THE RS17713054 AND RS1800629 POLYMORPHISMS OF GENES LZTFL1 AND TNF ARE ASSOCIATED WITH COVID-19 SEVERITY

Both genetic and non-genetic factors are responsible for high interindividual variability in response to SARS-CoV-2. Despite the fact that multiple genetic polymorphisms have been identified as risk factors of severe COVID-19, such polymorphisms are still insufficiently studied in the Russian population. The study was aimed to identify genetic determinants associated with severe COVID-19 in the sample of patients from the Russian Federation. The correlation of the rs17713054 polymorphism in gene LZTFL1 and rs1800629 polymorphism in gene TNF (tumor necrosis factor) with the COVID-19 severity was assessed. DNA samples obtained from 713 patients (324 males and 389 females) aged 18-95 with COVID-19 of varying severity were analyzed. The rs1800629 polymorphism of gene TNF (OR = 1.5;p = 0.02) and rs17713054 polymorphism of gene LZTFL1 (OR = 1.60;p = 0.0043) were identified as risk factors of severe disease. The TNF polymorphism rs1800629 and LZTFL1 polymorphism rs17713054 could be considered as potential predictive biomarkers. The rs17713054 G > A polymorphism was strongly associated with severe disease. In the future the findings may provide the basis for the development of test-systems for prediction of the risk of severe viral respiratory diseases.

Analysis of medication regularities of epidemic disease prescription in Treatise on Febrile Diseases and mechanism of core drugs in treatment of COVID-19

Objective To analyze the medication rules of related epidemic disease prescription in Treatise on Febrile Diseases based on data mining, and the mechanism of "Chaihu (Bupleuri Radix)-Huangqin (Scutellariae Radix)” as the core drugs in the treatment of coronavirus disease 2019 (COVID-19) by network pharmacology, in order to explore the contemporary value of classical prescriptions in the treatment of epidemic diseases. Methods The prescriptions for treating epidemic diseases in Treatise on Febrile Diseases were screened, and the medication rules such as drug frequency, flavor and meridian tropism as well as correlation, apriori algorithm were analyzed by using software such as R language. The mechanism of the core drugs in the medication pattern in the treatment of COVID-19 was explored by the network pharmacology. A "disease-drug-ingredient-target” network was constructed on the selected components and targets with Cytoscape. The key targets were introduced into String database for network analysis of protein-protein interaction (PPI), and gene ontology (GO) functional analysis and Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis were conducted in R language. Results A total of 61 prescriptions for treating epidemic diseases in Treatise on Febrile Diseases were included, including 52 traditional Chinese medicines (TCMs). In the top 20 high-frequency drugs, warm drugs, spicy drugs and qitonifying drugs were mainly used, mostly in the spleen and lung meridian. Chaihu (Bupleuri Radix) and Huangqin (Scutellariae Radix) herb pair had the strongest correlation. A total of five clusters were excavated: supplemented formula of Xiaochaihu Decoction (小柴胡汤), Sini Decoction (四逆汤), supplemented formule of Maxing Shigan Decoction (麻杏石甘汤), Fuling Baizhu Decoction (茯苓白术汤) and Dachengqi Decoction (大承气汤). A total of 45 active ingredients, 189 action targets of Bupleuri Radix-Scutellariae Radix herb pair, and 543 targets of COVID-19 were obtained from TCMSP and Genecards, and 64 intersection targets were generated. The results of the network analysis showed that the main components of core drugs pair against COVID-19 may be quercetin, wogonin, kaempferol baicalein, acacetin etc., and the core targets may be VEGFA, TNF, IL-6, TP53, AKT1, CASP3, CXCL8, PTGS2, etc. A total of 1871 related entries and 164 pathways were obtained by GO and KEGG enrichment analysis, respectively. Conclusion In Treatise on Febrile Diseases, the treatment of epidemic diseases mainly chose pungent, warm, spleen-invigorating and qi-tonifying herbs, such as Xiaochaihu Decoction, Sini Decoction and Dachengqi Decoction, etc. It was found that Bupleuri Radix-Scutellariae Radix core herb pair prevent and treat COVID-19 through multi-target targets such as PTGS2, IL-6 and TNF. The ancient prescriptions for treating epidemic disease in Treatise on Febrile Diseases may have significant reference value for the prevention and treatment of new epidemic diseases today. © 2023 Editorial Office of Chinese Traditional and Herbal Drugs. All rights reserved.

ENDOTHELIAL INFLAMMATION AND DYSFUNCTION INDUCED BY SARS-COV-2 SPIKE PROTEIN 1 INVOLVE ADAM17 AND INTERFERON ACTIVATION PATHWAYS

Objective: COVID19 is associated with vascular inflammation. IFN-alpha (IFNa) and IFN-lambda3 (IFNl3) are potent cytokines produced in viral infections. Their effects involve interferon-stimulated genes (ISGs) and may influence expression of angiotensin-converting enzyme 2 (ACE2), the receptor for S-protein (S1P) of SARS-CoV-2. We hypothesized that S1P-induced immune/inflammatory responses in endothelial cells (EC) are mediated via IFN-activated pathways Design and methods: Human ECs were stimulated with S1P (1 mg/mL), IFNa (100ng/mL) or IFNl3 (100IU/mL). Because ACE2, ADAM17 and TMPRSS2 are important for SARS-CoV-2 infection, we used inhibitors of ADAM17 (marimastat, 3.8 nM), ACE2 (MLN4760, 440pM), and TMPRSS2 (camostat, 50 mM). Gene and protein expression was investigated by real-time PCR and immunoblotting, respectively. Vascular function was assessed in mesenteric arteries from wild-type (WT) normotensive and hypertensive (LinA3) mice and in ISG15-deficient (ISG15KO) mice. Results: S1P increased expression of IFNa (3-fold), IFNl3 (4-fold) and ISGs (2-fold) in EC (p < 0.05). EC responses to IFNa (ISG15: 16-fold) were greater than to IFNl3 (ISG15: 1.7-fold) (p < 0.05). S1P increased gene expression of IL-6 (1.3-fold), TNFa (6.2-fold) and IL-1b (3.3-fold), effects that were amplified by IFNs. Only the ADAM17 inhibitor marimastat inhibited S1P effects. IFNa and IFNl3 increase protein expression of ADAM17 (27%) and TMPRSS2 (38%). No changes were observed on ACE2 expression. This was associated with increased phosphorylation of Stat1 (134%), Stat2 (102%), ERK1/2 (42%). EC production of IL-6 was increased by IFNa (1,230pg/mL) and IFNl3 (1,124pg/mL) vs control (591pg/mL). Nitric oxide generation and eNOS phosphorylation (Ser1177) were reduced by IFNa (40%) and IFNl3 (40%). Vascular functional responses demonstrated that endothelium-dependent vasorelaxation (% Emax) in vessels from WT-mice stimulated with IFNa (67%) and IFNl3 (71%) were reduced vs control (82%) (p < 0.05). Responses were not altered in vessels from ISG15KO mice. Increased contraction was observed only in vessels from hypertensive mice treated with IFNa (9.1 ± 0.5mN vs control: 7.3 ± 0.3mN) (p < 0.05). Conclusions: In ECs, S1P, IFNa and IFNl3 increased ISG15 and IL-6 by mechanisms dependent on ADAM17. IFNs amplifies endothelial cell inflammatory responses and induced vascular dysfunction through ISG15-dependent mechanisms, with augmented effects in hypertension. Our findings demonstrate that S1P induces immune/inflammatory responses that may be important in endotheliitis associated with COVID-19. This may be especially important in the presence of cardiovascular risk factors, including hypertension.

Potential Cardiac Tamponade Development Secondary to SARS-CoV-2 Infection

Upon initial discovery in late 2019, severe acute respiratory syndrome coronavirus 2, SARS-CoV-2, has managed to spread across the planet. A plethora of symptoms affecting multiple organ systems have been described, with the most common being nonspecific upper respiratory symptoms: cough, dyspnea, and wheezing. However, the cardiovascular system is also at risk following COVID-19 infection. Numerous cardiovascular complications have been reported by physicians globally, in particular cardiac tamponade Physicians must hold a high index of suspicion in identifying and treating patients with cardiac tamponade who may have contracted the novel coronavirus. This review will describe the current epidemiology and pathophysiology of SARS-CoV-2 and cardiac tamponade, highlighting their clinical course progression and the implications it may have for the severity of both illnesses. The paper will also review published case reports of cardiac tamponade, clinical presentation, and treatment of this complication, as well as the disease as a whole. © 2022 Elsevier Inc.

Known *Anti Sars-Cov Protease Inhibitors* On Sars-Cov-2 Related Intracellular Reception Sites: *Docking Interaction* And Computer Aided Optimization Of Molecular Structure For *Chemioselective Interactions*

Molecular docking and molecular dynamics aided virtual search of OliveNet™ directory identified potential secoiridoids that combat SARS-CoV-2 entry, replication, and associated hyperinflammatory responses. OliveNet™ is an active directory of phytochemicals obtained from different parts of the olive tree, Olea europaea (Oleaceae). Olive oil, olive fruits containing phenolics, known for their health benefits, are indispensable in the Mediterranean and Arabian diets. Secoiridoids is the largest group of olive phenols and is exclusive to the olive fruits. Functional food like olive fruits could help prevent and alleviate viral disease at an affordable cost. A systematized virtual search of 932 conformers of 78 secoiridoids utilizing Autodock Vina, followed by precision docking using Idock and Smina indicated that Nüzhenide oleoside (NZO), Oleuropein dimer (OED), and Dihydro oleuropein (DHO) blocked the SARSCoV-2 spike (S) protein-ACE-2 interface;Demethyloleuropein (DMO), Neo-nüzhenide (NNZ), and Nüzhenide (NZE) blocked the SARS-CoV-2 main protease (Mpro). Molecular dynamics (MD) simulation of the NZO-S-protein-ACE-2 complex by Desmond revealed stability during 50 ns. RMSD of the NZO-S-protein-ACE-2 complex converged at 2.1 Å after 20 ns. During MD, the interaction fractions confirmed multiple interactions of NZO with Lys417, a crucial residue for inhibition of S protein. MD of DMO-Mpro complex proved its stability as the RMSD converged at 1.6 Å. Analysis of interactions during MD confirmed the interaction of Cys145 of Mpro with DMO and, thus, its inhibition. The docking predicted IC50 of NZO and DMO was 11.58 and 6.44 μM, respectively. Molecular docking and dynamics of inhibition of the S protein and Mpro by NZO and DMO correlated well. Docking of the six-hit secoiridoids to IL1R, IL6R, and TNFR1, the receptors of inflammatory cytokines IL1β, IL6, and TNFα, revealed the anti-inflammatory potential except for DHO. Due to intricate structures, the secoiridoids violated Lipinski's rule of five. However, the drug scores of secoiridoids supported their use as drugs. The ADMET predictions implied that the secoiridoids are non-toxic and pose low oral absorption. Secoiridoids need further optimization and are a suitable lead for the discovery of anti-SARS-CoV-2 therapeutics. For the moment, olive secoiridoids presents an accessible mode of prevention and therapy of SARS-CoV-2 infection.

Pathogenicity of Type I Interferons in Mycobacterium tuberculosis.

Tuberculosis (TB) is a leading cause of mortality due to infectious disease and rates have increased during the emergence of COVID-19, but many of the factors determining disease severity and progression remain unclear. Type I Interferons (IFNs) have diverse effector functions that regulate innate and adaptive immunity during infection with microorganisms. There is well-documented literature on type I IFNs providing host defense against viruses; however, in this review, we explore the growing body of work that indicates high levels of type I IFNs can have detrimental effects to a host fighting TB infection. We report findings that increased type I IFNs can affect alveolar macrophage and myeloid function, promote pathological neutrophil extracellular trap responses, inhibit production of protective prostaglandin 2, and promote cytosolic cyclic GMP synthase inflammation pathways, and discuss many other relevant findings.

Response to COVID-19 vaccine is reduced in patients with inflammatory bowel disease, but improved with additional dose.

BACKGROUND: Coronavirus disease 2019 (COVID-19) vaccination is recommended for patients with inflammatory bowel disease (IBD); however, suppressed immune responses have been reported for fully vaccinated patients under immunosuppressive therapy, mainly from Western countries. We prospectively analyzed antibody titers of IBD patients in Asia induced by two-dose and additional dose of messengerRNA COVID-19 vaccine. METHODS: After measuring high-affinity antibody titers, factors associated with antibody titers were identified by multiple regression analyses using the following covariates: sex, age (≥60 or <60 years), disease type (Crohn's disease or ulcerative colitis), vaccine type (BNT162b2 or mRNA-1273), time from second/third vaccination, molecular-targeted agent (anti-tumor necrosis factor [TNF] agents, ustekinumab, vedolizumab, tofacitinib, or no molecular-targeted agents), thiopurine, steroid, and 5-aminosalicylic acid. RESULTS: Among 409 patients analyzed, mean titer was 1316.7 U/mL (SD, 1799.3); 403 (98.5%) were judged to be seropositive (≥0.8 U/mL), and 389 (95.1%) had neutralizing antibodies (≥15 U/mL). After the third vaccination, mean titer raised up to 21 123.8 U/mL (SD, 23 474.5); all 179 were seropositive, and 178 (99.4%) had neutralizing antibodies. In 248 patients with genetic data, there was no difference in mean titer after two/third doses between carriers and non-carriers of HLA-A24 associated with severe disease during COVID-19 infection. A multiple regression analyses using covariates revealed that older age, vaccine type (BNT162b2), time from second/third dose, anti-TNF agent, tofacitinib, and thiopurine were independently associated with lower antibody titers. CONCLUSIONS: Our findings further support the recommendation for COVID-19 vaccination in patients under immunosuppressive therapy, especially additional third dose for patients receiving anti-TNF agents and/or thiopurine or tofacitinib.

Repurposing of drugs for combined treatment of COVID-19 cytokine storm using machine learning.

Severe acute respiratory syndrome coronavirus 2 (SARS­CoV­2) induced cytokine storm is the major cause of COVID­19 related deaths. Patients have been treated with drugs that work by inhibiting a specific protein partly responsible for the cytokines production. This approach provided very limited success, since there are multiple proteins involved in the complex cell signaling disease mechanisms. We targeted five proteins: Angiotensin II receptor type 1 (AT1R), A disintegrin and metalloprotease 17 (ADAM17), Nuclear Factor­Kappa B (NF­κB), Janus kinase 1 (JAK1) and Signal Transducer and Activator of Transcription 3 (STAT3), which are involved in the SARS­CoV­2 induced cytokine storm pathway. We developed machine learning (ML) models for these five proteins, using known active inhibitors. After developing the model for each of these proteins, FDA-approved drugs were screened to find novel therapeutics for COVID­19. We identified twenty drugs that are active for four proteins with predicted scores greater than 0.8 and eight drugs active for all five proteins with predicted scores over 0.85. Mitomycin C is the most active drug across all five proteins with an average prediction score of 0.886. For further validation of these results, we used the PyRx software to conduct protein-ligand docking experiments and calculated the binding affinity. The docking results support findings by the ML model. This research study predicted that several drugs can target multiple proteins simultaneously in cytokine storm-related pathway. These may be useful drugs to treat patients because these therapies can fight cytokine storm caused by the virus at multiple points of inhibition, leading to synergistically effective treatments.

Long COVID-19 in autoimmune and rheumatic diseases: data from COVID-19 vaccination in autoimmune diseases study

Background/Aim: Long COVID-19 is one of the post-infection challenging issues. We aimed to assess the prevalence and characteristics of this syndrome in patients with autoimmune and rheumatic diseases (AIRDs) through a multicentre international e-surveys (The COVID-19 Vaccination in Autoimmune Diseases) COVAD study. Method(s): The COVAD group comprised of collaborators from 109 countries. An online survey platform was conducted in Jan-July 2022 to capture self-reported COVID-19 infection and vaccination data in patients with AIRDs and healthy controls (HCs). Long COVID-19 was defined as per WHO definitions as persistence of symptoms beyond 3 months of COVID-19 infection. Descriptive statistics and multivariable regression adjusted for age, gender, ethnicity, and disease modifying anti-rheumatic drugs (DMARDs) were employed. Result(s): Among the 7666 complete survey respondents, 1677 who had taken the survey >90 days of last COVID-19 infection were analyzed. Among them, a total of 8.1% (n = 136) had long COVID-19 syndrome and the median age was 46 (34-55) years, with Male: Female ratio of 1:6.3. The prevalence of long COVID-19 was significantly higher in patients with AIRDs compared to HCs (OR 2 [1.3-2.9], P < 0.001). Respondents with long COVID-19 had worse PROMIS 10a quality of life global physical and mental health score, as well as fatigue and pain VAS compared to those without post-COVID- 19 (all P < 0.001). Among patients with AIRDs, those with long COVID-19 reported to have higher flares of AIRDs following COVID-19 infection (OR 4.3, P < 0.01). On multivariable regression analysis, the characteristics of patients with long COVID-19 were female gender, Caucasian ethnicity and presence of comorbid insomnia. Presence of fatigue, muscle aches, dyspnoea and loss of taste during previous COVID-19 infection were the significant predictors of long COVID-19. Among patients with AIRDs, comorbidities (OR 2.0;95% CI: 1.08-3.6, P = 0.026), and advanced treatment (OR: 1.9;95% CI: 1.08-3.3, P = 0.024), or intensive care (OR: 3.8;95% CI: 1.01-14.4, P = 0.047) for severe COVID-19 were risk factors for long COVID-19. The use of rituximab, iv immunoglobulins (IVIG), mycophenolate mofetil and anti-TNF agents use also predicted long COVID-19. Conclusion(s): Patients with AIRDs are at higher risk of long-COVID- 19 syndrome. Associated comorbid conditions and advanced treatment or intensive care for severe COVID-19 confer a higher risk.

The Effects of Apium graveolens and Eucalyptus globulus in Decreasing Stress and Protecting Folliculogenesis Marker on Woman Reproductive Health during COVID-19 Pandemic

Stress during Coronavirus disease-2019 (COVID-19) pandemic affects the physiological and immunological response to women's reproductive health. Meanwhile, Apium graveolens and Eucalyptus globulus are immunomodulators related to women's reproductive health. This investigation had a goal to examine the effectiveness of A. graveolens and E. globulus towards the expression of Heat Shock Protein-70 (HSP70) as the primary biomarker of stress, Tumor Necrosis Factor-Alpha (TNF-alpha) as a pro-inflammatory protein, along with Luteinizing Hormone (LH) and Growth Differentiation Factor 9 (GDF-9) as folliculogenesis markers. An experimental randomized controlled trial was utilized by using a pre-test and post-test control group design. Sixty women, who had stress based on DASS-21 questionnaire, were divided into two groups in Nusukan Health Center, Indonesia. The intervention group was orally administered with 300 mg A. graveolens capsules and E. globulus essential oil for 14 days, while the control group was given a placebo. Blood samples and stress levels were then evaluated before and after the intervention. No significant difference was found in the stress levels of the control and treatment groups at the pre-test. Meanwhile, the intervention group had the decreased HSP70, TNF-alpha, and stress levels (p<0.001). In contrast, increased LH and GDF-9 levels were displayed in the intervention group compared to the control group (p<0.001). These findings revealed that A. graveolens supplementation and E. globulus essential oil have the ability to decrease stress and are able to protect folliculogenesis markers on women's reproductive health due to stressful conditions during pandemic COVID-19. Copyright © 2022 by Indonesian Journal of Pharmacy (IJP).

Cancer, Covid and Control of Ra - a Toxic Combination?

Case report - Introduction: This case highlights the dilemma of keeping rheumatoid arthritis disease under control in active cancer cases and establishing a consistent multidisciplinary dialogue during a pandemic and staffing crises. During chemotherapy and active cancer treatment, disease-modifying therapies (conventional and biologic) are often stopped. In some cases, the potential benefits versus risks of restarting usual therapies have to be balanced against risks of suppressing disease activity with highdose steroids. Risks of infection (common and atypical) need to be considered. Case report - Case description: A is a 67-year-old female nonsmoker diagnosed with seropositive rheumatoid arthritis (RF, anti - CCP positive) in 2008. Other conditions include type 2 diabetes, atrial fibrillation (on warfarin), hypothyroidism and obstructive sleep apnoea. Due to active disease, despite triple therapy (methotrexate, sulphasalazine and hydroxychloroquine), anti-TNF therapy (etanercept) commenced in 2009 with primary non-response. However, she responded well to B-cell therapy (rituximab) in conjunction with oral methotrexate (25mg weekly) receiving annual infusions from 2010 to 2016. In 2017, an elective sleeve gastrectomy procedure for high BMI was abandoned after peritoneal deposits of concern were noted. Histology and CT imaging were consistent with a primary peritoneal malignancy (Stage 3c low-grade serous adenocarcinoma). Treatment involved debulking surgery (total abdominal hysterectomy, bilateral salpinoophorectomy, omentectomy) and tamoxifen. Treatment for rheumatoid arthritis stalled during this period but as frequent steroids were required for active joint inflammation, in agreement with the oncologists, she had a rituximab cycle in 2018. Unfortunately, in 2019 she had signs of cancer progression (elevated tumour markers, CT imaging) and has subsequently started carboplatin chemotherapy. She has been unable to continue methotrexate or rituximab pending completion of the chemotherapy cycles (ongoing). However, her arthritis is now uncontrolled without increased steroids. Due to recurrent flares, her maintenance dose has been increased from 5mg to 7.5-10mg prednisolone daily until we can establish if it is safe and appropriate to recommence her usual arthritis regime. Even without disease-modifying therapy like methotrexate and rituximab, risk of infection (including atypical ones) is still significant with the combination of chemotherapy and steroids. Risk of progressive joint damage and adverse quality of life with active arthritis also needs to be considered. Staffing crises, exacerbated by COVID pandemic issues, have added to complexity of decision making and coordination of regular multidisciplinary discussions regarding treatment. Case report - Discussion: Cancer is a known association in rheumatoid arthritis patients with a twofold higher risk of lymphoma compared to the general population. Whether condition or treatment affects risk remains unclear as immune dysregulation is relevant in both autoimmunity and cancer. Paraneoplastic, recent onset arthritis, chemotherapy- or immunotherapy-induced arthralgia/arthritis are also well documented. This case had a seropositive rheumatoid arthritis phenotype quite a few years prior to cancer diagnosis. Primary peritoneal cancer is uncommon, often presenting as in this case as an incidental finding. It is usually treated like ovarian cancer Whilst methotrexate has been implicated in lung cancer, melanoma and non-Hodgkin lymphoma, overall safety data suggest any risk is quite low (e.g., EBV-associated lymphoproliferative disorders usually resolve with drug discontinuation). It is also a known chemotherapeutic agent. Anti-TNF treatment algorithms generally exclude patients with recent cancer. Rituximab, originally developed as a cancer drug, is not thought to affect risk of cancer development or progression. Treatment with disease-modifying therapy (conventional and biologics) is often withheld in patients with active malignancy undergoing chemotherapy due to a theo etical risk of potentiated immunosuppression and toxicity, particularly cytopaenias. However, maintaining arthritis control with glucocorticoids also has short- and long-term risks. Combining chemotherapy agents like carboplatin with methotrexate has been used for urothelial carcinoma and can be well tolerated with close monitoring of haematological parameters. Thus, it could be argued this patient is at risk of infections whichever treatment approach is taken and regaining control of arthritis with recommencement of methotrexate and rituximab is much better for her quality of life. Regular multidisciplinary discussions are important to outline risks versus benefits of combined treatment. This may be difficult in practice during staffing crises. Covid risk in patients receiving rituximab and/or chemotherapy, timing and response to COVID vaccination are also important considerations. Case report - Key learning points: . Primary peritoneal cancer is uncommon and can present as an incidental finding . Whilst treatment for progressive cancer is important, withholding rheumatoid arthritis treatment can have a significant adverse impact on quality of life . Morbidity and mortality risks of stopping treatment versus combined treatment (cancer therapy and disease-modifying therapy) ideally needs to be fully discussed and agreed with the patient and all care providers - lack of "named" providers, restructuring, redeployment, multi-specialty care and a global pandemic can make coordination of this difficult.

SARS-CoV-2 induces pro-inflammatory cytokines with an impact on mental health

In December 2019, the novel coronavirus strain SARS-CoV-2 caused an outbreak that quickly spread worldwide and led to the COVID-19 pandemic. COVID-19, the severe infectious disease caused by SARS-CoV-2, often presents with symptoms including fever, cough, and mental confusion and can cause the acute respiratory inflammatory disorder. Additionally, viral infection with SARS-CoV-2 is associated with mental health, neuronal degeneration, and psychiatric complications. With infection by the virus, cytokines are released by immune cells, causing acute systemic inflammation affecting the lungs. Lung damage can occur, resulting in hypoxia, brain damage, and mental health dysfunction. In addition, a cascade of inflammatory cytokines, including IL-1, IL-6, and TNF, are released, a phenomenon termed the "cytokine storm" that causes serious pathological damage to tissues and organs and mental health. This exaggerated production of cytokines leads to lymphopenia and disrupts the balance of Treg and Th17 cells, weakening the immune system. The elderly population is particularly at risk for damage associated with the "cytokine storm", which can affect neurological functions or result in death. Copyright © by BIOLIFE.

Incidence of COVID-19 hospitalization in patients with psoriasis taking systemic immunomodulators

Background: Current research on COVID-19-related outcomes in patients with psoriasis, particularly regarding influence of treatments, are subject to lack of comparator group, selection bias, and insufficient statistical power.1 Accordingly, it remains uncertain whether immunomodulatory treatments for psoriasis enhance or decrease the risk of severe COVID-19-related outcomes, including hospitalization. Objective(s): To compare the risk of COVID-19-related hospitalization according to immunomodulator treatment type in patients with psoriasis Methods: Retrospective cohort study of the Explorys database in the United States between March 1st, 2020 and December 31st, 2020. Psoriasis diagnosis was defined by at least 2 ICD-9 or ICD-10 diagnosis codes prior to March 1st, 2020. Drug exposure was classified as biologic or traditional immunosuppressive (methotrexate, cyclosporine, apremilast) treatment based on prescription order in the 3 months preceding March 1st, 2020. Biologic treatments included TNFalpha, IL-12/IL-23, IL-17A, IL-23 and JAK inhibitors. The primary outcome was defined as hospital admission with diagnosis of COVID-19 or positive lab test occurring between admission and discharge date. Propensity score weighting was used to compare COVID-19-related hospitalization between treatment groups, adjusting for comorbidities and demographic characteristics. Result(s): A total of 51,606 psoriasis patients aged 18-88 were included. Crude cumulative incidence of COVID-19 hospitalization per 1,000 psoriasis patients was 3.4 in the biologic group (9/2,669), 9.5 in the traditional immunosuppressive group (15/1,585), and 3.9 in those receiving neither drug class (184/47,352). Incidence was 4.7 (6/1,282) and 14 (13/898) per 1,000 patients among those receiving TNF-alpha inhibitors and methotrexate, respectively. After propensity-score weighting, risk of COVID-19-related hospitalization for patients receiving any biologic was lower than that of patients receiving traditional immunosuppressives (RR 0.39, 95% CI 0.16, 0.92), and those receiving neither drug class (RR 0.66, 95% CI 0.32, 1.34). TNF-alpha inhibitor use was associated with lower risk of hospitalization relative to methotrexate use (adjusted RR 0.39, 95% CI 0.14, 1.06). Adjusted relative risk of hospitalization for methotrexate users relative to those receiving neither drug class was 2.78 (95% CI 1.47, 5.26). Conclusion(s): During the first wave of the pandemic in 2020, psoriasis patients using biologics were at lower risk of COVID-19-related hospitalization compared to those using traditional immunosuppressives, particularly methotrexate. Methotrexate use was associated with a substantial increase in risk of hospitalization relative to those who did not receive systemic treatments.

The Risk of COVID-19 in People Having a Particular Set of Gene

These risk factors of advancing age, male gender and co-existing health conditions like cancer, cardiovascular diseases, diabetes and obesity do not fully explain why some people have no or mild symptoms whereas others have severe symptoms. Genomewide association study (GWAS) identify a 3p21.31 gene cluster as a genetic susceptibility locus in patients with COVID-19 with respiratory failure. They also found a higher risk among persons with blood group A and protective effect for blood group O than among patients with other blood groups. The particular haplotype in a region of chromosome 3 is contributed to modern humans by neandertals. Another Neanderthal haplotype on chromosome 12 is associated with a 22% reduction in relative risk of becoming severely ill with COVID-19. The ApoE e4e4 homozygous genotype was found to increase the risk of severe COVID-19. Change in angiotensin converting enzyme (ACE) 2 gene was also found to be associated with increased risk of COVID-19, cardiovascular and pulmonary conditions. Copyright © 2021, Kathmandu University. All rights reserved.

Predictive Value of Specific Cytokines for Lethal Covid-19 Outcome

In our study, we aimed to evaluate the significance of specific cytokines in blood plasma as predictive markers of COVID-associated mortality. Materials and methods. In plasma samples of 29 patients with PCR-confirmed COVID-19 we measured the concentrations of 47 molecules. These molecules included: interleukins and selected pro-inflammatory cytokines (IL-1alpha, IL-1beta, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-9, IL-12 (p40), IL-12 (p70), IL-13, IL-15, IL-17A/CTLA8, IL-17-E/IL-25, IL-17F, IL-18, IL-22, IL-27, IFNalpha2, IFNgamma, TNFalpha, TNFbeta/Lymphotoxin-alpha(LTA));chemokines (CCL2/MCP-1, CCL3/MIP-1alpha, CCL4/MIP-1beta, CCL7/MCP-3, CCL11/Eotaxin, CCL22/MDC, CXCL1/GROalpha, CXCL8/IL-8, CXCL9/MIG, CXCL10/IP-10, CX3CL1/Fractalkine);anti-inflammatory cytokines (IL-1Ra, IL-10);growth factors (EGF, FGF-2/FGF-basic, Flt-3 Ligand, G-CSF, M-CSF, GM-CSF, PDGF-AA, PDGFAB/BB, TGFalpha, VEGF-A);and sCD40L. We used multiplex analysis based on xMAP technology (Luminex, USA) using Luminex MagPix. As controls, we used plasma samples of 20 healthy individuals. Based on the results, we applied Receiver Operating Characteristic (ROC) analysis and Area Under Curve (AUC) values to compare two different predictive tests and to choose the optimal division point for disease outcome (survivors/non-survivors). To find optimal biomarker combinations, we as used cytokines concentrations as dependent variables to grow a regression tree using JMP 16 Software.Results. Out of 47 studied cytokines/chemokines/growth factors, we picked four pro-inflammatory cytokines as having high significance in evaluation of COVID-19 outcome: IL-6, IL-8, IL-15, and IL-18. Based on the results received, we assume that the highest significance in terms of predicting the outcome of acute COVID-19 belongs to IL-6 and IL-18. Conclusion. Analyzing concentrations of IL-6 and IL-18 before administering treatment may prove valuable in terms of outcome prognosis. Copyright © Arsentieva N.A. et al., 2022.

Adult and Paediatric Case-based Conference 2021

The proceedings contain 68 papers. The topics discussed include: post-transplant lymphoproliferative disorder (PTLD) in a patient with rheumatoid arthritis;cancer, covid and control of RA - a toxic combination?;continuation of golimumab (anti-TNF) in a patient with SpA and low-risk prostate cancer, what is the right decision?;orbital lymphoma in a 72-year-old lady with rheumatoid arthritis: an argument for rituximab;a case of cancer mimicking inflammatory arthritis;managing relapsing and refractory lupus nephritis in juvenile systemic lupus erythematosus: a case report;a case of juvenile systemic lupus erythematosus with pyrexia of unknown origin;recurring brachial plexopathy- the zebra among the horses;and Neisseria meningitidis as a cause of isolated bilateral polyarticular native knee joint septic arthritis.

Response to COVID-19 vaccine is reduced in patients with inflammatory bowel disease, but improved with additional dose.

BACKGROUND: Coronavirus disease 2019 (COVID-19) vaccination is recommended for patients with inflammatory bowel disease (IBD); however, suppressed immune responses have been reported for fully vaccinated patients under immunosuppressive therapy, mainly from Western countries. We prospectively analyzed antibody titers of IBD patients in Asia induced by two-dose and additional dose of messengerRNA COVID-19 vaccine. METHODS: After measuring high-affinity antibody titers, factors associated with antibody titers were identified by multiple regression analyses using the following covariates: sex, age (≥60 or <60 years), disease type (Crohn's disease or ulcerative colitis), vaccine type (BNT162b2 or mRNA-1273), time from second/third vaccination, molecular-targeted agent (anti-tumor necrosis factor [TNF] agents, ustekinumab, vedolizumab, tofacitinib, or no molecular-targeted agents), thiopurine, steroid, and 5-aminosalicylic acid. RESULTS: Among 409 patients analyzed, mean titer was 1316.7 U/mL (SD, 1799.3); 403 (98.5%) were judged to be seropositive (≥0.8 U/mL), and 389 (95.1%) had neutralizing antibodies (≥15 U/mL). After the third vaccination, mean titer raised up to 21 123.8 U/mL (SD, 23 474.5); all 179 were seropositive, and 178 (99.4%) had neutralizing antibodies. In 248 patients with genetic data, there was no difference in mean titer after two/third doses between carriers and non-carriers of HLA-A24 associated with severe disease during COVID-19 infection. A multiple regression analyses using covariates revealed that older age, vaccine type (BNT162b2), time from second/third dose, anti-TNF agent, tofacitinib, and thiopurine were independently associated with lower antibody titers. CONCLUSIONS: Our findings further support the recommendation for COVID-19 vaccination in patients under immunosuppressive therapy, especially additional third dose for patients receiving anti-TNF agents and/or thiopurine or tofacitinib.