Immune System Development Processes with Special Emphasis on Relationship to Potential Mechanisms of MIS-C

Development of the mammalian immune system requires the intersection of myriad internal and external signals, from the migration of pluripotent stem cells to interactions with the vaginal microbiome during partuition to environmental factors that shape immune processes throughout life. Because the sequence of immune developmental events is fairly transcripted across time, multiple windows of susceptibility exist that can lead to immune dysfunction when these developmental events are perturbed. Additionally, early-life immune dysfunction can persist, leading to increased disease risk across the lifespan. Immune dysfunction can present functionally as suppression, hyperresponsivity, or inappropriate inflammation and molecularly, may involve multiple cells and signaling pathways. Thus, scenarios that lead to multisystem inflammatory syndrome in children (MIS-C) can be complex and multifaceted. This presentation will consider windows of susceptibility as well as external factors that may increase the risk of MIS-C.

Revitalizing myocarditis treatment through gut microbiota modulation: unveiling a promising therapeutic avenue.

Numerous studies have demonstrated that gut microbiota plays an important role in the development and treatment of different cardiovascular diseases, including hypertension, heart failure, myocardial infarction, arrhythmia, and atherosclerosis. Furthermore, evidence from recent studies has shown that gut microbiota contributes to the development of myocarditis. Myocarditis is an inflammatory disease that often results in myocardial damage. Myocarditis is a common cause of sudden cardiac death in young adults. The incidence of myocarditis and its associated dilated cardiomyopathy has been increasing yearly. Myocarditis has gained significant attention on social media due to its association with both COVID-19 and COVID-19 vaccinations. However, the current therapeutic options for myocarditis are limited. In addition, little is known about the potential therapeutic targets of myocarditis. In this study, we review (1) the evidence on the gut-heart axis, (2) the crosslink between gut microbiota and the immune system, (3) the association between myocarditis and the immune system, (4) the impact of gut microbiota and its metabolites on myocarditis, (5) current strategies for modulating gut microbiota, (6) challenges and future directions for targeted gut microbiota in the treatment of myocarditis. The approach of targeting the gut microbiota in myocarditis is still in its infancy, and this is the study to explore the gut microbiota-immune system-myocarditis axis. Our findings are expected to pave the way for the use of gut microbiota as a potential therapeutic target in the treatment of myocarditis.

Promising roles of Zingiber officinale roscoe, Curcuma longa L., and Momordica charantia L. as immunity modulators against COVID-19: A bibliometric analysis.

Zingiber officinale, Curcuma longa, and Momordica charantia are medicinal plants that are commonly used in the form of herbal tea, which is formulated to strengthen the immune system, especially against COVID-19 infection. Excellent antioxidant, anti-inflammatory, and immunostimulatory properties have been reported for their bioactive compounds, which have been shown to aid in stimulating immune systems as well as lowering the risk of severe COVID-19 such as lung injury. Yet, no bibliometric study on the subject is available. Hence, the purpose of this study is to quantitatively examine the existing articles related to the therapeutic potential of these three herbs, as well as their mechanisms of action in combating the SARS-CoV-2 virus. A total of 121 papers were retrieved from Scopus database up to 14th March 2023. The bibliometric analysis was conducted using VOSviewer software. Based on the literature search, Z. officinale was the most researched plant. India appeared as the most prolific country, with the highest number of articles contributed by two authors from India (Rathi, R. and Gayatri Devi, R.). In terms of keywords, the plants were associated with immune modulation, management of symptoms, antioxidant, anti-inflammatory and antiviral activities. Several important bioactive compounds were responsible for these effects such as gingerol, paradol, shogaol, curcumin, calebin A, momordicoside, karaviloside and cucurbitadienol. These compounds were hypothesized to prevent and cure COVID-19 by regulating inflammatory response, downregulating oxidative stress and modulating immunostimulatory activity. This review paper therefore supports the potential of Z. officinale, C. longa, and M. charantia to be formulated as a herbal blend for treating and preventing COVID-19 infection.

SARS-CoV-2 Evasion of the Interferon System: Can We Restore Its Effectiveness?

Type I and III Interferons (IFNs) are the first lines of defense in microbial infections. They critically block early animal virus infection, replication, spread, and tropism to promote the adaptive immune response. Type I IFNs induce a systemic response that impacts nearly every cell in the host, while type III IFNs' susceptibility is restricted to anatomic barriers and selected immune cells. Both IFN types are critical cytokines for the antiviral response against epithelium-tropic viruses being effectors of innate immunity and regulators of the development of the adaptive immune response. Indeed, the innate antiviral immune response is essential to limit virus replication at the early stages of infection, thus reducing viral spread and pathogenesis. However, many animal viruses have evolved strategies to evade the antiviral immune response. The Coronaviridae are viruses with the largest genome among the RNA viruses. Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) caused the coronavirus disease 2019 (COVID-19) pandemic. The virus has evolved numerous strategies to contrast the IFN system immunity. We intend to describe the virus-mediated evasion of the IFN responses by going through the main phases: First, the molecular mechanisms involved; second, the role of the genetic background of IFN production during SARS-CoV-2 infection; and third, the potential novel approaches to contrast viral pathogenesis by restoring endogenous type I and III IFNs production and sensitivity at the sites of infection.

New Insights on the Mechanisms of Myocardial Injury in Hypertensive Patients With COVID-19.

PURPOSE: Myocardial injury is common in hypertensive patients with 2019 coronavirus disease (COVID-19). Immune dysregulation could be associated to cardiac injury in these patients, but the underlying mechanism has not been fully elucidated. METHODS: All patients were selected prospectively from a multicenter registry of adults hospitalized with confirmed COVID-19. Cases had hypertension and myocardial injury, defined by troponin levels above the 99th percentile upper reference limit, and controls were hypertensive patients with no myocardial injury. Biomarkers and immune cell subsets were quantified and compared between the two groups. A multiple logistic regression model was used to analyze the associations of clinical and immune variables with myocardial injury. RESULTS: The sample comprised 193 patients divided into two groups: 47 cases and 146 controls. Relative to controls, cases had lower total lymphocyte count, percentage of T lymphocytes, CD8+CD38+ mean fluorescence intensity (MFI), and percentage of CD8+ human leukocyte antigen DR isotope (HLA-DR)+ CD38-cells and higher percentage of natural killer lymphocytes, natural killer group 2A (NKG2A)+ MFI, percentage of CD8+CD38+cells, CD8+HLA-DR+MFI, CD8+NKG2A+MFI, and percentage of CD8+HLA-DR-CD38+cells. On multivariate regression, the CD8+HLA-DR+MFI, CD8+CD38+MFI, and total lymphocyte count were associated significantly with myocardial injury. CONCLUSION: Our findings suggest that lymphopenia, CD8+CD38+MFI, and CD8+HLA-DR+MFI are immune biomarkers of myocardial injury in hypertensive patients with COVID-19. The immune signature described here may aid in understanding the mechanisms underlying myocardial injury in these patients. The study data might open a new window for improvement in the treatment of hypertensive patients with COVID-19 and myocardial injury.

Potential of macronutrients and probiotics to boost immunity in patients with SARS-COV-2: a narrative review.

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-COV-2) may cause inflammation and increased cytokine secretion. Dietary factors may play an important role in enhancing the immune responses against infectious diseases such as SARS-COV-2. This narrative review aims to determine the effectiveness of macronutrients and probiotics to improve immunity in SARS-COV-2 patients. Dietary proteins may boost pulmonary function in SARS-COV-2 patients through inhibitory effects on the Angiotensin-converting enzyme (ACE) and reduce Angiotensin (ANG-II). Moreover, omega-3 fatty acids may improve oxygenation, acidosis, and renal function. Dietary fiber may also produce anti-inflammatory effects by reducing the level of high-sensitivity C-Reactive Protein (hs-CRP), Interleukin (IL-6), and Tumor necrosis factor (TNF-α). In addition, some evidence indicates that probiotics significantly improve oxygen saturation which may enhance survival rate. In conclusion, the consumption of a healthy diet including adequate macronutrients and probiotic intake may decrease inflammation and oxidative stress. Following this dietary practice is likely to strengthen the immune system and have beneficial effects against SARS-COV-2.

Coronavirus-Related Searches on the Internet Predict COVID-19 Vaccination Rates in the Real World: A Behavioral Immune System Perspective.

According to the smoke detector and functional flexibility principles of human behavioral immune system (BIS), the exposure to COVID-19 cues could motivate vaccine uptake. Using the tool of Google Trends, we tested that coronavirus-related searches-which assessed natural exposure to COVID-19 cues-would positively predict actual vaccination rates. As expected, coronavirus-related searches positively and significantly predicted vaccination rates in the United States (Study 1a) and across the globe (Study 2a) after accounting for a range of covariates. The stationary time series analyses with covariates and autocorrelation structure of the dependent variable confirmed that more coronavirus-related searches compared with last week indicated increases in vaccination rates compared with last week in the United States (Study 1b) and across the globe (Study 2b). With real-time web search data, psychological scientists could test their research questions in real-life settings and at a large scale to expand the ecological validity and generalizability of the findings.

Gene expression profiling reveals a role of immune system and inflammation in innate and stress-induced anxiety-like behavior.

Anxiety is an evolutionarily conserved response that is essential for survival. Pathological anxiety, however, is a maladaptive response to nonthreatening situations and greatly affects quality of life. The recent COVID-19 pandemic has increased the prevalence of anxiety symptoms and highlighted the urge to identify the molecular events that initiate pathological anxiety. To this aim, we investigated the extent of similarity of brain region-specific gene expression patterns associated with innate and stress-induced anxiety-like behavior. We compared the cortico-frontal (FCx) and hippocampal (Hpc) gene expression patterns of five inbred mouse strains with high or low levels of innate anxiety-like behavior with gene expression patterns of mice subjected to chronic social defeat stress. We found significantly large overlap of the Hpc but small overlap of the FCx gene expression patterns in innate and stress-induced anxiety, that however, converged onto common inflammation and immune system canonical pathways. Comparing the gene expression data with drug-gene interaction datasets revealed drug candidates, including medrysone, simvastatin, captopril, and sulpiride, that produced gene expression changes opposite to those observed in innate or stress-induced anxiety-like behavior. Together, our data provide a comprehensive overview of FCx and Hpc gene expression differences between innate and stress-induced anxiety and support the role of inflammation and immune system in anxiety-like behavior.

COVID-19 virus: the immune reaction to vaccines

The immune system is developed to preserve its hosts from an ever-expanding cluster of pathogenic microbes. The elimination of toxic substances, allergens, or any other harmful existences that come in, passing the mucosal surfaces, is as well the responsibility of this special system. Its ability to distinguish self (our bodies' functioning cells and tissues) from non-self is the key aspect to its ability to mobilize some reaction to an invasion initiated by the stranger substances listed above. To identify and kill unsafe microorganisms, the host applies both natural and versatile systems, our innate and adaptive immune systems. Vaccines are used to combat the current SARS-CoV-2 strain by utilizing immune system mechanisms, specifically the adaptive immune system. Vectored vaccines, protein vaccines, genetic vaccine, and monoclonal antibody for passive vaccination are among the vaccine platforms under consideration for SARS-CoV-2. Each vaccine has its own benefits and drawbacks. This paper is written to describe the three major forms of COVID-19 vaccines, as well as the unique mechanisms of elements of the immune system associated with the virus. © 2023 SPIE.

IMPACT OF THE COVID-19 PANDEMIC ON SEPTIC ARTHRITIS MANAGEMENT

BackgroundSince 2020, the SARS-Cov-2 pandemic has disrupted the organization of healthcare systems worldwide.ObjectivesThis study aimed to assess the impact of this pandemic on septic arthritis management in a tertiary rheumatology department.MethodsIt was a single-center descriptive case-control study, which included patients hospitalized for septic arthritis between January 2018 and December 2021, whose diagnosis was retained after positive bacterial growthor on culture on according to presumptive criteria. Our patients were divided into two groups: G1: patients hospitalized during the COVID-19 pandemic (2020-2021), and G2: patients hospitalized during a similar period before the COVID-19 pandemic (2018-2019). In both groups, septic arthritis prevalence was calculated, socio-demographic characteristics, risk factors, clinical, paraclinical, and therapeutic data were collected. COVID-19 status was reported in the G1.ResultsTwenty-two patients were enrolled: G1 (n = 15), G2 (n = 7). The prevalence of septic arthritis was 0.77% and 0.36% respectively. The median age was 54.6±12.25 and 54.29±21.81 years old respectively. Diabetes was found in 26, 7% in G1 and 28.6% in G2. During the pandemic, arthropathy and oral corticosteroids use were noted in 53.3% and 28.6% of patients versus 26.7% and 14.3% in G2. The diagnosis delay and the prior use of antibiotic therapy were more significant in G1: 14.08[7-30] d versus 6.5[3.25-19.25] d, and 46.7% versus 14.3%. The knee was the most common localization in both groups. Other joints were affected in G1: shoulder (n = 2), hip (n = 1), and sacroiliac (n = 1). The most common germ was staphylococcus aureus. The duration of hospitalization and duration of antibiotic therapy in G1 and G2 were 26.07±9.12d versus 27.43±10.87d and 50±10d versus 48±25.79d, respectively. Concerning COVID-19 status, 33.3% of patients in G1 have received their vaccination and no recent SARS-Cov2 infection was noted before hospitalization. During the pandemic, synovectomy was required in three patients, one of whom was also transferred to intensive care for septic shock (two of these three patients are being followed for rheumatoid arthritis, and only one has never been vaccinated against COVID-19).ConclusionDuring the COVID-19 pandemic, the prevalence of septic arthritis in our department was higher and the diagnosis was delayed. Duration of hospitalization was not impacted, however, atypical localisations, prior use of antibiotics, recourse to synovectomy, and transfer to intensive care were reported. These results suggest an inadequate and difficult access to healthcare services during the lockdown, as well as an impact of social distancing on the immune system [1, 2]. More studies are needed to confirm these findings.References[1]Robinson E. Pires et al, What Do We Need to Know about Musculoskeletal Manifestations of COVID-19? A Systematic Review, JBJS Rev. 2022 Jun 3;10(6)[2]Pantea Kiani et al, Immune Fitness and the Psychosocial and Health Consequences of the COVID-19 Pandemic Lockdown in The Netherlands: Methodology and Design of the CLOFIT Study, Eur J Investig Health Psychol Educ. 2021 Feb 20;11(1):199-218Acknowledgements:NIL.Disclosure of InterestsNone Declared.

Glucosaminylmuramyl dipeptide efficacy in post-COVID-19 patient rehabilitation treatment.

The COVID-19 pandemic has altered people's lifestyles around the world. Prevention of recurrent episodes of the disease and mitigation of its consequences are especially associated with effective post-COVID-19 rehabilitation in patients. The aim of the study was to evaluate the effects of the drug Likopid (glucosaminylmuramyl dipeptide, GMDP) for post-COVID-19 rehabilitation in patients. Material and methods. Patients who recovered from mild to moderate COVID-19 (n=60, mean age 54+/- 11.7 years) were randomized into the observation group (n=30, 15 men and 15 women) who received 2 courses of Licopid (1 mg twice a day) and the comparison group (n=30, 15 men and 15 women). Analysis of the phenotypic and functional characteristics of the innate immune cellular factors was carried out before the start of immunomodulatory therapy, immediately after the end of the course, and also after 6 months observations. In order to assess the quality of life of all patients, we used the SF-36 Health Status Survey and the Hospital Anxiety and Depression Scale questionnaires. Results. During assessing the effect of immunomodulatory therapy on the parameters of innate immunity of patients at the stage of rehabilitation after COVID-19, an increase in the protective cytolytic activity of CD16+ and CD8+Gr+ cells, as well as a persistent increase in TLR2, TLR4 and TLR9 expression was found, which indicates the antigen recognition recovery and presentation at the level of the monocytic link of the immune system. The use of GMDP as an immunomodulatory agent resulted in an 8-fold reduction in the frequency and severity of respiratory infections due to an increase in the total monocyte count. As a result of assessing patients' quality of life against the background of the therapy, a positive dynamic in role functioning was revealed in patients. In the general assessment of their health status, an increase in physical and mental well-being was noted during 6 months of observation. The comparison group showed no improvement in the psychoemotional state. Discussion. The study demonstrated the effectiveness of GMDP immunomodulatory therapy in correcting immunological parameters for post-COVID-19 rehabilitation in patients. The data obtained are consistent with the previously discovered ability of GMDP to restore impaired functions of phagocytic cells and induce the expression of their surface activation markers, which in turn contributes to an adequate response to pathogens. Conclusion. The study revealed that the correction of immunological parameters with the use of GMDP in COVID-19 convalescents contributed not only to a decrease in the frequency and severity of respiratory infections, but also to an improvement in the psycho-emotional state of patients, and a decrease in anxiety and depression.Copyright © Eco-Vector, 2023. All rights reserved.

GENE ANALYSIS REVEALED THE USEFULNESS OF TRIPLE THERAPY WITH BARICITINIB, RITUXIMAB AND TACROLIMS FOR ANTI-MDA5 ANTIBODY POSITIVE DERMATOMYOSITIS (MDA5-DM)

BackgroundAnti-MDA5 antibody positive dermatomyositis (MDA5-DM) is characterized by high mortality due to rapid progressive ILD. MDA5 is a cytosolic protein and a family of RIG-I like receptor, which functions as a virus RNA sensor and induces the production of such as type-1 IFN. Although little is known about the pathogenesis of MDA5-DM, it is notable that the similarities were reported between COVID-19 infection and MDA5-DM. It may suggest that there is a common underlying autoinflammatory mechanism. We reported that in MDA5-DM, (1) RIG-I-like receptor signaling is enhanced and (2) antiviral responses such as type 1 IFN signaling are also enhanced as compare with anti-ARS-antibody positive DM, and (3) the key for survival is suppression of RIG-I-like and IFN signaling (EULAR2022, POS0390). We also found that a significant role for uncontrolled macrophage in the pathogenesis of ILD by our autopsy case. Recently, it has been reported that tacrolimus (TAC) and cyclophosphamide (CY) combination therapy (TC-Tx) has improved the prognosis of cases with early onset of the disease, but there are cases that cannot be saved. Therefore, we devised BRT therapy (BRT-Tx). The Tx combines baricitinib (BAR), which inhibits GM-CSF and IFN-mediated signaling and effectively suppresses uncontrolled macrophages, with rituximab (RTX) and TAC, which rapidly inhibits B and T cell interaction and ultimately prevents anti-MDA5 antibody production.ObjectivesTo determine the differences in gene expression between BRT and TC-Tx for MDA5-DM in peripheral blood.MethodsTotal of 6 MDA5-DM (TC: 3, BRT: 3) were included and all of them had multiple poor prognostic factors. Peripheral whole blood was collected at just before and 2-3 months after the treatment. RNA was extracted, and quantified using a next-generation sequencer. Differentially Expressed Genes (DEGs) were identified by pre vs. post treatment. Gene Ontology (GO), clustering and Gene Set Variation Analysis (GSVA) were performed to DEGs. As one BRT case was added since our last year's report, we also reanalyzed the surviving vs. fatal cases. The IFN signature was scored separately for Types 1, 2, and 3, and the changes between pre- and post-treatment were investigated.ResultsTwo of three cases with TC died during treatment, while all three cases on BRT recovered. The cluster analysis of the DEGs separated deaths from survivors, not by type of treatment. Comparing surviving and dead cases, GO analysis revealed that the immune system via immunoglobulins and B cells was significantly suppressed in surviving cases. GO analysis of DEGs in each therapeutic group showed that expression of B cell-related genes such as lymphocyte proliferation and B cell receptor signaling pathway were significantly suppressed in BRT-Tx. On the other hand, TC-Tx significantly suppressed such pathways as cell proliferation and cell surface receptor signaling, and was less specific for the target cells than BRT-Tx. The changes in IFN signature score after treatment showed an increase in type 2 and 3 IFN scores in all fatal cases and an increase in type 1 IFN score in one fatal case.ConclusionBRT-Tx significantly suppressed gene expression associated with B cells, while TC-Tx was characterized by low specificity of therapeutic targets and suppression of total cell proliferation. Comparison of surviving and dead cases revealed that the combination of RTX contributed to the success of treatment, as suppression of the immune system mediated by immunoglobulins and B cells is the key for survival. Analysis of the IFN signature revealed an increase in IFN score after treatment in fatal cases, indicating that the combination of BAR is beneficial. The superiority of BRT-Tx seems clear from the fact that all patients survived with BRT-Tx while only one/three patients survived with TC-Tx.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of InterestsMoe Sakamoto: None declared, Yu Nakai: None declared, Yoshiharu Sato: None declared, Yoshinobu Koyama Speakers bureau: Abbvie, Asahikasei, Ayumi, BMS, Esai, Eli-Lilly, Mitsubishi Tanabe, Grant/research support from: Abbvie, GSK.

Boosting the Immune System with Vitamin D: Special Focus on Prevention of COVID-19 and Complications

In addition to the classical functions of the musculoskeletal system and calcium homeostasis, the function of vitamin D as an immune modulator is well established. The vitamin D receptors and enzymes that metabolize vitamin D are ubiquitously expressed in most cells in the body, including T and B lymphocytes, antigen-presenting cells, monocytes, macrophages and natural killer cells that trigger immune and antimicrobial responses. Many in vitro and in vivo studies revealed that vitamin D promotes tolerogenic immunological action and immune modulation. Vitamin D adequacy positively influences the expression and release of antimicrobial peptides, such as cathelicidin, defensin, and anti-inflammatory cytokines, and reduces the expression of proinflammatory cytokines. Evidence suggestss that vitamin D's protective immunogenic actions reduce the risk, complications, and death from COVID-19. On the contrary, vitamin D deficiency worsened the clinical outcomes of viral respiratory diseases and the COVID-19-related cytokine storm, acute respiratory distress syndrome, and death. The study revealed the need for more preclinical studies and focused on well-designed clinical trials with adequate sizes to understand the role of vitamin D on the pathophysiology of immune disorders and mechanisms of subduing microbial infections, including COVID-19.Copyright © 2023 Bentham Science Publishers.

IDENTIFICATION OF FACTORS ASSOCIATED WITH A WORSE OUTCOME -EXITUS- IN PATIENTS WITH RHEUMATOID ARTHRITIS AND SEVERE INFECTION

BackgroundInfections constitute an important and frequent cause of morbidity and mortality in patients with chronic inflammatory and systemic autoimmune rheumatic diseases. In rheumatoid arthritis (RA), this increased risk has been related to the immune system alterations inherent to the disease, the drugs used to control it (corticosteroids, DMARDs and immunosuppressants) and associated comorbidities. Most studies focus on the search for factors associated with the development of infections but do not explore the worst outcome: patient failure.ObjectivesTo identify factors that help to predict an unfavorable outcome (exitus) after a severe infection in patients with rheumatoid arthritis.MethodsThis study was a retrospective case-control study at a single institution over a 10-year period. Patients with a diagnosis of rheumatoid arthritis with hospital admission for infection from January 1, 2010, to December 31, 2019 (pre-pandemic SARS-COV-2) were selected. The main variable was exitus due to the infectious episode. We collected: age, sex, time of evolution of RA, previous treatment and at the time of admission, number of admissions for infection, location of the infection, comorbidities, and other associated serious diseases. The statistics included a descriptive analysis of the different variables (expressed as median and interquartile range -IR- for quantitative variables and percentages for qualitative variables), and the association study using the χ2 test or Fisher's exact test for qualitative variables, and t-student or Mann-Whitney U and Kruskal Wallis for quantitative variables.ResultsWe obtained 152 patients (71.7% female, 28.3% male), with a total of 214 episodes of admission for infection (115 patients with 1 episode (75.7%), 25 (16.4%) with 2 episodes, 6 being the maximum number of episodes recorded). The median age at admission was 77 years, and the median time of RA evolution was 8 years (IR 4-16). The location of the infection responsible for admission was mainly respiratory and urinary. Forty-eight patients died in the episode (31.6% of the sample, 15 males and 33 females, median age 81.5 years (IR 69.5-86.5)). Comparing the patients with unfavorable outcomes (exitus) with the rest, we only found a statistically significant difference in the number of previous admissions (p=0.011), and in the coexistence of some other serious disease (exitus 85.4%, rest 61.5% p=0.003). There were no differences by sex, age, time of RA evolution, drugs, location of the infection, or comorbidities.ConclusionA history of hospital admission due to infection, and having another serious disease, are factors associated with an unfavorable outcome (exitus) in patients with RA admitted for an infectious process.References[1] Listing J, Gerhold K, Zink A. The risk of infections associated with rheumatoid arthritis, with its comorbidity and treatment. Rheumatology 2013;52(1):53-61.[2] George MD, Baker JF, Winthrop K, Hsu JY, Wu Q, Chen L, et al. Risk for serious infection with low-dose glucocorticoids in patients with Rheumatoid Arthritis: A cohort study. Ann Intern Med. 2020;173(11):870-8.[3] Singh JA, Cameron C, Noorbaloochi S, Cullis T, Tucker M, Christensen R, et al. Risk of serious infection in biological treatment of patients with rheumatoid arthritis: A systematic review and meta-analysis. The Lancet. 2015;386(9990):258-65.Acknowledgements:NIL.Disclosure of InterestsNone Declared.

Case study from Kosovo - repetitive COVID-19 infection and pregnancy

A 25-year-old woman, gravida 2, with no medical history of cardiovascular nor other chronic diseases, came to the gynaecologist and described symptoms of a flu-like disease, including very high fever. The gyneacologist prescribed her antibiotics and paracetamol to calm down the fever. At 37 week of gestation she was admitted to the provincial COVID-19 treatment center for isolation and health care in University Clinical Center of Kosovo in Gynecology/Obstetrics department. All bacteriological tests, including hemocultures and cultures of urines were negative. She received antipyretics (acetaminophen), antispasmodics trimethylphloroglucinol and antibiotics (oral azithromycin for 5 days and intravenous ceftriaxone). Despite this treatments, fever and uterine contractions persisted therefor the commission of doctors decided to deliver the baby via ceserean section. The peritoneal cavity and uterus were found to be very inflamed. Fetal appendages as well as the bladder were strewn with eruptive, vesicular lesions bleeding on contact. After few hours after the delivery her temperature (36.5 degreeC) and blood pressure (120/60 mmHg) were normal. The baby was healthy and tested negative on the COVD-19 tests performed. The patients after 2 weeks of treatment and a negative COVID-19 result she was released to go home and was counselled to eat healthy and prescribed multivitamins for her immune system and regular follow ups with the gynecologist. In a period of 8 months the patient became pregnant again and got infected with the COVID-19 again at 25 weeks pregnant. This time the symptoms were not severe and she was followed up at home. The delivery was planned with cesarean section and the baby was in healthy conditions. The patient got vaccinated with Astra Zeneca COVID-19 vaccine after the delivery. Because of their changed physiology, susceptibility to infections, and weakened mechanical and immunological processes, pregnant women are a particularly vulnerable group in any infectious disease outbreak. The requirement to protect the fetus adds to the difficulty of controlling their health. Keywords: COVID-19, pregnant women, cesarean section, Kosovo, astra-zeneca vaccineCopyright © 2023

COVID-19 SYMPTOMS AND DISEASE COURSE IN GERMAN PEDIATRIC RHEUMATOLOGY PATIENTS REPORTED TO BIKER

BackgroundCOVID-19 has shaped the world over the last 3 years. Although the risk for severe COVID-19 progression in children is low it might be aggravated by chronic rheumatic disease or treatment with immunosuppressive drugs.ObjectivesWe analyzed clinical data of COVID-19 cases among paediatric patients with rheumatic diseases reported to BIKER between March 2020 and December 2022.MethodsThe main task of the German BIKER (Biologics in Pediatric Rheumatology) registry is safety monitoring of biologic therapies in JIA. After the onset of the COVID-19 pandemic, the survey was expanded with a standardized form to proactively interview all participating centers about occurrence, presentation and outcome of SARS-CoV-2 infections in children with rheumatic diseases.ResultsA total of 68 centres participated in the survey. Clinical data from 928 COVID infections in 885 patients with rheumatic diseases could be analyzed. JIA was the most common diagnosis with (717 infections), followed by genetic autoinflammation (103 infections), systemic autoimmune diseases (78 infections), idiopathic uveitis (n=25), vasculitis (n=5).In 374 reported COVID infections (40%), patients were receiving conventional DMARDs, in 331 (36%) biologics, mainly TNF inhibitors (TNFi, n=241 (26%)). In 567 reports (61%) patients used either a biologic or a DMARD, in 339 reports patients (37%) did not use any antirheumatic medication including steroid.Over the last 3 years, COVID-19 occurred in Germany in 5 distinguishable waves, calendar weeks (CW) 10-30 in 2020, CW 21/2020 – 8/2021(both predominantly wild-type variant), CW 9-27 in 2021 (Alpha variant in the majority of infections), CW 28-51 in 2021 (Delta variant), since CW 52/2021 (several Omikron variants;Robert-Koch Institute: VOC_VOI_Tabelle.xlsx;live.com))In our cohort, patients with SARS-CoV-2 infection were slightly older during the 1st and 2nd wave (mean age 12.7+/-3.5 and 12.8+/-4.3 years) compared to the 4th and 5th wave with 11.4+/-3.9 and 11.4+/-4.2 years;p=0.01.160 asymptomatic SARS-CoV-2 infections were reported, frequencies of symptoms associated with COVID-19 are shown in table 1.Five patients were hospitalized for 4-7 days. A 3½-year-old female patient succumbed during the first wave with encephalopathy and respiratory failure. The patient had been treated with MTX and steroids for systemic JIA. Genetic testing revealed a congenital immunodeficiency. No other patient needed ventilation or intensive care. One case of uncomplicated PIMS in an MTX treated JIA patient was reported.The duration of SARS-CoV-2 infection-associated symptoms was markably shorter during the 5th wave with 6.7+/-5.1 days, compared with reports from the other 4 waves (Table1).The duration of symptoms was higher in MTX treated patients (10.2+/-8.4 days) compared to patients without treatment (7.7+/-10.8;p=0.004) or patients treated with TNFi (8.2+/-4.8, p=0.002). Although patients treated with steroids also had a longer duration of symptoms (9.7+/-7.0), this was not significant.ConclusionExcept for one patient with congenital immunodeficiency who died, no case of severe COVID-19 was reported in our cohort. At the time of infection, over 60% of patients had been treated with conventional DMARDs and/or biologics. Although MTX treated patients had a slightly longer duration of symptoms, antirheumatic treatment did not appear to have a negative impact on severity or outcome of SARS-CoV-2 infection.Table 1.Characteristics and frequency of symptoms in SARS-CoV-2 infectionsN or mean (SD)1st wave N=202nd wave N=843rd wave N=384th wave N=1245th wave N=662female14532775432age at COVID-19, years12.7 (3.5)12.8 (4.3)11.8 (3.5)11.4 (3.9)11.4 (4.2)asymptomatic126132694duration of symptoms;days,11.9 (14.7)9.2 (7.0)14.1 (11.6)10.3 (7.6)6.7 (5.1)fever1218541306cough1015652245rhinitis5261344289headache4161227171sore throat61139132musculosceletal pain2751348loss of smell/taste71162113fatigue4882680dizziness122116gastrointestinal symptoms151864dyspnea1117pneumonia11bronchitis1REFERENCES:NIL.Acknowledgements:NIL.Disclosure of Inter stsAriane Klein Speakers bureau: Novartis, Toni Hospach Speakers bureau: Speaking fee Novartis and SOBI., Frank Dressler Speakers bureau: Abbvie, Novartis, Pfizer, Advisory Boards Novartis and Mylan, Daniel Windschall Grant/research support from: research funds by Novartis, Roche, Pfizer, Abbvie, Markus Hufnagel: None declared, Wolfgang Emminger: None declared, Sonja Mrusek: None declared, Peggy Ruehmer: None declared, Alexander Kühn: None declared, Philipp Bismarck: None declared, Maria Haller: None declared, Gerd Horneff Speakers bureau: Pfizer, Roche, MSD, Sobi, GSK, Sanofi, AbbVie, Chugai, Bayer, Novartis, Grant/research support from: Pfizer, Roche, MSD, AbbVie, Chugai, Novartis.

Transcriptomic analysis in patients with SARS-CoV-2 virus infection. Identification of the association of risk/ protective profiles against the disease

Background/Objectives: SARS-CoV2 causes the COVID-19 disease, capable of producing a severe acute respiratory syndrome. Several clinical variables and genetic variants have been related to a worse prognosis. The aim of this study is to measure if difference in the gene expression are associated with COVID-19 severity. Method(s): We performed RNA-seq Transcriptome in RNA extracted from lymphoblastoid cell line in 20 patients who require hospitalization (10 from the intensive care unit) in a GeneStudio S5 Plus Sequencer (Ion Torrent Technology). FASTQ files were obtained and trimmed using BBtools, BBduk for cutting, filtering and masking the data, and Dedupe for the elimination of duplicates. Mapping and counting matrix was done in bash using the Salmon program. Differential expression analysis and subsequent functional enrichment was performed using Rstudio (DESeq2, ClusterProfiler, GO and KEGG). Result(s): We observed that 2042 differentially expressed genes (1996 overexpressed, LFC>0 and 406 underexpressed, LFC<0) were obtained between patients who require hospitalization versus those in the intensive care unit. We found some genes previously SARS-CoV-2 associated (PGLYRP1, HDAC9 and FUT4). Furthermore, genes involved in the activity of the immune system and in inflammatory processes showed significant differences between cohorts (ABCF1 (LFC = -25.14, padj = 1.05e-13), ABHD16A (LFC = 25.00, padj = 1.05e-13) and IER3 (LFC = -24.45, padj = 2.43e-13)). Conclusion(s): We described differential expression in genes of the immune system and inflammatory processes that might be have a role in the risk of develop severe symptoms of COVID-19, including admission in the intensive care unit. This results should be validated by additional functional studies.

Immunotherapy: ADOPTIVE T CELL IMMUNOTHERAPY FOR SARS-COV-2

Background & Aim: Despite the successful implementation of vaccines worldwide, COVID-19 remains a risk in patients with a compromised immune system. Emerging viral variants have also reduced the effectiveness of monoclonal antibody therapies in these patients. New treatment options are therefore required to improve clinical outcomes. Methods, Results & Conclusion(s): T cell immunotherapy has proven effective for the treatment of a number of refractory viral diseases in patients with a compromised immune system. We have now completed the manufacture of a bank of SARS-CoV-2 specific T cells and commenced an open-label phase I clinical trial at the Royal Brisbane and Women's Hospital, Australia. Patients enrolled in the study receive two doses of partially HLA-matched allogeneic T cells at a fortnightly interval. We have thus far recruited and treated three immune compromised patients with SARS-CoV-2 T cells. In two of the three patients treated thus far, the administration of T cell therapy was coincident with the clearance of viral load after 28 days. Viral clearance in these patients was also associated with an increase in circulating SARS-CoV-2 specific T cells. Our preliminary observations suggest that SARS-CoV-2 specific T cell therapy is well tolerated and has the potential to impact viral control in immune compromised patients.Copyright © 2023 International Society for Cell & Gene Therapy

Komposisi Nutrien Susu Ibu, Imunologi dan COVID-19

Breast milk is the best food that a mother can give to a newborn baby up to the first six months of age. The purpose of this writing is to provide information on the nutrient content found in breast milk, the antibodies involved in helping reduce the infection of COVID-19 and how to breastfeed. The composition of breast milk will change according to the nutrient needs of the baby at every moment. The enzyme content in breast milk will help digestion and the nutrient content can prevent the baby from getting infections that cannot be replaced by formula milk. Antibodies or immunoglobulins are proteins produced by cells in the body's immune system to fight allergens, bacteria, and viruses that cause disease. The body has different types of antibodies such as IgA, IgG, IgM, and IgE. Newborns have immunoglobulins from the placenta. This immunoglobulin will quickly decrease immediately after the baby is born, while the newborn baby's body is not yet able to form the immunoglobulin. This condition will decrease when the baby gets breast milk. This is because breast milk contains a high level of secretory immunoglobulin A antibodies (sIgA) that will protect babies from various bacterial, viral, parasitic and fungal infections. Antibodies help the body's immune system recognize and destroy pathogens such as COVID-19. All mothers who recover from COVID-19 have antibodies to COVID-19 in their milk. These antibodies are very good at fighting diseases that attack the lining of the lungs such as COVID-19. Women with COVID-19 can breastfeed and the virus cannot be detected in breast milk. Safe breastfeeding involves following good respiratory hygiene, skin-to-skin contact for newborns, sharing a room with their baby, washing hands before and after touching the baby, and keeping all surfaces clean. Susu ibu merupakan makanan terbaik yang dapat diberikan ibu kepada bayi yang baru lahir sehingga usia enam bulan pertama. Tujuan penulisan ini memberikan informasi mengenai kandungan nutrien yang terdapat dalam susu ibu, antibodi yang terlibat membantu menurunkan jangkitan COVID-19 dan cara penyusuannya. Komposisi susu ibu akan berubah sesuai dengan keperluan nutrien bayi pada setiap saat. Kandungan enzim dalam susu ibu akan membantu pencernaan dan kandungan nutrien pula mampu mencegah bayi mendapat infeksi yang sememangnya tidak boleh diganti oleh susu formula. Antibodi atau immunoglobulin adalah protein yang dihasilkan oleh sel dalam sistem imuniti tubuh untuk melawan alergen, bakteria, serta virus penyebab penyakit. Tubuh memiliki pelbagai jenis antibodi seperti IgA, IgG, IgM, dan IgE. Bayi yang baru dilahirkan mempunyai immunoglobulin daripada plasenta. Immunoglobulin ini akan cepat menurun segera setelah bayi dilahirkan, sedangkan tubuh bayi yang baru lahir belum mampu membentuk immunoglobulin tersebut. Keadaan ini akan berkurangan apabila bayi mendapatkan susu ibu. Hal ini kerana susu ibu mengandungi kadar antibodi immunoglobulin A rembesan (sIgA) yang tinggi yang akan melindungi bayi daripada pelbagai penyakit infeksi bakteria, virus, parasit dan kulat. Antibodi membantu sistem imuniti tubuh mengenali dan menghancurkan patogen seperti COVID-19. Semua ibu yang pulih daripada COVID-19 memiliki antibodi untuk COVID-19 dalam susu mereka. Antibodi ini sangat baik dalam melawan penyakit yang menyerang lapisan paru-paru seperti COVID-19. Wanita yang menghidap COVID-19 boleh menyusukan bayi dan virus ini tidak dapat dikesan pada susu ibu. Penyusuan yang selamat harus mengikuti kebersihan pernafasan dengan baik, melakukan kontak kulit ke kulit untuk bayi yang baru lahir, berkongsi bilik dengan bayi mereka, mencuci tangan sebelum dan selepas menyentuh bayi, dan menjaga semua permukaan agar bersih.