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Coronavirus disease 2019 (COVID-19) is a fatal pandemic viral disease caused by the severe acute respiratory syndrome corona virus type-2 (SARS-CoV-2). The aim of this study is to observe the associations of IL-6, SARS-COV-2 viral load (RNAemia), IL- 6 gene polymorphism and lymphocytes and monocytes in peripheral blood with disease severity in COVID-19 patients. This study was carried out from March 2021 to January 2022. RT-PCR positive 84 COVID-19 patients and 28 healthy subjects were enrolled. Blood was collected to detect SARS-COV-2 viral RNA (RNAemia) by rRT-PCR, serum IL-6 level by chemiluminescence method, SNPs of IL-6 by SSP-PCR, immunophenotyping of lymphocytes and monocyte by flow cytometry. Serum IL-6 level (pg/ml) was considerably high among critical patients (102.02 +/- 149.7) compared to severe (67.20 +/- 129.5) and moderate patients (47.04 +/- 106.5) and healthy controls (3.5 +/- 1.8). Serum SARS-CoV-2 nucleic acid positive cases detected mostly in critical patients (39.28%) and was correlated with extremely high IL-6 level and high mortality (R =.912, P < 0.001). Correlation between IL-6 and monocyte was statistically significant with disease severity (severe group, p < 0.001, and 0.867*** and critical group p < 0.001 and 0.887***). In healthy controls, moderate, severe and critically ill COVID-19 patients, IL-6 174G/C (rs 1800795) GG genotype was 82.14%, 89.20%, 67.85% and 53.57% respectively. CC and GC genotype had strong association with severity of COVID-19 when compared with GG genotype. Significant statistical difference found in genotypes between critical and moderate groups (p < 0.001, OR-10.316, CI-3.22-23.86), where CC genotype was associated with COVID-19 severity and mortality. The absolute count of T cell, B cell, NK cell, CD4+ T cells and CD8+ T cells were significantly decreased in critical group compared to healthy, moderate and severe group (P < 0.001). Exhaustion marker CD94/NKG2A was increased on NK cells and CD8+ cytotoxic T cell among critical and severe group. Absolute count of monocyte was significantly increased in critical group (P < 0.001). Serum IL-6, IL-6 174 G/C gene and SARS-CoV-2 RNAaemia can be used in clinical practice for risk assessment;T cell subsets and monocyte as biomarkers for monitoring COVID-19 severity. Monoclonal antibody targeting IL-6 receptor and NKG2A for therapeutics may prevent disease progression and decrease morbidity and mortality.Copyright © 2023 Elsevier Inc.
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Background/Objectives: Latest studies have stressed the relevance of cholesterol metabolism with susceptibility to COVID-19 and its severity. We have previously shown downregulation of low-density lipoprotein particle receptor pathway in severe COVID-19 patient surviving compared to non-surviving(1). We aimed to assess the over-time expression changes of its relevant genes in severe COVID-19 patients with different outcomes (survivors/ non-survivors). Method(s): Blood samples were taken from 39 severe COVID-19 patients without chronic diseases twice: on the day of admission to the intensive care (T1) and in one week (T2). Within 30-day follow-up 18 patients recovered and 21 patients died. 20 individuals never previously infected with COVID-19 were also enrolled. Expression levels of studied genes in peripheral blood lymphocytes were analyzed by real-time PCR with TaqMan assay. Result(s): Increased expression of STAB1 at T2, PPARgamma at T1 and CD36 at T1 and T2 were revealed in COVID-19 patients regardless of the outcome compared to controls (p < 0.05). Interesting, that in respective groups of COVID-19 patients increased STAB1, decreased PPARgamma and in survivors decreased LRP6 expression were revealed at T2 compared to T1 (p < 0.01). Also, STAB1 expression was decreased in survivors compared to non-survivors at T2 (p=0.017). Conclusion(s): Our study revealed, that patients with severe COVID-19 are characterized by increased expression of cholesterol metabolism related genes, withmore pronounced decrease of expression of these genes over time for survivors. Increased STAB1 expression may be considered as a predictor of poor COVID-19 prognosis.
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The pathogenesis of severe coronavirus infection COVID-19 is associated with activation of immune system, cytokine storm, impaired blood clotting, microvascular thrombosis, organ ischemia and multiple organ dysfunction syndrome. The role of various lymphocyte subpopulations in COVID-19 is still debated. The aim of our study was to analyze the subpopulational profile of peripheral blood lymphocytes in COVID-19 patients as compared with healthy donors. The study included 20 COVID-19 patients (11 males and 9 females,) and 26 healthy donors. Average age of the patients was 52 and 56 years, respectively. Clinical examinations were performed by standard laboratory methods. Peripheral blood lymphocytes were isolated in the Ficoll gradient. The cells were stained with antibodies to specific antigens of main lymphocyte populations, endothelial cells, and apoptotic cell markers. The analysis was performed by flow cytometry. The results showed that all patients had elevated C-reactive protein (14- to 35-fold), ferritin (1.2- to 13-fold), D-dimers (1.2- to 90-fold). 55% of men had a decrease in the absolute number of lymphocytes, in women this index was at the low normal limit. Cytometric analysis showed that, among peripheral blood lymphocytes, the proportion of functional cells expressing the CD45 marker ranged from 2 to 12% in 70% of patients, as compared with 80-99% among the donors. The proportion of CD45+ lymphocytes significantly correlated with the level of hemoglobin, but not with the levels of inflammatory biochemical markers. Among the functional lymphocytes of patients, there was a decrease in the proportion of CD3+, CD4+, CD8+T cells, increased proportion of natural killer CD56+ and the apoptotic (AnnexinV+) cell contents, but the proportion of CD19 and HLA-DR+B cells was not changed. Analysis of the lymphocyte (LC) subpopulations that did not express CD45 marker showed that this fraction contained different lymphocyte subsets with reduced expression of CD4, CD8, CD19, CD56 etc. in the blood of patients and donors. Higher percentage of endothelial cells expressing CD62P marker made the difference between patients and donors. Laboratory determination of lymphocyte subsets in blood samples of COVID-19 patients does not reflect the real severity pattern of the disease, thus requiring studies of the CD45-expressing functional cell populations.Copyright © Svirshchevskaya E.V. et al., 2023 The article can be used under the Creative Commons Attribution 4.0 License.
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The pathogenesis of severe coronavirus infection COVID-19 is associated with activation of immune system, cytokine storm, impaired blood clotting, microvascular thrombosis, organ ischemia and multiple organ dysfunction syndrome. The role of various lymphocyte subpopulations in COVID-19 is still debated. The aim of our study was to analyze the subpopulational profile of peripheral blood lymphocytes in COVID-19 patients as compared with healthy donors. The study included 20 COVID-19 patients (11 males and 9 females,) and 26 healthy donors. Average age of the patients was 52 and 56 years, respectively. Clinical examinations were performed by standard laboratory methods. Peripheral blood lymphocytes were isolated in the Ficoll gradient. The cells were stained with antibodies to specific antigens of main lymphocyte populations, endothelial cells, and apoptotic cell markers. The analysis was performed by flow cytometry. The results showed that all patients had elevated C-reactive protein (14- to 35-fold), ferritin (1.2- to 13-fold), D-dimers (1.2- to 90-fold). 55% of men had a decrease in the absolute number of lymphocytes, in women this index was at the low normal limit. Cytometric analysis showed that, among peripheral blood lymphocytes, the proportion of functional cells expressing the CD45 marker ranged from 2 to 12% in 70% of patients, as compared with 80-99% among the donors. The proportion of CD45+ lymphocytes significantly correlated with the level of hemoglobin, but not with the levels of inflammatory biochemical markers. Among the functional lymphocytes of patients, there was a decrease in the proportion of CD3+, CD4+, CD8+T cells, increased proportion of natural killer CD56+ and the apoptotic (AnnexinV+) cell contents, but the proportion of CD19 and HLA-DR+B cells was not changed. Analysis of the lymphocyte (LC) subpopulations that did not express CD45 marker showed that this fraction contained different lymphocyte subsets with reduced expression of CD4, CD8, CD19, CD56 etc. in the blood of patients and donors. Higher percentage of endothelial cells expressing CD62P marker made the difference between patients and donors. Laboratory determination of lymphocyte subsets in blood samples of COVID-19 patients does not reflect the real severity pattern of the disease, thus requiring studies of the CD45-expressing functional cell populations.Copyright © Svirshchevskaya E.V. et al., 2023 The article can be used under the Creative Commons Attribution 4.0 License.
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Case report Introduction: Good's syndrome (GS) represents an acquired adult-onset immunodeficiency associated with thymoma. GS affects patients over 40 yrs in form of recurrent infections especially with encapsulated bacteria, opportunistic viral and fungal invasions as a result of combined T/B cell deficiency. The imbalanced immunity may also provoke autoimmune phenomena and tumorigenesis. Case report: We present a 40-year- old male with a newly onset of dull thoracic pain and with no history of previous diseases. Chest CT revealed an anterior mediastinal mass in 2021, without lympadenopathy. A CT-guided core biopsy was suggestive for malignant thymoma, so the patient underwent total thymectomy. Histology indicated a thymoma of the AB type (WHO), and stage I. (Masaoka-Koga);(pT1a pNo). After surgery he was readmitted due to recurrent febrile respiratory tract infections, caused by Gram (-) bacteria or fungi;combination therapy of antibiotics and antifungal drugs was used. With suspicion of GS we determined immunoglobulin levels and the distribution of peripheral lymphocyte subsets. Hypogammaglobulinemia (IgG/A/M), and by flow cytometry markedly reduced peripheral B cells, and an inverse ratio of CD4+/CD8+ T cells were detected, confirming the diagnosis. Blast transformation assay indicated decreased T cell proliferation. Thus, following thymectomy, the patient exhibited severe T/B cell alterations with subsequent recurrent infections. Detailed autoantibody and complement analyses indicated no autoimmune laboratory abnormalities so far. There are still no effective protocols for GS therapy, except of antibiotic prophylaxis, preventive vaccination, and regular immunoglobulin replacement, so IVIG was introduced. As part of the follow-up repeated CT indicated no thymoma recurrence or metastasis. In December 2021 the vaccination refusing patient survived a severe bilateral organizing pneumonia secondary to SARS-CoV2. Conclusion(s): Incidence of the thymic epithelial tumor, thymoma is 0.15-0.33 cases/100.000/year. Depending on histology it could be linked to various immunological abnormalities. Appr. 0.2%-6% of thymomas corresponds to GS. GS, with a still elusive pathogenesis is considered as an uncommon combined immunodeficiency of adults with a variable phenotype and certain similarities to CVID. The prevalence is estimated appr. as 1/500.000. Combination of the high infection susceptibility and concomitant autoimmune diseases could make the diagnosis a challenging task.
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Background: Although many aspects of the COVID-19 disease have not yet been clarified, dysregulation of the immune system may play a crucial role in the progression of the disease. In this study, the lymphocyte subsets were evaluated in patients with different severities of COVID-19. Material(s) and Method(s): In this prospective study, the frequencies of peripheral lymphocyte subsets (CD3+, CD4+, and CD8+ T cells;CD19+ and CD20+ B cells;CD16+/CD56+ NK cells, and CD4+/CD25+/FOXP3+ regulatory T cells) were evaluated in 67 patients with confirmed COVID-19 on the first day of their admission. Result(s): The mean age of patients was 51.3 +/- 14.8 years. Thirty-two patients (47.8%) were classified as severe cases, and 11 (16.4%) were categorized as critical. The frequencies of blood lymphocytes, CD3+ cells, CD25+FOXP3+ T cells, and absolute count of CD3+ T cells, CD25+FOXP3+ T cells, CD4+ T cells, CD8+ T cells, and CD16+56+ lymphocytes were lower in more severe cases compared to the milder patients. The percentages of lymphocytes, T cells, and NK cells were significantly lower in the deceased patients. (p= 0.002 and p= 0.042, p=0.006, respectively). Conclusion(s): Findings of this cohort study demonstrated that the frequencies of CD4+, CD8+, CD25+FOXP3+ T cells, and NK cells differed in the severe cases of COVID-19. Moreover, lower frequency of T cells and NK cells could be predictors of mortality in these patients.Copyright © 2022, Shaheed Beheshti University of Medical Sciences and Health Services. All rights reserved.
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Currently, as the SARS-CoV-2 pandemic evolves, there has been increasingly more attention paid to building natural and vaccine-induced immunity against SARS-CoV-2 and related disease known as COVID-19. Widespread preventive vaccination plays an important role in effectively protecting people from viral infections and can reduce national economic costs. Purpose - to study peripheral blood cell subset composition and magnitude of humoral response in vaccinated Gam-COVID-Vac subjects. The prospective study included 352 patients, of which 194 (119 women and 75 men) underwent an immunogram study and assessed level of anti-SARS-CoV-2 antibodies. In patients, the study of the lymphocyte subset composition and estimation of anti-SARS-CoV-2 antibodies was carried out at two time points - prior to vaccination and 90 days after inoculated component 1 of the Gam-COVID-Vac vaccine. In general, vaccination was well tolerated by patients, with no serious adverse events after immunization. The reaction to the vaccine (fever, malaise, headache, local reactions) was short-term (1-2 days) and more often noted after inoculated vaccine component 2. Comparatively analyzed immunogram parameters in females before and after vaccination revealed increased relative level of T-lymphocytes (CD3+), T-helper cell subset (CD3+CD4+), increased absolute and relative level of activated CD3+CD25+ T-lymphocytes, but decreased absolute and relative level of natural killer (CD3-CD56+CD16+) and natural killer T-cell (CD3+CD56+CD16+) cell subsets as well as decreased CD147 receptor expression on T-lymphocytes. Similar patterns were also found while examining the immunogram in males exepting increased level of lymphocytes and lowered CD147 expression on both T- and B-lymphocytes. No changes in the parameters of the immune T-cell arm was found. The high efficacy of the vaccine was confirmed by development of SARS-CoV-2-specific class G antiviral antibodies in 97.5% and 92.3% of vaccinated females and males, respectively. The data obtained evidence that: 1) vaccination induces a specific humoral immune response determined three months post-vaccination, and 2) it caused no serious disturbances in the immune system functioning, which could be reflected in the peripheral blood lymphocyte subset composition. Thus, the data presented allow to conclude that Gam-COVID-Vac is effective vaccine against SARS-CoV-2 infection. Copyright © 2022 Saint Petersburg Pasteur Institute. All rights reserved.
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In the context of the COVID-19 pandemic, scientific interest is growing in studying the impact of the proposed vaccination on women's reproductive health. As is known, alterations in the state of the immune system and activation of an autoimmune response can lead to reproductive failure in women and potential complications of subsequent pregnancy. Objective(s): to evaluate the effect of the "Gam-COVID-Vac" on the immune status parameters, the relationship of their changes and the specific immune response to vaccination with the dynamics of the level of autoantibodies in women of reproductive age. The prospective study included 120 women who were vaccinated against COVID-19 with the "Gam-COVID-Vac". The criteria for inclusion in the study were: the age from 18 to 49 years, the absence of COVID-19 in the anamnesis, a negative result of a study on SARS-CoV-2 by PCR and negative results of tests for antibodies of classes G and M to SARS-CoV-2 before vaccination, the absence of pregnancy and serious somatic diseases. The patients were examined twice: immediately before vaccination and 90-100 days after the introduction of the 1st component of the vaccine. The level of IgG antibodies to SARS-CoV-2 after vaccination was assessed using ELISA. Before and after vaccination, the levels of antiphospholipid, anti-nuclear, organ-specific and antihormonal autoantibodies were determined, peripheral blood lymphocytes were immunophenotyped to determine the main subpopulations (CD3, CD4, CD8, CD19, CD5, CD16, CD56), as well as the expression of activation markers of lymphocytes (HLA-DR, CD25, CD147) using monoclonal antibodies. The effectiveness and safety of the combined vector vaccine against COVID-19 were high. Specific IgG antibodies to SARS-CoV-2 were produced in 98.3% of vaccinated women, no serious adverse reactions were observed. After vaccination, there was an increase in the level of some autoantibodies within the reference ranges, only IgM antibodies to phosphatidylethanolamine (PE) and IgG antibodies to DNA increased above the reference values. However, this increase was transient. After vaccination, the following changes in the parameters of the immunogram were observed: an increase in the content of cells with CD3+CD25+, CD19+ phenotype in peripheral blood and a decrease in the content of cells with CD56+CD16+ phenotype within the reference ranges, a decrease in CD147+/CD3+. Weak correlations were noted between these changes in immunogram parameters and the levels of some autoantibodies. The specific antiviral immune response to vaccination did not correlate with the autoimmune response. Vaccination with "Gam-COVID-Vac" is effective and safe and does not lead to disorders in the immune system. The observed increase in the level of autoantibodies to PE and DNA is transient. Changes in the parameters of the immune status within the reference ranges may be due to vaccination and the development of a specific antiviral immune response. Copyright © 2022, SPb RAACI.
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Background: Patients with hematological malignancies are at a higher risk of developing severe form and protracted course of COVID-19. Remdesivir, an inhibitor of RNA polymerase was identified early as a promising therapeutic regimen for COVID-19, while convalescent plasma (CP) therapy with anti-SARS-CoV-2 antibodies can aid the treatment of COVID-19 in B-cell depleted patients. Aims: Here we investigated whether the combination of externally administered immunoglobulins (Ig) via CP therapy and specific inhibition of viral replication might be sufficient to effectively treat B-cell depleted patients with COVID-19. Methods: We enrolled a series of 20 consecutive patients who suffered from various hematological malignancies with profound B-cell lymphopenia and COVID-19 pneumonia between December 2020 and May 2021. These patients demonstrated a profound B-cell lymphopenia based on flow cytometry analysis of peripheral blood lymphocyte subpopulations. Consequently, they showed undetectable baseline anti-SARS-CoV-2 Ig levels before CP therapy according to anti-SARS-CoV-2 nucleocapsid-and S1-RBD-specific total Ig tests. Each patient received a complete course of remdesivir and at least one unit (200 ml) of AB0 compatible convalescent plasma during their treatment for COVID-19. Results: Previous anti-CD20 therapy resulted in a more prolonged SARS-CoV-2 PCR positivity compared to other causes of Bcell lymphopenia (p=0.004). Timing of CP therapy showed a significant impact on the clinical outcome. Simultaneous use of remdesivir and CP reduced time period for oxygen weaning after diagnosis (p=0.017), length of hospital stay (p=0.007), and PCR positivity (p=0.012) compared to patients who received remdesivir and CP consecutively. In addition, time from the diagnosis to CP therapy affected the length of oxygen dependency (p<0.001) and hospital stay (p<0.0001). In those cases where there were at least ten days from the diagnosis to plasma administration, oxygen dependency was prolonged vs. patients with shorter interval (p<0.001). Summary/Conclusion: Via combined administration of remdesivir and CP, we experienced an overwhelming survival rate in COVID-19 patients with hematological malignancies. Inhibition of viral replication with passive immunization proved to be efficient and safe. Our results suggest the clear benefit of early administration of CP to avoid protracted COVID-19 disease in patients with B-cell lymphopenia.
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Background: Vaccination is considered the most promising approach for ending or containing the coronavirus disease 2019 (COVID-19) pandemic. Available vaccines have proven highly safe and effective. The morphology appearance of the blood film is an excellent tool to analyse the disease severity. In late February of 2021, a prothrombotic syndrome was observed in a small number of individuals who received the ChAdOx1 CoV-19 vaccine (AstraZeneca, University of Oxford, and Serum Institute of India), an adenoviral vector-based vaccine. This syndrome has been designated vaccine-induced immune thrombotic thrombocytopenia (VITT) with a particular and intriguing characteristic. Aims: An examination of peripheral blood smear findings in COVID-19 patients was performed in 50 consecutive patients at the first wave of the disease and prior to the full vaccination program instituted with current-acute respiratory syndrome coronavirus 2 (SARS-CoV-2) confirmed disease (PCR)-Pneumonia Methods: A morphology analysis was aimed at identifying the principal abnormalities in patients diagnosed with COVID-19. Interestingly (but not surprisingly) the most severe forms were associated with a more prominent abnormalities, including leukoerythorblastic features and secondary hemophagocytic lymphohistiocytosis, leading to an often fatal outcomes. In this study, absolute lymphopenia (despite non constant) were the predominant feature despite its not specific to COVID-19. A spectrum of variant lymphocytes is seen in COVID-19 cases, albeit constituting less than 1% prolymphocytes in most cases. Plasmacytoid lymphocytes were more common as well as acquired Pelger-Huët were significantly observed (but not representative). Results: A laboratory findings reported in association with COVID-19 included leukopenia, lymphopenia, monocytosis, neutrophilia, eosinopenia, These abnormalities mainly highlight the severe, transitory and reversible perturbation of myelopoiesis, especially in the form of accelerated and disordered granulopoiesis, in patients with COVID19 in severe symptomatic phase. The hypothesis of quantitative and qualitative abnormalities can be related to the cytokine storm and hyperinflammation, which is a pathogenic factor in the evolution of COVID19 pneumonia. Summary/Conclusion: An early identification of severe lymphoid abnormality could represent a high risk factor for poor outcomes with COVID-19. A decreased number of mature lymphocytes, and eosinophils in peripheral blood smear were observed in the severe stage patients (p <0.05). The limitation of the study is in the small numbers of the analysed population and the absent of the control comparative group. The subsequent analysis after patient received at least two dose of the vaccination shows a less severe lymphopenia (P< 0.05) and disease severity.
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Background: Besides the ability to induce antigen-specifc responses, vaccines can be endowed with immunomodulatory properties including the capacity to induce or downregulate regulatory T cells (Treg) that suppress adaptative and autoreactive immune responses (1). Objectives: We asked if an anti-SARS-CoV-2 mRNA vaccine could also induce an accumulation of Treg cells in patients with mixed cryoglobulinemia vasculitis (MCV), who have a defciency of Treg cells (2) and in healthy individuals. We also investigated immunologic variables possibly associated with a low immunogenic-ity of SARS-CoV-2 mRNA vaccine in patients with MCV (3). Methods: We analyzed peripheral blood lymphocyte subpopulations and anti-SARS-CoV-2 serological response in 24 patients with MCV and 9 Healthy donors (HD) before and after 2 weeks after the second dose of the Pfzer/BioNTech vaccine. Results: Among MCV patients we found 15 serological responders and 9 non-responders. All 5 seronegative patients treated recently with rituximab had <5 B cells/μ L, whereas the absolute B cell count was increased in 2 of 4 untreated patients due to monoclonal B cell lymphocytosis, with monoclonal cells representing more than 90% of B cells, associated with non-Hodgkin lymphoma. The percentage of pathologic CD21low B cells was signifcantly increased in seronegative patients. Before receiving the Pfzer/BioNTech vaccine, patients with MCV had a signifcantly reduced frequency of Treg cells among CD4+ T cells compared to HD. After the second dose of the vaccine, there was in MCV patients a signifcant increase in the percent and absolute count of Treg among CD4+ T cells Concerning the pre-vaccination distribution of T cells subpopulations, including the percentages and absolute counts of total CD3+, CD4+, CD8+, HLA-DR+ activated, Treg or CD56+ natural killer T cells, we could not reveal any pattern signifcantly associated with lack of serological response to vaccine. Conclusion: Our fndings show that lack of immunoreactivity in patients with MCV may be associated with expansion of pathologic B cells and that anti-SARS-CoV2 mRNA vaccine may induce an increase of Treg cells.
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Background: Patients with inflammatory bowel disease (IBD), either Crohn's disease (CD) or ulcerative colitis (UC), treated with immunosuppressants and/or biotherapy might have an altered immune response to SARS-CoV-2 infection. The aim of this study was to evaluate the incidence of COVID-19 in a French cohort of IBD patients treated with infliximab or vedolizumab during the first epidemic wave and to identify factors associated with the risk of infection. Methods: All patients with IBD treated with infliximab or vedolizumab from March to June 2020 in 16 French centres were included and followed for 6 months. At baseline, clinical, demographic, family and socio-professional data were collected. At each of their day hospitalization, patients reported the occurrence of symptoms of COVID-19, and the performance of a diagnostic test, if so. Serum was collected at each visit to detect immunisation by SARS-CoV-2 at the end of follow-up and to measure trough levels. Peripheral blood lymphocytes (PBLs) were frozen at each visit for 50% of patients to further analyse the immunological changes associated with COVID-19. Results: 1079 patients were included (CD n=690, mean age 41.6 years, mean disease duration 13.3 years). Clinical and demographic data at baseline are detailed in Tables 1 and 2, respectively. 143 patients (13.3%) had one or more co-morbidities associated with a risk of severe COVID-19 (hypertension 5.6%, chronic lung disease 5%, diabetes 2.4%, obesity 0.3%). Over the 6 months of followup, 458 patients (42%) had active disease defined by an HBI score >4 or Mayo score >2 and/or treatment optimisation (dose increase, shortening of infusion interval, addition of an immunosuppressant or change of biotherapy). 111 patients (10.2%) received corticosteroids at least occasionally (self-medication was not excluded). 341 patients (32%) were tested for COVID-19 by nasal swab, of whom 23 were positive. Three patients were hospitalized. Regarding serology, in the first 13 centres analysed hitherto (886 patients), 20 patients were seropositive at the end of follow-up before the start of the vaccination campaign (January 2021), i.e. 2.2%, compared to 4.5% in the general population at the same period according to Santé Publique France data. Conclusion: The preliminary analysis of this French cohort confirms that patients with IBD are not at higher risk of severe COVID-19 despite the use of biotherapy and repeated hospital stays. This population was significantly less infected than the general population. Clinical, demographic and immunological factors associated with SARS-CoV-2 infection are being analysed as well as factors associated with a lower incidence of infection compared to the general population. (Table Presented) (Table Presented)
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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for an ongoing global pandemic. Phase III trials have demonstrated excellent efficacies of mRNA vaccines against SARS-CoV-2 in large population studies (Baden LR, NEJM, 2021;Polack FP, NEJM, 2020). Immunosuppressed individuals such as chronic lymphocytic leukemia (CLL) patients are at risk for a suboptimal response to 2 vaccine doses (Herishanu Y, Blood, 2021). The French National Authority for Health recommends the use of a third dose in immunosuppressed patients. However, seroconversion rate after the triple-dose vaccine is not yet known. The objective of our study was to evaluate SARS-CoV-2 antibody responses after the first, second and third doses of the BNT162b2 and mRNA-1273 vaccines. Data were collected from 17 French Innovative Leukemia Organization (FILO) investigating centers and the French CLL patients' association (SILLC). SARS-CoV-2 IgG anti-Spike levels were measured at 4-6 weeks after each vaccine dose. A total of 530 patients and 14 controls were included in the study. Vaccine response was evaluated post-dose 1 for 158 CLL patients, post-dose 2, for 506 patients and post-dose 3 for 66 patients. Peripheral blood lymphocyte subsets were studied post-dose 2 by flow cytometry in 80 CLL patients and 14 controls. The median age of the patients was 71 years (range 37-93), 218 (40%) were treatment-naïve (TN), 136 (26%) had a prior CLL treatment and 176 (34%) were on therapy. Post-dose 1, the global response rate was 27% (43/158). TN patients had a response rate of 34% (23/67), similar to those who had a prior CLL treatment (33%,12/36), and higher compared to on-therapy patients (15%, 8/55, P=0.02). Post-dose 2, the global response rate was 52% (265/506). TN patients had the highest response rate of 72% (151/210) compared to previously treated patients, mostly by immunochemotherapy (60%, 78/130, P=0.02) and on-therapy patients (22%, 36/166, P<0.001) (Figure 1A). Among the 166 on-therapy patients, mostly receiving targeted agents, those receiving venetoclax monotherapy achieved a significantly higher response rate (52%, 12/23) than those treated with BTK inhibitors (BTKi) ibrutinib or acalabrutinib (22%, 23/104, P<0.001). Patients treated with venetoclax+anti-CD20 monoclonal antibodies (n=19) or venetoclax+BTKi (n=6) were all seronegative after the second dose of vaccine (Figure 1B). In multivariate analysis, the variables found to be significantly associated with seroconversion were age >65 years (OR 0.55, 95% CI 0.33-0.92, P=0.02), ongoing CLL treatment (OR 0.13, 95% CI 0.07-0.23, P<0.001) and gamma-globulins ≤6g/L (OR 0.41, 95% CI 0.19-0.88, P=0.03). Flow cytometry results suggest a differential balance of the T CD4+ cell subpopulations in Binet stage A and in patients on targeted therapy compared to healthy controls. Post-dose 2 seronegative patients were proposed a third dose and to date, 66 have been tested for the antibody response 4-6 weeks post-dose 3. The post-dose 3 response rate was 42% (28/66). TN patients and previously treated patients had a significantly higher response rate (57%, 16/28) compared to on-therapy patients (32%, 12/38, P=0.03). We further analyzed patients tested post-dose 2 with the Abbott Architect SARS-CoV-2 IgG anti-Spike assay (n=24). Those who achieved seroconversion after the third dose (n=10) had significantly higher titers post-dose 2 (median 12, IQR 3.0-40.8) compared to those who remained seronegative (n=14) (median 2.2, IQR 0.5-5.1, p<0.01), although both median values are considered below the threshold by the manufacturer. An additional cohort of 40 CLL patients who presented a SARS-CoV-2 infection prior to vaccination participated to the study and was analyzed independently. All patients achieved seroconversion after infection and a single dose of vaccine, even though 30% (n=12) had an ongoing CLL treatment. In conclusion, double-dose mRNA vaccination generated a humoral response in 52% of our CLL cohort and a third dose induced seroconversion in 42% of the patients who remained seronegat ve after the second dose. The major independent predictor of negative antibody response was ongoing treatment with BTKi. The strongest boost to immune response against the virus seems to be SARS CoV-2 infection, as a substantial increase in anti-Spike antibodies was observed in all CLL patients with prior infection, after a single dose vaccination.
ABSTRACT
Background: Patients with Inflammatory Bowel Disease (IBD), either Crohn's Disease (CD) or Ulcerative Colitis (UC), treated with immunosuppressants and/or biotherapy might have an altered immune response to SARS-CoV-2 infection. The aim of this study was to evaluate the incidence of COVID-19 in a French cohort of IBD patients treated with infliximab or vedolizumab during the first epidemic wave and to identify factors associated with the risk of infection. Methods: All patients with IBD treated with infliximab or vedolizumab from March to June 2020 in 16 French centres were included and followed for 6 months. At baseline, clinical, demographic, family and socio-professional data were collected. At each of their day hospitalization, patients reported the occurrence of symptoms of COVID-19, and the performance of a diagnostic test, if so. Serum was collected at each visit to detect immunisation by SARS-CoV-2 at the end of follow-up and to measure trough levels. Peripheral blood lymphocytes (PBLs) were frozen at each visit for 50% of patients to further analyse the immunological changes associated with COVID-19. Results: 1079 patients were included (CD n=690, mean age 41.6 years, mean disease duration 13.3 years). Clinical and demographic data at baseline are detailed in Tables 1 and 2, respectively. 143 patients (13.3%) had one or more co-morbidities associated with a risk of severe COVID-19 (hypertension 5.6%, chronic lung disease 5%, diabetes 2.4%, obesity 0.3%). Over the 6 months of follow-up, 458 patients (42%) had active disease defined by an HBI score >4 or Mayo score >2 and/or treatment optimisation (dose increase, shortening of infusion interval, addition of an immunosuppressant or change of biotherapy). 111 patients (10.2%) received corticosteroids at least occasionally (self-medication was not excluded). 341 patients (32%) were tested for COVID-19 by nasal swab, of whom 23 were positive. Three patients were hospitalized. Regarding serology, in the first 13 centres analysed hitherto (886 patients), 20 patients were seropositive at the end of follow-up before the start of the vaccination campaign (January 2021), i.e. 2.2%, compared to 4.5% in the general population at the same period according to Santé Publique France data. Conclusion: The preliminary analysis of this French cohort confirms that patients with IBD are not at higher risk of severe COVID-19 despite the use of biotherapy and repeated hospital stays. This population was significantly less infected than the general population. Clinical, demographic and immunological factors associated with SARS-CoV-2 infection are being analysed as well as factors associated with a lower incidence of infection compared to the general population.