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1.
Hum Immunol ; 2022.
Article in English | PubMed | ID: covidwho-2028070

ABSTRACT

We examined the correlation between class I HLA evolutionary divergence (HED), a surrogate for the capacity to present different peptides, and the outcomes of 234 adult inpatients with confirmed SARS-CoV-2 infection. Genomic DNA was extracted from peripheral blood and genotyped by next-generation sequencing (NGS). HED scores for HLA class I (HLA-A, -B, and -C) genotypes were calculated using Grantham's distance. Higher HED scores for HLA-B, but not HLA-A or -C, are significantly associated with a decreased probability of poor outcomes including ICU admission, mechanical ventilation, and death (OR = 0.93;P = 0.04) in the univariate analysis. In the multivariate analysis, increased HLA-B HED score, younger age, and no comorbidity were independently associated with favorable outcomes (P = 0.02, P = 0.01, and P = 0.05, respectively). This finding is consistent with the notion that broader peptide repertoires presented by class I HLA may be beneficial in infection control.

2.
Journal of Personalized Medicine ; 12(8):1233, 2022.
Article in English | ProQuest Central | ID: covidwho-2023822

ABSTRACT

Precision prevention for T1D considers the individual’s unique T1D risk profile (genetic susceptibility given from human leukocyte antigen HLA and non-HLA loci) to predict the individual response to the preventive agents (immune therapy or dietary intervention);however, we need to learn more about the role of environment in the onset of T1D, considering urban versus rural setting, the contribution of virus as SARS-COV2, life stressors or traumatic events, and food [6,7,8]. Precision prevention for T2D does not consider intervening in everyone with prediabetes, because it is not cost-effective [17], but on a subset of prediabetic patients chosen on the basis of other relevant risk factors (lifestyle, socioeconomic status, family history of diabetes, ethnicity, overweight–obesity, signs of insulin resistance, genetics). Unfortunately most cases of monogenic diabetes remain misdiagnosed, mainly due to the cost of performing genetic testing [3];other limits in implementing precision medicine in diabetes include epidemiological differences among varied populations (ethnic and racial barriers) and that some ethnic groups are underrepresented in clinical trials [20]. [...]the application of precision medicine in diagnosis and in treatment of monogenic diabetes is a standard of care [3].

3.
Nature Communications ; 13(1), 2022.
Article in English | Web of Science | ID: covidwho-2016695

ABSTRACT

The SARS-CoV-2 pandemic has differentially impacted populations across race and ethnicity. A multi-omic approach represents a powerful tool to examine risk across multi-ancestry genomes. We leverage a pandemic tracking strategy in which we sequence viral and host genomes and transcriptomes from nasopharyngeal swabs of 1049 individuals (736 SARS-CoV-2 positive and 313 SARS-CoV-2 negative) and integrate them with digital phenotypes from electronic health records from a diverse catchment area in Northern California. Genome-wide association disaggregated by admixture mapping reveals novel COVID-19-severity-associated regions containing previously reported markers of neurologic, pulmonary and viral disease susceptibility. Phylodynamic tracking of consensus viral genomes reveals no association with disease severity or inferred ancestry. Summary data from multiomic investigation reveals metagenomic and HLA associations with severe COVID-19. The wealth of data available from residual nasopharyngeal swabs in combination with clinical data ed automatically at scale highlights a powerful strategy for pandemic tracking, and reveals distinct epidemiologic, genetic, and biological associations for those at the highest risk. There is a genetic component to the risk of severe COVID-19, but the genetic effects are difficult to separate from social constructs that covary with genetic ancestry. To address this, the authors identify determinants of COVID-19 severity using admixture mapping, viral phylodynamics, and host immune and metagenomic sequencing.

4.
Frontiers in Medicine ; 9, 2022.
Article in English | EMBASE | ID: covidwho-2009878
5.
Frontiers in Immunology ; 13, 2022.
Article in English | EMBASE | ID: covidwho-2009860

ABSTRACT

Allelic diversity of human leukocyte antigen (HLA) class II genes may help maintain humoral immunity against infectious diseases. In this study, we investigated germline genetic variation in classical HLA class II genes and employed a systematic, unbiased approach to explore the relative contribution of this genetic variation in the antibody repertoire to various common pathogens. We leveraged a well-defined cohort of 800 adults representing the general Arab population in which genetic material is shared because of the high frequency of consanguineous unions. By applying a high-throughput method for large-scale antibody profiling to this well-defined cohort, we were able to dissect the overall effect of zygosity for classical HLA class II genes, as well as the effects associated with specific HLA class II alleles, haplotypes and genotypes, on the antimicrobial antibody repertoire breadth and antibody specificity with unprecedented resolution. Our population genetic studies revealed that zygosity of the classical HLA class II genes is a strong predictor of antibody responses to common human pathogens, suggesting that classical HLA class II gene heterozygosity confers a selective advantage. Moreover, we demonstrated that multiple HLA class II alleles can have additive effects on the antibody repertoire to common pathogens. We also identified associations of HLA-DRB1 genotypes with specific antigens. Our findings suggest that HLA class II gene polymorphisms confer specific humoral immunity against common pathogens, which may have contributed to the genetic diversity of HLA class II loci during hominine evolution.

6.
PloS one ; 17(8):e0273577, 2022.
Article in English | MEDLINE | ID: covidwho-2009701

ABSTRACT

Multiple immunoinformatic tools have been developed to predict T-cell epitopes from protein amino acid sequences for different major histocompatibility complex (MHC) alleles. These prediction tools output hundreds of potential peptide candidates which require further processing;however, these tools are either not graphical or not friendly for non-programming users. We present Epitope-Evaluator, a web tool developed in the Shiny/R framework to interactively analyze predicted T-cell epitopes. Epitope-Evaluator contains six tools providing the distribution of epitopes across a selected set of MHC alleles, the promiscuity and conservation of epitopes, and their density and location within antigens. Epitope-Evaluator requires as input the fasta file of protein sequences and the output prediction file coming out from any predictor. By choosing different cutoffs and parameters, users can produce several interactive plots and tables that can be downloaded as JPG and text files, respectively. Using Epitope-Evaluator, we found the HLA-B*40, HLA-B*27:05 and HLA-B*07:02 recognized fewer epitopes from the SARS-CoV-2 proteome than other MHC Class I alleles. We also identified shared epitopes between Delta, Omicron, and Wuhan Spike variants as well as variant-specific epitopes. In summary, Epitope-Evaluator removes the programming barrier and provides intuitive tools, allowing a straightforward interpretation and graphical representations that facilitate the selection of candidate epitopes for experimental evaluation. The web server Epitope-Evaluator is available at https://fuxmanlab.shinyapps.io/Epitope-Evaluator/.

7.
Annals of the Rheumatic Diseases ; 81:1497-1498, 2022.
Article in English | EMBASE | ID: covidwho-2009179

ABSTRACT

Background: The anti-SARS2 vaccination is considered the best way to reduce the frequency and the subsequent effects of COVID19 pandemic. To this aim, the most used in western countries are mRNA vaccines BNT16162b2 (Pfzer-Bi-oNT) and mRNA-1273 (Moderna). With both these vaccines the risk/benefts balance is largely favorable and severe adverse effects are almost rare. In keeping, although transient myalgia and arthralgia are frequently seen, myositis have been until now rarely reported. Objectives: To report two cases of myositis occurring in two patients after BNT16162b2 vaccine administration evaluated at the Center for Rheumatic Diseases in Venice, Italy. Methods: In these patients clinical examination, blood and instrumental investigations for myositis and, in addition HLA typing, were performed. Patients were followed for at least six months after the onset of symptoms. Results: The frst patient, a 54-year-old male, complained of high-grade fever 4 days after the I dose of BNT16162b2 (Pfzer-BioNT) followed, by mild fatigue, muscle soreness and increasing weakness. He was sent to the emergency department of the local Hospital. The physical examination confrmed the muscle weakness. Blood investigation revealed an increase of AST: 509 U/L (NV< 37), ALT:189 U/L (NV <78), LDH 609, CPK 11394 U/L (NV<, 309), Myoglobin 3571 ng/ml (VN <96), CRP 1. 6 mg/dl. Prednisone (PN) was started (50 mg orally day) and tapered to 5 mg in two weeks. At high doses, the symptoms slightly improved, but when < 10 mg, all the symptoms reappeared. Thus, he was hospitalized again. The new examination confrmed the increase of all indices of myositis;antinuclear antibodies and myositis antibodies were absent and PN was restarted at 10 mg/day without beneft;echo-cardiography and TC scan were negative. He was then sent to our observation. We increased the dose of PN at 1 mg/PN/kg and we required HLA typing. Two weeks later symptoms disappared almost completely and then we tapered PN 5 mg/day weekly. At present the patients is completely well and muscle indices negative since two months. HLA typing revealed the presence of B∗35 and DRB1∗15. The second case was a 29-year-old female presented with a history of complaints appeared two days after the vaccination with BNT16162b2 administration (Pfzer-BioNT) characterized by three days of high-degree fever, followed by sever weakness, especially in the arms. The family doctor decide to hear our advise. At the initial presentation arm strenght was very decrease and the patient was accompanied. We required a serie of investigations which revealed: CPK 8950 U/L (NV 250), CRP 3.5 mg/dl increased;antinuclear and anti-myositis antibodies absent;cardiac (Ultrasound) and thoracic (CT) investigation and electro-myography negative. HLA typing revealed the presence of haplotypes B∗35 and DRB1∗15. PN (50 mg orally day) was started;two weeks later she improved and both muscle indices and CRP negative. Thus, we reduce the dosage at 25 mg/day with tapering 5 mg weekly. She was completely remitted at end of PN cycle. At present, three month later she is well. Conclusion: The rare occurrence of some particular side effects is not predictable. Our cases of severe myositis which in both cases completely remitted in some months are associated with haplotypes HLA-B∗35 and DRB1∗15. These are both binding sites linked to high-affinity interactions to S-protein T-cell epitope which account for high potentials to trigger immunogenic responses to the S protein of SARS-CoV-2 (1). Furthermore classically, HLA-B35 is associated with reactive arthritis and self-limiting, unclassifed rheumatism (2).

8.
Annals of the Rheumatic Diseases ; 81:1700, 2022.
Article in English | EMBASE | ID: covidwho-2009135

ABSTRACT

Background: Besides the ability to induce antigen-specifc responses, vaccines can be endowed with immunomodulatory properties including the capacity to induce or downregulate regulatory T cells (Treg) that suppress adaptative and autoreactive immune responses (1). Objectives: We asked if an anti-SARS-CoV-2 mRNA vaccine could also induce an accumulation of Treg cells in patients with mixed cryoglobulinemia vasculitis (MCV), who have a defciency of Treg cells (2) and in healthy individuals. We also investigated immunologic variables possibly associated with a low immunogenic-ity of SARS-CoV-2 mRNA vaccine in patients with MCV (3). Methods: We analyzed peripheral blood lymphocyte subpopulations and anti-SARS-CoV-2 serological response in 24 patients with MCV and 9 Healthy donors (HD) before and after 2 weeks after the second dose of the Pfzer/BioNTech vaccine. Results: Among MCV patients we found 15 serological responders and 9 non-responders. All 5 seronegative patients treated recently with rituximab had <5 B cells/μ L, whereas the absolute B cell count was increased in 2 of 4 untreated patients due to monoclonal B cell lymphocytosis, with monoclonal cells representing more than 90% of B cells, associated with non-Hodgkin lymphoma. The percentage of pathologic CD21low B cells was signifcantly increased in seronegative patients. Before receiving the Pfzer/BioNTech vaccine, patients with MCV had a signifcantly reduced frequency of Treg cells among CD4+ T cells compared to HD. After the second dose of the vaccine, there was in MCV patients a signifcant increase in the percent and absolute count of Treg among CD4+ T cells Concerning the pre-vaccination distribution of T cells subpopulations, including the percentages and absolute counts of total CD3+, CD4+, CD8+, HLA-DR+ activated, Treg or CD56+ natural killer T cells, we could not reveal any pattern signifcantly associated with lack of serological response to vaccine. Conclusion: Our fndings show that lack of immunoreactivity in patients with MCV may be associated with expansion of pathologic B cells and that anti-SARS-CoV2 mRNA vaccine may induce an increase of Treg cells.

9.
Annals of the Rheumatic Diseases ; 81:959, 2022.
Article in English | EMBASE | ID: covidwho-2009047

ABSTRACT

Background: Several studies have demonstrated immunogenicity after COVID-19 vaccination in patients with autoimmune rheumatic diseases (AIRD) [1], but the differences between mRNA-based and vector vaccines and the cellular responses to COVID-19 vaccines according to distinct immunogenicity in AIRD patients are still unclear. Objectives: To investigate the differences in efficacy and safety between the vector vaccine ChAdOx1 nCoV-19/AZD1222 (Oxford-AstraZeneca) and mRNA-based vaccine mRNA-1273 (Moderna) in patients with AIRD, and to explore the cell-cell interactions between high and low anti-SARS-CoV-2 IgG levels in patients with rheumatic arthritis (RA) by single-cell RNA sequencing (scRNA-seq). Methods: From September 16 to November 15, 2021, we consecutively enrolled 243 participants aged ≥20 years with AIRD who received COVID-19 vaccination, of whom 113 were immunized with AZD1222 and 130 with mRNA-1273. The level of serum IgG antibodies to the SARS-CoV-2 receptor-binding domain on the spike protein S1 subunit was quantifed by electrochemiluminescence immuno-assay at 4-6 weeks after vaccination. Moreover, peripheral blood mononuclear cells were isolated from two RA patient with high anti-SARS-CoV-2 IgG level and four RA patients with low level for scRNA-seq and cell-cell communication signal was analyzed by CellChat. Results: The anti-SARS-CoV-2 IgG seropositivity rate was 78.8% (89/113) for AZD1222 and 83.1% (108/130) for mRNA-1273. The level of anti-SARS-CoV-2 IgG was higher in patients who received mRNA-1273 than in those who received AZD1222 (β: 30.15, 95% CI: 11.67-48.63, p=0.002) (Table 1). Prednisolone-equivalent dose >5 mg/day and methotrexate (MTX) use in AIRD patients, and non-anti-tumor necrosis factor (TNF)-α biologics and Janus kinase (JAK) inhibitor use in RA patients were associated with inferior immunogenicity. ScRNA-seq revealed CD16-monocytes were predominant in RA patients with high anti-SARS-CoV2-IgG antibody level, and enriched pathways related to antigen presentation via major histocompatibility complex class II (MHC class II) were found (Figure 1). HLA-DRA and CD4 interaction was vigorous among all identifed MHC-II pathway and was enhanced in high anti-SARS-CoV2-IgG antibody group. Conclusion: mRNA-1273 and AZD1222 vaccines exhibited differential immunogenicity in patients with AIRD. Enriched pathways related to antigen presentation via MHC class II in CD16-monocytes might be associated with higher anti-SARS-CoV2-IgG level in RA patients and further study is warranted.

10.
Annals of the Rheumatic Diseases ; 81:402-403, 2022.
Article in English | EMBASE | ID: covidwho-2008967

ABSTRACT

Background: Upadacitinib (UPA) was shown to be safe and effective through 2 years in patients (pts) with active ankylosing spondylitis (AS) naïve to biologic disease-modifying antirheumatic drugs (bDMARDs) in the pivotal phase 2/3 SELECT-AXIS 1 trial.1,2 Objectives: To assess the efficacy and safety of UPA in pts with active AS with an inadequate response (IR) to bDMARDs. Methods: SELECT-AXIS 2 (NCT04169373) was conducted under a master protocol and includes two separate studies (one for AS bDMARD-IR and one for non-radiographic axial spondyloarthritis [nr-axSpA]). The AS bDMARD-IR study is a randomized, double-blind, placebo (PBO)-controlled, phase 3 trial that enrolled adults ≥18 years with AS who met modifed New York criteria, had BAS-DAI and pt's assessment of total back pain scores ≥4 (numeric rating scale 0-10) at study entry, and had an IR to one or two bDMARDs (TNF inhibitor or IL-17 inhibitor). Pts were randomized 1:1 to receive oral UPA 15 mg once daily (QD) or PBO during the 14-week (wk) double-blind treatment period. The primary endpoint was ASAS40 response at wk 14. Multiplicity-controlled secondary endpoints evaluated at wk 14 were improvements from baseline in disease activity (ASDAS [CRP], ASDAS ID [<1.3], ASDAS LDA [<2.1], BASDAI50, ASAS20, and ASAS PR), pain (total and nocturnal back pain), function (BASFI), objective measure of infammation (SPARCC MRI score of the spine), spinal mobility (BASMI), enthesitis (MASES), and quality of life (ASQoL and ASAS HI). Non-responder imputation incorporating multiple imputation (NRI-MI) was used to handle intercurrent events and missing data for binary endpoints. Cochran-Mantel-Haenszel (CMH) test and mixed-effect model for repeated measures (MMRM) were used for analyzing binary and continuous endpoints, respectively. Treatment-emergent adverse events (TEAEs) assessed through wk 14 are reported for pts who had ≥1 dose of study drug. Results: All 420 randomized pts with active AS received assigned treatment (UPA 15 mg, n=211;PBO, n=209);409 (97%) received study drug through wk 14. Baseline demographic and disease characteristics were generally similar between treatment groups and refective of an active AS bDMARD-IR population (74% male;mean age 42.4 years;mean disease duration 7. 7 years;83% HLA-B27 positive;mean BASDAI 6.8). Signifcantly more pts achieved the primary endpoint of ASAS40 response at wk 14 with UPA vs PBO (45% vs 18%;P<0.0001;Figure 1);UPA showed onset of effect in ASAS40 as early as wk 4 (nominal P≤0.05). All multiplicity-controlled secondary endpoints met statistical signifcance for UPA vs PBO at wk 14 across multiple clinical domains of AS (P<0.0001;Figure 1). The rate of TEAEs was similar between treatment groups through wk 14 (UPA, 41%;PBO, 37%). TEAEs led to discontinuation in 3 (1.4%) pts treated with PBO and none with UPA. Serious infections occurred with UPA (2.4%) but not with PBO and included 4 events of COVID-19 and 1 event of uveitis. Additional events of uveitis were reported in 3 (1.4%) pts treated with PBO. Infammatory bowel disease (IBD) occurred in 1 (0.5%) pt on UPA and none on PBO. No malignancy, major adverse cardiovascular events, venous thromboembolic events, or death were reported with UPA;1 event of malignancy was observed with PBO. Conclusion: UPA 15 mg QD was signifcantly more effective than PBO over 14 wks of treatment in pts with active AS and IR to bDMARDs. No new safety risks were identifed with UPA compared with its known safety profile.3,4 These fndings are consistent with and complementary to those of SELECT-AXIS 1 (bDMARD-naïve AS population),1,2 and support the use of UPA in pts with active AS, including those who had a previous IR to bDMARD therapy.

11.
Annals of the Rheumatic Diseases ; 81:1672, 2022.
Article in English | EMBASE | ID: covidwho-2008900

ABSTRACT

Background: SARS-Cov-2 infection had a major impact on patients with infam-matory rheumatic diseases. Spondyloarthritis (SpA) patients were one of the most affected groups of these patients. Objectives: To assess the impact of Covid19 in spondyloarthritis patients under biological disease modifying anti-rheumatic drugs (bDMARDs). Methods: A retrospective observational study was conducted using registry data of patients with SpA under bDMARD therapy, followed at a tertiary level hospital, that have been diagnosed with COVID19 from March 2019 to December 2021. At least one evaluation previous (t0) and two evaluations after SARS-CoV-2 infection (t1, t2) were included in our analysis. Sociodemographic, clinical, disease activity, therapeutic response, function and general health status data were collected. Statistical analysis (signifcance at p < 0.05) was performed using paired T-test, Wilcoxon test and McNemar tests for paired samples. Linear and logistic regression models were performed to assess direction and strength of association Results: Thirty-two patients with SpA under bDMARD had COVID19, mostly women (20, 62.5%), with a disease course time averaged 18.65 (± 9.69) years, mainly with axial involvement (19, 59.4%) and positive for HLA-B27 antigen (11, 64.7%). The majority were under TNF inhibitors (30, 93.75%), with golimumab being the most common (9, 28.1%), and with a median bDMARD persistence of 2.63 (5.09) years. Seven (21.9%) were under a cDMARD, 3 (9.4%) under NSAID and 18 (56.3%) under corticosteroids. Three (9.4%) were already vaccinated against SARS-CoV-2, 2 (66.6%) with the mRNA-1273 vaccine, presenting a medium time since inoculation of 240 (± 234.01) days. Arterial hypertension was the most common comorbidity (5, 15.6%) and one patient (3.1%) had a previous diagnosis of type 2 diabetes. Most were never-smokers (17, 53.1%) and never-drinkers (29, 90.6%). The average age at infection was 40.97 (± 6.15) years and the most common symptom was cough (22, 68.8%), followed by headache (20, 62.5%) and myalgia (19, 59.4%). Event tree analysis didn't show association with SpA subtype, education level, work status, tobacco or alcohol consumption. Only one patient needed hospital admission but without needing of oxygen, therapy, ventilator or ECMO. Only one patient had an overlaid bacterial infection and no thromboembolic complications were observed. Two patients needed specific SARS CoV-2 infection treatment, one with hydroxychloroquine and another with azithromycin. Twelve (37.5%) patients suspended bDMARD at the time of infection, with only 2 (6.3%) maintaining suspension at the time of the first post-infection visit. When comparing clinical variables, higher disease activity was seen at t1 only for BASDAI mean values, without statistical signifcance. Higher all domains VAS scores were also observed at t1, but not at t2, also without statistical signifcance;moreover, physical function didn't change signifcantly. No differences were observed according to gender or SpA subtype, nor with the use of cDMARDs, NSAIDs or corticosteroids. The only statistically signifcant difference concerned MASES score between t0 and t1 (1 ± 4 vs. 2 ± 6, p=0.04), but not between t0 and t2. Higher baseline tender joint score (p < 0.01) and higher baseline LEI (p=0.03) negatively correlated with MASES score variation. Several baseline variables correlated positively with MASES at t1, including female gender (p < 0.01), corticosteroid use (p = 0.04), BASDAI (p < 0.01), ASDAS-ESR (p < 0.01), ASDAS-CRP (p < 0.01), DAS28 (p < 0.01), SPARCC (p = 0.04), physician VAS (p = 0.03) and total spine VAS (p = 0.01). Working status varied signifcantly after SARS-Cov-2 infection (at least part-time-29, 90.6% vs. 22, 68.8%, p= 0.016). Conclusion: SpA patients on bDMARD had a mild course of SARS-CoV-2 infection, with slight changes in enthesitis score in the short term, the latter particularly in those with higher disease activity in the pre-infection period. Long-term effects on work status could represent confounding factors related to the e onomic constraints of the pandemic.

12.
Annals of the Rheumatic Diseases ; 81:1414-1415, 2022.
Article in English | EMBASE | ID: covidwho-2008823

ABSTRACT

Background: Behçet's disease (BD) is an systemic infammatory vasculitis characterized by recurrent oral aphthae and genital ulcers. In the course of the disease, skin, eye, musculoskeletal, nervous system and gastrointestinal system involvements can be detected. Objectives: To evaluate the clinical, laboratory and radiological fndings of pedi-atric cases diagnosed with BD. Methods: Fifty patients (0-20 years old) who were followed up with the diagnosis of BD at the Pediatric Rheumatology outpatient clinic of Uludag University Faculty of Medicine between January 2011 and July 2021 were included in our study. The patients were diagnosed according to the diagnostic criteria of the International BD Study Group. Results: Twenty-four (48%) of the patients were male and 26 (52%) were female. The mean age at the diagnosis of patients was 9 ±4.55 years (10.75±4.55 years in boys, 12.35±3.65 years in girls). Twenty patients (36.3%) had a family history of Behçet's Disease. Oral aphthae were present in 96% (n=48) patients, while genital ulcers were in 32% (n=16) (Table 1). Of the nine patients with uveitis, 6 had panu-veitis, 2 had anterior uveitis and 1 had posterior uveitis. There was no difference in the distribution of symptoms according to the gender of the patients. HLA-B51 allel was found in 39 (78%) and ANA was positive in 14 patients (28%). Immunological tests showed that serum immunoglobulins were low in 11 (32.3%) of 34 patients. Low IgG levels were detected in 6 patients, low IgM levels were in 3, and low IgA levels were in 2. Thrombus was presented in three cases (thrombus in the right ventricle in one case, in the intracranial transverse sigmoid sinus and left jugular vein in two cases). The most commonly used drug for aphthae was colchicine (n=45, 82%). The use of biological agents according to patient manifestations is shown in Table 2. In the follow-up, clinical fndings improved in 35 patients (70%) Complete improvement was detected only with biological agents in 8 patients with uveitis. One patient was operated due to the development of complicated cataracts secondary to uveitis. Three patients were diagnosed with Covid-19, one of them was followed without treatment, while two of them were treated with favipiravir at home. Three patients with Covid-19 infection were using only colchicine treatment. Conclusion: Behçet's disease is rare in childhood. Although it is not common, life-threatening complications can be observed. To reduce morbidity and complications, physicians should be aware of manifestations and rare clinical pictures of the BD.

13.
Annals of the Rheumatic Diseases ; 81:240-241, 2022.
Article in English | EMBASE | ID: covidwho-2008807

ABSTRACT

Background: Vaccination is considered efficient in controlling infections incl. SARS-CoV-2. Prior studies showed that patients receiving rituximab (RTX) with low B cell counts are at increased infectious risk (1) and risk of inadequate vaccination responses (2, 3). Thus, the ability to further defne and predict vaccination responses in these patients may guide their optimal protection. Objectives: To assess predictive biomarkers of vaccination responses upon SARS-CoV-2 vaccination in RTX treated patients. Methods: B cell characteristics before vaccination were evaluated to predict responses in 15 patients with autoimmune infammatory rheumatic diseases receiving RTX. 11 patients with rheumatoid arthritis on other therapies (RA), 11 kidney transplant recipients (KTR) and 15 healthy volunteers (HC) served as controls. A multidimensional analysis of B cell subsets and a correlation matrix were performed to identify predictive biomarkers. Results: Signifcant differences regarding absolute B cell counts and specifc subset distribution pattern between the groups were validated at baseline. Here, the majority of B cells from vaccination responders of the RTX group (RTX IgG+) comprised naïve and transitional B cells, whereas vaccination non-responders (RTX IgG-) carried preferentially plasmablasts and double negative (CD27-IgD-) B cells (Figure 1). Moreover, there was a positive correlation between neutralizing antibodies and absolute B cell numbers with B cells expressing HLA-DR and CXCR5 (involved in antigen presentation and germinal center formation) as well as an inverse correlation with CD95 expression and CD21low expression (marker for activation and exhaustion) on B cells. Conclusion: Substantial repopulation of naïve B cells upon RTX therapy appears to be essential for an adequate vaccination response requiring germinal center formation. In contrast, expression of exhaustion markers (CD21low, CXCR5-, CD95+) indicate negative predictors of vaccination responses. These results may guide optimized vaccination strategies in RTX treated patients clearly requiring antigen-inexperienced B cells for appropriate protection.

14.
Zeitschrift fur Rheumatologie ; 2022.
Article in German | EMBASE | ID: covidwho-2007138

ABSTRACT

The introduction of the term reactive arthritis (ReA) for the joint inflammation observed after infection with Yersinia enterocolitica, in which “a causative pathogen cannot be isolated from the synovial fluid”, and the association with the HLA-B27 were the historical milestones for a new classification and assignment to the spondylarthritides (SpA). The division into postinfectious and reactive arthritis proposed in 1976 was put into perspective in the 1990s because of investigations with the newly available molecular biological method of the polymerase chain reaction. Microbial products could be identified from joint samples of patients with ReA. Therefore, it was proposed to abandon the distinction between the two groups of diseases and to prefer the term ReA for both. This created a terminological and nosological issue. On the one hand, there are generally accepted classification and diagnostic criteria for the classical HLA-B27-associated ReA that are assigned to SpA. On the other hand, an increasing number of bacterial pathogens, viruses, amoebas, helminths as well as antiviral and antibacterial vaccinations are described as triggers of arthritis, which have been published under the term ReA. Since the beginning of the SARS-CoV‑2 pandemic, cases of acute post-COVID-19 arthritis have been described, which were also classified as ReA because of comparable clinical features.

15.
Medical Immunology (Russia) ; 24(3):629-640, 2022.
Article in Russian | EMBASE | ID: covidwho-2006567

ABSTRACT

The relevance of the current epidemic situation of a new coronavirus infection is determined by new strains of the virus and the registration of cases of re-infection in COVID-19 survivors earlier. In this regard, the questions about the expediency and nature of vaccination of those who have been ill attract close attention, moreover it has affected the formation of the concept of “hybrid immunity”. The aim of this study was to analyze changes in the parameters of the immune system, reflecting their regulatory and functional potential, in response to the introduction of the peptide vaccine EpiVacCorona to persons who have suffered from the new coronavirus infection. To study the features of the formation of hybrid immunity, a retrospective analysis of the observation of 43 study participants was carried out. The inclusion criteria were data confirming COVID-19 in mild and moderate forms of the course in the period from six months to a year ago, a low level or absence of antibodies to the nucleocapsid protein SARS-CoV-2, a negative PCR result for the presence of the SARS-CoV-2 virus, the absence of comorbid pathology. The subpopulation composition, regulatory and functional potential of the immune system were determined by flow cytofluorimetry using a set of monoclonal antibodies corresponding to the goals. 21 days after the administration of a single dose of EpiVacCorona, antibodies to the vaccine peptide antigens were registered in all study participants at the highest coefficient of positivity values for the SARS-CoV-2-IgG-Vector test system used. In addition, there was a fourfold increase in the number of specific IgG to the N protein. A specific immune response to recombinant SARS-CoV-2 antigens was accompanied by a decrease in the circulation of the number of monocytes expressing TLR4, T helper cells expressing the interaction coreceptor with antigen-presenting cells, unconnected B memory with an increase in the number of B lymphocytes expressing the CD40 T-B coreceptor interaction molecule. The remaining differences in the functioning of the immune system identified in patients with COVID-19 before the vaccination in comparison with the control data have not changed. The differences consist in a decrease in the proportion of monocytes expressing HLA-DR, an increase in the expression of interaction molecules on T and B lymphocytes, an increase in the number of Treg, B1 cells, activated B lymphocytes with a decrease in the proportion of suppressor Breg and B memory. The totality of the presented data demonstrates that the COVID-19 infection that preceded vaccination in mild and moderate clinical course contributes to the formation of immunological memory, which made it possible to form a secondary immune response even to a single injection of peptide antigens of the virus.

16.
Ieee Transactions on Engineering Management ; 2022.
Article in English | Web of Science | ID: covidwho-2005239

ABSTRACT

Hospitals and other healthcare settings use various simulation methods to improve their operations, management, and training. The COVID-19 pandemic, with the resulting necessity for rapid and remote assessment, has highlighted the critical role of modeling and simulation in healthcare, particularly distributed simulation (DS). DS enables integration of heterogeneous simulations to further increase the usability and effectiveness of individual simulations. This article presents a DS system that integrates two different simulations developed for a hospital intensive care unit (ICU) ward dedicated to COVID-19 patients. AnyLogic has been used to develop a simulation model of the ICU ward using agent-based and discrete event modeling methods. This simulation depicts and measures physical contacts between healthcare providers and patients. The Unity platform has been utilized to develop a virtual reality simulation of the ICU environment and operations. The high-level architecture, an IEEE standard for DS, has been used to build a cloud-based DS system by integrating and synchronizing the two simulation platforms. While enhancing the capabilities of both simulations, the DS system can be used for training purposes and assessment of different managerial and operational decisions to minimize contacts and disease transmission in the ICU ward by enabling data exchange between the two simulations.

17.
Pediatric Dermatology ; 39(4):601-605, 2022.
Article in English | ProQuest Central | ID: covidwho-2001730

ABSTRACT

Toxic epidermal necrolysis (TEN) is a rare and acute life‐threatening condition and one of the severe cutaneous adverse drug reactions. There are limited data on TEN from the COVID‐19 vaccine regarding its pathogenesis, treatment, and prognosis, particularly in children. We report a case of COVID‐19 vaccine‐induced TEN and the patient's human leukocyte antigen pharmacogenomic profile.

18.
Stem Cell Res Ther ; 13(1): 408, 2022 Aug 12.
Article in English | MEDLINE | ID: covidwho-2002225

ABSTRACT

BACKGROUND: The increasing number of clinical trials for induced pluripotent stem cell (iPSC)-derived cell therapy products makes the production on clinical grade iPSC more and more relevant and necessary. Cord blood banks are an ideal source of young, HLA-typed and virus screened starting material to produce HLA-homozygous iPSC lines for wide immune-compatibility allogenic cell therapy approaches. The production of such clinical grade iPSC lines (haplolines) involves particular attention to all steps since donor informed consent, cell procurement and a GMP-compliant cell isolation process. METHODS: Homozygous cord blood units were identified and quality verified before recontacting donors for informed consent. CD34+ cells were purified from the mononuclear fraction isolated in a cell processor, by magnetic microbeads labelling and separation columns. RESULTS: We obtained a median recovery of 20.0% of the collected pre-freezing CD34+, with a final product median viability of 99.1% and median purity of 83.5% of the post-thawed purified CD34+ population. CONCLUSIONS: Here we describe our own experience, from unit selection and donor reconsenting, in generating a CD34+ cell product as a starting material to produce HLA-homozygous iPSC following a cost-effective and clinical grade-compliant procedure. These CD34+ cells are the basis for the Spanish bank of haplolines envisioned to serve as a source of cell products for clinical research and therapy.


Subject(s)
Induced Pluripotent Stem Cells , Antigens, CD34/genetics , Antigens, CD34/metabolism , Blood Banks , Fetal Blood , Homozygote , Induced Pluripotent Stem Cells/metabolism
19.
Russian Journal of Cardiology ; 27(7):147-157, 2022.
Article in Russian | EMBASE | ID: covidwho-1998086

ABSTRACT

The presence of coronavirus-associated myocarditis remains controversial despite elevations in cardiac troponin and natriuretic peptide in many patients. Aim. To assess the morphological changes in the myocardium of patients who died due to coronavirus disease 2019 (COVID-19) and compare them with the intravital level of cardiac biomarkers. Material and methods. A total of 420 hospital charts and 77 autopsies of those who died from COVID-19 were analyzed. In 15 of 77 cases (19%) with histologically suspected myocarditis, an immunohistochemical examination of the myocardium with antibodies to CD3, CD45, CD8, CD68, CD34, Ang1, VWF, VEGF, HLA-DR, MHC1, C1q, VP1 of enteroviruses was performed, and in 8 patients with immunohistochemically confirmed myocarditis (10%) — polymerase chain reaction for SARS-CoV-2. Results. Hemorrhage, intramural thrombosis, necrosis of non-coronary origin, myocardial infarction and lymphocytic myocarditis were detected in 43%, 10%, 17%, 19% and 10% of cases, respectively, without coronavirus N and E gene sequences in the myocardium. Dysplasia, hyperplasia and hypertrophy of the vascular endothelium, expression of Ang1, VWF, VEGF, MHC1, C1q, VP1 of enteroviruses were determined in 100, 100, 87, 100, 75 and 62% of cases of myocarditis, respectively. There were no significant correlations between inflammatory biomarkers and myo-carditis. Conclusion. The main morphological manifestation of COVID-19 in the myo-cardium is the so-called endotheliitis with dysplasia and endothelial activation, leading to hemorrhages, intramural thrombosis and necrosis. There is no con-vincing evidence of a direct involvement of coronavirus in myocarditis induction.

20.
Cytotherapy ; 24(5):S109-S110, 2022.
Article in English | EMBASE | ID: covidwho-1996725

ABSTRACT

Background & Aim: Background. Immunological characteristics of COVID-19 show pathological hyperinflammation associated with lymphopenia and dysfunctional T cell responses. These features provide a rationale for restoring functional T cell immunity in COVID-19 patients by adoptive transfer of SARS-CoV-2 specific T cells. Methods, Results & Conclusion: Methods. To generate SARS-CoV-2 specific T cells, we isolated peripheral blood mononuclear cells from 7 COVID-19 recovered and 13 unexposed donors. Consequently, we stimulated cells with SARS-CoV-2 peptide mixtures covering spike, membrane and nucleocapsid proteins. Then, we culture expanded cells with IL-2 for 21 days. We assessed immunophenotypes, cytokine profiles, antigen specificity of the final cell products. Results. Our results show that SARS-CoV-2 specific T cells could be expanded in both COVID-19 recovered and unexposed groups. Immunophenotypes were similar in both groups showing CD4+ T cell dominance, but CD8+ and CD3+CD56+ T cells were also present. Antigen specificity was determined by ELISPOT, intracellular cytokine assay, and cytotoxicity assays. One out of 14 individuals who were previously unexposed to SARS-CoV-2 failed to show antigen specificity. Moreover, ex-vivo expanded SARS-CoV-2 specific T cells mainly consisted of central and effector memory subsets with reduced alloreactivity against HLA-unmatched cells suggesting the possibility for the development of third-party partial HLA-matching products. Conclusion. In conclusion, our findings show that SARS-CoV-2 specific T cell can be readily expanded from both COVID-19 and unexposed individuals and can therefore be manufactured as a biopharmaceutical product to treat severe COVID-19 patients.

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