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1.
Neurology ; 93(23 Supplement 2):S34, 2022.
Artigo em Inglês | EMBASE | ID: covidwho-2196705

RESUMO

Objective To determine cumulative incidence and point prevalence of neuromyelitis optica spectrum disorder (NMOSD), multiple sclerosis (MS), and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) in Thailand using population-based data of Chumphon province. Background CNS inflammatory demyelinating diseases (CNSIDDs) have a great interracial heterogeneity. The epidemiology of CNSIDDs in Thailand, a Mainland Southeast Asian country, is unknown. Design/Methods Searching for CNSIDD patients at a public secondary care hospital in Chumphon from January 2016 to December 2021 was performed using relevant ICD-10-CM codes. All neurology patients were systematically referred to this hospital as it was the only hospital in the province with a neurologist. Diagnoses were individually ascertained by retrospective chart review. Cumulative incidence over 2016-2021, point prevalence on December 31st, 2021, attack rate, mortality rate, and disabilityadjusted life years (DALYs) were calculated. Population data were obtained from the National Statistical Office of Thailand. As of December 31st, 2021, the population census of Chumphon was 509,479. Results NMOSD was the most prevalent CNSIDD in adult Thai population at 3.33 per 100,000 persons (crude prevalence 2.55). The age-adjusted prevalence of aquaporin-4 antibody-positive NMOSD alone was 3.08 per 100,000 persons. Age-adjusted incidence rate of NMOSD was 1.65 per 100,000 persons/year (crude incidence rate 0.20). Age-adjusted prevalence of MS followed at 0.77 and MOGAD at 0.51 per 100,000 persons (crude prevalence 0.59 and 0.39, respectively). Although most had a fair recovery, disability was worst amongNMOSD with a DALY of 3.47 years per 100,000 persons. Mortality and attack rates were highest in NMOSD as well. No increase in incidence or attack rate were observed during the COVID-19 pandemic. Conclusions CNSIDDs are rare diseases in Thailand. The prevalence is comparable to that of East Asian countries. NMOSD caused the highest DALYs among CNSIDDs.

2.
Neurology ; 93(23 Supplement 2):S30-S31, 2022.
Artigo em Inglês | EMBASE | ID: covidwho-2196704

RESUMO

Objective Acquired neuromyotonia or Isaacs' syndrome is an immune mediated inflammatory disorder characterized by involuntary continuous muscle fiber activity manifesting as twitching and stiffness along with autonomic dysfunctions like hyperhidrosis and/or tachycardia. Here we report a young male who developed acquired neuromyotonia following COVID- 19 vaccination. Background A 20-year-old male presented in our clinic with gradually progressive pain and numbness in bilateral lower limbs, tremors in both hands, shivering while walking, excessive sweating and difficulty in micturition for last 15 days. He also noticed twitching of muscles in calf and thigh muscles along with these symptoms. According to patient, these symptoms started after he took his first dose of COVID-19 vaccination (Covishield- Oxford- AstraZeneca viral vector vaccine) 10 days back. There was no history of fever or backache. He had no chronic illness and was not on any medications. Examination revealed hyperhidrosis, mild proximal muscle weakness in both lower limbs with twitching in muscles suggestive of myokymia. There were quivering and rippling movements of intrinsic muscles of both hands resembling polyminimyoclonus. In view of the above findings, possibility of acquired neuromyotonia possibly following COVID-19 vaccination was kept and further evaluation was done. Design/Methods Routine blood investigations, thyroid function test, anti-thyroid peroxidase antibodies and anti-nuclear antibodies were normal. Cerebrospinal fluid analysis was normal. Anti-VGKC antibodies were detected in serum with strongly positive anti-CASPR and weakly positive anti-LGI1 antibodies confirming diagnosis of acquired neuromyotonia. Results Pulse dose of intravenous methylprednisolone for 5 days was given which resulted in visible improvement in pain, twitching, hyperhidrosis and urinary symptoms. He was continued on oral steroids and complete resolution of his symptoms was noted over a period of 2 months. Conclusions COVID-19 vector vaccine associated acquired neuromyotonia is a rare condition, but its early recognition and treatment is the key for a favorable prognosis.

3.
Neurology ; 93(23 Supplement 2):S30, 2022.
Artigo em Inglês | EMBASE | ID: covidwho-2196703

RESUMO

Objective The goal of this study is to compile published data reporting neurological immune-related adverse events following COVID-19 vaccination, not including those relating to hematologic abnormalities such as thrombosis or hemorrhage. Background COVID-19 vaccination has been repeatedly shown to reduce the incidence and severity of COVID-19 infection. The expedited timeline of these vaccines has given rise to many discussions pertaining to their safety. Many neurological and non-neurological adverse events have been linked to COVID-19 vaccination including acute MI, anaphylaxis, appendicitis, Bell's palsy, deep vein thrombosis, disseminated intravascular coagulation, encephalomyelitis, transverse myelitis, and many others. Design/Methods The following databases were searched in April 2021 using different keywords: PubMed, Medline, Embase, Scopus, Web of Science, Science, Direct, MedRxiv, and Lens.org. Studies were included if they reported any adverse immune-related neurological events secondary to COVID-19 vaccination. Studies were excluded if they were not in English, included self-reported events only, or did not report primary data. Screening and extraction were conducted by 2 different reviewers using Covidence. Results The search strategy yielded 18 studies which reported a total of 61 patients who had received a COVID-19 vaccination and experienced = 1 neurological adverse events. Most reported adverse events were facial nerve palsy (52.5%), reactivation of herpes zoster (11.5%), Guillian-Barre syndrome (6.6%), demyelinating disease (6.6%), and neuropathy (11.5%). Other reported adverse effects were delirium, periauricular vesicular rash, bilateral sensorineural hearing loss, visual disturbance, gait disturbance, serotonin syndrome, and vestibular ataxia (16.4%). Conclusions The symptoms were time-limited and self-resolving in nature. In addition, the incidence of the reported events following COVID-19 vaccination compared to the general population is similar. Hence, there is little to no evidence suggesting a causal relationship between COVID-19 vaccination and neurological adverse events.

4.
Neurology ; 93(23 Supplement 2):S29, 2022.
Artigo em Inglês | EMBASE | ID: covidwho-2196702

RESUMO

Objective To describe clinical and paraclinical features of non-paraneoplastic NIFmediated disease associated with concurrent SARS-CoV-2 infection. Background Neurologic syndromes associated with neuronal intermediate filament (NIF) immunoglobulin G (IgG) most often are characterized by encephalopathy, cerebellar ataxia, or myelopathy. NIF-IgG has been strongly correlated with the presence of an underlying malignancy, with neuroendocrine tumors being most prevalent. Despite the intracellular target of this antibody, patients with NIF-IgG mediated disease tend to improve clinically with immunotherapy. While some cases have been described in a parainfectious context, this is the first such case in the context of a SARS-CoV-2 infection. Design/Methods NA. Results We reported a case of non-paraneoplastic NIF-mediated disease in the setting of SARS-CoV-2 infection. The patient presented with first time seizure. He was found to have frequent left temporal lobe spikes then two left temporal lobe seizures on neurotelemetry. Brain MRI displayed abnormal signal throughout the left hippocampus and mesial temporal lobe, without contrast enhancement. LP was subsequently performed. CSF showed elevated protein, 14-3-3, T-tau, interleukin 13, interleukin 2 receptor, and interleukin 6. The meningitis/encephalitis panel, and HSV-1/2 IgG were negative. Serum autoimmune encephalitis panel revealed a high-positive titer for anti-NIF 1:960, with concurrent NIF heavy chain cell-based assay positive. He improved with three days of IV steroids and treatment with levetiracetam and lacosamide. He has since been seizure free. Conclusions NIF-mediated diseases usually present with encephalopathy, cerebellar ataxia, or myelopathy and are generally seen in the setting of malignancy. Our case illustrated an example of NIF-mediated disease presenting as seizure in the setting of infection. This highlights the importance of consideration of parainfectious autoimmunity.

5.
Neurology ; 93(23 Supplement 2):S67-S68, 2022.
Artigo em Inglês | EMBASE | ID: covidwho-2196701

RESUMO

Objective To report a case of Anti-Contactin-Associated Protein-like2 (CASPR-2) autoimmunity in a patient with low-grade Chronic Lymphocytic Leukemia (CLL) following COVID-19 vaccination and infection. Background Anti-CASPR2 antibody disorder has been associated with neoplastic disorders like thymoma. Recent reports enlist COVID-19 as apotential trigger of CASPR2 autoimmunity. While the clinical presentations are similar, management differs based on the underlying etiology. Design/Methods We review a case of anti-CASPR2-antibody associated disorder with concurrent low grade CLL and recent history of COVID-19 vaccination and infection. Additionally, we review the literature and discuss the therapeutic challenges. Results A 73-years old male presented with five months of progressive fatigue, weight loss, diffuse sweating, muscle cramps, and neuropathic pain. He eventually developed bilateral upper and lower facial weakness. Patient contracted a mild COVID-19 infection two months prior and COVID- 19 vaccination one month prior to his symptom onset. His exam was remarkable for bilateral facial weakness, diffuse fasciculations and sensory neuropathy on his trunk and extremities. His diagnostic work up including bone marrow biopsy was consistent with a chronic lymphocytic leukemia (CLL)-like immunophenotype. Cerebrospinal fluid (CSF) analysis was remarkable for five WBC (lymph-dominant) and protein of 74 mg/dl. Serum paraneoplastic panel revealed positive CASPR2 antibody with a titer of 1:100. Magnetic Resonance Imaging (MRI) of the brain showed enhancement of bilateral cranial nerve VII. After lack of clinical response to IV methylprednisone (1 gram for 5 days), patient was treated with a single cycle of IV immunoglobulin (IVIG). He had complete recovery of his symptoms except for residual facial weakness. He remains stable at his six months post-treatment follow-up. Conclusions Anti-CASPR2 associated autoimmunity following COVID-19 infection or in the setting of CLL has previously been reported. However, cranial neuropathy in association with CASPR2 antibody has never been. A trial of IVIG could be beneficial in patients with viral-spike protein-induced autoimmunity and CLL who do not otherwise meet the criteria for CLL treatment.

6.
Neurology ; 93(23 Supplement 2):S61-S62, 2022.
Artigo em Inglês | EMBASE | ID: covidwho-2196700

RESUMO

Objective NA. Background Prior case studies suggest that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its vaccines may unmask neuroinflammatory conditions. We present a case of relapsing steroidresponsive encephalomyelitis after SARS-CoV-2 infection and subsequent COVID-19 vaccination. Design/Methods NA. Results A 47-year-old man with a history COVID-19 presented with subacute lower extremity weakness, erectile dysfunction, and gait instability with falls. His symptoms started several weeks after COVID-19 vaccination which he underwent 3 months afterCOVID-19 infection. His initial exam demonstrated weakness at the knees and ankles and extensor plantar responses. MRI demonstrated innumerable enhancing lesions involving the subcortical white matter, basal ganglia, thalami, brainstem, cerebellum, and the entire spinal cord parenchyma. CSF testing revealed a lymphocytic pleocytosis (10 WBC, 88% lymphocytes), and transient matched serum and CSF oligoclonal bands. Testing was unremarkable for infections, malignancies, primary demyelinating conditions, etc. He responded dramatically to five days of high dose methylprednisolone but had recurrence of symptoms with weaning of oral prednisone, requiring another pulse of IV steroids. After 2 months, his steroids were weaned again, with clinical and radiographic recurrence, requiring another course of IV steroids. He was subsequently transitioned to mycophenolate as a steroidsparing agent. Literature review identified 20 additional cases of CNS neuroinflammatory disease after either SARS-CoV-2 infection or vaccination (11 transverse myelitis, 6 optic neuritis, 3 encephalomyelitis). Conclusions Our patient's steroid-dependency and relapsing course suggests unmasking of an underlying CNS neuroinflammatory condition. Temporal associations of neurological conditions with vaccinations or infections do not prove causality despite previous reports of such sequelae. Vaccines containing SARS-CoV-2 antigens may enhance autoimmunity by mechanisms including polyclonal activation, epitope spreading, or molecularmimicry. This case highlights that the resulting inflammation may be insidious and extensive, though treatable. As COVID-19 constitutes a life-threatening infection in some patients, the benefits of vaccination outweigh the smaller risk of unmasking an immune-related condition.

7.
Neurology ; 93(23 Supplement 2):S60, 2022.
Artigo em Inglês | EMBASE | ID: covidwho-2196699

RESUMO

Objective We describe a case of bilateral sequential optic neuropathies with pachymeningitis and aortitis, with findings that raised suspicion of Erdheim-Chester disease versus IgG-4 related disease. Background Erdheim-Chester disease (ECD) is a rare histiocytic neoplasm characterized by tissue infiltration by foamy histiocytes, and chronic, uncontrolled inflammation. IgG4-related disease (IgG4-RD) is an insidiously progressive immune-mediated fibrotic disease typified by tumour-likemass formation in many affected organs. Neurologic manifestations are diverse. Design/Methods A 58-year-old male was transferred to our centre for acute onset sequential optic neuropathies. His visual acuity was light perception for the right eye and 20/50 in the left eye. Results Enhanced MRI of the brain and orbits showed focal pachymeningeal thickening and enhancement in the anterior cranial fossa and over the left frontal lobe with eccentric enhancement of the right optic nerve sheath. CRP was elevated (23 mmol/L to 62 mmol/L);extensive CSF and serum infectious and inflammatory investigations were unrevealing. PET body demonstrated aortitis and CT angiography suggested coronary artery vasculitis. Bone scan showed symmetric involvement of the long bones. Dural biopsy was delayed due to the Covid-19 pandemic and was completed following a protracted steroid course and a 15 mg/kg dose of cyclophosphamide. Pathology showed mixed inflammatory infiltrate and increased expression of IgG4 neutrophils.Clusters ofCD68+,CD1a, and S100-negative macrophages were seen in all layers of dura. No BRAF mutation was identified. Conclusions This case demonstrates classic imaging findings of ECD including pachymeningitis, symmetric long bone involvement and aortitis. Pathology in ECD may show characteristic foamy histiocytes, that were absent in this case. This case demonstrates the challenge of biopsy interpretation following immunosuppressive and cytotoxic therapy and the difficulty of differentiating ECD from IgG4-RD.

8.
Neurology ; 93(23 Supplement 2):S69, 2022.
Artigo em Inglês | EMBASE | ID: covidwho-2196698

RESUMO

Objective Our objective was to evaluate the incidence of seizures, pattern of EEG abnormalities, and localization of abnormal discharges in hospitalized patients with COVID-19. Background The COVID-19 epidemic has revealed significant neurological manifestations including de novo seizures in patients who do not have a prior history of epilepsy or clear epilepsy risk factors. Our center is located in Arizona, which in the early part of January 2021 had more cases per capita than any other place in the world. Design/Methods We performed a retrospective review to observe the electroencephalogram (EEG) patterns of hospitalized adult patients with COVID-19 between March 2020 and February 2021. Results We identified 99 patients who were COVID-19 positive and had EEG testing during the same hospitalization. The most common EEG abnormality was diffuse background slowing, which was seen in 63.6% of patients (n = 63/99), compare to 15.1% of focal background slowing. Epileptiform discharges were seen in 11.1% of patients and seizures were found in 5.1% of patients, as newly diagnosed seizures. When combining all focal abnormalities, the most common location for these abnormalities was in the frontal regions 36.4% (n = 8/22). Even though 21 patients had acute focal neuroradiologic findings, only 5 had correlated EEG abnormalities within the same region. When EEG was obtained with suspected seizures (n = 33), 4 cases (12.1%, n = 4/33) indeed showed ictal pattern compared to 1.6% when seizures was not suspected (p = 0.087). Conclusions Abnormal EEG findings are most commonly found in the frontal lobe among hospitalized patients with acute COVID-19 symptoms. De novo seizures may be seen with COVID-19 infection. Suspicion of seizures should be raised in patients with COVID-19 encephalopathy. The utility of an EEG may help allow us better insight into how and where the COVID infection affects our central nervous system.

9.
Neurology ; 93(23 Supplement 2):S28, 2022.
Artigo em Inglês | EMBASE | ID: covidwho-2196697

RESUMO

Objective To demonstrate a case of suspected post-vaccine autoimmune encephalitis associated with leucine-rich glioma-inactivated protein (LGI1) antibodies with significant clinical improvement after initiation of immunotherapy nearly a year after symptom onset. Background Although the autoimmune encephalitides have overlap in presentation, some have unique manifestations (such as orofacial dyskinesias seen with NMDA encephalitis). These unique associations can serve as a clinical marker of response to treatment and even allow for earlier initiation of immunotherapy while awaiting results from antibody testing. LGI1 encephalitis characteristically presents with faciobrachial dystonic seizures (FBDS) that are refractory to anti-seizure medications (ASMs) but responsive to immunotherapy. Design/Methods Case report Results A previously healthy and highly independent 89-year-old woman developed what she described as abnormal posturing and spasms of the right shoulder two to three weeks after receiving the J&J COVID-19 vaccine. The abnormal movements progressed to involve the right side of her face and were refractory to multiple ASMs. EEG captured multiple events without epileptiform correlate. Several months later she developed paranoia, delusions, and hallucinations. Autoimmune encephalopathy panel returned positive for the LGI1-antibody around nine months after the onset of FBDS. Upon our initial exam, she had a fluctuating level of arousal, impaired recall of recent events, and was tangential in conversation. There were frequent, brief, repetitive, dystonic movements of the right side of the face consistent with FBDS. Admission was arranged for immunotherapy (intravenous methylprednisolone and intravenous immunoglobulin). Upon follow-up four weeks later, there was significant improvement in arousal and concentration with resolution of FBDS and delusions. Conclusions This case highlights a classic case of LGI1 encephalitis after vaccination presenting with FBDS and progressive cognitive changes. Despite immunotherapy being delayed, there was marked clinical improvement. It is important to recognize this entity and that it typically has a favorable outcome.

10.
Neurology ; 93(23 Supplement 2):S34-S35, 2022.
Artigo em Inglês | EMBASE | ID: covidwho-2196696

RESUMO

Objective To describe features of central nervous system (CNS) demyelinating events following vaccination against coronavirus disease 19 (COVID- 19). Background Several reports suggest a potential association between COVID-19 vaccines and acute CNS inflammation. Design/Methods A case series was performed at the BARLO MS Centre in Toronto, Ontario, Canada. Clinicians reported patients who experienced an acute CNS demyelinating event within 60 days after receiving at least one COVID-19 vaccination from March 2021 to January 2022. Clinical characteristics were evaluated. Results Twenty patients were identified (median age 39 years (range 25-82);13 (65.0%) female). Two had pre-existing multiple sclerosis (MS). Individuals received the Pfizer (n = 14), Moderna (n = 5) or Astrazeneca (n = 1) COVID-19 vaccines. Within 1-53 days (median 12) of the first (n = 8) or second (n = 12) vaccine dose, patients developed transverse myelitis (TM) (n = 15), optic neuritis (n = 4) or brain demyelination (n = 4). Diagnoses at last follow up (median 114 days (range 39-255)) were relapsing remitting MS (n = 8), post-vaccine TM (n = 5), clinically isolated syndrome (n = 3), myelin oligodendrocyte glycoprotein antibody disease (n = 2), MS relapse (n = 1) and neuromyelitis optica spectrum disorder (n = 1). Thirteen patients received pulse corticosteroids, and of these, 4 received plasma exchange. Seven did not receive acute treatment. 20.0% returned to baseline (n = 4), 75.0% partially recovered (n = 15) and 5.0% worsened (n = 1). At last follow up, 11 were on disease modifying therapy and 9 were not. Nine patients received a subsequent COVID-19 vaccine. Of these, one experienced symptom recrudescence without radiologic evidence of a new demyelinating attack. Conclusions To our knowledge, this is the largest series to date describing acute CNS demyelination after vaccination against COVID-19. The rate of vaccination in the eligible general population was high during the time of the cases and we could not determine whether the number of demyelinating events was higher than expected. Repeat vaccination was not associated with recurrent adverse events in this small observational series.

11.
Neurology ; 93(23 Supplement 2):S37-S38, 2022.
Artigo em Inglês | EMBASE | ID: covidwho-2196695

RESUMO

Objective To evaluate the safety and efficacy of efgartigimod in patients with generalized myasthenia gravis (MG) enrolled in the ADAPT+ longterm extension study. Background Treatment with efgartigimod, a human IgG1 antibody Fc-fragment that blocks neonatal Fc receptor, resulted in clinically meaningful improvement (CMI) in MG-specific outcome measures in the ADAPT phase 3 clinical trial. All patients who completed ADAPT were eligible to enroll in its ongoing open-label, 3-year extension study, ADAPT+. Design/Methods Efgartigimod (10 mg/kg IV) was administered in cycles of once-weekly infusions for 4 weeks, with subsequent cycles initiated based on clinical evaluation. Efficacy was assessed during each cycle utilizing Myasthenia Gravis Activities of Daily Living (MG-ADL) and Quantitative Myasthenia Gravis (QMG) scales. Results Ninety-one percent of ADAPT patients (151/167) entered ADAPT+. As of February 2021, 106 AChR-Ab+ and 33 AChR-Ab- patients had received at least 1 dose of open-label efgartigimod (including 66 ADAPT placebo [PBO] patients). The mean (SD) study duration was 363 (114) days, resulting in 138 patient-years of observation. Similar incidence rates per patient year (IR/PY) of serious adverse events were seen in ADAPT (efgartigimod: 0.11;placebo: 0.29) compared to ADAPT+ (0.25). Five deaths (acute myocardial infarction, COVID-19 pneumonia/septic shock, bacterial pneumonia/MG crisis, malignant lung neoplasm, and unknown [multiple cardiovascular risk factors identified on autopsy]) occurred;none were considered related to efgartigimod by the investigator. AEs were predominantly mild or moderate. CMI was observed in AChR-Ab+ patients during each cycle (up to 10 cycles) at magnitudes comparable to improvements observed at week 3 of cycle 1 (mean[SE] improvements: MG-ADL, -5.1[0.34];QMG, -4.7[0.41]). Clinical improvements mirrored maximal reductions in total IgG and AChR-Abs across all cycles. Conclusions This analysis suggests the efficacy of long-term treatment with efgartigimod was consistent across multiple cycles. No new safety signals were identified, despite being conducted before vaccine availability during the COVID-19 pandemic.

12.
Neurology ; 93(23 Supplement 2):S71-S72, 2022.
Artigo em Inglês | EMBASE | ID: covidwho-2196694

RESUMO

Objective To study the COVID-19 vaccine three-dose safety and risk of COVID- 19 in patients with myasthenia gravis Background Various vaccines, including those against SARS-CoV-2, were reported to trigger or exacerbate myasthenia gravis (MG). As COVID-19 may potentially contribute to the tendency of MG patients to develop respiratory failure, it is important to study the safety of vaccines against SARS-CoV-2 and assess the risk of COVID-19 in MG patients. Design/Methods Among 215 MG patients treated in Tel Aviv Medical Center, 160 were interviewed about their response to the three-dose BNT162b2 mRNA vaccine. We assessed exacerbation rate and safety in a period of up to 6 weeks from each vaccine dose, as well as patient morbidity and mortality during COVID-19 compared to the general population. Results 430 vaccine doses were administered across 150 patients. Thirteen patients (8.7%) complained of exacerbation within 6 weeks (risk period) of each vaccine dose, 8 (5.3%) confirmed by physician report. The exacerbation rates were similar during the risk period (5.6%) compared to corresponding period the previous year (4.8%). MG onset rates during the vaccination period were unaffected compared to previous years. Exacerbation rate among 15 patients who had COVID-19 was significantly higher (40%) compared to rate in the risk period following vaccination, with higher severe or lethal COVID-19 (26.7%) compared to the general population (0.96%), occurring in unvaccinated, steroidtreated, generalized MG patients. Conclusions Three-dose BNT162b2 vaccination is neither associated with exacerbation nor the new onset of MG, whereas COVID-19 is associated with severe disease and death in unvaccinated, steroid-treated generalized MG patients. Hence, it is strongly recommended for generalized MG patients to get vaccinated.

13.
Neurology ; 93(23 Supplement 2):S52-S53, 2022.
Artigo em Inglês | EMBASE | ID: covidwho-2196693

RESUMO

Objective To assess adaptive immunity to SARS-CoV-2 in anti-CD20 treated individuals with mRNA vaccination. Background Anti-CD20 therapies attenuate humoral responses to vaccines. However, their effect on T cell responses is less clear. We examined B and T cell responses following COVID-19 vaccination in patients receiving anti-CD20 therapy for multiple sclerosis (MS) and other autoimmune inflammatory neurologic diseases (AINDs, e.g., autoimmune encephalitis, stiff person syndrome, etc.). Design/Methods MS and AIND patients on anti-CD20 therapies were prospectively enrolled for longitudinal analysis of antibody and T cell responses after a 3rd COVID-19 vaccination. Serum antibodies against the receptorbinding domain of the S1 spike protein (RBD-S1 IgG), neutralizing antibodies, and SARS-CoV-2 CD8 T cell responses, using activationinduced markers (AIM) and INF-gamma release assays (EUROIMMUN, Germany), were measured at various time points including prevaccination, post initial vaccination series, and 4 and 12 weeks after 3rd dose. Results Thirty-four MS and AIND participants are enrolled. Results for these patients (mean age 52 years-old, 79% female, 21 Pfizer, 13 Moderna) demonstrated attenuated RBD IgG antibody responses. However, a robust CD8 T cell response was observed, following a two-dose series, compared to non-immunosuppressed, age-matched vaccinated controls or unvaccinated with severe SARS-CoV-2 infection (p = 0.01). T cell response was sustained long-term (>12 weeks post 3rd dose) in all 11 anti-CD20 patients analyzed thus far. Collections are completed for all participants at 12 weeks and analysis to be completed by 05/15/22. Further analysis includes correlation of the INF- gamma release assay compared to RBD-CD8 T cell response detected by AIM assay. Conclusions Results suggest that patients treated with anti-CD20 therapy generate a robust CD8 T cell response to SARS-CoV-2 mRNA after three doses but remain with attenuated humoral immune responses. Our observational study will provide important data to guide vaccine management in patients on or anticipating anti-CD20 therapy.

14.
BMC Proceedings. Conference: 6th International Conference on Molecular Diagnostics and Biomarker Discovery, MDBD ; 16(Supplement 7), 2022.
Artigo em Inglês | EMBASE | ID: covidwho-2196279

RESUMO

Background Severe Acute Respiratory Disease 2 (SARS-CoV-2) has been identified as the causal factor to the recent COVID-19 pandemic [1]. One of the capacities required to study this virus is to isolate and propagate them according to the requirement of the studies. To date, the majority of studies utilized monkey-derived Vero cells to rapidly propagate the virus. However, due to its highly susceptibility to SARS-CoV-2 infection and limited capacity to metabolize drugs, this cell line is not suitable for pathophysiology and anti-viral research. Vero cells are not preferred for investigation of pathological mechanism of host cell's response to virus infection because they are not derived from human lung tissue. Furthermore, they are difficult to be used in the study to assess cytopathic effects as they do not express type 1 interferon genes [2]. In this study, we adapted the SARS-CoV-2 isolates into selected human lung-derived cell lines, i.e., MRC-5 and A549, to investigate the capacity of these cell lines as a platform for the characterization of SARS-CoV-2 isolated in Malaysia. MRC-5 has already been identified to be highly susceptible to the infection of various human coronaviruses, including HCoV-OC43, HCoV-229E and Middle East respiratory syndrome coronavirus (MERS-CoV) [3]. Meanwhile, A549 was selected due to its origin of lung derived. Methodology To determine the growth profile of SARS-CoV-2 in human-derived cell lines, a local SARS-CoV-2 clinical isolate obtained from the IMR archive was first adapted into Vero E6, thus resulting in the generation of passage 1 (P1). The P1 isolate was used to study the growth profile of the virus in MRC-5 and A549 cell lines. P1 isolate was subjected to Whole Genome Sequencing (WGS) to identify the genomic sequence of the isolate. The replication kinetics of these isolates in MRC-5 and A459 were evaluated based on the on the formation of cytopathic effect (CPE), Cq value, plaque forming unit (pfu) as well as observation by electron microscope (EM). Whole Genome Sequencing (WGS) was repeated on the propagated SARS-CoV-2 passages to examine the genomic stability. Results and Discussion There was no formation of CPE observed after inoculation of SARSCoV- 2 into MRC-5 and A549 cells after 7 days of culture. In parallel, the qRT-PCR results suggested that the virus did not multiply well in these cells. Plaque assay and EM images further supported these findings. In terms of genome stability, WGS data revealed several genetic polymorphisms in the genome of the virus adapted in MRC- 5 and A549 cells. Conclusion MRC-5 and A549 are not susceptible to SARS-CoV-2 infection.

15.
BMC Proceedings. Conference: 6th International Conference on Molecular Diagnostics and Biomarker Discovery, MDBD ; 16(Supplement 7), 2022.
Artigo em Inglês | EMBASE | ID: covidwho-2196278

RESUMO

Background Impaired liver function upon admission has been linked to the severity of COVID-19 infection, yet the data is debated [1]. Therefore, this retrospective study aimed to evaluate the liver function among COVID-19 patients during hospitalization and its association with the disease severity. Methodology Patients aged 18 to 80 years with positive COVID-19 at Hospital Raja Perempuan Zainab II (HRPZ II), Kota Bharu, Kelantan, with available AST, ALT, Bilirubin, and AST/ALT ratio data on admission, were retrospectively evaluated from March 2021 until March 2022. Disease severity was categorized based on the Annex 2e guidelines by Ministry of Health Malaysia, which further classified them into mild to moderate disease (Stage 1-3) and severe to critical illness (Stage 4-5). The AST, ALT, Bilirubin, and AST/ALT ratio levels on Day 1 admission were archived from the electronic medical record system and compared between the two groups. Statistical analysis was performed using SPSS version 27. This study was approved by (JEPeM-USM) with protocol code USM/JEPeM/21100691 and the Ministry of Health Malaysia NMRR-21-762-58458 (IIR). Results and Discussion The study involved a total of 168 COVID-19 patients with a mean (SD) age of 46.67(16.10) for mild to moderate and 56.66(12.41) for severe to critical. There was a significant age group for both groups (pvalue= 0.002). During hospitalization, 16(14.41%) patients progressed to death from severe to critically ill patients. Upon admission, the median (IQR) of AST and ALT were significantly higher in the severe to critical group compared to the mild to moderate group, [AST;39.0(49.0) and 24.0(14.0), ALT 38.0(43.0) and 21.0(18.0)], p<0.05. However, there were no significant differences between both groups for bilirubin level and AST/ALT ratio. Non-survivors had higher AST and ALT levels compared to survivors, with median (IQR) of [AST 98.0(88.0) and 32.0 (26.0), ALT of 67.5(90.0) and 28.0(31.0), (p<0.05). Similarly, there were no significant differences between nonsurvivors and survivors for bilirubin and AST/ALT ratio. Our study supports the idea that abnormal liver function at admission has been shown to be associated with the disease severity and mortality of COVID-19 infection. Therefore, there is a need to observe hepatobiliary sequelae in COVID-19 survivors as there are dynamic changes in liver function following hospital discharge. Conclusion Abnormal AST and ALT level at admission has been shown to be associated with the disease severity and mortality of COVID-19 infection. Further study needed to evaluate liver damage in COVID-19 post-discharge.

16.
BMC Proceedings. Conference: 6th International Conference on Molecular Diagnostics and Biomarker Discovery, MDBD ; 16(Supplement 7), 2022.
Artigo em Inglês | EMBASE | ID: covidwho-2196277

RESUMO

Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as an emergent zoonotic virus since December 2019, has caused coronavirus disease 2019 (COVID-19) as the first coronavirus pandemic in history [1]. Neutralizing antibodies against SARS-CoV-2 is useful, however with the large size (~150 kilodaltons (kDa)), complex hetero-tetrameric structure and susceptibility to extreme ambient temperature for the conventional antibody may limit their performance in therapeutic and diagnostic applications [2]. Antibody surface display technology allows the exploration of antibody fragments from other organisms, including VNAR (variable domain of immunoglobulin new antigen receptor (IgNAR)) from shark with better thermostability [3]. The advantages of shark VNAR single-domain antibody are due to possessing smaller size (~12 kDa) and simpler structure, with its antigen-binding capability comparable to conventional antibody [2, 3]. The aim of this study is to evaluate the potential of shark VNAR as binders towards SARS-CoV-2 as target antigen. Methodology A proprietary phage-displayed semi-synthetic shark VNAR library was subjected to 3 rounds of biopanning. The commercial wild-type SARSCoV- 2 receptor binding domain (RBD) diluted in various concentration was used as target antigen in this study. The biopanning steps per round involved immobilizing antigen on immunotube, blocking immunotube with skimmed milk, incubating phages from antibody library in immunotube, washing off unbound phages while eluting bound phages, followed by the re-propagation of specific phage clones in Escherichia coli TG1. The phage particles harvested from culture supernatant were applied in the next round of biopanning. Polyclonal phage pool and monoclonal phage clones from each biopanning round were analysed by agarose gel electrophoresis, to detect the presence of VNAR insert. Results and Discussion Throughout rounds of biopanning, the amplification of phage clones was observed in Round 3, with 11-fold enrichment as compared to Round 1. Based on agarose gel electrophoresis result, the presence of VNAR insert increased from 60% (Round 1) to 100% (Round 3), indicated that SARS-CoV-2 RBD-targeted phage clones have been enriched throughout subsequent rounds of biopanning. The identification and functional characterization of potential clones are in process. Conclusion Shark VNAR has been proven as potential binders targeting towards SARS-CoV-2. Thus, further biological characterization is required to determine the specificity and sensitivity of the potential binders.

17.
BMC Proceedings. Conference: 6th International Conference on Molecular Diagnostics and Biomarker Discovery, MDBD ; 16(Supplement 7), 2022.
Artigo em Inglês | EMBASE | ID: covidwho-2196276

RESUMO

Background Coronaviruses are well-known to possess high mutation rate. The recent pandemic has demonstrated this fact that multiple SARS-CoV-2 variants have emerged since the first occurrence in 2019. Variants such as Beta, Delta and Omicron variant, even showed the ability of immune evasion in convalescent and vaccinated individuals [1], raising global concern about the efficacies of existing vaccines. Immunoinformatics approach is gaining traction in vaccine development due to significant time and cost reduction in immunogenicity studies and improved reliability [2]. Viral genome can be analysed for the mapping of potential T-cell and B-cell epitopes. Structural proteins, particularly spike protein (S) have been studied extensively as promising vaccine candidates. One rationale is that the RBD of SARS-CoV- 2 attaches to the ACE2 receptor on the host cells to initiate infection. Taken together, a vaccine that offers protection over a wide spectrum of coronaviruses is crucially demanded. Methodology The sequences of S proteins of the SARS-CoV-2 variants as well as SARS-CoV and MERS-CoV were retrieved from the NCBI database. Multiple sequence alignment (MSA) was performed to identify the conserved regions among S proteins from different human coronaviruses. All conserved regions were analysed for the antigenicity through VaxiJen. The conserved regions that passed the threshold value of 0.5 were then analysed for T-cell and B-cell epitope predictions using NetMHCpan EL4.1, IEDB recommended 2.22 and BepiPred 2.0, respectively. The antigenic conserved regions were also used to construct 3D model using SWISS-MODEL followed by structural refinement using GalaxyRefine2. All refined models were validated using ERRAT and PROCHECK. Lastly, the docking of 3D models against TLR-3 was performed via PatchDock and FireDock. Results and Discussion Based on the MSA result, S protein contains 12 conserved regions, which were then subjected to further analyses. Altogether 9 conserved regions were above the antigenicity threshold value and therefore selected. In terms of epitope prediction, the antigenic conserved regions were predicted to contain a total of 69 MHC Class-I epitopes, 45 MHC Class-II epitopes and 5 linear B-cell epitopes. Furthermore, all antigenic conserved regions were sent for 3D model building followed by structural refinement. The best refined model for each conserved region was chosen based on the Galaxy energy. These refined models were validated and the results showed that the models were of good quality. Following that, the refined model for each conserved region was docked against TLR-3. The global energies of complexes formed between the conserved regions and TLR-3 fell within the range of -11.74 to -7.36 kcal/mol. This implies that the conserved regions have good binding affinities with TLR-3. Conclusion The identified conserved regions of S protein were predicted to have a significant number of epitopes and showed promising docking results. This study provides some insights about the interaction of conserved S peptides with TLR-3, contributing to the vaccine design. Still, further analyses such as molecular dynamics and immune simulation are required to polish the results. In vitro and in vivo validation are also essential to evaluate the immunological roles of designed universal coronavirus vaccine.

18.
BMC Proceedings. Conference: 6th International Conference on Molecular Diagnostics and Biomarker Discovery, MDBD ; 16(Supplement 7), 2022.
Artigo em Inglês | EMBASE | ID: covidwho-2196275

RESUMO

Background Coronavirus disease 2019 (COVID-19), a highly contagious and rapidly spreading disease with significant fatality in the elderly population has swept across the world for the past three years since 2019. The enormity scale of this pandemic has resulted in the emergence of several SARS-CoV-2 variants with Omicron, the current main circulating variant of concern [1]. Nonetheless, all the variants identified to date share the same cell entry mechanism where the process is initiated when the spike protein of the viruses attach to the angiotensinconverting enzyme 2 (ACE2) receptors on their host cells [2]. Therefore, blocking the spike protein-ACE2 interaction using a biological binder targeting the ACE2 is a viable strategy for COVID-19 treatment. Aptamer is a short length of nucleic acid [RNA or singlestranded DNA (ssDNA)] which is selected through an in vitro selection called systematic evolution of ligands by exponential enrichment (SELEX). The selected aptamers have a 3D conformation that can specifically bind to their target with high affinity and pose many superior properties such as being smaller in size, thermally stable, and nearly non-immunogenic. Methodology Single-stranded DNA library of 76-bp oligonucleotides containing a randomized core region of 40 nucleotides, flanked by primer binding regions of 18 nucleotides on each side (5'-ATACCAGCTTATTCAATTN40- AGATAGTAAGTGCAATCT-3') was synthesized. Recombinant Histagged ACE2 protein (BBI Life Sciences, China) was immobilized to Ni-NTA Magnetic Beads (Gold Biotechnology, USA). Aptamers which showed high affinity towards the ACE2 were then selected from the initial library using SELEX. The isolated aptamers were cloned using the PCR Cloning Kit (NEB, USA) and the plasmids were extracted using DNA-spin Plasmid DNA Extraction Kit (iNtRON Biotechnology, Korea). The plasmids were sequenced and the resulting aptamer sequences were subjected to the UNAFOLD web server (http://www. unafold.org/) for ssDNA secondary structure prediction, followed by RNA tertiary structure prediction using RNAComposer (https:// rnacomposer.cs.put.poznan.pl/), and finally, converted to equivalent ssDNA tertiary structure using Discovery Studio Visualizer v3.5. The aptamer-ACE2 interaction was predicted using the HDOCK docking program (http://hdock.phys.hust.edu.cn/). Results and Discussion Aptamers specifically bound to ACE2 were isolated after 13 rounds of magnetic bead-based SELEX. Here, we reported one of the isolated aptamers, Apt15, which potentially binds to the ACE2. The UNAFOLD revealed that this aptamer has a hairpin loop structure and singlestranded region with a Gibbs free energy value of -0.10. The low free energy value indicates that the ssDNA structure is thermodynamically stable [3]. In silico 3D molecular docking demonstrated that the single-stranded region of Apt15 binds to the ACE2 at the site recognized by the SARS-CoV-2 spike protein with a confidence score of 0.9894, thus suggesting the potential application of this aptamer as a therapeutic target for COVID-19 infection. Conclusion In conclusion, one ssDNA aptamer targeting ACE2 with therapeutic potential against COVID-19 was successfully identified in this study. Further investigations are necessary to determine its binding affinity to ACE2 and its ability to block the virus spike protein-ACE2 interaction. In future, this aptamer could serve as a broad-spectrum inhibitor against any existing or future emerging viruses that also use ACE2 for cell entry.

19.
Craniomaxillofacial Trauma and Reconstruction ; 15(1 Supplement):6, 2022.
Artigo em Inglês | EMBASE | ID: covidwho-2195467

RESUMO

Objective: Excessive use of corticosteroids therapy along with gross immunocompromised conditions in the Coronavirus Disease 2019 (COVID-19) pandemic has raised the risks of contracting opportunistic fungal infections. Here, we describe our experience with the implementation of a surgical protocol to treat and reconstruct Rhino-orbitalcerebral mucormycosis. Material(s) and Method(s): We conducted a prospective, single institution study utilizing our Mucormycosis Management Protocol. All patients included in this study underwent reconstruction after recovering from COVID-19. Wide local excision was performed in all cases removing all suspected and edematous tissue. Reconstruction was done primarily after clear margins were achieved on clinical assessment under a cover of injectable liposomal amphotericin B. Result(s): Fourteen patients were included. The average age was 43.6 years and follow up was 24.3 months. Thirteen patients had been admitted for inpatient care of COVID-19. Steroid therapy was implemented for 2 weeks in eleven patients and for 3 weeks in 3 patients. Eight patients (57.1%) had a maxillectomy and mucosal lining resection with/without skin excision, and six patients (42.8%) underwent maxillectomy and wide tissue excision: (Maxillectomy and partial zygomatic resection, orbital exenteration, orbital floor resection, nose debridement, or skull base debridement). Anterolateral thigh flaps were used to cover defects in all patients. All flaps survived. No major or minor complications occurred. No recurrence of mucormycosis was noted. Conclusion(s): The approach presented in this study indicates immediate reconstruction is safe and reliable in cases when appropriate tissue resection is accomplished. Further studies are required to verify the external validity of these findings.

20.
Craniomaxillofacial Trauma and Reconstruction ; 15(1 Supplement):41, 2022.
Artigo em Inglês | EMBASE | ID: covidwho-2195466

RESUMO

Background: Electric scooters (e-scooters) have become a popular mode of transportation. There use has been accelerated by the COVID-19 pandemic, which called for methods of transport allowing social distancing. Here we investigated injury patterns in patients presenting with escooter related trauma in a major trauma centre. Method(s): We retrospectively evaluated all e-scooter injuries presenting to our adult emergency department unit between March 2018 and March 2021. Case notes were retrieved through our electronic patient record system. Specifically, we focused on facial injuries and calculated costs associated with managing them. Result(s): A total of 299 patients were seen with injuries relating to e-scooter. 209 (70%) were male and 90 (30%) Female. Age range was between 18 and 78. 31 cases had major injuries and needed admission. The majority of injuries (30%) were related to upper extremity followed by (26%) lower extremity. 19% (53) of injuries involved the head and neck area. 20% (11) of these specifically needed admission. There was more than 50% increase in total number of injury in quarter 1 in 2021 comparing to same period in 2020 in keeping with the UK opening up from lockdown. Conclusion(s): Our results show there is an increase in number of injuries caused by e-scooter. This is in keeping with e-scooter becoming more popular mode of transport after the start of the pandemic. A significant proportion of these injuries are treated in the maxillofacial department. We believe our study can make treating clinicians aware of common injury patterns, guide further research and help inform policy change to improve e-scooter safety.

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