Role of B Cell Profile for Predicting Secondary Autoimmunity in Patients Treated With Alemtuzumab

Células B; Alemtuzumab; AutoinmunidadLimfòcits B; Alemtuzumab; AutoimmunitatB cells; Alemtuzumab; AutoimmunityObjective: To explore if baseline blood lymphocyte profile could identify relapsing remitting multiple sclerosis (RRMS) patients at higher risk of developing secondary autoimmune adverse events (AIAEs) after alemtuzumab treatment. Methods: Multicenter prospective study including 57 RRMS patients treated with alemtuzumab followed for 3.25 [3.5-4.21] years, (median [interquartile range]). Blood samples were collected at baseline, and leukocyte subsets determined by flow cytometry. We had additional samples one year after the first cycle of alemtuzumab treatment in 39 cases. Results: Twenty-two patients (38.6%) developed AIAEs during follow-up. They had higher B-cell percentages at baseline (p=0.0014), being differences mainly due to plasmablasts/plasma cells (PB/PC, p=0.0011). Those with no AIAEs had higher percentages of CD4+ T cells (p=0.013), mainly due to terminally differentiated (TD) (p=0.034) and effector memory (EM) (p=0.031) phenotypes. AIAEs- patients also showed higher values of TNF-alpha-producing CD8+ T cells (p=0.029). The percentage of PB/PC was the best variable to differentiate both groups of patients. Baseline values >0.10% closely associated with higher AIAE risk (Odds ratio [OR]: 5.91, 95% CI: 1.83-19.10, p=0.004). When excluding the 12 patients with natalizumab, which decreases blood PB/PC percentages, being the last treatment before alemtuzumab, baseline PB/PC >0.1% even predicted more accurately the risk of AIAEs (OR: 11.67, 95% CI: 2.62-51.89, p=0.0007). The AIAEs+ group continued having high percentages of PB/PC after a year of alemtuzumab treatment (p=0.0058). Conclusions: A PB/PC percentage <0.1% at baseline identifies MS patients at low risk of secondary autoimmunity during alemtuzumab treatment.​This work was supported by grants from Red Española de Esclerosis Múltiple (REEM) (RD16/0015/0001; RD16/0015/0004; RD16/0015/0006; RD16/0015/0013) and PI18/00572 integrated in the Plan Estatal I+D+I and co-funded by ISCIII-Subdirección General de Evaluación and Fondo Europeo de Desarrollo Regional (FEDER, “Una manera de hacer Europa”)

Value contribution of blood-based neurofilament light chain as a biomarker in multiple sclerosis using multi-criteria decision analysis

IntroductionMultiple sclerosis (MS) is a chronic autoimmune demyelinating disease that represents a leading cause of non-traumatic disability among young and middle-aged adults. MS is characterized by neurodegeneration caused by axonal injury. Current clinical and radiological markers often lack the sensitivity and specificity required to detect inflammatory activity and neurodegeneration, highlighting the need for better approaches. After neuronal injury, neurofilament light chains (NfL) are released into the cerebrospinal fluid, and eventually into blood. Thus, blood-based NfL could be used as a potential biomarker for inflammatory activity, neurodegeneration, and treatment response in MS. The objective of this study was to determine the value contribution of blood-based NfL as a biomarker in MS in Spain using the Multi-Criteria Decision Analysis (MCDA) methodology.Materials and methodsA literature review was performed, and the results were synthesized in the evidence matrix following the criteria included in the MCDA framework. The study was conducted by a multidisciplinary group of six experts. Participants were trained in MCDA and scored the evidence matrix. Results were analyzed and discussed in a group meeting through reflective MCDA discussion methodology.ResultsMS was considered a severe condition as it is associated with significant disability. There are unmet needs in MS as a disease, but also in terms of biomarkers since no blood biomarker is available in clinical practice to determine disease activity, prognostic assessment, and response to treatment. The results of the present study suggest that quantification of blood-based NfL may represent a safe option to determine inflammation, neurodegeneration, and response to treatments in clinical practice, as well as to complement data to improve the sensitivity of the diagnosis. Participants considered that blood-based NfL could result in a lower use of expensive tests such as magnetic resonance imaging scans and could provide cost-savings by avoiding ineffective treatments. Lower indirect costs could also be expected due to a lower impact of disability consequences. Overall, blood-based NfL measurement is supported by high-quality evidence.ConclusionBased on MCDA methodology and the experience of a multidisciplinary group of six stakeholders, blood-based NfL measurement might represent a high-value-option for the management of MS in Spain

Role of B Cell Profile for Predicting Secondary Autoimmunity in Patients Treated With Alemtuzumab

UDHEBRONTo explore if baseline blood lymphocyte profile could identify relapsing remitting multiple sclerosis (RRMS) patients at higher risk of developing secondary autoimmune adverse events (AIAEs) after alemtuzumab treatment. Multicenter prospective study including 57 RRMS patients treated with alemtuzumab followed for 3.25 [3.5-4.21] years, (median [interquartile range]). Blood samples were collected at baseline, and leukocyte subsets determined by flow cytometry. We had additional samples one year after the first cycle of alemtuzumab treatment in 39 cases. Twenty-two patients (38.6%) developed AIAEs during follow-up. They had higher B-cell percentages at baseline (p=0.0014), being differences mainly due to plasmablasts/plasma cells (PB/PC, p=0.0011). Those with no AIAEs had higher percentages of CD4+ T cells (p=0.013), mainly due to terminally differentiated (TD) (p=0.034) and effector memory (EM) (p=0.031) phenotypes. AIAEs- patients also showed higher values of TNF-alpha-producing CD8+ T cells (p=0.029). The percentage of PB/PC was the best variable to differentiate both groups of patients. Baseline values >0.10% closely associated with higher AIAE risk (Odds ratio [OR]: 5.91, 95% CI: 1.83-19.10, p=0.004). When excluding the 12 patients with natalizumab, which decreases blood PB/PC percentages, being the last treatment before alemtuzumab, baseline PB/PC >0.1% even predicted more accurately the risk of AIAEs (OR: 11.67, 95% CI: 2.62-51.89, p=0.0007). The AIAEs+ group continued having high percentages of PB/PC after a year of alemtuzumab treatment (p=0.0058). A PB/PC percentage <0.1% at baseline identifies MS patients at low risk of secondary autoimmunity during alemtuzumab treatment.

SARS-CoV-2-induced Acute Respiratory Distress Syndrome: Pulmonary Mechanics and Gas-Exchange Abnormalities

In January 2020, the first cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection were reported in Europe. Multiple outbreaks have since then led to a global pandemic, as well as to massive medical, economic, and social repercussions. SARS-CoV-2 pneumonia can develop into acute respiratory distress syndrome (ARDS) when mechanical ventilation (MV) is needed (3, 4). ARDS produces abnormalities in gas exchange with a variable degree of shunt (5), high dead space ventilation (dead space volume [Vd]/tidal volume [Vt] ratio) (6), diminished pulmonary compliance (7), and alterations to the pulmonary circulation (8). The cornerstone of ARDS management is to provide adequate gas exchange without further lung injury as a result of MV. To date, information regarding the characteristics of SARS-CoV-2-induced ARDS is not completely known. However, this information is crucial to better apply MV and facilitate organ support strategies. We therefore present the characteristics of gas exchange, pulmonary mechanics, and ventilatory management of 50 patients with laboratory-confirmed SARS-CoV-2 infection, who developed ARDS and underwent invasive MV (IMV). Methods: Descriptive analysis included 50 consecutive patients with laboratory-confirmed SARS-CoV-2 infection who developed ARDS (9) and underwent IMV. These patients were admitted to the SARS-CoV-2-dedicated intensive care units (ICUs) at Hospital Clinic of Barcelona, Spain, between March 7 and March 25, 2020. Upon ICU admission, epidemiological characteristics, the severity of SARS-CoV-2 infection with the Acute Physiology and Chronic Health Evaluation II score, prognostic biomarkers of SARS-CoV-2 infection (described in Reference 4), time from hospital to ICU admission, time from ICU admission to intubation, oxygen therapy or noninvasive ventilation (NIV) use, and microbiology were investigated. On the day that criteria for ARDS diagnosis were met (9) and IMV was needed, the following assessments were performed: impairment in oxygenation was analyzed with the partial pressure of oxygen (PaO2)/fraction of inspired oxygen (FiO2) ratio, and abnormalities of CO2 metabolism were studied with the ventilatory ratio (VR), a surrogate parameter of Vd/Vt. In addition, adjunctive therapies and MV parameters related with ventilation-induced lung injury (VILI) described elsewhere (11-15) were investigated. Correlations of SARS-CoV-2 prognostic biomarkers (4), pulmonary mechanics, and gas-exchange data were performed. Twenty-eight-day and hospital mortality, ventilator- and ICU-free days at Day 28, hospital and ICU lengths of stay, and need for tracheostomy were also evaluated (16). Finally, a subanalysis assessing differences before and after prone positioning was performed. For additional detail on the method, see the online supplement. Results: By March 25th, 2020, 50 patients with laboratory-confirmed SARS-CoV-2 infection and ARDS had been admitted to our hospital. Table 1 shows the demographic and clinical characteristics of these patients. The median (interquartile range [IQR]) age was 66 (57-74) years. Thirty-six patients (72%) were men. Upon ARDS diagnosis, 44% of patients were initially classified as having moderate ARDS, whereas 24% were classified as having mild ARDS and 32% were classified as having severe ARDS. The outcomes of these patients are shown in Table 1. ICU and hospital lengths of stay were prolonged, and tracheostomy was performed in 30 (60%) patients. Hospital mortality was 34%

Risk and outcomes of COVID-19 in patients with multiple sclerosis

Background and purpose Limited information is available on incidence and outcomes of COVID-19 in patients with multiple sclerosis (MS). This study investigated the risks of SARS-CoV-2 infection and COVID-19-related outcomes in patients with MS, and compared these with the general population. Methods A regional registry was created to collect data on incidence, hospitalization rates, intensive care unit admission, and death in patients with MS and COVID-19. National government outcomes and seroprevalence data were used for comparison. The study was conducted at 14 specialist MS treatment centers in Madrid, Spain, between February and May 2020. Results Two-hundred nineteen patients were included in the registry, 51 of whom were hospitalized with COVID-19. The mean age ± standard deviation was 45.3 ± 12.4 years, and the mean duration of MS was 11.9 ± 8.9 years. The infection incidence rate was lower in patients with MS than the general population (adjusted incidence rate ratio = 0.78, 95% confidence interval [CI] = 0.70–0.80), but hospitalization rates were higher (relative risk = 5.03, 95% CI = 3.76–6.62). Disease severity was generally low, with only one admission to an intensive care unit and five deaths. Males with MS had higher incidence rates and risk of hospitalization than females. No association was found between the use of any disease-modifying treatment and hospitalization risk. Conclusions Patients with MS do not appear to have greater risks of SARS-CoV-2 infection or severe COVID-19 outcomes compared with the general population. The decision to start or continue disease-modifying treatment should be based on a careful risk–benefit assessment.post-print996 K

Association Between Preexisting Versus Newly Identified Atrial Fibrillation and Outcomes of Patients With Acute Pulmonary Embolism

Background Atrial fibrillation (AF) may exist before or occur early in the course of pulmonary embolism (PE). We determined the PE outcomes based on the presence and timing of AF. Methods and Results Using the data from a multicenter PE registry, we identified 3 groups: (1) those with preexisting AF, (2) patients with new AF within 2 days from acute PE (incident AF), and (3) patients without AF. We assessed the 90-day and 1-year risk of mortality and stroke in patients with AF, compared with those without AF (reference group). Among 16 497 patients with PE, 792 had preexisting AF. These patients had increased odds of 90-day all-cause (odds ratio [OR], 2.81; 95% CI, 2.33-3.38) and PE-related mortality (OR, 2.38; 95% CI, 1.37-4.14) and increased 1-year hazard for ischemic stroke (hazard ratio, 5.48; 95% CI, 3.10-9.69) compared with those without AF. After multivariable adjustment, preexisting AF was associated with significantly increased odds of all-cause mortality (OR, 1.91; 95% CI, 1.57-2.32) but not PE-related mortality (OR, 1.50; 95% CI, 0.85-2.66). Among 16 497 patients with PE, 445 developed new incident AF within 2 days of acute PE. Incident AF was associated with increased odds of 90-day all-cause (OR, 2.28; 95% CI, 1.75-2.97) and PE-related (OR, 3.64; 95% CI, 2.01-6.59) mortality but not stroke. Findings were similar in multivariable analyses. Conclusions In patients with acute symptomatic PE, both preexisting AF and incident AF predict adverse clinical outcomes. The type of adverse outcomes may differ depending on the timing of AF onset.info:eu-repo/semantics/publishedVersio

Comparison of seven prognostic tools to identify low-risk pulmonary embolism in patients aged <50 years

publishersversionPeer reviewe

D-dimer levels and 90-day outcome in patients with acute pulmonary embolism with or without cancer

International audienceBACKGROUND:The prognostic value of D-dimer testing in patients with acute pulmonary embolism (PE) has not been thoroughly studied.METHODS:We used the RIETE Registry data to assess the 90-day prognostic value of increased IL Test D-dimer levels at baseline in patients with PE, according to the presence or absence of cancer.RESULTS:As of May 2013, 3,283 patients with acute PE underwent D-dimer testing using IL Test D-dimer. Among 2,588 patients without cancer, those with D-dimer levels in the highest quartile had a higher rate of fatal PE (2.6% vs. 0.9%; p=0.002), fatal bleeding (1.1% vs. 0.3%; p=0.017) and all-cause death (9.1% vs. 4.4%; p<0.001) at 90 days compared with those with levels in the lowest quartiles. Among 695 patients with cancer, those with levels in the highest quartile had a similar rate of fatal PE or fatal bleeding but higher mortality (35% vs. 24%; p<0.01). On multivariate analysis, non-cancer patients with D-dimer levels in the highest quartile had an increased risk for fatal PE (odds ratio [OR]: 3.3; 95% CI: 1.6-6.6), fatal bleeding (OR: 4.3; 95% CI: 1.4-13.7) and all-cause death (OR: 2.1; 95% CI: 1.4-3.1) compared with patients with levels in the lowest quartiles.CONCLUSIONS:Non-cancer patients with acute PE and IL Test D-dimer levels in the highest quartile had an independently higher risk for fatal PE, fatal bleeding and all-cause death at 90 days than those with levels in the lowest quartiles. In patients with cancer, D-dimer levels failed to predict fatal PE or fatal bleeding

PICO Questions and DELPHI Methodology for the Management of Venous Thromboembolism Associated with COVID-19

Patients with coronavirus disease 2019 (COVID-19) have a higher risk of venous thromboembolic disease (VTE) than patients with other infectious or inflammatory diseases, both as macrothrombosis (pulmonar embolism and deep vein thrombosis) or microthrombosis. However, the use of anticoagulation in this scenario remains controversial. This is a project that used DELPHI methodology to answer PICO questions related to anticoagulation in patients with COVID-19. The objective was to reach a consensus among multidisciplinary VTE experts providing answers to those PICO questions. Seven PICO questions regarding patients with COVID-19 responded with a broad consensus: 1. It is recommended to avoid pharmacological thromboprophylaxis in most COVID-19 patients not requiring hospital admission; 2. In most hospitalized patients for COVID-19 who are receiving oral anticoagulants before admission, it is recommended to replace them by low molecular weight heparin (LMWH) at therapeutic doses; 3. Thromboprophylaxis with LMWH at standard doses is suggested for COVID-19 patients admitted to a conventional hospital ward; 4. Standard-doses thromboprophylaxis with LMWH is recommended for COVID-19 patients requiring admission to Intensive Care Unit; 5. It is recommended not to determine D-Dimer levels routinely in COVID-19 hospitalized patients to select those in whom VTE should be suspected, or as a part of the diagnostic algorithm to rule out or confirm a VTE event; 6. It is recommended to discontinue pharmacological thromboprophylaxis at discharge in most patients hospitalized for COVID-19; 7. It is recommended to withdraw anticoagulant treatment after 3 months in most patients with a VTE event associated with COVID-19. The combination of PICO questions and DELPHI methodology provides a consensus on different recommendations for anticoagulation management in patients with COVID-19

Prediction of ventilator-associated pneumonia outcomes according to the early microbiological response: a retrospective observational study

Ventilator-associated pneumonia is a leading infectious cause of morbidity in critically ill patients; yet current guidelines offer no indications for follow-up cultures.We aimed to evaluate the role of follow-up cultures and microbiological response 3 days after diagnosing ventilator-associated pneumonia as predictors of short- and long-term outcomes.We performed a retrospective analysis of a cohort prospectively collected from 2004 to 2017. Ventilator-associated pneumonia was diagnosed based on clinical, radiographic, and microbiological criteria. For microbiological identification, a tracheobronchial aspirate was performed at diagnosis and repeated after 72?h. We defined three groups when comparing the two tracheobronchial aspirate results: persistence, superinfection, and eradication of causative pathogens.One-hundred-fifty-seven patients were enrolled in the study, among whom microbiological persistence, superinfection, and eradication was present in 67 (48%), 25 (16%), and 65 (41%), respectively, after 72hs. Those with superinfection had the highest mortalities in the intensive care unit (p=0.015) and at 90?days (p=0.036), while also having the fewest ventilation-free days (p=0.024). Multivariable analysis revealed shock at VAP diagnosis (odds ratios [OR] 3.43; 95% confidence interval [CI] 1.25 to 9.40), Staphylococcus aureus isolation at VAP diagnosis (OR 2.87; 95%CI 1.06 to 7.75), and hypothermia at VAP diagnosis (OR 0.67; 95%CI 0.48 to 0.95, per +1°C) to be associated with superinfection.Our retrospective analysis suggests that ventilator-associated pneumonia short-term and long-term outcomes may be associated with superinfection in follow-up cultures. Follow-up cultures may help guiding antibiotic therapy and its duration. Further prospective studies are necessary to verify our findings