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1.
Chest ; 162(4):A602, 2022.
Article in English | EMBASE | ID: covidwho-2060644

ABSTRACT

SESSION TITLE: Post-COVID-19 Infection Complications SESSION TYPE: Case Report Posters PRESENTED ON: 10/17/2022 12:15 pm - 01:15 pm INTRODUCTION: We present two cases of symptomatic post-COVID eosinophilic pneumonia responsive to steroids. CASE PRESENTATION: Case 1: A 73-year-old gentleman with underlying asymptomatic rheumatoid arthritis (RA), was admitted with COVID pneumonia for which he received tocilizumab, remdesivir, and 12 days of dexamethasone. His course was complicated by MRSA pneumonia and bacteremia, so was discharged on IV Vancomycin. Six days post discharge, he redeveloped respiratory distress. Labs showed a WBC 18,000 and proBNP 2828. A chest CT revealed bilateral ground-glass opacities, worsening right upper lung airspace disease and bilateral pleural effusions. Despite receiving Furosemide, Vancomycin, and Ceftazidime, he required high-flow nasal cannula oxygenation (HFNC). Bronchoscopy demonstrated thick right bronchial secretions. BAL fluid revealed 7% eosinophils and grew MRSA. Case 2: A 70-year-old gentleman with extensive smoking history, emphysema, psoriasis, Guillain-Barré syndrome and a recent hospitalization for COVID pneumonia was discharged on a steroid taper. He returned 23 days post discharge in respiratory distress requiring HFNC, 5 days after discontinuing steroids. The chest CT revealed worsening fibrosis and bronchiectasis. Intravenous Levofloxacin and Vancomycin resulted in no clinical improvement. Bronchoscopy showed inflamed bronchi with secretions and BAL analysis revealed 6% eosinophils. For both patients, BAL was negative for fungi and PJP and CTA ruled out PE. Both patients were started on Prednisone with a prolonged taper. They improved clinically with decreased oxygen requirements to 4L nasal cannula and dramatic decrease in subjective dyspnea within 48 hours of starting steroids. DISCUSSION: The differential diagnosis for the clinical deterioration and worsening radiographs in both patients includes bacterial/fungal superinfection, PE, post-COVID-ILD and eosinophilic pneumonia. For the first patient, his RA was inactive. His BAL was positive for MRSA but did not improve until steroids were initiated. Neither of the patients were stable for VATS biopsy. Eosinophilic pneumonia is defined as pulmonary infiltrates with peripheral blood eosinophilia =500/ml, BAL eosinophils > 5% or eosinophilic infiltration on lung biopsy [1]. Both of our patients had >5% BAL eosinophils. Potentially, prolonged COVID-ILD stimulates T-Helper-2 cells, causing the release of IL-4/5/13 with recruitment of eosinophils. Studies report post-COVID-ILD biopsies show organizing pneumonia and fibrosis but have not yet been associated with eosinophilia. In both patients, we observed eosinophilia on BAL. It can be hypothesized that a delayed inflammatory response mediated by eosinophils play a role. CONCLUSIONS: Pulmonary eosinophilic pneumonia is a complication of post-COVID-ILD and can be successfully managed with steroids. Reference #1: De Giacomi F, Vassallo R, Yi ES, Ryu JH. Acute Eosinophilic Pneumonia. Causes, Diagnosis, and Management. Am J Respir Crit Care Med. 2018 Mar 15;197(6):728-736. doi: 10.1164/rccm.201710-1967CI. PMID: 29206477. DISCLOSURES: No relevant relationships by farrukh ahmad No relevant relationships by Deborah Markowitz No relevant relationships by Dhiraj Shah No relevant relationships by Garima Singh No relevant relationships by Aakriti Soni

2.
Embase; 2021.
Preprint in English | EMBASE | ID: ppcovidwho-344405

ABSTRACT

As the SARS-COV-2 pandemic evolves, what is expected of vaccines extends beyond efficacy to include consideration of both durability and variant cross-reactivity. This report expands on previously reported immunogenicity results from a Phase 1 trial of an AS03-adjuvanted, plant-based coronavirus-like particle (CoVLP) displaying the spike (S) glycoprotein of the ancestral SARS-CoV-2 virus in healthy adults 18-49 years of age (NCT04450004). When humoral and cellular responses against the ancestral strain were evaluated 6 months post-second dose (D201), 100% of vaccinated individuals retained binding antibodies, and ~95% retained neutralizing antibodies;interferon gamma (IFN-gamma) and interleukin 4 (IL-4) responses directed against the ancestral S protein were also still detectable in ~94% and ~92% of vaccinees respectively. Variant-specific, cross-reactive neutralizing antibody (NAb) levels were assessed at D42 and D201 using both live wild-type and pseudovirion assays (Alpha, Beta, Gamma) or the wild-type assay alone (Delta, Omicron). In the wild-type assay, broad cross-reactivity was detected against all variants at D42 (100% Alpha and Delta, 94% Beta and Gamma, 74% Omicron). At D201, cross-reactive antibodies were detectable in almost all participants against Alpha, Gamma and Delta variants (94%) and the Beta variant (83%) and in a smaller proportion against Omicron (44%). Results were similar in the pseudovirion assay (D42, 100% cross-reactivity to Alpha and Gamma variants, 95% to Beta variant, D201, 94% for Alpha, Beta and Gamma variants). These data suggest that two doses of 3.75 microg CoVLP+AS03 elicit a durable and cross-reactive response that persists for at least 6 months post-vaccination. Copyright The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.

3.
Front Immunol ; 13: 945063, 2022.
Article in English | MEDLINE | ID: covidwho-2032774

ABSTRACT

Type 2 helper T (Th2) cells, a subset of CD4+ T cells, play an important role in the host defense against pathogens and allergens by producing Th2 cytokines, such as interleukin-4 (IL-4), IL-5, and IL-13, to trigger inflammatory responses. Emerging evidence reveals that Th2 cells also contribute to the repair of injured tissues after inflammatory reactions. However, when the tissue repair process becomes chronic, excessive, or uncontrolled, pathological fibrosis is induced, leading to organ failure and death. Thus, proper control of Th2 cells is needed for complete tissue repair without the induction of fibrosis. Recently, the existence of pathogenic Th2 (Tpath2) cells has been revealed. Tpath2 cells produce large amounts of Th2 cytokines and induce type 2 inflammation when activated by antigen exposure or tissue injury. In recent studies, Tpath2 cells are suggested to play a central role in the induction of type 2 inflammation whereas the role of Tpath2 cells in tissue repair and fibrosis has been less reported in comparison to conventional Th2 cells. In this review, we discuss the roles of conventional Th2 cells and pathogenic Th2 cells in the sequence of tissue inflammation, repair, and fibrosis.


Subject(s)
Cytokines , Th2 Cells , Allergens , Fibrosis , Humans , Inflammation
4.
Acta Microbiologica Sinica ; 7(23), 2022.
Article in Chinese | CAB Abstracts | ID: covidwho-2025659

ABSTRACT

Objective: The aim of this study is to screen an ideal adjuvant for an inactivated porcine deltacoronavirus(PDCoV) vaccine to induce mucosal immunity and reduce the side effect of the vaccine. We used different mucosal adjuvants to prepare the inactivated PDCoV vaccines. We then used mouse model to evaluate the humoral, cellular and mucosal immune responses induced by the inactivated vaccines via different immunization routes.

5.
Annals of the Rheumatic Diseases ; 81:938-939, 2022.
Article in English | EMBASE | ID: covidwho-2008904

ABSTRACT

Background: The impact of immunosuppressants on COVID-19 vaccination response and durability in patients with immune-mediated infammatory diseases (IMID) is yet to be fully characterized. Humoral response may be attenuated in these patients especially those on B cell depleting therapy and higher doses of corticosteroids, but data regarding other immunosuppressants are scarce. Objectives: We aimed to investigate antibody and T cell responses and durability to SARS-CoV-2 mRNA vaccines (BNT162b and/or mRNA 1273) in IMID patients on immunomodulatory maintenance therapy other than B-cell depleting therapy and corticosteroids. Methods: This prospective observational cohort study examined the immuno-genicity of SARS-CoV-2 mRNA vaccines in adult patients with IMIDs (psoriatic arthritis, psoriasis, infammatory bowel disease and rheumatoid arthritis) with or without maintenance immunosuppressive therapies (anti-TNF, methotrexate/azathioprine [MTX/AZA], anti-TNF + MTX/AZA, anti IL12/23, anti-IL-17, anti-IL23) compared to healthy controls. Automated ELISA for IgGs to spike trimer, spike receptor binding domain (RBD) and the nucleocapsid (NP) and T-cell release of 9 cytokines (IFNg, IL2, IL4, IL17A, TNF) and cytotoxic molecules (sFasL, GzmA, GzmB, Perforinin) in cell culture supernatants following stimulation with spike or NP peptide arrays were conducted at 4 time points: T1=pre vaccination, T2=me-dian 26 days after dose 1, T3=median 16 days after dose 2 and T4=median 106 days after dose 2. Neutralization assays against four SARS-CoV-2 variants (wild type, delta, beta and gamma) were conducted at T3. Results: We followed 150 subjects: 26 healthy controls and 124 IMID patients: 9 untreated, 44 on anti-TNF, 16 on anti-TNF with MTX/AZA, 10 on anti-IL23, 28 on anti-IL12/23, 9 on anti-IL17, 8 on MTX/AZA (Table 1). Most patients mounted antibody and T cell responses with increases from dose 1 to dose 2 (100% sero-conversion at T3) and some decline by T4, with variability within groups. Antibody levels and neutralization efficacy was lower in anti-TNFgroups (anti-TNF, anti-TNF + MTX/AZA) compared to controls and waned by T4 (Figure 1). T cell responses were not consistently different between groups. Pooled data showed a higher antibody response to mRNA-1273 compared to BNT162b. Conclusion: Following 2 doses of mRNA vaccination there is 100% seroconver-sion in IMID patients on maintenance therapy. Antibody levels and neutralization efficacy in anti-TNF group are lower than controls, and wane substantially by 3 months after dose 2. These fndings highlight the need for third dose in patients undergoing treatment with anti-TNF therapy and continued monitoring of immunity in these patient groups, taking into consideration newer variants and additional vaccine doses.

6.
Journal of Clinical Oncology ; 40(16), 2022.
Article in English | EMBASE | ID: covidwho-2005707

ABSTRACT

Background: Patients with non-Hodgkin's lymphomas (NHL) develop abnormalities in the structural and functional organization of the immune system leading to immune deficiency. Chemotherapy (CT) in patients after SARS-CoV infection is associated with a more severe disease course affecting the treatment results. The cytokine-producing activity (CPA) of blood cells is poorly studied, while it determines the effectiveness of antitumor and anti-infective functions of the immune system. The purpose of this study was to evaluate CPA of peripheral blood mononuclear cells in patients receiving treatment for NHL after COVID-19. Methods: The study included 8 patients with large B-cell NHL with PCR-confirmed COVID-19 infection in past medical history. All patients received from 3 to 4 chemotherapy cycles. K2EDTA blood samples obtained before and after 3-4 CT cycles were divided into 2 parts after dilution with a sterile nutrient medium solution: part 1, to assess spontaneous CPA;part 2, with addition of a sterile mitogen (phytohemagglutinin 4 μg, concanavalin A 4 μg, and lipopolysaccharide 2 μg) to assess stimulated CPA. The samples were incubated for 24 hours at 370C, and the levels of IL-1β, IL-6, IL-8, IL-10, IL-18, IL-4, IL-2, TNF- α, INF-γ, INF-α were determined in the obtained plasma. The stimulation coefficient (SC) was calculated as the ratio of stimulated CPA to spontaneous CPA. Results: 3-4 CT cycles in patients after COVID-19 was accompanied by an elevation of spontaneous CPA of the blood cells IL-6, INF-γ, TNF-α, IL-8, compared to the initial levels, by 678%, 127%, 64% and 57%, respectively. The ability of cells to spontaneous production of IL-10 and INF-α decreased by 30% and 100%. The mitogen-induced CPA of mononuclear cells in relation to IL-10, IL-6, IL-2, IL-1β and INF-α increased by 300%, 130%, 92%, 52% and 52%, respectively. Stimulated CPA in relation to INF-γ decreased by 21% compared to initial levels. As a result of the revealed CPA changes, SC in NHL patients after COVID-19 receiving CT increased, compared to the initial levels, by 465%, 92% and 48% respectively for IL-10, IL-2, IL-1β, as well as the appearing ability to INF-α production. SC for IL-6, INF-γ, TNF-α, and IL-8 decreased by 70%, 66%, 33% and 27% respectively. Conclusions: Certain features of spontaneous and mitogen-activated CPA of blood mononuclear cells were revealed in NHL patients after COVID-19, indicating a change in the functional activity of immune cells which could affect the development of the disease and the effectiveness of the therapy. The data obtained require additional studies and can be used to assess the condition of patients, as well as to predict the therapy efficacy.

7.
Chinese Journal of Virology ; 36(2):160-164, 2020.
Article in Chinese | GIM | ID: covidwho-1975406

ABSTRACT

To determine the clinical value of diammonium glycyrrhizinate (DG) in treatment of patients with novel coronavirus pneumonia (NCP). According to the random-number method, 104 NCP patients were divided equally into control group and observation group in our hospital. In the control group, patients were treated according to the Pneumonia diagnosis and treatment scheme for new coronavirus infection (trial version 5). In the observation group, patients were administered DG enteric capsules (150 mg, t.d.s.). All patients were treated continuously for 2 weeks. The clinical effects in both groups were observed. Levels of inflammation indicators [C-reactive protein (CRP), interleukin (IL) -4, tumor necrosis factor (TNF) -a] and immune-function indicators [cluster of differentiation (CD)3+, CD4+, CD8+, CD4+/CD8+] were compared between the two groups. Adverse reactions were documented. The prevalence of cure [19.23% (10/52) vs. 7.69% (4/ 52)], significant efficacy [28.85% (15/52) vs. 17.31% (9/52)] and total efficacy [61.54% (32/52) vs. 40.38% (20/52)] of the observation group was significantly higher than that of the control group (P < 0.05 for all). After treatment, the serum levels of CRP [(1.90 +or- 085) vs. (3.26 +or- 1.63) mg/L], IL-4 [(21.35 +or- 8.90) vs. (26.24 +or- 9.16) pg/mL], and TNF-a [(4.85 +or- 2.15) vs. (7.97 +or- 3.36) pg/mL] of the observation group were significantly lower than those of the control group (P < 0.05 for all). The levels of CD3+ [(6630 +or- 8.83)% vs. (54.19 +or- 7.79)%], CD4+ [(39.42 +or- 4.72)% vs, (33.18 +or- 4.10)%], CD8+ [(28.14 +or- 4.22)% vs. (23.39 +or- 3.88)%], and CD4+/CD8+ [(1.62+or- 043) vs. (1.21 +or- 0.29)] of the observation group were significantly higher than those of the control group (P < 0.05 for all). The prevalence of adverse reactions [15.38% (8/52) vs. 28.85% (15/52)] of the observation group was significantly lower than that of the control group (P < 0.05). DG has a significant clinical effect and a good safety profile for NCP treatment.

8.
Voprosy Prakticheskoi Pediatrii ; 17(2):16-22, 2022.
Article in Russian | EMBASE | ID: covidwho-1969924

ABSTRACT

Objective. To measure serum levels of some cytokines and chemokines in children depending on the severity of coronavirus infection. Patients and methods. We examined 33 children aged 4 to 17 years with coronavirus infection, including 25 patients with mild disease (Group 1;mean age 11 [6.5;14] years) and 8 children with moderate disease (Group 2;mean age 11 [8;13] years). The control group comprised 30 healthy children matched for age (mean age 10 [6;12] years). The following cytokines and chemokines were measured in all study participants using the LEGENDplexTM Human Essential Immune Response Panel (BioLegend, USA): interleukins (IL)-1β,-2,-4,-6,-8,-10,-12p70,-17A, interferon-induced protein (IP-10), monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ). Data analysis was performed using the IBM SPSS Statistics Version 25.0 (International Business Machines Corporation, license No Z125-3301-14, USA). Results. We found that children with coronavirus infection had elevated serum levels of IL-1β, IL-2, IL-4, IL-12p70, IL-17A, IP-10, and MCP-1 regardless of their disease severity compared to controls. Patients with moderate disease demonstrated higher serum levels of IL-12p70 and MCP-1 compared to those with mild disease. The ROC-analysis showed that IL-12p70 and MCP-1 can predict moderate course of coronavirus infection in children. Conclusion. Serum levels of IL-12p70 and MCP-1 can be used as an additional diagnostic marker to estimate the inflammation severity in children with coronavirus infection.

9.
Laryngo- Rhino- Otologie ; 101:S180, 2022.
Article in English | EMBASE | ID: covidwho-1967655

ABSTRACT

Introduction The use of biologics has been described as an effective therapy in phase 3 studies in severe CRSwNP. Relatively unexplored is the post-covid syndrome in CRSwNP patients. Method Case presentation. Results Presentation of a 75-year-old patient with CRSwNP, asthma, ASA intolerance and eosinophilic granulomatosis with polyangiitis. Drug therapy with daily 1-5 mg prednisolone oral and inhalation therapy with formoterol/ beclomethasone. In February 2021, the patient was diagnosed with SARS-CoV-2 infection. For four days, the patient was admitted to a hospital with pronounced physical weakness without respiratory insufficiency. Anosmia has long been known because of CRSwNP. After Covid-19 illness, the patient reported severe sleep impairment and a severe state of exhaustion compatible with a post-covid syndrome. In addition, the patient was impaired by a severe nasal obstruction. At presentation in the rhinological consultation 7 months after Covid-19 illness, severe nasal polyps (NP overall score 8) and anosmia were detected. Dupilumab therapy (anti IL-4/IL-13 antibody) was initiated for severe CRSwNP. In the course of 2 months, an improved quality of life with less nasal obstruction as well as a reduced NP overall score of 6 were shown. Furthermore, the sleep impairment and exhaustion of the patient did not improve. Conclusion Dupilumab therapy improves quality of life in patients with severe CRSwNP, which may be especially important in post-covid syndrome.

10.
American Journal of Respiratory and Critical Care Medicine ; 205(1), 2022.
Article in English | EMBASE | ID: covidwho-1927846

ABSTRACT

Introduction:Dupilumab is an anti-IL4R monoclonal antibody (mAb) with proven efficacy in severe eosinophilic asthma (SEA). We have previously identified that a suboptimal response to the eosinophil targeting anti-IL5/5R mAbs mepolizumab and benralizumab is seen in 27% and 14% of patients with SEA respectively1,2. The mechanism of this is not well-understood. It is unknown whether such patients respond in a clinically meaningful way following a switch to dupilumab. Methods:We performed a retrospective analysis of the clinical effectiveness of dupilumab (minimum 6 months treatment) in patients with SEA at our tertiary severe asthma centre who had failed to adequately respond to at least one of the anti-IL-5/5R mAbs. Change in the annualised exacerbation rate (AER), maintenance oral corticosteroids (mOCS) requirements, ACQ-6 and mAQLQ was recorded. Results:Thirty-two patients (mean age 41.2, 68.8% female, 71.9% atopic) were included in the analysis. 13/32(40.6%) had co-morbid nasal polyposis and 5/32(15.6%) had eczema. The baseline FeNO was 60ppb(IQR 39.6-87.5) and peak eosinophil count prior to any mAb was 0.6(IQR 0.5-0.9). 23/32(71.8%) were switched from benralizumab, of whom, 12/23(52.2%) had also failed to respond to at least one other anti-IL5 mAb previously. At six months, the daily median mOCS dose in those requiring mOCS at baseline (n=18) fell from 10mg(IQR 5-25mg) to 3mg(IQR 0-5mg), p≤0.001. 4/18(22%) were able to stop mOCS completely. Mean(SD) AER improved from 2.34(1.89) to 0.44(0.95), p≤0.001. There were also significant improvements in ACQ6 and mAQLQ that exceeded twice the MCID for both measures: mean (SD) ACQ6 improved from 3.04(1.26) to 1.82(1.28), p≤0.001;mAQLQ improved from 3.90(SD 1.40) to 5.36(SD 1.05), p≤0.001. Due to the COVID-19 pandemic, FEV1 data was only available for 8 patients. However, there was nonetheless a significant rise in FEV1 (%predicted) from 55.6% (9.78) to 68.5%(16.9), p=0.011. One patient discontinued dupilumab during the follow-up period. Conclusion: A minority of individuals with SEA have a suboptimal response to eosinophil targeted therapy with an anti-IL5/5R mAb. In these patients, we report significant clinical improvements following initiation with dupilumab suggesting an important role for the IL-4/-13 pathway in these patients. Further research is required to understand whether these patients represent a distinct subphenotype of T2-high asthma.

11.
American Journal of Respiratory and Critical Care Medicine ; 205(1), 2022.
Article in English | EMBASE | ID: covidwho-1927706

ABSTRACT

Rationale We have previously reported blocking the IL-25 receptor (IL-17RB) prevented viral increased allergic airways inflammation and this was associated with reduced lung viral load. To investigate IL-25 regulation of airway anti-viral immunity we hypothesised that IL-25 directly inhibits airway epithelial cell (AEC) type I/III interferon expression and antibody blockade of IL-25 in vivo boosts lung interferon expression and reduces lung viral load in parallel with reduced type 2 airway inflammation. Methods In vitro Immunofluorescence was used to visualise epithelial IL-25 and IL- 17RB proteins in endobronchial biopsies from patients with asthma and healthy subjects and in AEC differentiated at ALI. AEC from n = 14 donors with asthma were differentiated at the air-liquid interface (ALI) and infected with RV-A1, MOI=0.1. A subset of AECs was treated with anti-IL-25 mAb (LNR125) before infecting with RV-A1 or human coronavirus 229E. Differentiated AEC from healthy donors were treated with recombinant IL-25 protein and infected with RV-A1. Nanostring immune transcriptomic data expressed as digital mRNA counts for exact copy number or was expressed as log2 fold change ratio against -log10 Bejamini-Yekutieli-corrected p-values. In vivo 6- 8-week-old, BALB/c mice sensitised and intranasally challenged daily for 3 days with ovalbumin to induced allergic airways disease. A single subcutaneous injection of 250 μg LNR125 was administered during ovalbumin challenge. Mice were then infected i.n. with RV-A1, 6 hours after final allergen challenge. On day 1 and day 7 post-infection, BAL were collected, lung lobe tissue was collected for viral RNA and cytokine expression. Results IL-25 and IL-17RB were constitutively expressed at the apical surface of airway epithelium in biopsies and AEC cultures. RV infection increased IL-25 expression by AEC from asthmatic donors. LNR125 treatment reduced IL-25 mRNA and significantly increased RV induced IFN-β a and IFN-λ protein expression and this was confirmed by Nanostring transcriptomic analyses which also identified down-regulated type-2 immune genes CCL26 (eotaxin 3) and IL1RL1(IL-33 receptor). LN125 treatment also increased IFN-λ expression by 229E-infected differentiated AECs. IL-25 treatment increased viral load associated with 50% reduced expression of IFN-β and CXCL10 and 75% reduced IFN-λ. Allergen challenged, RV-infected mice treated with LNR125 had significantly increased BAL IFN-β protein and 60% reduction in lung viral load associated with reduced IL-25, IL-4, IL-5 and IL-13 BAL proteins compared to controls. Conclusion IL-25-induced inflammation combined with suppression of AEC anti-viral immunity identify IL-25 as a central mediator of viral asthma exacerbations and therefore a target for mAb-based treatment.

12.
Neurology ; 98(18 SUPPL), 2022.
Article in English | EMBASE | ID: covidwho-1925214

ABSTRACT

Objective: To investigate the humoral and T-cell immune response of multiple sclerosis (MS) patients under B-cell depleting therapy following SARS-CoV-2 vaccination compared to healthy controls (HC). Background: The SARS-CoV-2 pandemic has huge implications for the management of patients with MS under highly active immune therapies. First reports indicated that the humoral response of anti-CD20 treated, B-cell depleted patients might by attenuated. Data about dynamics of B-cell repopulation and T-cell response are scarce. Design/Methods: The study was authorized by the local ethics committee of the RuhrUniversity Bochum. Patients were recruited at the Department of Neurology. We included n=10 healthy age-matched controls and n=37 B-cell depleted MS patients (20 ocrelizumab, 17 off-label rituximab). Serum and Peripheral Blood Mononuclear Cells (PBMCs) were isolated 4-8 weeks after second vaccination. Serum was analyzed for anti-SARS-CoV-2-Spike antibodies. Lymphocyte subpopulations were analyzed in B-cell depleted patients by FACS analysis. PBMCs were stimulated with 2 μg/ml SARS-CoV-2 peptide-mix for 16-18 hours and analyzed via flow cytometry for cytokine-expressing T-cell populations. Results: 15/36 (40.5%) patients mounted an antibody response >10 U/ml (range 0.8-2,500). The anti-SARS-CoV-2-Spike titer correlated with B-cell repopulation (R2 =0.01841;r=0.4481;p=0.0069), whereas no significance could be detected correlating with the time to last infusion (R2 =0.1352;r=0.3058;p=0.0740). On the contrary, T-cell responses of B-cell depleted patients were higher or did not deviate from those of HC. Frequencies of CD4+ -T-cells expressing IFN-γ or IL-4 and CD8+ -T-cells expressing IFN-γ or IFN-γ and IL-2 were significantly higher in B-cell depleted patients, while CD4+ -T-cells expressing IL-2 or IFN-γ and IL-2 as well as CD8+ -T-cells expressing IL-2 did not differ from HC. Conclusions: Humoral vaccination responses in B-cell depleted patients are dependent on B-cell repopulation. Notably, patients with poor humoral response are able to mount a sustained T-cell response after SARS-CoV-2 vaccination. Those data suggest, that vaccinated B-cell depleted patients might be partially protected against SARS-CoV-2 infection.

13.
Nephrology Dialysis Transplantation ; 37(SUPPL 3):i234-i235, 2022.
Article in English | EMBASE | ID: covidwho-1915704

ABSTRACT

BACKGROUND AND AIMS: One of the complications described in critically ill patients in intensive care units with severe COVID-19 was acute kidney injury (AKI). The pathophysiology of AKI in patients with COVID-19 is multifactorial. In addition to the direct virulence of SARS-CoV-2 in renal cells, the tissue inflammation and local immune cell infiltration, cytokine storm, secondary infections and nephrotoxicity associated drugs may contribute to AKI [1]. Mounting evidence throughout the pandemic suggests that patients with severe COVID-19 may have a cytokine storm syndrome, one of the possible causes of AKI in these patients [2]. The present prospective cohort study analysed the correlation between circulating cytokine profile and estimated glomerular filtration rate (eGFR) in patients with COVID-19. METHOD: After signing the informed consent, patients positive for SARS-CoV- 2 infection (n = 74) had blood samples (n = 139) collected at hospital admission until the day of the outcome. ELISA measured the cytokines IL-10, IL-4, L-6, TNF- α and IFN-γ , and the eGFR was calculated by the CKD-EPI Cystatin C equation. Statistics description: Continuous variables were checked for normality and presented as mean ± standard deviation or median and interquartile range. The association between continuous variables is shown in scatterplots, and a predicted response with 95% confidence interval (95% CI) is plotted using fractional polynomials. For linear correlations, we obtained P-values using Pearson's correlation coefficient. RESULTS: There is a more significant distribution of eGFR below 90 mL/min in the population studied, associated with older patients. Glomerular filtration rates were negatively correlated with age as expected (-0.60;P < 0.0001). Lower eGFR was correlated with levels of proinflammatory cytokines such as IL-6 (-0.33;P < .0007) and TNF- α (-0.21;P < .03);but without positive correlation with IL-10 (0.04;P < 0.68) or IFN-γ (-0.14;P < .16), even though higher IFN-γ levels have been linked to a worse prognosis in patients with severe COVID-19 [3]. Curiously, a positive correlation was observed between lower eGFR and IL-4 levels. CONCLUSION: These results demonstrate that a shift in the immune response profile, cytokines with a Th2 profile such as IL-4, and cytokines with systemic functions such as IL-6 and TNF-α can be related to renal failure. The elucidation of the potential pathophysiological mechanisms of AKI associated with COVID-19 as well as monitoring of cytokine levels can (a) help to identify patients with severe COVID-19 at risk of loss of renal function, (b) provide information on specific therapeutic strategies. (Figure Presented).

14.
Future Virology ; 17(4):197-199, 2022.
Article in English | EMBASE | ID: covidwho-1887070
15.
Topics in Antiviral Medicine ; 30(1 SUPPL):72-73, 2022.
Article in English | EMBASE | ID: covidwho-1880801

ABSTRACT

Background: Critical COVID-19 occurs ca. 7d from symptoms onset, and is associated to immune dysregulation as well as SARS-CoV-2 detection in plasma (i.e. viremia). We hereby sought to detail the association between SARS-CoV-2 viremia measured at the end of the first week of disease and immune phenotypes/function in COVID-19 patients. Methods: We consecutively enrolled patients hospitalized in the acute phase of ascertained SARS-CoV-2 pneumonia. In this disease stage, we studied SARS-CoV-2 viremia (RT-PCR) and cytokines (MACSPlex), HLA-DR+CD38+ activated, GRZB+PRF+ pro-cytolitic T-cells, intracellular cytokine production (IL-2, IFNγ, TNFα, IL-4, IL-17A) after SARS-CoV-2 challenge (S-N-M-peptide pool). Simultaneous Th1-cytokines production (polyfunctionality) and amount (iMFI) was assessed. Humoral response: anti-S1/S2 IgG, anti-RBD total-Ig, IgM, IgA, IgG1 and IgG3 (ELISA), pseudoviruses neutralization (ID50) and Fc-mediated functions (%ADCC). Results: Out of 54 patients, 27 had detectable viremia (V+). Albeit comparable age and co-morbidities, V+ patients more frequently required non-invasive/invasive ventilatory support (p=0.035), with a trend to higher death (p=0.099) vs patients with undetectable viremia (V-)(Fig.1A). V+ displayed higher circulating IFN-α (p=0.002) and IL-6 (0.003), lower activated HLA-DR+CD38+CD4 (p=0.01) and CD8 (p=0.02), with no differences in GRZB+PRF+ T-cells. V+ featured reduced SARS-CoV-2-specific cytokine-producing T-cells, reaching significance for IFNγ+CD4 (p=0.02), TNFα+CD8, IL-4+CD8 (p=0.04) (Fig.1B-C), with lower bi-and tri-functional SARS-CoV-2-specific CD4 Th1, reaching significance for IL-2+TNFα+CD4 (p=0.03) (Fig.1D). A trend towards lower cytokines iMFI in bi-and tri-functional SARS-CoV-2-specific CD4 Th1 was observed in V+, reaching significance for IL-2+TNFα+CD4, p=0.004. V+ displayed lower anti-S IgG, anti-RBD total-Ig, IgM, IgG1 and IgG3 (Fig.1E), with lower ID50 and %ADCC vs V-(Fig.1F-G). Conclusion: Hospitalized COVID-19 patients with detectable plasma SARS-CoV-2 RNA in the acute phase of disease present worse outcome, higher inflammatory cytokines, fewer activated and SARS-CoV-2-specific polyfunctional T-cells, suggesting a link between SARS-CoV-2 viremia at the end of the first stage of disease and immune dysregulation. Whether high ab initium viral burden and/or intrinsic host factors contribute to a delayed and/or exhausted immune response in severe COVID-19 remains to be elucidated, to further inform strategies of targeted therapeutic interventions.

16.
Topics in Antiviral Medicine ; 30(1 SUPPL):92, 2022.
Article in English | EMBASE | ID: covidwho-1880775

ABSTRACT

Background: Currently available COVID-19 vaccination regimens in the US deliver either a homologous spike (S) mRNA prime-boost or a prime-only S DNA adenovirus-vectored antigen to elicit humoral and cell-mediated responses to confer protection against SAR-CoV-2 infection. Alternatively, heterologous vaccination using two different platforms has the potential to enhance and expand immune protection. Addition of a second SARS-CoV-2 antigen, the nucleocapsid (N) protein that is less subject to mutation and elicits vigorous T-cell responses, may also be advantageous. We report immunological responses to homologous and heterologous prime-boost vaccination regimens with a human DNA adenovirus serotype 5 S plus N (AdS+N) and/or a self-amplifying S-only mRNA vaccine (AAAH) delivered with a nanostructured lipid carrier (NLC). Methods: CD-1 mice received homologous or heterologous prime-boost combinations of AdS+N and AAAH. Priming doses were administered on Day 0, booster doses were delivered on Day 21, and mice were euthanized for blood and organ collection on Day 35. Serum was analyzed for anti-S (both wild type and variant) and anti-N IgG subtypes by ELISA. Spleen-resident CD4+ and CD8+ T cells were tested for IFN-γ, TNF-α, and IL-2 production in response to S-WT, S Delta variant and N protein overlapping peptides by intracellular cytokine staining (ICS). Splenocyte cytokine secretion upon stimulation with S-WT/N peptides was also assessed by IFN-γ and IL-4 ELISpot. Serum neutralization of the original Wuhan strain, Delta, and B.1.351 variants was assessed by a pseudovirus neutralization assay. Results: The highest humoral and T-cell responses were seen with the heterologous AAAH prime-AdS+N boost regimen, with a significant increase in T-cell responses relative to homologous vaccination. S protein-binding IgG was similar between wild type and Delta variant S proteins, with a strong/clear Th1/Th2 bias, and T cells responded to S wild type and S Delta peptides with similar levels of cytokine expression. Sera from AAAH prime-AdS+N boost mice showed the ability to neutralize Wuhan D614G, Delta, and B.1.351 (South Africa) variant pseudoviruses at high levels. Conclusion: Heterologous vaccination with the AAAH RNA vaccine prime and an AdS+N DNA boost may provide substantially improved humoral and cell-based immunity against SARS-CoV-2 variants by leveraging the advantages of each vaccine platform technology and by inclusion of immune responses to N.

17.
Drug Topics ; 165(11):9-12, 2021.
Article in English | EMBASE | ID: covidwho-1866103
18.
Hematology, Transfusion and Cell Therapy ; 43:S527, 2021.
Article in Portuguese | EMBASE | ID: covidwho-1859736

ABSTRACT

Objetivo: Comparar o perfil imunológico de indivíduos positivos e negativos para IgG anti-SARS-CoV-2. Métodos: Amostras de soro (n = 7.837) de doadores de sangue da Fundação Hemominas, coletadas no período de março a dezembro de 2020, foram testadas por quimioluminescência para IgG anti-SARS-CoV-2. As amostras positivas foram separadas em quatro grupos considerando-se os intervalos interquartis do index de anticorpos detectados no teste sorológico. Amostras positivas e negativas foram utilizadas na dosagem de citocinas (IL-2, IL-4, IL-6, IL-10, TNF, IFN-gama e IL-17A) e quimiocinas (CXCL8, CCL5, CXCL9, CCL2 e CXCL10). Resultados: Dos doadores testados, 441 (5,6%) foram positivos para IgG anti-SARS-CoV-2 com mediana de index de 3,65 (IQR 2,43-5,40). As concentrações séricas (ng/mL) de IL-10 (mediana, 0,51;IQR, 0,18-0,86;p < 0,0001), TNF (mediana, 0,65;IQR, 0,00-0,77;p = 0,0279) e IFN-gama (mediana, 0,36;IQR, 0,00-0,88;p < 0,0001) foram significativamente maiores em doadores de sangue positivos para IgG anti-SARS-CoV-2. As concentrações séricas (ng/mL) de CXCL8 (mediana, 13,60;IQR, 5,98-28,04;p = 0,0013), CCL5 (mediana, 4.017,00;IQR, 2.674,00-4.736,00;p < 0,0001), CXCL9 (mediana, 33,08;IQR, 17,88-54,14;p < 0,0001), CCL2 (mediana, 40,39;IQR, 23,38-61,52;p = 0,0068) e CXCL10 (mediana, 111,70;IQR, 56,98-178,00;p < 0,0001) foram significativamente maiores em doadores de sangue positivos para IgG anti-SARS-CoV-2. Análises de correlação revelaram que todas as citocinas (exceto IL-4, IL-6 e IL-17A) têm correlação negativa significativa com o index de IgG anti-SARS-CoV-2, mas com coeficiente de Spearman (r) menores que 0,5. Todas as quimiocinas testadas tiveram correlação negativa significativa, com destaque para CCL5 (r = -0,79), CXCL9 (r = -0,57) e CXCL10 (r = -0,51). Discussão: A análise do perfil imunológico de indivíduos positivos e negativos evidenciou que a produção de IgG anti-SARS-CoV-2 depende de uma resposta imune inata caracterizada pela alta concentração sérica de quimiocinas e de uma resposta pró-inflamatória potencializada por TNF e IFN-gama e regulada por IL-10. Os resultados evidenciam ainda que a produção de mais anticorpos contra o vírus depende de uma síntese controlada de citocinas e quimiocinas, indicando que menores níveis destes biomarcadores estão relacionados à maior produção de IgG anti-SARS-CoV-2. Conclusão: Os resultados deste estudo evidenciaram que um perfil imune pró-inflamatório associado a biomarcadores de resposta imune inata é importante para o desenvolvimento de anticorpos IgG anti-SARS-CoV-2. Suporte financeiro: Fundação HEMOMINAS, CNPq.

19.
Hematology, Transfusion and Cell Therapy ; 43:S508, 2021.
Article in Portuguese | EMBASE | ID: covidwho-1859701

ABSTRACT

Objetivos: Comparar níveis de citocinas e quimiocinas entre indivíduos infectados com SARS-CoV-2 com COVID-19 grave ou com a forma assintomática da infecção, a fim de avaliar quais destes marcadores biológicos de resposta inflamatória são indicadores de gravidade da infecção viral. Métodos: Foram analisados dados clínicos de 48 pacientes com COVID-19 hospitalizados no Hospital Eduardo de Menezes (FHEMIG, MG) no período de 07 de julho a 21 de novembro de 2020, que necessitaram ou não de assistência em terapia intensiva (grupos UTI e sem UTI, respectivamente). Foi feita a quantificação dos níveis de citocinas (IL-2, IL-4, IL-6, IL-10, TNF, IFN-, IL-17A) e quimiocinas (CCL2, CCL5, CXCL8, CXCL9 e CXCL10) do plasma de 14 pacientes UTI e 17 pacientes sem UTI que tinham COVID-19 grave no momento da coleta da amostra, além de 24 doadores de sangue da Fundação Hemominas com infecção ativa pelo SARS-CoV-2 (RT-PCR positiva) que eram assintomáticos no momento da coleta da amostra. Resultados: A análise clínica dos pacientes UTI (n = 19) em comparação àqueles que não usaram UTI (n = 29) não mostrou diferença estatística quanto à frequência de comorbidades e de sinais e sintomas para COVID-19 na admissão hospitalar. A comorbidade mais comum foi hipertensão (62,5%), seguida por diabetes (37,5%) e obesidade (22,9%). Tosse, dispneia, febre, fatiga e mialgia foram os sinais e sintomas mais prevalentes de COVID-19 em ambos os grupos. Entretanto, os pacientes UTI desenvolveram doença grave ou crítica que requereu um período de hospitalização em média duas vezes mais longo que o grupo sem UTI (p < 0,001). O conjunto dos pacientes com COVID-19 mostrou níveis significativamente mais altos de IL6, IL10 e CCL5 que os doadores assintomáticos. Na comparação dos grupos dos pacientes houve diferença significativa apenas para IFN, com níveis mais elevados nos pacientes UTI. Discussão: Apesar do grupo de pacientes UTI apresentarem quadro de COVID-19 mais grave que os pacientes sem UTI, a frequência de sinais e sintomas da doença e de comorbidades não foi significativamente diferente entre os grupos. A evolução da COVID-19 de assintomática para grave e crítica tem sido associada com intensa resposta inflamatória, o que está de acordo com maiores níveis de IL6, IL10 e CCL5 observados nos pacientes em comparação aos doadores assintomáticos. Nível de IFN pode ser especial indicador de gravidade da doença. Conclusão: Marcadores biológicos, como citocinas e quimiocinas, podem ser melhores preditores de evolução da COVID-19 que sinais clínicos e sintomas. Suporte financeiro: Fundação Hemominas e SES/MG.

20.
Modern Pathology ; 35(SUPPL 2):1006-1007, 2022.
Article in English | EMBASE | ID: covidwho-1857652

ABSTRACT

Background: COVID-19 pandemic has caused more than 4.7 million deaths worldwide to date and still continues globally unabated. Numerous studies have linked the mortality in COVID-19 to aggressive immune response and cytokine storm. However, little is known about the cytokine profiles of individual immune cells that are directly involved in tissue damage. Here we investigate intracellular cytokines in individual T and NK cells of COVID-19 patients. Design: We studied 50 blood samples from 22 COVID-19 patients, 4 with mild, 6 moderate and 12 severe disease. There were 6 healthy controls. We performed high-dimensional 30-color spectral flow cytometry to characterize the immune cell subsets. For cytokine study, cells were stimulated for 6 hours, and stained for surface antigens and intracellular cytokines (IL1b, IL2, IL4, IL6, IL8, IL10, IL12, IL17a, IL21, INFg, GnzB, TNFa, and GMCSF). Data ware acquired on FACSymphony 50-parameter analyzer and analysis performed using FlowJo. Results: Our studies revealed significant differences in lymphocyte cytokine profiles between COVID+ and healthy controls (Fig 1). CD4+ and CD8+ T-cells exhibited increased percentages of IL2+ and IFNg+ cells, indicating a shift towards Th1 reaction. Granzyme B is highly upregulated in all T and NK cell subsets, demonstrating highly armed cytotoxic cells in COVID patients. The most prominent changes were noted in NK cells, 7 cytokines were highly expressed, most are proinflammatory cytokines. Of particular interest are IL-21 and GMCSF, both are known to play important roles in inflammatory cell recruitment, activation and renewal, which can lead to augmented tissue inflammation and injury. These changes were already evident in patients with mild disease, but there is heightened cytokine production in severe cases. Conclusions: Using high-dimensional flow cytometry we demonstrated for the first time significantly increased production of multiple proinflammatory cytokines and cytotoxic molecules in individual T and NK cells of COVID-19 patients. NK cells are most drastically activated. It is conceivable that when recruited to the target tissue such as lung, these highly primed cells will play a major role in tissue injury and ultimately organ failure via their direct cytotoxicity and cytokine secretion. This is consistent with previous reports of increased NK cells in the COVID lungs. Analysis of NK cell cytokine profiles may serve to predict disease progression, and reveal new targets for immune-therapy for severe COVID patients. (Table Presented).

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