentially useful in the diagnostic evaluation and follow-up of pwMS. GLAST+ EVs might provide insights into the etiology of PPMS and could offer small windows to elucidate the molecular mechanisms behind its clinical presentation.

Background: Emerging evidence suggests that SARS-CoV-2 infection and vaccines may trigger autoimmune responses in predisposed individuals. Idiopathic inflammatory myopathies (IIMs) are diseases with diverse clinical manifestations, often associated with myositis autoantibodies (MAs). Diagnosing IIM is challenging due to limitations in classification criteria and diagnostic assays. This study aimed to describe the incidence of IIM following SARS-CoV-2 infection or vaccination and compare rates between exposures. Methods: A multicenter observational study was conducted with 788 patients from 11 Spanish referral centers. A total of 1209 autoantibodies including myositis-specific autoantibodies (MSAs) and myositis-associated autoantibodies (MAAs), were analyzed using line blot immunoassay (LIA). Results: The study identified distinct patterns in aminoacyl-tRNA synthetase (ARS) antibody frequencies compared to pre-pandemic periods. Anti-PL-7 was the most prevalent ARS antibody (14.85%), while anti-Jo-1 was less frequent (7.23%). Anti-MDA5, commonly linked to SARS-CoV-2 infection, was detected in 11.68%. ANA positivity was observed in 60.66%, suggesting an autoimmune background. The most frequent diagnoses were anti-synthetase syndrome (ASSD) or IIM-non-ASSD (21.31%), followed by other systemic autoimmune diseases (SAIDs) (13.57%). Among the cohort, 91.13% received at least one dose of a messenger RNA (mRNA) COVID-19 vaccine, with a median of three doses per patient. Patients with prior SARS-CoV-2 infection or heterologous vaccination showed a higher frequency of multiple autoantibody positivity (p < 0.05), reflecting distinct immune signatures. Conclusions: This study provides valuable insights into the autoimmune risks and phenotypes associated with SARS-CoV-2 infection and vaccination, establishing a basis for further research on IIM and its link to MSAs and MAAs.

Anti-dsDNA autoantibodies are listed as one of the classification criteria for systemic lupus erythematosus (SLE) and are relatively effective indicators for monitoring disease activity and treatment response. Therefore, clinicians rely on them to diagnose and adjust medication and treatment strategies for SLE patients. However, the use of anti-dsDNA antibodies is not free from controversy. Part of this controversy stems from the fact that anti-dsDNA antibodies are found in several disorders, besides SLE. In addition to this, anti-dsDNA antibodies are a heterogeneous group of antibodies, and their determination still lacks proper standardization. Moreover, anti-dsDNA testing specificity and diagnostic performance change depending on the population under study. These and other issues result in inconsistency and encumber the clinical use of anti-dsDNA antibodies. A panel of medical laboratory and clinical experts on SLE discussed such issues based on their clinical experience in a first meeting, establishing a series of recommendations. The proceedings of this first meeting, plus an exhaustive review of the literature, were used to compose a paper draft. The panel subsequently discussed and refined this draft in a second meeting, the result of which is this paper. This document is relevant to clinical laboratories as it guides to improving diagnosis and monitoring of SLE. Simultaneously, it will help laboratories compile more informative reports, not limited to a mere number. It is also relevant to clinical doctors who wish to better understand laboratory methods so that they can do a more efficient, better-aimed laboratory test ordering.

Antinuclear antibodies (ANA) are the most widely used immunological test for the diagnosis of autoimmune diseases. Despite the recommendations of experts, there is some variability in performing and interpreting this test in routine practice. In this context, the Spanish Group on Autoimmune Diseases (GEAI) of the Spanish Society of Immunology (SEI) conducted a national survey of 50 autoimmunity laboratories. Here we report the survey results on ANA testing, detection of related antigens, and our recommendations. The survey showed that most of the participating laboratories use a similar approach for most key practices: 84% perform ANA by indirect immunofluorescence (IIF) on HEp-2 cells as the screening methodology while the other laboratories use IIF to confirm positive screens; 90% report ANA test results as either negative or positive with titer and pattern; 86% indicated that the ANA pattern conditioned follow-up testing for specific antigen-related antibodies; and 70% confirm positive anti-dsDNA. However, testing practices were highly heterogeneous for certain items, such as sera dilutions and the minimum time period for repeating ANA and related antigen determinations. Overall, this survey shows that most autoimmune laboratories in Spain use a similar approach but that further standardization of testing and reporting protocols is needed.

IntroductionGood syndrome (GS) is a rare adult-onset immunodeficiency first described in 1954. It is characterized by the coexistence of a thymoma and hypogammaglobulinemia, associated with an increased susceptibility to infections and autoimmunity. The classification and management of GS has been long hampered by the lack of data about the underlying immune alterations, a controversy existing on whether it is a unique diagnostic entity vs. a subtype of Common Variable Immune Deficiency (CVID).MethodsHere, we used high-sensitive flow cytometry to investigate the distribution of up to 70 different immune cell populations in blood of GS patients (n=9) compared to age-matched CVID patients (n=55) and healthy donors (n=61).ResultsAll 9 GS patients displayed reduced B-cell counts -down to undetectable levels (<0.1 cells/μL) in 8/9 cases-, together with decreased numbers of total CD4+ T-cells, NK-cells, neutrophils, and basophils vs. age-matched healthy donors. In contrast, they showed expanded TCRγδ+ T-cells (p ≤ 0.05). Except for a deeper B-cell defect, the pattern of immune cell alteration in blood was similar in GS and (age-matched) CVID patients. In depth analysis of CD4+ T-cells revealed significantly decreased blood counts of naïve, central memory (CM) and transitional memory (TM) TCD4+ cells and their functional compartments of T follicular helper (TFH), regulatory T cells (Tregs), T helper (Th)2, Th17, Th22, Th1/Th17 and Th1/Th2 cells. In addition, GS patients also showed decreased NK-cell, neutrophil, basophil, classical monocyte and of both CD1c+ and CD141+ myeloid dendritic cell counts in blood, in parallel to an expansion of total and terminal effector TCRγδ+ T-cells. Interestingly, those GS patients who developed hypogammaglobulinemia several years after the thymoma presented with an immunological and clinical phenotype which more closely resembled a combined immune humoral and cellular defect, with poorer response to immunoglobulin replacement therapy, as compared to those in whom the thymoma and hypogammaglobulinemia were simultaneously detected.DiscussionOur findings provide a more accurate definition of the immune cell defects of GS patients and contribute to a better discrimination among GS patients between those with a pure B-cell defect vs. those suffering from a combined immunodeficiency with important consequences on the diagnosis and management of the disease.

COVID-19 pandemic has put the protocols and the capacity of our Hospitals to the test. The management of severe patients admitted to the Intensive Care Units has been a challenge for all health systems. To assist in this challenge, various models have been proposed to predict mortality and severity, however, there is no clear consensus for their use. In this work, we took advantage of data obtained from routine blood tests performed on all individuals on the first day of hospitalization. These data has been obtained by standardized cost-effective technique available in all the hospitals. We have analyzed the results of 1082 patients with COVID19 and using artificial intelligence we have generated a predictive model based on data from the first days of admission that predicts the risk of developing severe disease with an AUC = 0.78 and an F1-score = 0.69. Our results show the importance of immature granulocytes and their ratio with Lymphocytes in the disease and present an algorithm based on 5 parameters to identify a severe course. This work highlights the importance of studying routine analytical variables in the early stages of hospital admission and the benefits of applying AI to identify patients who may develop severe disease.

Aging population is at higher risk of developing severe COVID-19, including hospitalization and death. In this work, to further understand the relationship between host age-related factors, immunosenescence/exhaustion of the immune system and the response to the virus, we characterized immune cell and cytokine responses in 58 COVID-19 patients admitted to the hospital and 40 healthy controls of different age ranges. Lymphocyte populations and inflammatory profiles were studied in blood samples, using different panels of multicolor flow cytometry. As expected, our analysis reveals differences at both the cellular and cytokine level in COVID-19 patients. Interestingly, when the age range analysis was carried out, the immunological response to the infection was found to differ with age, being especially affected in the group of 30–39 years. In this age range, an increased exhausted T cell response and a decrease of naïve T helper lymphocytes was found in patients, as well as a reduced concentration of the proinflammatory TNF, IL-1β and IL-8 cytokines. Besides, the correlation between age and the study variables was evaluated, and multiple cell types and interleukins were found to correlate with donor age. Notably, the correlations of T helper naïve and effector memory cells, T helper 1–17 cells, TNF, IL-10, IL-1β, IL-8, among others, showed differences between healthy controls and COVID-19 patients. Our findings, in the context of other previous studies, suggest that aging affects the behavior of the immune system in COVID-19 patients. They suggest that young individuals are able to mount an initial response to SARS-CoV-2, but some of them present an accelerated exhaustion of the cell response and an insufficient inflammatory response, resulting in a moderate to severe COVID-19. On the other hand, in older patients there is a smaller immune cell response to the virus, reflected in fewer differences in immune populations between COVID-19 patients and controls. Nevertheless, old patients show more evidence of an inflammatory phenotype, suggesting that the underlying inflammation associated with their age is exacerbated by the SARS-CoV-2 infection.

Background One hundred fifty million contagions, more than 3 million deaths and little more than 1 year of COVID-19 have changed our lives and our health management systems forever. Ageing is known to be one of the significant determinants for COVID-19 severity. Two main reasons underlie this: immunosenescence and age correlation with main COVID-19 comorbidities such as hypertension or dyslipidaemia. This study has two aims. The first is to obtain cut-off points for laboratory parameters that can help us in clinical decision-making. The second one is to analyse the effect of pandemic lockdown on epidemiological, clinical, and laboratory parameters concerning the severity of the COVID-19. For these purposes, 257 of SARSCoV2 inpatients during pandemic confinement were included in this study. Moreover, 584 case records from a previously analysed series, were compared with the present study data. Results Concerning the characteristics of lockdown series, mild cases accounted for 14.4, 54.1% were moderate and 31.5%, severe. There were 32.5% of home contagions, 26.3% community transmissions, 22.5% nursing home contagions, and 8.8% corresponding to frontline worker contagions regarding epidemiological features. Age > 60 and male sex are hereby confirmed as severity determinants. Equally, higher severity was significantly associated with higher IL6, CRP, ferritin, LDH, and leukocyte counts, and a lower percentage of lymphocyte, CD4 and CD8 count. Comparing this cohort with a previous 584-cases series, mild cases were less than those analysed in the first moment of the pandemic and dyslipidaemia became more frequent than before. IL-6, CRP and LDH values above 69 pg/mL, 97 mg/L and 328 U/L respectively, as well as a CD4 T-cell count below 535 cells/μL, were the best cut-offs predicting severity since these parameters offered reliable areas under the curve. Conclusion Age and sex together with selected laboratory parameters on admission can help us predict COVID-19 severity and, therefore, make clinical and resource management decisions. Demographic features associated with lockdown might affect the homogeneity of the data and the robustness of the results.

The autoimmune GFAP astrocytopathy has been associated with meningoencephalomyelitis that usually responds to glucocorticoids. We report a 20-year-old man that developed an acute and severe meningoencephalomyelitis with remarkable CNS hyperexcitability and oculogyric crises. CSF analysis showed hypoglycorrhachia, pleocytosis, elevated ADA, and CSF-immunofluorescence characteristic of autoimmune GFAP astrocytopathy. MRI showed lesions at thalamus, corpus-callosum, dorsal pons and dentate nucleus with associated myelitis. Immunotherapy led to a full recovery, although MRI activity was observed at follow-up. CNS hyperexcitability, typically seen in other immune-mediated syndromes, represents a novel presenting form to be included as part of the clinical spectrum of this entity.

Additional file 1: Supplementary Table 1. Comparison between Phases I and II for clinical and demographic characteristics.

ABO blood groups have recently been related to COVID19 infection. In the present work, we performed this analysis using data from 412 COVID19 patients and 17796 blood donors, all of them from Gipuzkoa, a region in Northern Spain. The results obtained confirmed this relation, in addition to showing a clear importance of group O as a protective factor in COVID19 disease, with an OR = 0.59 (CI95% 0.481-0.7177, p<0.0001) while A, B and AB are risk factors. ABO blood groups are slightly differently distributed in the populations and therefore these results should be replicated in the specific areas with a proper control population.

BACKGROUND:The SARS-CoV-2 infection has widely spread to become the greatest public health challenge to date, the COVID-19 pandemic. Different fatality rates among countries are probably due to non-standardized records being carried out by local health authorities. The Spanish case-fatality rate is 11.22%, far higher than those reported in Asia or by other European countries. A multicentre retrospective study of demographic, clinical, laboratory and immunological features of 584 Spanish COVID-19 hospitalized patients and their outcomes was performed. The use of renin-angiotensin system blockers was also analysed as a risk factor.RESULTS:In this study, 27.4% of cases presented a mild course, 42.1% a moderate one and for 30.5% of cases, the course was severe. Ages ranged from 18 to 98 (average 63). Almost 60 % (59.8%) of patients were male. Interleukin 6 was higher as severity increased. On the other hand, CD8 lymphocyte count was significantly lower as severity grew and subpopulations CD4, CD8, CD19, and NK showed concordant lowering trends. Severity-related natural killer percent descents were evidenced just within aged cases. A significant severity-related decrease of CD4 lymphocytes was found in males. The use of angiotensin-converting enzyme inhibitors was associated with a better prognosis. The angiotensin II receptor blocker use was associated with a more severe course.CONCLUSIONS:Age and age-related comorbidities, such as dyslipidaemia, hypertension or diabetes, determined more frequent severe forms of the disease in this study than in previous literature cohorts. Our cases are older than those so far reported and the clinical course of the disease is found to be impaired by age. Immunosenescence might be therefore a suitable explanation for the hampering of immune system effectors. The adaptive immunity would become exhausted and a strong but ineffective and almost deleterious innate response would account for COVID-19 severity. Angiotensin-converting enzyme inhibitors used by hypertensive patients have a protective effect in regards to COVID-19 severity in our series. Conversely, patients on angiotensin II receptor blockers showed a severer disease.

The presence of anti-myelin lipid-specific oligoclonal IgM bands (LS-OCMBs) has been defined as an accurate predictor of an aggressive evolution of multiple sclerosis. However, the detection of this biomarker is performed in cerebrospinal fluid, a quite invasive liquid biopsy. In the present study we aimed at studying the expression profile of miRNA, snoRNA, circRNA and linearRNA in peripheral blood mononuclear cells (PBMCs) from patients with lipid-specific oligoclonal IgM band characterization. We included a total of 89 MS patients, 47 with negative LS-OCMB status and 42 with positive status. Microarray (miRNA and snoRNA) and RNA-seq (circular and linear RNAs) were used to perform the profiling study in the discovery cohort and candidates were validated by RT-qPCR in the whole cohort. The biomarker potential of the candidates was evaluated by ROC curve analysis. RNA-seq and RT-qPCR validation revealed that two circular (hsa_circ_0000478 and hsa_circ_0116639) and two linear RNAs (IRF5 and MTRNR2L8) are downregulated in PBMCs from patients with positive LS-OCMBs. Finally, those RNAs show a performance of a 70% accuracy in some of the combinations. The expression of hsa_circ_0000478, hsa_circ_0116639, IRF5 and MTRNR2L8 might serve as minimally invasive biomarkers of highly active disease.