Immunogenicity and safety of mixed COVID-19 vaccine regimens in patients with immune-mediated inflammatory diseases: a single-centre prospective cohort study.

OBJECTIVE: Among persons with immune-mediated inflammatory diseases (IMIDs) who received SARS-CoV-2 vaccines, we compared postvaccine antibody responses and IMID disease activity/states. DESIGN: Single-centre prospective cohort study. SETTING: Specialty ambulatory clinics in central Canada. PARTICIPANTS: People with inflammatory arthritis (n=78; 77% rheumatoid arthritis), systemic autoimmune rheumatic diseases (n=84; 57% lupus), inflammatory bowel disease (n=93; 43% Crohn's) and multiple sclerosis (n=72; 71% relapsing-remitting) (female 79.4%, white 84.7%, mean (SD) age 56.0 (14.3) years) received COVID-19 vaccinations between March 2021 and September 2022. PRIMARY OUTCOME: Postvaccination anti-spike, anti-receptor binding domain (anti-RBD) and anti-nucleocapsid (anti-NC) IgG antibodies tested by multiplex immunoassays compared across vaccine regimens and with responses in 370 age-matched and sex-matched vaccinated controls. SECONDARY OUTCOMES: COVID-19 infection and self-reported IMID disease activity/state. RESULTS: Most (216/327, 66.1%) received homologous messenger RNA (mRNA) (BNT162b2 or mRNA1273) vaccines, 2.4% received homologous ChAdOx1 and 30.6% received heterologous vaccines (23.9% ChAdOx1/mRNA, 6.4% heterologous mRNA) for their first two vaccines (V1, V2). Seroconversion rates were 52.0% (91/175) for post-V1 anti-spike and 58.9% (103/175) for anti-RBD; 91.5% (214/234) for post-V2 anti-spike and 90.2% (211/234) for anti-RBD; and were lower than controls (post-V2 anti-spike 98.1% (360/370), p<0.0001). Antibody titres decreased 3 months after V2 but increased 1 month after the third vaccine (V3) and 1 month after the fourth vaccine (V4) (BAU/mL median (IQR), anti-spike 1835 (2448) 1 month post-V2, 629.1 (883.4) 3 months post-V2, 4757.5 (7033.1) 1 month post-V3 and 4356.0 (9393.4) 1 month post-V4; anti-RBD 1686.8 (2199.44) 1 month post-V2, 555.8 (809.3) 3 months post-V2, 4280.3 (6380.6) 1 month post-V3 and 4792.2 (11 673.78) 1 month post-V4). If primed with a vector vaccine, an mRNA vaccine increased antibody titres to those comparable to homologous mRNA vaccines. Anti-RBD and anti-spike titres were higher in anti-NC seropositive (n=31; 25 participants) versus seronegative samples (BAU/mL median (IQR) anti-RBD 11 755.3 (20 373.1) vs 1248.0 (53 278.7); anti-spike 11 254.4 (15 352.6) vs 1313.1 (3106.6); both p<0.001). IMID disease activity/state and rates of self-reported moderate or severe IMID flare were similar across vaccinations. CONCLUSION: Heterologous COVID-19 vaccination improves seroconversion rates following a vector vaccine and does not lead to IMID disease flare. IMIDs benefit from at least three vaccines.

The effects of methotrexate on the immune responses to the COVID-19 vaccines in the patients with immune-mediated inflammatory disease: A systematic review of clinical evidence.

COVID-19 vaccines exhibit high levels of immunogenicity in the overall population. Data on the effects of immunomodulators on the consequences of COVID-19 in patients with Immune-mediated inflammatory diseases (IMIDs) remains scarce. This systematic review aimed to evaluate the immune responses to the COVID-19 vaccines in IMID patients receiving methotrexate (MTX) compared to healthy individuals. A comprehensive literature search was carried out using electronic databases such as PubMed, Web of Science, Scopus, Google Scholar, and Embase up to August 2022 to identify eligible RCTs evaluating the effect of MTX on immune responses in patients with COVID-19. The PRISMA checklist protocol was applied for the quality assessment of the selected trials. Our findings demonstrated that MTX lowered the responses of T cells and antibodies in IMID patients compared to healthy controls. We also discovered that young age (<60 years) was the main parameter influencing the antibody response after vaccination, while MTX had little effect. Following vaccination, MTX-hold and age were considered the main factors influencing the antibody response. In patients older than 60 years of age, the time point of 10 days of MTX discontinuation was critical to boosting the humoral response to anti-SARS-CoV-2 IgG. Because many IMID patients did not have adequate humoral and cellular responses, our findings highlighted the importance of second or booster doses of vaccine and temporary MTX discontinuation. As a result, it implies that individuals with IMIDs should be subjected to more research, particularly humoral and cellular immunity efficiency trials after COVID-19 vaccination, until credible information is achieved.

SARS-CoV-2 infection and COVID19 vaccination across eight immune-mediated inflammatory disorders: A prospective, real-life Belgian cohort study - the BELCOMID study.

Background: The risks and impact of COVID19 disease and vaccination in patients with Immune Mediated Inflammatory Diseases (IMID) remain incompletely understood. IMID patients and particularly patients receiving immunosuppressive treatment were excluded from the original, registrational phase-3 COVID19 vaccination efficacy and safety trials. Real-world observational data can help to fill this gap in knowledge. The BELCOMID study aims to explore the interaction between IMIDs, immune-modulating treatment modalities and SARS-CoV-2 infection and vaccination in a real-life patient cohort. Methods: A multidisciplinary, prospective, observational cohort study was set up. Consecutive patients with IMIDs of the gut, joints and skin followed at two high-volume referral centers were invited. Both patients under conventional treatment or targeted immune modulating therapies were included. Patient data and serological samples were collected at 3 predefined periods (before COVID19 vaccination, before booster vaccination, after booster vaccination). Primary endpoints were positive PCR-test and SARS-CoV-2 serology reflecting previous SARS-CoV-2 infection or vaccination. Associations with IMID treatment modality and IMID disease activity were assessed. Results of the first two inclusion periods (before booster vaccination) are reported. Results: At the first inclusion period data was assessed of 2165 IMID-patients before COVID19 vaccination. At the second inclusion period, data of 2065 patients was collected of whom 1547 had received complete baseline COVID19 vaccination and 222 were partially vaccinated. SARS-CoV-2 infection rate remained low in both groups. No significant increase in IMID flare-up rate was noted in patients with prior SARS-CoV-2 infection. Multiple logistic regression analyses did not show a significant influence of IMID-treatment modality or IMID activity on SARS-CoV-2 infection risk (based on PCR positivity or N-serology). Patients treated with conventional immunomodulators, systemic steroids, and patients on advanced therapies such as biologics or small molecules, had reduced S-antibody seroconversion. S-antibody response was also lower in patients without prior SARS-CoV-2 infection and in active smokers. A subset of patients (4.1%) had no S- nor N-antibody seroconversion following complete baseline vaccination. Conclusion: The BELCOMID study results confirm the benign course of COVID19 infection and vaccination in a large real-life IMID-population. However, our results underscore the need for repeated vaccination and smoking cessation in patients with IMIDs treated with immune-modulating therapies or systemic steroids during the pandemic.

Immunomodulatory Agents for Coronavirus Disease-2019 Pneumonia.

Morbidity and mortality from COVID-19 is due to severe inflammation and end-organ damage caused by a hyperinflammatory response. Multiple immunomodulatory agents to attenuate this response have been studied. Corticosteroids, specifically dexamethasone, have been shown to reduce mortality in hospitalized patients who require supplemental oxygen. Interleukin-6 antagonist, tocilizimab, and Janus kinase inhibitors have also been shown to reduce mortality. However, patients who have severe pulmonary end-organ damage requiring mechanical ventilation or extracorporeal membrane oxygenation appear not to benefit from immunomodulatory therapies. This highlights the importance of appropriate timing to initiate immunomodulatory therapies in the management of severe COVID-19 disease.

The effect of immunomodulators on seroconversion after BNT162b2 and AZD1222 vaccines in patients with immune-mediated inflammatory diseases: a prospective cohort study.

BACKGROUND: Biologic and nonbiologic immunomodulators, used to treat immune-mediated inflammatory diseases (IMIDs), could impair the immune response to COVID-19 vaccines and thus vaccine effectiveness. OBJECTIVES: Our objective was to investigate the association between biologic and nonbiologic immunomodulators and seroconversion following the first and second dose of COVID-19 vaccines in patients with IMIDs. METHODS: Serum samples were collected following the first or second dose of the BNT162b2 or AZD1222 vaccines from patients receiving biologic and/or nonbiologic immunomodulators for one or more of psoriasis, psoriatic arthritis, rheumatoid arthritis, inflammatory bowel disease or systemic lupus erythematosus. Seroconversion was defined as a positive Roche Elecsys® Anti-SARS-CoV-2 S (spike protein subunit S1/receptor binding domain) immunoassay (≥ 0.8 U mL-1). Association between immunomodulator exposure and seroconversion was assessed using logistic regression, adjusting for age and sex. RESULTS: After excluding those with prior COVID-19, post-first vaccine dose samples from 193 participants and post-second dose samples from 312 participants were included in the analysis. Following the first vaccine dose, 17.6% (n = 34) of participants did not seroconvert. Seroconversion was reduced for those on nonbiologic [adjusted odds ratio (OR) 0.29, 95% confidence interval (CI) 0.12-0.69] or combined nonbiologic and biologic treatment (adjusted OR 0.14, 95% CI 0.045-0.45) compared with those on biologic monotherapy. Subgroup analysis demonstrated reduced odds of seroconversion in those on methotrexate (adjusted OR 0.097, 95% CI 0.19-0.49) or prednisolone treatment (adjusted OR 0.044, 95% CI 0.002-1.00) relative to tumour necrosis factor-α inhibitor monotherapy. No participants receiving rituximab (n < 5) seroconverted after the first vaccine dose. Following the second vaccine dose, 1.6% of all participants did not seroconvert. Non-seroconversion was associated with receiving rituximab (n = 3 of 4) compared with those receiving other therapies (n = 2 of 308, P < 0.001). Post hoc analyses demonstrated that non-seroconversion was associated with age [adjusted OR 0.18, 95% CI 0.037-0.93 for those aged 60 years and over (reference category age 18-39 years)], but not sex, ethnicity or vaccine type. CONCLUSIONS: Treatment with nonbiologics, particularly methotrexate, is associated with impaired seroconversion following two BNT162b2 or AZD1222 vaccine doses, in patients with IMIDs. These findings are consistent with those of other published studies. While this could indicate reduced protection against COVID-19, the immunological parameters that correlate most closely with vaccine effectiveness need to be defined to reach this conclusion.

Immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination in patients receiving secukinumab: a literature review.

Purpose: There is a paucity of evidence on the impact of immune-mediated inflammatory disease (IMID) treatments on the immunogenicity of SARS-CoV-2 vaccination. The purpose of this literature review is to address the question of whether patients with IMIDs receiving secukinumab, a fully human anti-interleukin-17A monoclonal antibody, have an adequate immune response after SARS-CoV-2 vaccination. Materials and Methods: Clinical studies that evaluated the effect of secukinumab on immune responses in patients with IMIDs after SARS-CoV-2 vaccination were searched in publication databases, including Medline and Embase, until May 2022. Results: From the 53 articles identified, a total of 11 articles were included. Overall, the majority of the patients treated with secukinumab elicited an adequate immune response to SARS-CoV-2 vaccines. Patients receiving secukinumab for IMIDs developed cellular immune responses following vaccination with the BNT162b2 vaccine, and there were no significant differences in the overall humoral and cellular immune responses between patients and healthy individuals. The third dose of the BNT162b2 mRNA vaccine resulted in a positive antibody response in secukinumab-treated patients. Conclusion: The available data provide no evidence of impairment in immunological response to SARS-CoV-2 vaccines by secukinumab in patients with IMIDs.

Preferences for COVID-19 Vaccination in People With Chronic Immune-Mediated Inflammatory Diseases.

OBJECTIVE: To understand how people with chronic immune-mediated inflammatory diseases (IMIDs) trade off the benefits and risks of coronavirus disease 2019 (COVID-19) vaccine options. METHODS: We conducted an online discrete-choice experiment in people with IMIDs to quantify the relative importance (RI) of attributes relevant to COVID-19 vaccination. Participants were recruited between May and August 2021 through patient groups and clinics in Canada, and completed 10 choices where they selected 1 of 2 hypothetical vaccine options or no vaccine. The RI of each attribute was estimated and heterogeneity was explored through latent class analysis. RESULTS: The survey was completed by 551 people (89% female, mean age 46 yrs) with a range of IMIDs (inflammatory bowel disease [48%], rheumatoid arthritis [38%], systemic lupus erythematosus [16%]). Most had received 1 (94%) or 2 (64%) COVID-19 vaccinations. Across the ranges of levels considered, vaccine effectiveness was most important (RI = 66%), followed by disease flare (21%), rare but serious risks (9%), and number/timing of injections (4%). Patients would accept a risk of disease flare requiring a treatment change of ≤ 8.8% for a vaccine with a small absolute increase in effectiveness (10%). Of the 3 latent classes, the group with the greatest aversion to disease flare were more likely to be male and have lower incomes, but this group still valued effectiveness higher than other attributes. CONCLUSION: Patients perceived the benefits of COVID-19 vaccination to outweigh rare serious risks and disease flare. This supports COVID-19 vaccine strategies that maximize effectiveness, while recognizing the heterogeneity in preferences that exists.

Disease activity in patients with immune-mediated inflammatory diseases after SARS-CoV-2 vaccinations.

For patients with immune-mediated inflammatory diseases (IMIDs), concerns exist about increased disease activity after vaccination. We aimed to assess changes in disease activity after SARS-CoV-2 vaccination in patients with IMIDs, and determine risk factors for increased disease activity. In this substudy of a prospective observational cohort study (Target-to-B!), we included patients with IMIDs who received a SARS-CoV-2 vaccine. Patients reported changes in disease activity on a five-point Likert scale every 60 days for up to twelve months after first vaccination. In case of self-reported increased activity, hospital records were screened whether the treating physician reported increased activity, and for potential intensification of immunosuppressive (ISP) treatment. Mixed models were used to study determinants for self-reported increased disease activity. In total, 2111 patients were included for analysis after primary immunization (mean age 49.7 years [SD 13.7], 1329/2111 (63.0%) female), from which 1266 patients for analysis after first additional vaccination. Increased disease activity at 60 days after start of primary immunization was reported by 223/2111 (10.6%). In 96/223 (43.0%) the increase was confirmed by the treating physician and in 36/223 (16.1%) ISP treatment was intensified. Increased disease activity at seven to 60 days after additional vaccination, was reported by 139/1266 (11.0%). Vaccinations were not temporally associated with self-reported increased disease activity. Conversely, increased disease activity before first vaccination, neuromuscular disease, and multiple sclerosis were associated. Altogether, self-reported increased disease activity after vaccination against SARS-CoV-2 was recorded in a minority of patients and was generally mild. Moreover, multivariate analyses suggest that disease related factors, but not vaccinations are the major determinants for self-reported increased disease activity.

Preparing for the next pandemic: Simulation-based deep reinforcement learning to discover and test multimodal control of systemic inflammation using repurposed immunomodulatory agents.

Background: Preparation to address the critical gap in a future pandemic between non-pharmacological measures and the deployment of new drugs/vaccines requires addressing two factors: 1) finding virus/pathogen-agnostic pathophysiological targets to mitigate disease severity and 2) finding a more rational approach to repurposing existing drugs. It is increasingly recognized that acute viral disease severity is heavily driven by the immune response to the infection ("cytokine storm" or "cytokine release syndrome"). There exist numerous clinically available biologics that suppress various pro-inflammatory cytokines/mediators, but it is extremely difficult to identify clinically effective treatment regimens with these agents. We propose that this is a complex control problem that resists standard methods of developing treatment regimens and accomplishing this goal requires the application of simulation-based, model-free deep reinforcement learning (DRL) in a fashion akin to training successful game-playing artificial intelligences (AIs). This proof-of-concept study determines if simulated sepsis (e.g. infection-driven cytokine storm) can be controlled in the absence of effective antimicrobial agents by targeting cytokines for which FDA-approved biologics currently exist. Methods: We use a previously validated agent-based model, the Innate Immune Response Agent-based Model (IIRABM), for control discovery using DRL. DRL training used a Deep Deterministic Policy Gradient (DDPG) approach with a clinically plausible control interval of 6 hours with manipulation of six cytokines for which there are existing drugs: Tumor Necrosis Factor (TNF), Interleukin-1 (IL-1), Interleukin-4 (IL-4), Interleukin-8 (IL-8), Interleukin-12 (IL-12) and Interferon-γ(IFNg). Results: DRL trained an AI policy that could improve outcomes from a baseline Recovered Rate of 61% to one with a Recovered Rate of 90% over ~21 days simulated time. This DRL policy was then tested on four different parameterizations not seen in training representing a range of host and microbe characteristics, demonstrating a range of improvement in Recovered Rate by +33% to +56. Discussion: The current proof-of-concept study demonstrates that significant disease severity mitigation can potentially be accomplished with existing anti-mediator drugs, but only through a multi-modal, adaptive treatment policy requiring implementation with an AI. While the actual clinical implementation of this approach is a projection for the future, the current goal of this work is to inspire the development of a research ecosystem that marries what is needed to improve the simulation models with the development of the sensing/assay technologies to collect the data needed to iteratively refine those models.

Application of network composite module analysis and verification to explore the bidirectional immunomodulatory effect of Zukamu granules on Th1 / Th2 cytokines in lung injury.

ETHNOPHARMACOLOGICAL RELEVANCE: Zukamu granules (ZKMG), as the preferred drug for the treatment of colds in Uygur medical theory, has been used for 1500 years. It is also widely used in China and included in the National Essential Drugs List (2018 edition). It has unique anti-inflammatory, antitussive and analgesic effects. AIM OF THE STUDY: Aiming at the research of traditional Chinese medicine (TCM) with the characteristics of overall regulation of body diseases and the immune regulation mechanism with the concept of integrity, this paper put forward the integrated application of network composite module analysis and animal experiment verification to study the immune regulation mechanism of TCM. MATERIALS AND METHODS: The active components and targets of ZKMG were predicted, and network module analysis was performed to explore their potential immunomodulatory mechanisms. Then acute lung injury (ALI) mice and idiopathic pulmonary fibrosis (IPF) rats were used as pathological models to observe the effects of ZKMG on the pathological conditions of infected ALI and IPF rats, determine the contents of Th1, Th2 characteristic cytokines and immunoglobulins, and study the intervention of GATA3/STAT6 signal pathway. RESULTS: The results of network composite module analysis showed that ZKMG contained 173 pharmacodynamic components and 249 potential targets, and four key modules were obtained. The immunomodulatory effects of ZKMG were related to T cell receptor signaling pathway. The validation results of bioeffects that ZKMG could carry out bidirectional immune regulation on Th1/Th2 cytokines in the stage of ALI and IPF, so as to play the role of regulating immune homeostasis and organ protection. CONCLUSIONS: The network composite module analysis and verification method is an exploration to study the immune regulation mechanism of TCM by combining the network module prediction analysis with animal experiments, which provides a reference for subsequent research.

Identification of immunomodulatory drugs that inhibit multiple inflammasomes and impair SARS-CoV-2 infection.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces mild or asymptomatic COVID-19 in most cases, but some patients develop an excessive inflammatory process that can be fatal. As the NLRP3 inflammasome and additional inflammasomes are implicated in disease aggravation, drug repositioning to target inflammasomes emerges as a strategy to treat COVID-19. Here, we performed a high-throughput screening using a 2560 small-molecule compound library and identified FDA-approved drugs that function as pan-inflammasome inhibitors. Our best hit, niclosamide (NIC), effectively inhibits both inflammasome activation and SARS-CoV-2 replication. Mechanistically, induction of autophagy by NIC partially accounts for inhibition of NLRP3 and AIM2 inflammasomes, but NIC-mediated inhibition of NAIP/NLRC4 inflammasome are autophagy independent. NIC potently inhibited inflammasome activation in human monocytes infected in vitro, in PBMCs from patients with COVID-19, and in vivo in a mouse model of SARS-CoV-2 infection. This study provides relevant information regarding the immunomodulatory functions of this promising drug for COVID-19 treatment.

Reporting of COVID-19 Reinfection and Potential Role of Immunosuppressant/Immunomodulating Agents: A Cross-Sectional Observational Analysis Based on a Spontaneous Reporting Database.

BACKGROUND: The enduring presence of COVID-19 and subsequent increasing incidence of COVID-19 reinfection has prompted evaluation of associated risk factors, particularly the role of immunosuppression. OBJECTIVE: The objective of this study was to characterize cases indicative of COVID-19 reinfection with respect to their reported use of immunosuppressant/immunomodulating agents. METHODS: This cross-sectional observational study leveraged the Pfizer global safety database (SDB) containing adverse event data collected in association with use of Pfizer products between 1 October 2019, and 30 June 2022. Selected Medical Dictionary for Drug Regulatory Activities (MedDRA®) Preferred Terms were used to identify COVID-19 cases; the search was further refined to comprise cases that subsequently reported events potentially indicative of COVID-19 reinfection. RESULTS: Of the cumulative total of 218,242 COVID-19 cases reported into the SDB, 4590 cases (2.1%) involving potential COVID-19 reinfection were identified. Of these 4590 cases of potential Covid-19 reinfection, a total of 134 cases reported COVID-19 specifically during treatment with pharmaceutical products, of which approximately 16% (21/134) of cases reported use of immunosuppressant/immunomodulating agents. Likewise, in the overall dataset (213,652 cases; excluding the 4590 cases involving potential COVID-19 recurrence), the percentage of reported immunosuppressant/immunomodulating agents was low (12%). In applying similar parameters to a dataset that excludes COVID-19 vaccine cases, 18% of cases reported use of immunosuppressant/immunomodulating agents (similar to the aforementioned 16% of cases reported from the overall total dataset that was inclusive of vaccine cases). CONCLUSION: This pharmacovigilance study provides a characterization of cases indicative of COVID-19 reinfection with respect to reported use of immunosuppressant/immunomodulating agents. The observations generated from this cross-sectional observational analysis may prompt further research into the role of immunosuppression in COVID-19 reinfection, in an effort to better inform clinical practice and patient management.

Immunobiology of tubercle bacilli and prospects of immunomodulatory drugs to tackle tuberculosis (TB) and other non-tubercular mycobacterial infections.

The COVID-19 pandemic has set back progress made on antimicrobial resistance (AMR). Without urgent re-focus, we risk slowing down drug discovery and providing treatment for drug resistant Mycobacterium tuberculosis. Unique in its immune evasion, dormancy and resuscitation, the causal pathogens of tuberculosis (TB) have demonstrated resistance to antibiotics with efflux pumps and the ability to form biofilms. Repurposing drugs is a prospective avenue for finding new anti-TB drugs. There are many advantages to discovering novel targets of an existing drug, as the pharmacokinetic and pharmacodynamic properties have already been established, they are cost-efficient and can be commercially accelerated for the new development. One such group of drugs are non-steroidal anti-inflammatory drugs (NSAIDs) that are originally known for their ability to supress the host proinflammatory responses. In addition to their anti-inflammatory properties, some NSAIDs have been discovered to have antimicrobial modes of action. Of particular interest is Carprofen, identified to inhibit the efflux mechanism and disrupt biofilm formation in mycobacteria. Due to the complexities of host-pathogens interactions in the lung microbiome, inflammatory responses must carefully be controlled alongside the in vivo actions of the prospective anti-infectives. This critical review explores the potential dual role of a selection of NSAIDs, as an anti-inflammatory and anti-tubercular adjunct to reverse the tide of antimicrobial resistance in existing treatments.

The vital role of animal, marine, and microbial natural products against COVID-19.

CONTEXT: Since the outbreak of SARS-CoV-2, researchers have been working on finding ways to prevent viral entry and pathogenesis. Drug development from naturally-sourced pharmacological constituents may be a fruitful approach to COVID-19 therapy. OBJECTIVE: Most of the published literature has focussed on medicinal plants, while less attention has been given to biodiverse sources such as animal, marine, and microbial products. This review focuses on highlighting natural products and their derivatives that have been evaluated for antiviral, anti-inflammatory, and immunomodulatory properties. METHODS: We searched electronic databases such as PubMed, Scopus, Science Direct and Springer Link to gather raw data from publications up to March 2021, using terms such as 'natural products', marine, micro-organism, and animal, COVID-19. We extracted a number of documented clinical trials of products that were tested in silico, in vitro, and in vivo which paid specific attention to chemical profiles and mechanisms of action. RESULTS: Various classes of flavonoids, 2 polyphenols, peptides and tannins were found, which exhibit inhibitory properties against viral and host proteins, including 3CLpro, PLpro, S, hACE2, and NF-κB, many of which are in different phases of clinical trials. DISCUSSION AND CONCLUSIONS: The synergistic effects of logical combinations with different mechanisms of action emphasizes their value in COVID19 management, such as iota carrageenan nasal spray, ermectin oral drops, omega-3 supplementation, and a quadruple treatment of zinc, quercetin, bromelain, and vitamin C. Though in vivo efficacy of these compounds has yet to be established, these bioproducts are potentially useful in counteracting the effects of SARS-CoV-2.

Immunomodulatory and Anti-Inflammatory Properties of Selenium-Containing Agents: Their Role in the Regulation of Defense Mechanisms against COVID-19.

The review presents the latest data on the role of selenium-containing agents in the regulation of diseases of the immune system. We mainly considered the contributions of selenium-containing compounds such as sodium selenite, methylseleninic acid, selenomethionine, and methylselenocysteine, as well as selenoproteins and selenium nanoparticles in the regulation of defense mechanisms against various viral infections, including coronavirus infection (COVID-19). A complete description of the available data for each of the above selenium compounds and the mechanisms underlying the regulation of immune processes with the active participation of these selenium agents, as well as their therapeutic and pharmacological potential, is presented. The main purpose of this review is to systematize the available information, supplemented by data obtained in our laboratory, on the important role of selenium compounds in all of these processes. In addition, the presented information makes it possible to understand the key differences in the mechanisms of action of these compounds, depending on their chemical and physical properties, which is important for obtaining a holistic picture and prospects for creating drugs based on them.

Anti-Inflammatory and Immunoregulatory Action of Sesquiterpene Lactones.

Sesquiterpene lactones (SL), characterized by their high prevalence in the Asteraceae family, are one of the major groups of secondary metabolites found in plants. Researchers from distinct research fields, including pharmacology, medicine, and agriculture, are interested in their biological potential. With new SL discovered in the last years, new biological activities have been tested, different action mechanisms (synergistic and/or antagonistic effects), as well as molecular structure-activity relationships described. The review identifies the main sesquiterpene lactones with interconnections between immune responses and anti-inflammatory actions, within different cellular models as well in in vivo studies. Bioaccessibility and bioavailability, as well as molecular structure-activity relationships are addressed. Additionally, plant metabolic engineering, and the impact of sesquiterpene lactone extraction methodologies are presented, with the perspective of biological activity enhancement. Sesquiterpene lactones derivatives are also addressed. This review summarizes the current knowledge regarding the therapeutic potential of sesquiterpene lactones within immune and inflammatory activities, highlighting trends and opportunities for their pharmaceutical/clinical use.

Multisystem inflammatory syndrome in children (MIS-C) related to COVID-19 infection in the state of Qatar: Association with Kawasaki-like Illness.

INTRODUCTION: World Health Organization (WHO) is encouraging reporting of children with Multisystem Inflammatory Syndrome (MIS-C) associated with SARS-CoV-2 infection for better understanding and management of the disease. METHODOLOGY: This retrospective study included the first 15 pediatrics patient with a confirmed diagnosis of MIS-C associated with SARS-CoV-2 infection in the state of Qatar. We studied and analyzed their demographic data, clinical manifestations, laboratory tests, treatment, and outcome. RESULTS: A total of 15 children were studied (mean age 3.5 ± 2.7year). Recent severe acute respiratory syndrome coronavirus 2 infection was identified in all of them (100%). The majority of these patients had 4 or more systems involvement. Nine of the 15 presented with Kawasaki disease - picture and all had gastrointestinal symptoms (vomiting and diarrhea). Five required Pediatrics Intensive Care Unit (PICU) admission. Lab investigations revealed high D-Dimer, hyponatremia, and hypoalbuminemia in all. Low hemoglobin (Hb) , thrombocytopenia, and sterile pyuria occurred in 86.6%, 60% and 75% of them, respectively. Treatment with combined anti-inflammatory medications (intravenous immunoglobulin, corticosteroids) was used in along with immunomodulatory agents (Anakinra) in a selected group of refractory patients. No mortality happened. CONCLUSION: Our young children who presented with MIS-C related to SARS-CoV-2 infection had significantly higher Kawasaki-disease picture compared to other reports. One third of them required PICU admission but no mortality occurred.

Cerebral lesions in hematological malignancies: a case report.

BACKGROUND: Progressive multifocal leukoencephalopathy is a rare central nervous system disease, resulting from reactivation of latent John Cunningham virus. Monoclonal antibodies have recently become a relevant risk factor for developing progressive multifocal leukoencephalopathy. We report the case of a 62-year-old Caucasian man who was admitted to our department in June 2020 because of right homonymous hemianopia. Magnetic resonance imaging findings were first interpreted as an intracranial relapsed lymphoma, so brain biopsy was performed, but no neoplastic cell was found. Histological sample only showed a large number of macrophages. The patient came back to our attention because of the worsening of neurological symptoms. A second magnetic resonance imaging showed widespread lesions suggestive of a demyelinating process. John Cunningham virus DNA was detected by polymerase chain reaction assay of the cerebrospinal fluid (over 9 million units/µL). The patient was treated supportively, but the outcome was poor. DISCUSSION: A multidisciplinary assessment should be performed for differential diagnosis of cerebral lesions in hematologic malignancies. Progressive multifocal leukoencephalopathy should be suspected in cases of subacute neurological symptoms and imaging findings consistent with it, especially if the patient received immunosuppressive or immunomodulatory drugs.