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1.
Mult Scler ; : 13524585221102158, 2022 Jun 20.
Article in English | MEDLINE | ID: covidwho-1896284

ABSTRACT

BACKGROUND: Development of long-lasting anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) T-cell responses in persons with multiple sclerosis (pwMS) treated with ocrelizumab is questioned. OBJECTIVE: Investigate antiviral T-cell responses after infection with SARS-CoV-2 in ocrelizumab-treated pwMS. Control groups included ocrelizumab-treated pwMS without SARS-CoV-2 infection, and non-MS individuals with and without SARS-CoV-2 infection. METHODS: Peripheral blood mononuclear cells were stimulated with SARS-CoV-2 peptide pools and T-cell reactivity was assessed by ELISPOT for interferon (IFN)-γ detection, and by multiparametric fluorescence-activated cell sorting (FACS) analyses for assessment and characterization of T-cell activation. RESULTS: ELISPOT assay against the spike and the N protein of SARS-CoV-2 displayed specific T-cell reactivity in 28/29 (96%) pwMS treated with ocrelizumab and infected by SARS-CoV-2, similar to infected persons without MS. This reactivity was present 1 year after infection and independent from the time of ocrelizumab infusion. FACS analysis following stimulation with SARS-CoV-2 peptide pools showed the presence of activation-induced markers (AIMs) in both CD4+ and CD8+ T-cell subsets in 96% and 92% of these individuals, respectively. Within naïve AIM+ CD4+ and CD8+ T-cells, we detected T memory stem cells, suggesting the acquisition of long-term memory. CONCLUSIONS: B-cell depletion using ocrelizumab does not impair the development of long-lasting anti-SARS-CoV-2 T-cell responses.

2.
J Neurol Sci ; 439: 120315, 2022 Aug 15.
Article in English | MEDLINE | ID: covidwho-1882260

ABSTRACT

INTRODUCTION: Symptoms referable to central and peripheral nervous system involvement are often evident both during the acute phase of COVID-19 infection and during long-COVID. In this study, we evaluated a population of patients with prior COVID-19 infection who showed signs and symptoms consistent with neurological long-COVID. METHODS: We prospectively collected demographic and acute phase course data from patients with prior COVID-19 infection who showed symptoms related to neurological involvement in the long-COVID phase. Firstly, we performed a multivariate logistic linear regression analysis to investigate the impact of demographic and clinical data, the severity of the acute COVID-19 infection and hospitalization course, on the post-COVID neurological symptoms at three months follow-up. Secondly, we performed an unsupervised clustering analysis to investigate whether there was evidence of different subtypes of neurological long COVID-19. RESULTS: One hundred and nine patients referred to the neurological post-COVID outpatient clinic. Clustering analysis on the most common neurological symptoms returned two well-separated and well-balanced clusters: long-COVID type 1 contains the subjects with memory disturbances, psychological impairment, headache, anosmia and ageusia, while long-COVID type 2 contains all the subjects with reported symptoms related to PNS involvement. The analysis of potential risk-factors among the demographic, clinical presentation, COVID 19 severity and hospitalization course variables showed that the number of comorbidities at onset, the BMI, the number of COVID-19 symptoms, the number of non-neurological complications and a more severe course of the acute infection were all, on average, higher for the cluster of subjects with reported symptoms related to PNS involvement. CONCLUSION: We analyzed the characteristics of neurological long-COVID and presented a method to identify well-defined patient groups with distinct symptoms and risk factors. The proposed method could potentially enable treatment deployment by identifying the optimal interventions and services for well-defined patient groups, so alleviating long-COVID and easing recovery.


Subject(s)
Ageusia , COVID-19 , Ambulatory Care Facilities , COVID-19/complications , Humans , SARS-CoV-2
3.
Clin Infect Dis ; 2022 May 24.
Article in English | MEDLINE | ID: covidwho-1860837

ABSTRACT

BACKGROUND: Patients with solid or hematological tumors, neurological and immune-inflammatory disorders are potentially fragile subjects at increased risk of experiencing severe COVID-19 and an inadequate response to SARS-CoV-2 vaccination. METHODS: We designed a prospective Italian multicentrer study to assess humoral and T-cell responses to SARS-CoV-2 vaccination in patients (n = 378) with solid tumors (ST), hematological malignancies (HM), neurological disorders (ND) and immunorheumatological diseases (ID). A group of healthy controls was also included. We analyzed the immunogenicity of the primary vaccination schedule and booster dose. RESULTS: The overall seroconversion rate in patients after 2 doses was 62.1%. Significantly lower rates were observed in HM (52.4%) and ID (51.9%) than in ST (95.6%) and ND (70.7%); a lower median antibody level was detected in HM and ID versus ST and ND (P < 0.0001). Similar rates of patients with a positive SARS-CoV-2 T-cell response were found in all disease groups, with a higher level observed in ND. The booster dose improved the humoral response in all disease groups, although to a lesser extent in HM patients, while the T-cell response increased similarly in all groups. In the multivariable logistic model, independent predictors of seroconversion were disease subgroup, treatment type and age. Ongoing treatment known to affect the immune system was associated with the worst humoral response to vaccination (P < 0.0001) but had no effect on T-cell responses. CONCLUSIONS: Immunosuppressive treatment more than disease type per se is a risk factor for a low humoral response after vaccination. The booster dose can improve both humoral and T-cell responses.

4.
EBioMedicine ; 80: 104042, 2022 Jun.
Article in English | MEDLINE | ID: covidwho-1819477

ABSTRACT

BACKGROUND: In this study we aimed to monitor the risk of breakthrough SARS-CoV-2 infection in patients with MS (pwMS) under different DMTs and to identify correlates of reduced protection. METHODS: This is a prospective Italian multicenter cohort study, long-term clinical follow-up of the CovaXiMS (Covid-19 vaccine in Multiple Sclerosis) study. 1855 pwMS scheduled for SARS-CoV-2 mRNA vaccination were enrolled and followed up to a mean time of 10 months. The cumulative incidence of breakthrough Covid-19 cases in pwMS was calculated before and after December 2021, to separate the Delta from the Omicron waves and to account for the advent of the third vaccine dose. FINDINGS: 1705 pwMS received 2 m-RNA vaccine doses, 21/28 days apart. Of them, 1508 (88.5%) had blood assessment 4 weeks after the second vaccine dose and 1154/1266 (92%) received the third dose after a mean interval of 210 days (range 90-342 days) after the second dose. During follow-up, 131 breakthrough Covid-19 infections (33 during the Delta and 98 during the Omicron wave) were observed. The probability to be infected during the Delta wave was associated with SARS-CoV-2 antibody levels measured after 4 weeks from the second vaccine dose (HR=0.57, p < 0.001); the protective role of antibodies was preserved over the whole follow up (HR=0.57, 95%CI=0.43-0.75, p < 0.001), with a significant reduction (HR=1.40, 95%CI=1.01-1.94, p=0.04) for the Omicron cases. The third dose significantly reduced the risk of infection (HR=0.44, 95%CI=0.21-0.90,p=0.025) during the Omicron wave. INTERPRETATION: The risk of breakthrough SARS-CoV-2 infections is mainly associated with reduced levels of the virus-specific humoral immune response. FUNDING: Supported by FISM - Fondazione Italiana Sclerosi Multipla - cod. 2021/Special-Multi/001 and financed or co-financed with the '5 per mille' public funding.


Subject(s)
COVID-19 , Viral Vaccines , COVID-19/prevention & control , COVID-19 Vaccines , Cohort Studies , Humans , Prospective Studies , RNA, Messenger , SARS-CoV-2 , Vaccination , Vaccines, Synthetic , mRNA Vaccines
5.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-321913

ABSTRACT

Background: In patients with Multiple Sclerosis (pwMS) disease-modifying therapies (DMTs) are known to affect immune response to antigens and possibly to SARS-CoV2 vaccine. Therefore, post-vaccination serological assessments are needed to evaluate the effect of the vaccine on SARS-CoV-2 antibody response.Methods: We designed a prospective multicenter cohort study enrolling pwMS who were scheduled for SARS-Cov-2 vaccination with mRNA vaccines (BNT162b2, Pfizer/BioNTech, Inc or mRNA-1273, Moderna Tx, Inc). A blood collection for the measure of SARS-CoV-2 antibody before the first vaccine dose and 4 weeks after the second dose was planned, with a centralized serological assessment (electrochemiluminescence immunoassay, ECLIA, Roche Diagnostics).Findings: 780 pwMS (76% BNT162b2 and 24% mRNA-1273) had pre- and 4-week post-vaccination blood assessments. 87 (11·2%) were untreated, 154 (19·7%) on ocrelizumab, 25 (3·2%) on rituximab, 85 (10·9%) on fingolimod, 25 (3·2%) on cladribine and 404 (51·7%) on other DMTs. 677 patients (86·8%) had detectable post-vaccination SARS-CoV-2 antibodies. At multivariate analysis, the antibody levels of patients on ocrelizumab (178-fold decrease, p<0·001), fingolimod (26-fold decrease, p<0·001) and rituximab (17-fold decrease, p<0·001) were significantly reduced as compared to untreated patients. mRNA-1273 vaccine resulted in a systematically 3·5-fold higher antibody level than the BNT162b2 vaccine (p<0·001).Interpretation: In pwMS, therapy with anti-CD20 and fingolimod led to a reduced humoral response to SARS-CoV-2 vaccines. As mRNA-1273 elicits 3·5-higher antibody titers than BNT162b2, this vaccine may be preferentially considered for patients under anti-CD20 or fingolimod. Since it is still unknown the role of T-cells vaccine response, further information is required about the role of cellular immunity triggered by vaccination to better define the most appropriate strategy to vaccinate pwMS under specific DMTs.Funding Information: FISM [2021/Special-Multi/001];the Italian Ministry of Health grant ‘Progetto Z844A 5x1000’.Declaration of Interests: MPS reports grants from Roche, during the conduct of the study;personal fees from Biogen, Merck, Roche, Sanofi, personal fees from Novartis, Medday, Geneuro, Celgene, Mylan, outside the submitted work;MI reports consulting fees from Roche, Merck-Serono, Novartis, Sanofi-Genzyme, Biogen;AL has received personal compensation from Novartis, Sanofi Genzyme, Biogen, Merck, and Roche for public speaking and advisory boards. AL received funding for research by Fondazione Italiana Sclerosi Multipla, the Italian Ministry of Health, and the Italian Ministry of University;CC reports personal fees from Novartis, personal fees from Biogen Idec, personal fees from Almirall, personal fees from Merck Serono, outside the submitted work;DL reports consulting fees Roche, Biogen, Teva, Mylan, Sanofi-Genzyme, fess for advisory boards from Bristol-Celgene, Merck, Novartis, JF reports consulting fees fromSanofi, Biogen, Admirall;ADS reports personal consulting fees from Biogen, Novartis, Genzyme;MS reports research support and personal consulting fees from Merk, Sanofi, Novartis, Biogen, Roche;AU has received personal compensation from Novartis, Biogen, Merck, Roche and Sanofi Genzyme for public speaking and advisory boards. AU received funding for research by Fondazione Italiana Sclerosi Multipla, the Italian Ministry of Health and the European Community. IS, LC, CL, GDR, CS, IG, TT, GP, PG, GPB, AM, MLS, MC, ES, MTF, LP, MU, FM, GC, RI, GL, AMR, FC, SC, MAB, DF, have nothing to dislcose.Ethics Approval Statement: The study is done in compliance with the principles of the Declaration of Helsinki. The protocol is approved by the regional (CER Liguria: 5/2021 - DB id 11169- 21/01/2021) and the centralized national ethical committee AIFA/Spallanzani (Parere n 351, 2020/21). Written informed consent was obtained from all participants before starting any study procedures.

6.
Curr Neuropharmacol ; 2021 Dec 17.
Article in English | MEDLINE | ID: covidwho-1596109

ABSTRACT

The COVID-19 pandemic and the mass vaccination campaign highlighted the situation of the most vulnerable patients. In this work, we focused attention on patients who have Multiple Sclerosis (MS), particularly in treatment with cladribine tablets, trying to understand if and when it is possible to administer the vaccine successfully. Considering the innovative topic, we reviewed the existing literature with an analysis of the experiences also related to other vaccinations, including influenza and VZV, and very recent data from countries with vaccination campaigns already advanced. Overall, we have taken into account the mechanism of action, the pharmacokinetic/pharmacodynamic of cladribine and the changes in the immune system after its administration, together with the preliminary data about the humoral response to influenza, VZV and SARS-CoV-2 vaccinations in cladribine treated patients. In conclusion, data showed that the use of cladribine tablets seems to permit flexibility regarding vaccination timing and we suggest that vaccination in those patients should be safe and effective.

7.
EBioMedicine ; 72: 103581, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1433160

ABSTRACT

BACKGROUND: In patients with Multiple Sclerosis (pwMS) disease-modifying therapies (DMTs) affects immune response to antigens. Therefore, post-vaccination serological assessments are needed to evaluate the effect of the vaccine on SARS-CoV-2 antibody response. METHODS: We designed a prospective multicenter cohort study enrolling pwMS who were scheduled for SARS-Cov-2 vaccination with mRNA vaccines (BNT162b2, Pfizer/BioNTech,Inc or mRNA-1273, Moderna Tx,Inc). A blood collection before the first vaccine dose and 4 weeks after the second dose was planned, with a centralized serological assessment (electrochemiluminescence immunoassay, ECLIA, Roche-Diagnostics). The log-transform of the antibody levels was analyzed by multivariable linear regression. FINDINGS: 780 pwMS (76% BNT162b2 and 24% mRNA-1273) had pre- and 4-week post-vaccination blood assessments. 87 (11·2%) were untreated, 154 (19·7%) on ocrelizumab, 25 (3·2%) on rituximab, 85 (10·9%) on fingolimod, 25 (3·2%) on cladribine and 404 (51·7%) on other DMTs. 677 patients (86·8%) had detectable post-vaccination SARS-CoV-2 antibodies. At multivariable analysis, the antibody levels of patients on ocrelizumab (201-fold decrease (95%CI=128-317), p < 0·001), fingolimod (26-fold decrease (95%CI=16-42), p < 0·001) and rituximab (20-fold decrease (95%CI=10-43), p < 0·001) were significantly reduced as compared to untreated patients. Vaccination with mRNA-1273 resulted in a systematically 3·25-fold higher antibody level (95%CI=2·46-4·27) than with the BNT162b2 vaccine (p < 0·001). The antibody levels on anti-CD20 therapies correlated to the time since last infusion, and rituximab had longer intervals (mean=386 days) than ocrelizumab patients (mean=129 days). INTERPRETATION: In pwMS, anti-CD20 treatment and fingolimod led to a reduced humoral response to mRNA-based SARS-CoV-2 vaccines. As mRNA-1273 elicits 3·25-higher antibody levels than BNT162b2, this vaccine may be preferentially considered for patients under anti-CD20 treatment or fingolimod. Combining our data with those on the cellular immune response to vaccines, and including clinical follow-up, will contribute to better define the most appropriate SARS-CoV-2 vaccine strategies in the context of DMTs and MS. FUNDING: FISM[2021/Special-Multi/001]; Italian Ministry of Health'Progetto Z844A 5 × 1000'.


Subject(s)
Antibody Formation/drug effects , COVID-19 Vaccines/therapeutic use , COVID-19/prevention & control , Immunosuppressive Agents/adverse effects , Multiple Sclerosis/drug therapy , Adult , Antibodies, Monoclonal, Humanized/adverse effects , Antibodies, Monoclonal, Humanized/therapeutic use , COVID-19/immunology , Cladribine/adverse effects , Cladribine/therapeutic use , Female , Fingolimod Hydrochloride/adverse effects , Fingolimod Hydrochloride/therapeutic use , Humans , Immunosuppressive Agents/therapeutic use , Italy , Male , Middle Aged , Prospective Studies , Rituximab/adverse effects , Rituximab/therapeutic use , Treatment Outcome
8.
Front Immunol ; 12: 704110, 2021.
Article in English | MEDLINE | ID: covidwho-1376699

ABSTRACT

Patients diagnosed with malignancy, neurological and immunological disorders, i.e., fragile patients, have been excluded from COVID-19 vaccine trials. However, this population may present immune response abnormalities, and relative reduced vaccine responsiveness. Here we review the limited current evidence on the immune responses to vaccination of patients with different underlying diseases. To address open questions we present the VAX4FRAIL study aimed at assessing immune responses to vaccination in a large transdisease cohort of patients with cancer, neurological and rheumatological diseases.


Subject(s)
COVID-19 Vaccines/administration & dosage , Adult , COVID-19 Vaccines/immunology , Clinical Protocols , Humans , Immune System Diseases/immunology , Immunocompromised Host/immunology , Neoplasms/immunology , Nervous System Diseases/immunology , Patient Selection , Prospective Studies
10.
Front Neurol ; 11: 602114, 2020.
Article in English | MEDLINE | ID: covidwho-983702

ABSTRACT

Purpose: The incidence and the clinical presentation of neurological manifestations of coronavirus disease-2019 (COVID-19) remain unclear. No data regarding the use of neuromonitoring tools in this group of patients are available. Methods: This is a retrospective study of prospectively collected data. The primary aim was to assess the incidence and the type of neurological complications in critically ill COVID-19 patients and their effect on survival as well as on hospital and intensive care unit (ICU) length of stay. The secondary aim was to describe cerebral hemodynamic changes detected by noninvasive neuromonitoring modalities such as transcranial Doppler, optic nerve sheath diameter (ONSD), and automated pupillometry. Results: Ninety-four patients with COVID-19 admitted to an ICU from February 28 to June 30, 2020, were included in this study. Fifty-three patients underwent noninvasive neuromonitoring. Neurological complications were detected in 50% of patients, with delirium as the most common manifestation. Patients with neurological complications, compared to those without, had longer hospital (36.8 ± 25.1 vs. 19.4 ± 16.9 days, p < 0.001) and ICU (31.5 ± 22.6 vs. 11.5±10.1 days, p < 0.001) stay. The duration of mechanical ventilation was independently associated with the risk of developing neurological complications (odds ratio 1.100, 95% CI 1.046-1.175, p = 0.001). Patients with increased intracranial pressure measured by ONSD (19% of the overall population) had longer ICU stay. Conclusions: Neurological complications are common in critically ill patients with COVID-19 receiving invasive mechanical ventilation and are associated with prolonged ICU length of stay. Multimodal noninvasive neuromonitoring systems are useful tools for the early detection of variations in cerebrovascular parameters in COVID-19.

11.
Mult Scler ; 27(14): 2126-2136, 2021 12.
Article in English | MEDLINE | ID: covidwho-934217

ABSTRACT

The CoronaVirus Disease 19 (COVID-19) pandemic is a threat of particular concern for people affected by chronic immune-mediated diseases, such as multiple sclerosis (MS), who are often treated with immunomodulatory and immunosuppressive drugs, which may increase the risk of infections in general. At the beginning of the COVID-19 pandemic, empirical guidelines on how to manage treatments for immune-mediated diseases, including MS, were released. Subsequently, the first clinical pictures and data sets have been published, describing the outcomes of COVID-19 in patients with MS treated with immunomodulatory and immunosuppressive drugs. Here we will review available information on how infections by human coronaviruses affect the immune system in untreated subjects and in patients affected by MS treated with drugs which modulate the immune system.


Subject(s)
COVID-19 , Multiple Sclerosis , Humans , Immunosuppressive Agents/therapeutic use , Multiple Sclerosis/drug therapy , Multiple Sclerosis/epidemiology , Pandemics , SARS-CoV-2
12.
J Neurol Sci ; 418: 117114, 2020 11 15.
Article in English | MEDLINE | ID: covidwho-850023

ABSTRACT

Recently, during the pandemic infection of the novel SARS-CoV-2, some cases of Guillan-Barré Syndrome (GBS) have been reported. The aim of this work is to report the natural history of patients with GBS, both COVID and not-COVID related, hospitalized in Liguria region, during lock down period, in order to assess clinical features of both groups and possible managements pitfalls due to pandemic emergency. Fifteen GBS patients were admitted to the Hospitals of Liguria, from February 15th to May 3rd 2020, six with SARS-CoV-2 infection and nine without infection. In COVID-19 related GBS five patients presented with classical GBS and one with variant. Two patients presented neurologic symptoms during or shortly after the viral syndrome, suggesting the pattern of a para-infectious profile. Multi-organ involvement, delay in the diagnosis, incomplete work up and start of therapy, were registered in 50% of cases with a GBS-Disability scale ≥4 at follow-up evaluation. In not-COVID-19 related GBS, main problem was diagnostic delay. In three patients the first neurological observation took place after a mean of 33,6 days. Moreover, five patients went to emergency room after an average of 30 days since the onset of neurological symptoms because of fear of contagion. In conclusion, not only SARS-CoV-2 infection can cause GBS, but it can also, due to effects of pandemic on the health organization, affect the outcome of patients with not COVID-19 related GBS.


Subject(s)
COVID-19/epidemiology , Guillain-Barre Syndrome/epidemiology , Social Isolation , Aged , Case-Control Studies , Comorbidity , Delayed Diagnosis/statistics & numerical data , Disease Management , Female , Guillain-Barre Syndrome/diagnosis , Guillain-Barre Syndrome/therapy , Humans , Italy/epidemiology , Male , Middle Aged , Pandemics , SARS-CoV-2 , Time-to-Treatment/statistics & numerical data
13.
Mult Scler Relat Disord ; 42: 102120, 2020 Jul.
Article in English | MEDLINE | ID: covidwho-101811

ABSTRACT

BACKGROUND: Coronavirus disease 19 (COVID-19) is a novel disease entity that is spreading throughout the world. It has been speculated that patients with comorbidities and elderly patients could be at high risk for respiratory insufficiency and death. Immunosuppression could expose infected patients to even higher risks of disease complications due to dampened immune response. However, it has been speculated that overactive immune response could drive clinical deterioration and, based on this hypothesis, several immunosuppressants are currently being tested as potential treatment for COVID-19. METHODS: In this paper we report on a patient that has been treated with ocrelizumab (a B-cell depleting monoclonal antibody) for primary progressive multiple sclerosis who developed COVID-19. RESULTS: Despite complete B cell depletion, patient symptoms abated few days after hospitalization, and he was discharged to home-quarantine. Phone interview follow-up confirmed that, after 14 days, no new symptoms occurred. DISCUSSION: This report supports the putative role of immunosuppressive therapy in COVID-19 affected patients.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Coronavirus Infections/physiopathology , Immunologic Factors/therapeutic use , Multiple Sclerosis, Chronic Progressive/drug therapy , Pneumonia, Viral/physiopathology , Betacoronavirus , COVID-19 , Coronavirus Infections/complications , Humans , Male , Middle Aged , Multiple Sclerosis, Chronic Progressive/complications , Pandemics , Pneumonia, Viral/complications , Protective Factors , SARS-CoV-2 , Severity of Illness Index
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