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BackgroundData on serological immunity after three doses and the long-term immunogenicity (persistence) of COVID-19 vaccine in patients with inflammatory rheumatic diseases (IRD) treated with different immunomodulating drugs are still limited.ObjectivesTo elucidate if 1) a third dose COVID-19 vaccine improves antibody responses, compared to two doses, in patients with IRD treated with biologic or targeted synthetic DMARD (b/tsDMARDs) treatment given as monotherapy or in combination with conventional synthetic DMARDs (csDMARDs) compared to controls, and 2) the persistence of antibody response after two doses of COVID-19 vaccine in IRD patients.MethodsAntibody levels to two antigens representing Spike full length protein and Spike S1 and a Nucleocapsid C-terminal fragment (used to confirm previous COVID-19 infection) were measured in serum samples collected 2-12 and 21-40 weeks after the second vaccine dose and 2-12 weeks after the third dose using a multiplex bead-based serology assay. A sufficient antibody response (seropositivity) was defined as having antibodies over the cut-off level for both spike antigens (1). WT (wild type) anti-Spike IgG and omicron BA.1 and BA.2 variants were measured. Patients with IRD receiving immunomodulating treatment, regularly followed at a rheumatology department and a group of controls were recruited from five Swedish region.ResultsIn total, 323 of 414 patients with IRD and 36 controls who received three vaccine doses participated in this part of the study. Following treatment groups were included: rituximab (n=118;68% female;mean age 67 years), abatacept (n=18;72% female;mean age 64 years), IL6r inhibitors (n=60;73% female;mean age 64 years), JAK-inhibitors (n=44;80% female, mean age 52 years), TNF-inhibitors (n=59;70% female;mean age 47 years;), IL12/23/17 inhibitors (n=24;46% female;mean age 54 years) and controls (n=36;75% female, mean age 51 years). b/ts DMARD treatment was given as monotherapy or in combination with csDMARD, methotrexate (MTX) being the most frequently used csDMARD (32.5%). Compared to results after two vaccine doses, proportion (%) of seropositivity after three vaccine doses increased significantly in groups rituximab +/- DMARD (p=0.003 and p=0.004, respectively), IL6r inhibitors +DMARD (p=0.02), and abatacept+DMARD (p=0.01). However, the proportion of seropositivity after three vaccine doses was still significantly lower in rituximab treated patients (52%) compared to other treatment groups or controls (p<0.001) (Figure 1A/B). Antibody response to WT, omicron sBA.1 and sBA.2 showed similar pattern with the lowest levels among patients treated with rituximab.When antibody response was compared between 2-12 weeks and 21-40 weeks after second dose, the proportion of seropositive rituximab treated patients decreased from 34.9 % to 32.6%. All patients with JAK inhibitors and with JAK-inhibitors and IL6r-inhibitors seropositive 21-40 weeks after the second vaccine dose. Patients treated with other bDMARDs were not included in this analysis due to limited number participants.ConclusionIn this Swedish study including IRD patients receiving different b/t DMARDs, a sufficient immunogenicity of the third dose of COVID-19 vaccine was observed in all treatments with exception for rituximab. However, the increased proportion of seropositivity after the third COVID-19 vaccine doses in rituximab and other patients with insufficient response to two doses including response to the omicron variants, supports the current recommendations on additional booster doses. The immunogenicity of two vaccine doses was preserved to 40 weeks in majority of patients treated with different immunomodulating treatment with exception for rituximab.Figure 1.AcknowledgementsThe study has been supported by the independent research grants from Roche.Disclosure of InterestsMartina Frodlund: None declared, Per Nived: None declared, Katerina Chatzidionysiou Consultant of: consultancy fees from Eli Lilly, AbbVie and Pfizer., Grant/research support from: Research grand from Galapagos, Anna ödergren: None declared, Eva Klingberg: None declared, Monika Hansson: None declared, Elisa Pin: None declared, Lars Klareskog: None declared, Meliha C Kapetanovic Grant/research support from: independent research grants från Pfizer and Roche.
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Background: Lymphoproliferation is the persistent proliferation of lymphoid cells and it's incidence in inborn errors of immunity varies from 0.7 to 18%. Material(s) and Method(s): This is a retrospective analysis of patients referred to the department of Immunology, B. J. Wadia Hospital for Children, Mumbai between March 2017 to December 2022. Inclusion criteria consisted of 3 months duration of significant lymphadenopathy and/or splenomegaly or history of lymphoma. The clinical characteristics, laboratory and molecular findings of the included patients were analyzed. Result(s): A total of 66 patients were included. There was a male preponderance with male:female ratio of 25:8. Median age of onset of lymphoproliferation was 4.75 years(Range 1 year to 60 years). Splenomegaly was seen in 75%. Infections included recurrent pneumonia (14/66), recurrent ear infections(5/66), COVID(4/66), one episode of pneumonia(6/66), herpes zoster(3/66), recurrent subcutaneous abscess (3/66), abdominal koch(3/66), chronic sinusitis(2/66), dermatophytosis(2/66), esophageal candidiasis(2/66), recurrent malaria(1/66), recurrent varicella(1/66), cryptococcal meningitis(1/66), gram negative sepsis(1/66), BCG adenitis(1/66), pseudomonas osteomyelitis(1/66), impetigo (1/66), pseudomonas urinary tract infection (1/66), chicken pox(1/66), herpes keratitis(1/66), dengue(1/66), Other manifestations included Evans plus phenotype(10/66), Evans phenotype(8/66), Autoimmune hemolytic anemia(5/66), bronchiectasis(5/66), Type 1 diabetes(3/66), hyper reactive airway disease(2/66), inflammatory bowel disease(4/66), autoimmune thrombocytopenia(2/66), stroke(3/66), hemophagocytic lymphohistiocytosis(2/66), hypertriglyceridemia(2/66), hypothyroidism(2/66), celiac disease(1/66), Type 2 diabetes(1/66), autoimmune encephalitis(1/66), autoimmune hepatitis(2/66), anti-parietal cell antibody(1/66), arthritis(1/66), autoimmune enteropathy(1/66), systemic lupus erythromatosus(1/66), primary biliary cirrhosis requiring liver transplant(1/66), nephrotic syndrome(1/66), lymphoedema(1/66), hypersplenism(1/66), recurrent oral ulcers(1/66), gout(1/66), dermatitis(1/66), ovarian teratoma(1/66), alopecia areata(1/66). Hodgkin's lymphoma(HL) was the most common malignancy(9/66), followed by non Hodgkin lymphoma(NHL)(6/66), transformation from NHL to HL(1/66), Burkitt to T-cell lymphoma(1/66), HL to DLBCL(1/66), HL to anaplastic T-cell lymphoma(1/66). EBV driven lymphoproliferation was seen in biopsy of21/66. Genetic testing showed mutations in LRBA(11/66), PIK3CD(5/66), CTLA4(3/66), TET2(2/66), IL2RA (1/66), IL12RB1(1/66), BACH2(1/66), PRKCD(1/66), TNFSFR13B(1/66), TNFAIP3(1/66), FAS(2/66), FASL(1/66), Caspase8(1/66), CARD11(1/66), RTEL1(1/66), AICD(1/66), PIK3R1(1/66), IKBKB(1/66). Treatment included IVIG, chemotherapy, rituximab, sirolimus, abatacept, HSCT. Conclusion(s): All children with persistent lymphoproliferation, with or without autoimmunity and/or infections should be worked up for an underlying monogenic disorder of immune dysregulation. Lymphomas presenting at abnormal site and/or age, relapse and EBV driven lymphomas require further evaluation. Presence of monogenic cause helps in providing targeted therapy.Copyright © 2023 Elsevier Inc.
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Background/Objectives: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing coronavirus disease (COVID-19) enters the lung tissue through exocytosis, leading to the release of a large amount of pro-inflammatory cytokines called 'cytokine storm'. The aim was to provide more insight into relationship between plasma cytokines profile and fatal outcome of COVID-19. Method(s): Plasma cytokines (IL-17F,GM-CSF,IFNg,IL-10,CCL20/ MIP3a,IL-12P70,IL-13, IL-15,IL-17A,IL-22,IL-9,IL-1b,IL-33,IL-2,IL-21,IL-4,IL-23,IL-5,IL-6,IL-17E/IL-25,IL-27,IL-31,TNFa,TNFb,IL-28A) were detected in 30 patients with severe COVID-19 by a Luminex assay system with Milliplex Human Th17 Magnetic Premix 25 Plex Kit (HT17MG-14K-PX-25, Merk-Millipore, USA) according to the instructions. Patients were followed up for 30 days since admission to intensive care. 18 patients died and 12 patients survived during the period of observation. The control group comprised 10 individuals who had never been diagnosed with COVID-19. Result(s): IL-10 and CCL20/MIP3a plasma levels were elevated in non-survivors patients with COVID-19 compared to controls (p = 0.0027, p = 0.012, respectively). IL-15, IL-6, IL-27 plasma levels were higher in survivors with COVID-19 compared to controls (p = 0.049, p = 0.026, p = 0.00032, respectively). Interestingly, IL-15, IL-27 plasma levels were increased in non-survivors with COVID-19 compared to controls and survivors with severe COVID-19 (IL-15: p = 0.00098, p = 0.00014, respectively;IL-27: p = 0.011, p < 0.0001, respectively). Receiver operating characteristic (ROC) analysis has been conducted for IL-15 and IL-27. Cut-off value was estimated as 25.50 pg/ml for IL-15 and 1.51 pg/ml for IL-27. Conclusion(s): Our study demonstrated a more pronounced immune response in non-surviving patients with severe COVID-19. IL-15, IL-27 could be considered as a sensitive biomarker of the fatal outcome from COVID-19.
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It is known that inflammatory cytokines exacerbate the persistence and severity of various disease states. Breast cancer is the most frequently detected cancer among women worldwide and our recent studies suggest that the inflammatory state of breast (BrCa) cancer, a byproduct of elevated cytokine expression, induces epigenetic modifications leading to increased recurrence. Ongoing NCI clinical trial data (ClinicalTrials.gov, CCC19, NCT04354701) indicates that among patients with cancer and COVID-19, the mortality is high, and the most prevalent malignancies are of breast [21%] and prostate [16%] origin. Due to the risk of cytokine storm during SARS-CoV-2 infection, it is crucial to identify potential mechanisms of hyperinflammation in BrCa patients. In this study, we have evaluated the level of copy number alteration (CNA) of different inflammatory cytokines including IL-8, IL-1b, IL6, IL-8, GM-CSF, TNF-alpha and many others using cBioportal platform which includes over sixty-nine thousand tumor samples (n>69,000 from 213 different studies) from over 33 different cancers. We found that IL-8 has the highest level of amplification in different breast cancers subtypes. Besides, we also analyzed serum samples from BrCa patients, both recurrent and non-recurrent, by different proteomics methods to identify serum cytokines involved in prognosis and recurrence. Comparative data analysis between non-recurrent BrCa against recurrent BrCa patients identified several proteins with very high significance, mostly proteins associated with epigenetic pathways including HDAC9 (P = 0.0035), HDAC5 (P = 0.013), and HDAC7 (P = 0.020). Besides, we identified differential expression of several pro-inflammatory cytokines and immune regulators (IL-8, IL-4, IL-18, IL-12p70) that were present only in recurrent BrCa patient serum. Our data indicate that inflammatory processes contribute to epigenetic modifications that ultimately play a critical role in breast cancer recurrence. In terms of COVID-19 associated co-morbidity, the already dysregulated inflammatory state of BrCa patients may increase their susceptibility to cytokine-storm, leading to increased severity of COVID-related complications and increased mortality rate. Specifically, we hypothesize that the identified elevated level of IL-8 in BrCa patients may lead to a higher basal level of inflammation and contribute to the risk of attaining cytokine-storm during SARS-CoV-2 infection, making it a valuable target for future studies.
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The coronavirus illness (COVID-19) is caused by serious acute respiratory disorder coronavirus 2 (SARS-CoV-2), moreover known as the COVID-19 virus. After the first-ever reports of COVID-19 in December 2019, the malady spread quickly. In January 2020, the WHO announced the outbreak a Public Health Emergency of Worldwide Concern, and by March 2020, the WHO characterized the episode as a global widespread . The current study aimed to detect the effect of SARS-CoV-2 infection in heart patients and study their immune response by detecting the levels of some cytokines, which may end in a cytokine storm and may lead to death. In this study, one hundred-eight subjects were enrolled on two comparison case-control groups, the case group included 54 patients suffering from SARS-COV2, all were selected from those who were admitted to the Intensive Care Unit (ICU), and were diagnosed by a specialist physician with severe acute respiratory syndrome due to SARS-COV2 documented by Real-Time Polymerase Chain Reaction( RT-PCR ) besides other clinical and laboratory criteria in Marjan Medical City in Babylon province, AL-Amal Hospital for Communicable Diseases and AL-Hakeem Hospital, Najaf/Iraq, for a period from March 2022 to October 2022 to evaluate the role of some selected serological among patients with SARA-COV2 . The control group in this study included 54 subjects, divided into three groups (Apparent Healthy, patients suffered from SARS-COV2, patients suffered from CVD). Blood samples were examined through immunological methods, and an enzyme-linked immunosorbent assay (ELISA) was adopted for the detection of the concentration of TNF-alpha, IL6, IL-10,1L-12 and CCL2 .The immunological evaluation to clarify the theory of cytokines storm carried in the present study revealed that (TNF-alpha, IL6, IL-10,1L-12, and CCL2) for patients with COVID-19 and CVD was significantly higher than all the comparison group. The study reported that interleukin (6, 10, 12) and TNF-a are significantly increased in patients with covid19, CVD, and COVID-19 patients only, compared to healthy people. furthermore, IL-6 and IL-12 levels increased in patients with CVD only when compared to healthy people. There is a significant increase in CCL2 in all study groups compared to healthy people who have lower levels and this study indicated that the infection with Covid disease was severe and critical in most patients with CVD. This increased the number of deaths among them.Copyright © 2021 Muslim OT et al.
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Introduction: Encephalopathy and delirium are common following coronavirus infection [1], and the associated neuroinflammation often results in long-term behavioral and cognitive impairment. Neurovirulent cytokines (NVC) are strongly implicated in the pathogenesis of coronavirus encephalopathy [2]. We hypothesized that characterizing the abnormal signaling in NVC exposed neurons will enable us to identify targets to treat encephalopathy and prevent its downstream effects. Method(s): We incubated primary mouse neocortical cultures in NVC known to be increased in coronavirus encephalopathy (TNF-alpha, IL-1beta, IL-6, IL-12 and IL-15). Using whole-cell patch clamp methods, we tested how neuronal function was impacted by 22-28-h exposure to NVC. Result(s): We found that NVC depolarized the resting membrane potential (RMP), reduced the firing threshold of neocortical neurons, and increased baseline spontaneous action potential (AP) firing. NVC altered the sensitivity (or input-output properties) of single neurons to changes in their microenvironment. Specifically, decreasing external Ca2+ and Mg2+ from physiological to low (1.1-0.2 mM) levels increased evoked AP firing in control, but not following exposure to NVC. AP firing threshold and spontaneous firing rates returned to control levels 1 h after NVC wash-out. However, the RMP and attenuated sensitivity of evoked APs to changes in the microenvironment remained persistently abnormal suggesting two distinct mechanisms were at play. Interestingly, hyperpolarizing the RMP reversed this altered response. Conclusion(s): Sustained exposure to NVC reversibly depolarizes neocortical neuronal RMP, altering excitability and the ability of neurons to respond to microenvironment changes. By characterizing the pathogenesis of the underlying changes in neuronal function in our model of coronavirus encephalopathy we will identify intervenable drug targets.
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Background: It is unknown whether individuals with neurological post-acute sequelae of COVID-19 (NeuroPASC) display altered levels of neuroimmune activity or neuronal injury. Method(s): Participants with new or worsened neurologic symptoms at least 3 months after laboratory-confirmed COVID-19 were enrolled in The COVID Mind Study at Yale. Never COVID controls (no history of COVID-19;nucleocapsid (N) antibody negative) were pre-pandemic or prospectively enrolled volunteers. CSF and plasma were assessed for neopterin and for IL-1beta, IL-1RA, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p40, IL-12p70, IL-13, MCP-1, TNFalpha by bead-based multiplex assay;and for anti-SARS-CoV-2 N antibodies by Luminex-based multiplex assay in technical replicate, normalized against bovine serum albumin conjugated beads. Plasma concentrations of D-dimer, C-reactive protein, neurofilament light chain (NFL), and glial fibrillary acid protein (GFAP) were measured using high-sensitivity immunoassays. Group comparisons used non-parametric tests. Result(s): NeuroPASC participants (n=38) were studied 329 (median) days (range 81-742) after first positive test for acute COVID-19. Cognitive impairment (84%) and fatigue (82%) were the most frequent post-COVID symptoms. NeuroPASC and controls (n=22) were median 49 vs 52 yrs old (p=0.9), 74% vs 32% female (p< 0.001), 76% vs 23% white race (p< 0.001), and 6% vs 57% smokers (p< 0.001). CSF white blood cells/mL, CSF protein, and serum:CSF albumin ratio were normal in both groups. CSF TNFalpha (0.66 vs 0.55 pg/ul) and plasma IL12p40 were higher (103.3 vs 42.7);and MCP-1 (503 vs 697 pg/ul) and IL-6 (1.32 vs 1.84 pg/ul;p < 0.05 for IL-6) were lower in NeuroPASC vs controls (p< 0.05);but none of these differences were significant after adjusting for multiple comparisons. Plasma GFAP was elevated in NeuroPASC vs controls (54.4 vs 42.3 pg/ml;adjusted p< 0.03). There were no differences in the other biomarkers tested. 10/31 and 7/31 NeuroPASC had anti-N antibodies in CSF and plasma, respectively. Conclusion(s): When comparing NeuroPASC to never COVID controls, we found no evidence of neuroinflammation (normal CSF cell count, inflammatory cytokines) or blood-brain barrier dysfunction (normal albumin ratio), and no support for ongoing neuronal damage (normal plasma NFL). Future studies should include better gender and race matched controls and should explore the significance of a persistent CNS humoral immune response to SARS-CoV-2 and elevated plasma GFAP after COVID-19. (Figure Presented).
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Background: COVID-19 vaccines that expand immunity against emerging variants of concern (VOC) are needed to protect against ongoing viral evolution. We investigated the impact of boosting nonhuman primates pre-immune to the original WA-1 strain with updated VOC vaccines on the breadth and magnitude of mucosal and systemic antibody (Ab) and T cell (Tc) responses. Method(s): Cynomolgus macaques were primed with 2 doses of WA-1 Spike protein encoded by either an IL-12 adjuvanted DNA vaccine administered by gene gun (GG) or a self-amplifying RNA vaccine (repRNA) delivered intramuscularly (IM) with a cationic nanocarrier (LIONTM/IM, HDT Bio) or by GG (FIG 1). A booster dose was administered at week 17 with DNA or repRNA vaccines expressing B.1.351 (Beta) and B.1.617 (Delta) Spike receptor-binding domains (RBDs) fused to influenza HA2 stem domain (SHARP, designed by AIR/ JP) followed by a final Beta + Delta + WA-1 SHARP boost at week 34. Blood and bronchoalveolar lavages (BAL) were collected before and after each dose. Binding and neutralizing Ab to VOCs, including Omicron strains, were measured by ELISA and pseudovirus neutralization assays. Tc responses to Spike protein (WA-1 peptides) were measured by ELISpot. Immune responses were compared between groups and between blood vs lung using non-parametric statistical tests. Result(s): Two doses of WA-1 DNA or repRNA vaccines induced broad Ab against all VOC with the repRNA vaccine inducing the highest titers. Boosting with VOC SHARP significantly increased mucosal and systemic Ab responses against all VOCs tested including Omicron. After final boost, all groups had comparable binding and neutralization Ab titers and Tc responses regardless of method of delivery (GG or LIONTM/IM) or formulation (DNA or repRNA). Tc responses were significantly higher in the BAL vs PBMC after WA-1 Spike doses (p=0.0420) and VOC SHARP boosters (p=0.0009). Conclusion(s): The WA-1 strain primed for broad responses against VOCs that were significantly boosted with updated SHARP vaccines including responses against Omicron, even though this strain was not included in any dose. This suggests that sequential immunization with updated vaccines may broaden mucosal and systemic immunity against future VOCs. The repRNA vaccine initially induced the strongest responses, but there were no differences between RNA and DNA following additional booster doses, a result that supports development of a more cost-effective, room temperature stable DNA vaccine for worldwide boosters. (Figure Presented).
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Objective: The Aim of our research was to look into the association between various biochemical indicators and COVID-19 infection in Baghdad, Iraq. Methods: From the 15th of March to the August 2022, a cohort of 45 people with positively COVID-19 and 45 healthy controls visited Al-Yarmouk Teaching Hospital in Baghdad, Iraq. All of the patients have been diagnosed with COVID-19 and are experiencing symptoms and indicators. Each of the patients and healthy controls had their whole blood samples taken to be analyzed for;Lipid profile (triglycerides, Total cholesterol, low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein (HDL) values) Kidney function test (Urea and Creatinine), by using an enzymatic method , Anti-inflammation parameters (INF-, TGF, Interleukin-12, and Interleukin 18), The (Biosours) ELISA kit was used to assess the results., and D-dimer was quantified using mini vidas kits donated by Bio Meriux-France. Results: The results showed that The majority of COVID-19 patients showed elevated lipid profiles and kidney function tests, as well as the anti-inflammatory parameters with increase the levels of D-dimer compared to healthy controls. Conclusion: The present study concludes that Covid-19 cause alteration in lipid profile, kidney functions, D-dimer and some anti-inflammatory parameters.
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Emerging research shows that innate immunity can also keep the memory of prior experiences, challenging the long-held notion that immunological memory is only the domain of the adaptive immune cells. However, the absence of immunological memory in innate immune responses has recently been brought into question. Now it is known that after a few transient activations, innate immune cells may acquire immunological memory phenotype, resulting in a stronger response to a subsequent secondary challenge. When exposed to particular microbial and/or inflammatory stimuli, trained innate immunity is characterized by the enhanced non-specific response, which is regulated by substantial metabolic alterations and epigenetic reprogramming. Trained immunity is acquired by two main reprogramming, namely, epigenetic reprogramming and metabolic adaptation/reprogramming. Epigenetic reprogramming causes changes in gene expression and cell physiology, resulting in internal cell signaling and/or accelerated and amplified cytokine release. Metabolic changes due to trained immunity induce accelerated glycolysis and glutaminolysis. As a result, trained immunity can have unfavorable outcomes, such as hyper inflammation and the development of cardiovascular diseases, autoinflammatory diseases, and neuroinflammation. In this review, the current scenario in the area of trained innate immunity, its mechanisms, and its involvement in immunological disorders are briefly outlined.Copyright © 2022
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Background: Infections with SARS-CoV- 2 cause the coronavirus disease 2019 (COVID-19) pandemic. Alterations in immune cells of COVID-19 patients may predict the subsequent severity of disease. The changes in composition of immune cells in COVID-19 patients include lymphopenia, lower neutrophil to lymphocyte-ratios and an eosinopenia in about 50 to 80% of hospitalized patients. Eosinophils and neutrophils can interact with T cells via immune checkpoints receptors such as programmed death (PD)-1 on T cells and its counterpart PD-ligand 1 (PD-L1) on eosinophils or neutrophils. There are only limited studies on PD-1 and PD-L1 expressions in viral infections, we aimed to elucidate the interplay of T cells and other peripheral cells by analysing the immune checkpoints PD-1 and PD-L1 in expression during COVID-19. Method(s): Using flow cytometry, we have now analysed the immune checkpoint receptor expressions on whole blood cells from a total of 38 COVID-19 patients. The patient cohort comprises all ages and both sexes with the disease severity ranging from mild, moderate to severe, with ~10% mortality. We have further been investigating 21 biomarkers (G-CSF, GM-CSF, IFN-gamma, TGF-beta1, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12p70, IL-13, IL-17A, IL-18, IL-23, IL-33, IP-10, MCP-1, MIP-1beta, TNF-alpha, and YKL-40) in plasma on a cohort of 76 COVID-19 patients using the MesoScale Multiplex Assay platform, with 48 healthy controls. Result(s): PD-L1 expression on eosinophils was significantly lower in COVID-19 patients in initial stages of infection, relative to healthy controls. There was an inverse relationship between disease progression and the expression of PD-1 on CD8+ T cells. These data suggests that analysis of PD-L1- PD1 cell networks in immune cells of EDTA blood of COVID-19 patients can predict disease outcomes. While most detectable biomarkers are strongly increased in COVID samples overall compared to healthy controls, the more severe the disease the higher the blood biomarker concentration. Conclusion(s): Taken together, the analysis of PD-L1- PD1 cell networks in immune cells together with plasma biomarkers of COVID-19 patients can predict disease outcomes.
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BACKGROUND: Severe acute respiratory syndrome-related Coronavirus 2 (SARS-CoV-2) infection induces a pro-inflammatory state of an organism with long-term systemic consequences as a result. Systemic inflammation, characterized by a high circulating level of inflammatory cytokines, is a significant factor influencing articular cartilage metabolism in osteoarthritis (OA). This study aimed to determine the levels of pro-inflammatory and anti-inflammatory cytokines in plasma of patients with OA following SARS-CoV-2 infection and to compare them with those of healthy controls. METHOD(S): The experiment involved patients of the Orthopedic Specialty Clinic aged 46 to 69 diagnosed with knee OA. Among persons with joint pathology a group of convalescent patients from 6-9 months after COVID-19 was identified. The control group involved relatively healthy donors. The plasma levels of pro-inflammatory (IL-1beta, IL-6, IL-8, IL-12beta, tumor necrosis factor alpha [TNF-alpha], interferon-gamma [IFN-gamma]) and anti-inflammatory (IL-4 and IL-10) cytokines were determined by enzyme-linked immunosorbent assay. RESULT(S): It was established that in patients with OA, as well as after suffering from SARS-CoV-2 infection, an increase in the plasma levels of IL-1beta was observed against the background of a decrease in the levels of IL-4, IL-8, IL-10, IL- 12beta, TNF-alpha and IFN-gamma, compared to the healthy controls. COVID-19 more significantly influenced the plasma levels of pro-inflammatory cytokines IL-1beta and IL-12beta. CONCLUSION(S): The results indicate the imbalance of pro- and anti-inflammatory cytokines in the plasma in patients with OA for a long post-COVID. Shanges in the levels of inflammatory mediators suggest distinct immunoregulatory mechanisms involved in the pathogenesis of both joint pathology and systemic disorders caused by SARS-COV-2.Copyright © 2022 EDIZIONI MINERVA MEDICA.
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Introduction: In hospitalized COVID-19 patients, disease progression leading to acute kidney injury (AKI) may be driven by immune dysregulation. We explored the role of urinary cytokines and their relationship with the kidney stress biomarkers neutrophil gelatinase-associated lipocalin (NGAL), tissue inhibitor of metalloproteinases-2 (TIMP-2) and insulin-like growth factor binding protein (IGFBP7) in COVID-19 patients without AKI at study entry. Method(s): Prospective, longitudinal cohort study included critically ill COVID-19 patients without AKI at the time they were enrolled to the study. Urine samples were collected on admission to critical care areas for determination of NGAL, [TIMP-2]*[IGFBP7] and cytokines concentrations with a second sample 5 days after the first urine sample. Demographic information, clinical and laboratory data were collected. Diagnosis and staging of AKI were based on KDIGO criteria using serum creatinine (sCr) levels and urine output. The urinary concentrations of TIMP-2 and IGFBP7 were determined ELISA in the same way NGAL. The concentrations of cytokines and chemokines in urine were measured with a Luminex 200 instrument. We performed descriptive statistics including means and standard deviations for normally distributed continuous variables;medians and interquartile ranges (IQR) for non-parametric distributions;and proportions for categorical variables. Logistic regression analysis was used to identify the association between relevant covariates with AKI. Principal component analysis (PCA) was performed to compress and simplify the size of the data set by keeping the most important information and analyzing the structure of the observations and the variables. Correlation of identified cytokines with kidney stress biomarkers was explored using the Spearman test. All statistical tests were two-sided, p values <0.05 were considered statistically significant. The analysis was conducted using R Studio 1.4.1717. Result(s): Of included 51 patients. Of those, 30 were males (58.8%);the median age was 53 years (IQR: 40-61);14 had systemic arterial hypertension (27.5%);16 had diabetes (31.4%);and 21 were obese (41.2%). 54.9% developed AKI. After adjusting for possible confounding variables, only EGF >4600 pg/ml remained associated with lower risk of AKI (OR=0.095, 95% CI: 0.01-0.81, p=0.031.In the PCA of day 1, Epidermal Growth Factor (EGF) and interferon (IFN)-alpha were associated with a lower risk of AKI (OR=0.24, 95% CI: 0.07-0.78, p=0.017), while Interleukin (IL)-12 and macrophage inflammatory protein (MIP)-1b were associated with a higher risk of AKI (OR=51.09, 95% CI: 2.12-1233, p=0.015). In the PCA of day 5, EGF and IFN-alpha remained associated with a lower risk of AKI (OR=0.09, 95% CI: 0.01-0.74;p=0.024), while IL-1 Receptor, granulocyte-colony stimulating factor (G-CSF), interferon-gamma-inducible protein 10 (IP-10) and IL-5 were associated with a higher risk of AKI (OR=7.7, 95% CI: 1.06-55.74, p=0.043). EGF had an inverse correlation with [TIMP2] x IGFBP7] (R-0.73, p=<0.001) and with NGAL (R= -0.63, p=0.002). Conclusion(s): Subclinical AKI was characterized by a significant up-regulation of NGAL, TIMP-2, IGFBP7 and proinflammatory cytokines. The lack of EGF regenerative effects and IFN-alpha antiviral activity seemed crucial for renal disease progression. AKI involved a proinflammatory urinary cytokine storm. No conflict of interestCopyright © 2023
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Background and Aims Viral infections occur acutely but can also progress chronically, with the immune system having a central role in immunopathoge-nesis. The question arises whether all alterations in immune responses are reversible after viral elimination (spontaneously or by therapy). Therefore, the aim of this study is to compare soluble infammatory markers (SIM) during and after infection with SARS-CoV-2 and acute and chronic HCV-infections. Patients and Method Patients with acute HCV (n = 29), chronic HCV (n = 54), SARS-CoV-2 (n = 39) and 31 healthy-controls were included. Blood samples were tested at baseline, end of treatment/infection, and follow-up ( >= 9 months after baseline). IL-12p70, IL-1b, IL-4, IL-5, IL-6, IL-8, TNF, IFN-g, IL-10, IL-22, CXCL-10, MCP-1, MIP-1b, ITAC were quantified using the HD-SP-X Imaging and Analysis SystemTM. Results SIM profiles in patients with acute HCV were substantially elevated at baseline and the decrease during follow-up was considerably less compared to the SARS-CoV-2 cohort. In chronic HCV-patients, viral elimination by therapy resulted in a decrease in SIM, although not always to those of controls. Cirrhotic HCV patients had higher SIM levels after HCV elimination than non-cirrhotic chronic HCV-patients. In the SARS-CoV-2 cohort, most SIM returned to levels of controls 3 months after baseline. Conclusions SIM profiles and kinetics after viral elimination difer between blood-borne acute and chronic HCV- and respiratory SARS-CoV-2-infections. The immunologic imprint 9 months after cured HCV-infection (both acute and chronic) appears to be more pronounced than after SARS-CoV-2-infection. Further analysis is needed to correlate the SIM profle with the clinical pheno-type (long-HepC vs. long-COVID-19).
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Ulcerative colitis is a relapsing and remitting inflammatory bowel disease of the large intestine. Risk factors include recent Salmonella or Campylobacter infection and a family history of ulcerative colitis. Diagnosis is suspected based on symptoms of urgency, tenesmus, and hematochezia and is confirmed with endoscopic findings of continuous inflammation from the rectum to more proximal colon, depending on the extent of disease. Fecal calprotectin may be used to assess disease activity and relapse. Medications available to treat the inflammation include 5-aminosalicylic acid, corticosteroids, tumor necrosis factor-alpha antibodies, anti-integrin antibodies, anti-interleukin-12 and -23 antibodies, and Janus kinase inhibitors. Choice of medication and method of delivery depend on the location and severity of mucosal inflammation. Other treatments such as fecal microbiota transplantation are considered experimental, and complementary therapies such as probiotics and curcumin have mixed data. Surgical treatment may be needed for fulminant or refractory disease. Increased risk of colorectal cancer and use of immunosuppressive therapies affect the preventive care needs for these patients. (Am Fam Physician. 2022;105(4):406-411. Copyright © 2022 American Academy of Family Physicians.)Copyright © 2022 American Academy of Family Physicians. All rights reserved.
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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.
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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.
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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.
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Mendelian susceptibility to mycobacterial disease (MSMD) is a rare genetic disorder characterized by impaired immunity against intracellular pathogens, such as mycobacteria, attenuated Mycobacterium bovis-Bacillus Calmette-Guérin (BCG) vaccine strains, and environmental mycobacteria in otherwise healthy individuals. Retrospective study reviewed the clinical, immunological, and genetic characteristics of patients with MSMD in Mexico. Overall, 22 patients diagnosed with MSMD from 2006 to 2021 were enrolled: 14 males (64%) and eight females. After BCG vaccination, 12 patients (70%) developed BCG infection. Furthermore, 6 (22%) patients developed bacterial infections mainly caused by Salmonella, as what is described next in the text is fungal infections, particularly Histoplasma. Seven patients died of disseminated BCG disease. Thirteen different pathogenic variants were identified in IL12RB1 (n = 13), IFNGR1 (n = 3), and IFNGR2 (n = 1) genes. Interleukin-12Rß1 deficiency is the leading cause of MSMD in our cohort. Morbidity and mortality were primarily due to BCG infection.
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Purpose : Patients on systemic immunomodulatory therapy (IMT) for uveitis are at higher risk of infection and infectious complications. While other medical specialties have studied the safety of IMT in non-ocular, autoimmune conditions vis-à-vis coronavirus disease 2019 (COVID-19), little is known about the effects of these drugs in uveitis patients specifically. The objective of this study was to determine if uveitis patients with COVID-19 were at higher risk of hospitalization for this pandemic illness and whether systemic IMT affected this risk. Methods : Retrospective cohort study of uveitis patients in 2020 in the United States. The Symphony health insurance claims dataset was used. Inclusion criteria were an ICD10 code for COVID-19, a code for any form of non-infectious uveitis or scleritis, and age 18 or greater. Drugs studied included methotrexate, mycophenolate, azathioprine, tacrolimus, cyclosporine, adalimumab, infliximab, tocilizumab, rituximab, and JAK, IL-17, and IL-12/23 inhibitors. The main outcome measure was adjusted odds of hospitalization for COVID19. Multivariable logistic regression was used to adjust for major risk factors for severe COVID-19 disease, including age, biological sex, cardiac, pulmonary, hepatic, and renal disease, obesity, organ transplant, stroke, and certain cancers. Results : 3,974,272 patients in the dataset were diagnosed with COVID-19 in 2020. Of these, 6389 (0.16%) had established diagnoses of uveitis or scleritis. Within the uveitis group, mean age was 54 years (SD 16), and 62% were female. 708 (11.1%) of the uveitis patients were hospitalized for COVID-19, significantly greater than the 7.3% rate amongst all adult, COVID-19-positive patients in the dataset (p < 0.001) and the CDC estimate of 7.5% for the US population in 2020 (p < 0.001). No agent showed a statistically significant effect on hospitalization. The higher rate of hospitalization in uveitis patients was partly, though not completely, explained by higher rates in uveitis-associated autoimmune conditions in the dataset as a whole. Conclusions : Uveitis patients have a greater risk of hospitalization for COVID-19 compared with the general population. As a whole, conventional IMT and biologics do not increase the risk of COVID-19 hospitalization amongst uveitis patients infected with the virus.