ABSTRACT
The COVID-19 pandemic has altered people's lifestyles around the world. Prevention of recurrent episodes of the disease and mitigation of its consequences are especially associated with effective post-COVID-19 rehabilitation in patients. The aim of the study was to evaluate the effects of the drug Likopid (glucosaminylmuramyl dipeptide, GMDP) for post-COVID-19 rehabilitation in patients. Material and methods. Patients who recovered from mild to moderate COVID-19 (n=60, mean age 54+/- 11.7 years) were randomized into the observation group (n=30, 15 men and 15 women) who received 2 courses of Licopid (1 mg twice a day) and the comparison group (n=30, 15 men and 15 women). Analysis of the phenotypic and functional characteristics of the innate immune cellular factors was carried out before the start of immunomodulatory therapy, immediately after the end of the course, and also after 6 months observations. In order to assess the quality of life of all patients, we used the SF-36 Health Status Survey and the Hospital Anxiety and Depression Scale questionnaires. Results. During assessing the effect of immunomodulatory therapy on the parameters of innate immunity of patients at the stage of rehabilitation after COVID-19, an increase in the protective cytolytic activity of CD16+ and CD8+Gr+ cells, as well as a persistent increase in TLR2, TLR4 and TLR9 expression was found, which indicates the antigen recognition recovery and presentation at the level of the monocytic link of the immune system. The use of GMDP as an immunomodulatory agent resulted in an 8-fold reduction in the frequency and severity of respiratory infections due to an increase in the total monocyte count. As a result of assessing patients' quality of life against the background of the therapy, a positive dynamic in role functioning was revealed in patients. In the general assessment of their health status, an increase in physical and mental well-being was noted during 6 months of observation. The comparison group showed no improvement in the psychoemotional state. Discussion. The study demonstrated the effectiveness of GMDP immunomodulatory therapy in correcting immunological parameters for post-COVID-19 rehabilitation in patients. The data obtained are consistent with the previously discovered ability of GMDP to restore impaired functions of phagocytic cells and induce the expression of their surface activation markers, which in turn contributes to an adequate response to pathogens. Conclusion. The study revealed that the correction of immunological parameters with the use of GMDP in COVID-19 convalescents contributed not only to a decrease in the frequency and severity of respiratory infections, but also to an improvement in the psycho-emotional state of patients, and a decrease in anxiety and depression.Copyright © Eco-Vector, 2023. All rights reserved.
ABSTRACT
Neutrophilic granulocytes (NG) are the main drivers of pathological inflammation in COVID-19. Objective. To specify the mechanisms of immunopathogenesis of COVID-19 based on a comparative immunological study of the number and phenotype of CD16+SD62L+CD11b+CD63- and CD16+SD62L+CD11b+CD63+ subsets with an assessment of their effector functions against changing profile of NG-associated cytokines IL-8, IL-18, IL-17A, VEGF-A, IFNalpha, and IFNgamma. Patients and methods. In patients with moderate-to-severe and severe COVID-19, we determined IL-1beta, TNFalpha, IL-6, IL-8, IL-18, IL-17A, VEGF-A, IFNalpha, and IFNgamma (ELISA), the phenotype of CD16+SD62L+CD11b+CD63- and CD16+SD62L+CD11b+CD63+ subsets, NF-kappaB-NG (CYTOMICS FC500), phagocytically active NG (%), neutrophil extracellular traps (NETs), NG in apoptosis, and the activity of NADPH oxidase. Results. In COVID-19 against the background of IFNalpha and IFNgamma production blockade and high levels of NG-associated IL-8, IL-18, IL-17A, VEGF-A, a reduction in the number of mature and functionally active CD16brightSD62LbrightCD11bbrightCD63-NG subsets was revealed, as well as an increase in the number of CD16dimSD62LdimSD11bbrightCD63-NG subsets with an immunosuppressive phenotype and CD16brightSD62LbrightSD11bbrightCD63bright-NG subsets with high cytotoxic activity and ability to form NETs, a decrease in the percentage of phagocytically active NG and an increase in the activity of NADPH oxidase, NETs, and NG in apoptosis. Conclusion. IFNalpha deficiency provokes a hyperergic response of NG-associated cytokines, which leads to the formation of uncontrolled immune inflammation involving NG subsets with an immunosuppressive and cytotoxic phenotype, exacerbating the course of COVID-19. The use of recombinant IFNalpha-2b with antioxidants (Viferon) in the early stages of the disease can help to restore immune homeostasis, normalize the level of NG-associated cytokines, reduce NERTs, and achieve good clinical efficacy.Copyright © 2022, Dynasty Publishing House. All rights reserved.
ABSTRACT
Objective This study aimed to investigate the immune response of a pregnant woman who recovered from the coronavirus disease 2019 (COVID_RS) by using single-cell transcriptomic profiling of peripheral blood mononuclear cells (PBMCs) and to analyze the properties of different immune cell subsets. Methods PBMCs were collected from the COVID_RS patient at 28 weeks of gestation, before a cesarean section. The PBMCs were then analyzed using single-cell RNA sequencing. The transcriptional profiles of myeloid, T, and natural killer (NK) cell subsets were systematically analyzed and compared with those of healthy pregnant controls from a published single-cell RNA sequencing data set. Results We identified major cell types such as T cells, B cells, NK cells, and myeloid cells in the PBMCs of our COVID_RS patient. The increase of myeloid and B cells and decrease of T cells and NK cells in the PBMCs in this patient were quite distinct compared with that in the control subjects. After reclustering and Augur analysis, we found that CD16 monocytes and mucosal-Associated invariant T (MAIT) cells were mostly affected within different myeloid, T, and NK cell subtypes in our COVID_RS patient. The proportion of CD16 monocytes in the total myeloid population was increased, and the frequency of MAIT cells in the total T and NK cells was significantly decreased in the COVID-RS patient. We also observed significant enrichment of gene sets related to antigen processing and presentation, T-cell activation, T-cell differentiation, and tumor necrosis factor superfamily cytokine production in CD16 monocytes, and enrichment of gene sets related to antigen processing and presentation, response to type II interferon, and response to virus in MAIT cells. Conclusion Our study provides a single-cell resolution atlas of the immune gene expression patterns in PBMCs from a COVID_RS patient. Our findings suggest that CD16-positive monocytes and MAIT cells likely play crucial roles in the maternal immune response against severe acute respiratory syndrome coronavirus 2 infection. These results contribute to a better understanding of the maternal immune response to severe acute respiratory syndrome coronavirus 2 infection and may have implications for the development of effective treatments and preventive strategies for the coronavirus disease 2019 in pregnant women.Copyright © Wolters Kluwer Health, Inc. All rights reserved.
ABSTRACT
Background: SARS CoV 2 infection alters the immunological profiles of natural killer (NK) cells. However, whether NK anti-viral functions (direct cytotoxicity and/or antibody-dependent cell cytotoxicity (ADCC)) are impaired during severe COVID-19 and what host factors modulate these functions remain unclear. Method(s): Using functional assays, we examined the ability of NK cells from SARS-CoV-2 negative controls (n=12), mild COVID-19 patients (n=26), and hospitalized COVID-19 patients (n=41) to elicit direct cytotoxicity and ADCC [NK degranulation by flow] against cells expressing SARS-CoV-2 antigens. SARS-CoV- 2 N antigen plasma load was measured using an ultra-sensitive Simoa assay. We also phenotypically characterized the baseline expression of NK activating (CD16 and NKG2C), maturation (CD57), and inhibitory (NKG2A and the glyco-immune negative checkpoint Siglec-9) by flow cytometry. Finally, an anti-Siglec-9 blocking antibody was used to examine the impact of Siglec-9 expression on anti-SARS-CoV-2-specific ADCC [degranulation and target cell lysis]. Result(s): NK cells from hospitalized COVID-19 patients degranulate less against SARS-CoV-2-antigen-expressing cells (in direct cytolytic and ADCC assays) than did cells from mild COVID-19 patients or negative controls (Fig. 1A). The lower NK degranulation was associated with higher plasma levels of SARS-CoV-2 N-antigen (P<=0.02). Phenotypic and functional analyses showed that NK cells expressing Siglec-9 elicited higher ADCC than Siglec-9- NK cells (P<0.05;Fig. 1B). Consistently, Siglec-9+ NK cells expressed an activated and mature phenotype with higher expression of CD16, CD57, and NKG2C, and lower expression of NKG2A, than Siglec-9- NK cells (P<=0.03). These data are consistent with the concept that the NK cell subpopulation expressing Siglec-9 is highly activated and cytotoxic. However, the Siglec-9 molecule itself is an inhibitory receptor that restrains NK cytotoxicity during cancer and other infections. Indeed, blocking Siglec-9 significantly enhanced the ADCC-mediated NK degranulation and lysis of SARS-CoV-2-antigen-positive target cells (P<=0.05;Fig. 1C). Conclusion(s): These data support a model (Fig. 1D) in which the Siglec-9+ CD56dim NK subpopulation is cytotoxic even while being restrained by the inhibitory effects of Siglec-9. However, alleviating the Siglec-9-mediated restriction on NK cytotoxicity can further improve NK immune surveillance and presents an opportunity to develop novel immunotherapeutic tools against SARS-CoV-2 infected cells. (Figure Presented).
ABSTRACT
Neutrophilic granulocytes (NG) are the main drivers of pathological inflammation in COVID-19. Objective. To specify the mechanisms of immunopathogenesis of COVID-19 based on a comparative immunological study of the number and phenotype of CD16+SD62L+CD11b+CD63- and CD16+SD62L+CD11b+CD63+ subsets with an assessment of their effector functions against changing profile of NG-associated cytokines IL-8, IL-18, IL-17A, VEGF-A, IFNalpha, and IFNgamma. Patients and methods. In patients with moderate-to-severe and severe COVID-19, we determined IL-1beta, TNFalpha, IL-6, IL-8, IL-18, IL-17A, VEGF-A, IFNalpha, and IFNgamma (ELISA), the phenotype of CD16+SD62L+CD11b+CD63- and CD16+SD62L+CD11b+CD63+ subsets, NF-kappaB-NG (CYTOMICS FC500), phagocytically active NG (%), neutrophil extracellular traps (NETs), NG in apoptosis, and the activity of NADPH oxidase. Results. In COVID-19 against the background of IFNalpha and IFNgamma production blockade and high levels of NG-associated IL-8, IL-18, IL-17A, VEGF-A, a reduction in the number of mature and functionally active CD16brightSD62LbrightCD11bbrightCD63-NG subsets was revealed, as well as an increase in the number of CD16dimSD62LdimSD11bbrightCD63-NG subsets with an immunosuppressive phenotype and CD16brightSD62LbrightSD11bbrightCD63bright-NG subsets with high cytotoxic activity and ability to form NETs, a decrease in the percentage of phagocytically active NG and an increase in the activity of NADPH oxidase, NETs, and NG in apoptosis. Conclusion. IFNalpha deficiency provokes a hyperergic response of NG-associated cytokines, which leads to the formation of uncontrolled immune inflammation involving NG subsets with an immunosuppressive and cytotoxic phenotype, exacerbating the course of COVID-19. The use of recombinant IFNalpha-2b with antioxidants (Viferon) in the early stages of the disease can help to restore immune homeostasis, normalize the level of NG-associated cytokines, reduce NERTs, and achieve good clinical efficacy.Copyright © 2022, Dynasty Publishing House. All rights reserved.
ABSTRACT
Background: Long COVID can be developed by individuals after an infection with SARS-CoV-2 as described by the WHO. Although this condition is more commonly described in adults, it can occur in children and adolescents with a wide range of estimated prevalence of 1-25%. Little is known about the role of the immune system in long COVID. However, one of the main hypotheses about the underlying mechanism in long COVID is that there is an immune and inflammatory dysregulation that persists after the acute infection. The objective of this study is to compare immune cells populations, and inflammatory biomarkers in paediatric populations with and without long COVID. Method(s): We analyzed 55 blood samples from the pediaCOVID cohort (Hospital Germans Trias i Pujol), which includes more than 130 children diagnosed with long COVID and 23 controls. We measured different immune cell populations using spectral cytometry with a panel of 37 cellular markers, and 42 inflammatory markers using Luminex or ELISA. EdgeR was used for statistical analysis of the spectral data;p-values of inflammatory markers were calculated using the likelihood ratio test and they were corrected for multiple comparisons. Result(s): The study cohort had a median age of 14.3 (IQR, 12.5-15.2) and 69.1% female. Patients had at least 3 symptoms associated with long COVID (median [IQR];10 [7-16]). The most common symptom was asthenia/fatigue (98.2%). Compared to the control cohort, children with long COVID had increased numbers of CD4+CD8+ T cells, IgA+CD21+CD27+ memory B cells, and IgA+CD21-CD27- memory B cells, while CD4+ TEMRA cells (CD45RA+, CCR7-), intermediate monocytes (CD14+, CD16+) and classical monocytes (CD14+, CD16-) were decreased (all p< 0.05;q=n.s.). None of the 42 inflammatory biomarkers showed significant differences between children with and without long COVID. Conclusion(s): The results of this study suggest that specific populations of peripheral blood immune cells might be involved in the mechanisms underlying prolonged COVID in children and adolescents. The increase in both IgA+CD21-CD27- and IgA+CD21+CD27+ memory B cells could be associated with the persistence of viral antigen in the gut and/or gut dysbiosis. Moreover, the decrease in CD4+ TEMRA cells could be related to autoantibodies against G-protein coupled receptors (GPCRs), since this cell population can express GPR56, and autoantibodies against GPCRs were previously reported to be elevated in adults with long COVID.
ABSTRACT
Background: The hyperactivated subsets of neutrophilic granulocytes (NG) play a negative role on the development, course and outcome of the COVID-19. With this position, NG are interesting target for creation of new therapeutic approaches. Method(s): The study group (SG) included 31 patients with moderate COVID-19, aged 61(57;71)years. Before and after incubation of whole blood with HP (106 g/l, 60 min., 37degreeC) 2 NG subsets were tested: major -CD64- CD16+CD32+CD11b+, minor -CD64+ CD16+CD32+CD11b+ with detection of their phenotypes using MFI (FC 500, Beckman Coulter, USA). Phagocytic activity of NG against S. aureus was studied. Comparison group(CG) consisted 22 healthy volunteers 58 (57;70) years old. Result(s): In patients with COVID-19 the minor subset of NG CD64+CD16+CD32+CD11b+(% ) was significantly increased in 5-fold versus the CG (p <= 0.005) and had transformed phenotype: CD64dimCD16brightCD32midCD11bbright versus CD64midCD16dimCD32midCD11b brightin the CG (p <= 0.005). This transformed phenotype had high expression levels of receptors of activation: CD16 and CD11b, that suggested its negative hyperactivation. The % of the major subset NG did not change (p > 0.05), but an altered phenotype of CD64-CD16brightCD32midCD11bdimNG was determine against CD64-CD16dimCD32midCD11boNG in the CG. Defects of phagocytic activities of NG were found: the decrease of % an active phagocytic NG, absorbing and digesting abilities (p1 <= 0.005;p2 <= 0.005;p3 <= 0.005).The effects of HP in vitro were shown: the significant decreasing of NG minor subset (%) in comparison with it's level before HP influences (p <= 0.005) reached to the values of the CG (p > 0.05). In parallel, the phenotype of minor subset changed to CD64brightCD16dimCD32midCD11bo, with decreasing level of CD16 to normal (p > 0.05). The transformed phenotype of the major subset was changed to CD64-CD16midCD32brightCD11 bmidNG: a decrease in MFI CD16, an increase in MFI CD32 and MFI CD11b (p1 <= 0.005;p2 <= 0.005;p3 <= 0.005). The restoration of defective phagocytic function of NG was received. Conclusion(s): Immunomodulating effects of HP in vitro on NG in moderate COVID-19 were shown: positive remodeling of the phenotype of minor aggressive NG subset from hyperactivated to normal and the restoration of defective NG phagocytic function.
ABSTRACT
The long term consequences of severe COVID-19 in the lungs remain speculative, however interstitial abnormalities in these patients may arise. In this study previously identified fibrotic markers from the BAL were evaluated in PostCOVID-19 patients. 26 patients were referred for evaluation of respiratory symptoms and/or abnormalities on HRCT, on average 5.3 months from the acute disease phase, to the Post COVID-19 clinic. 20 patients showed persistent radiological findings with fibrotic changes and/or altered respiratory function. Bronchoalveolar lavage cellular composition was determined by MGG staining and CD45, CD14, CD11c, CD163 and Osteopontin staining. Airway monocytes were identified by SSClo/CD45+ parameters and surface expression of CD11c, CD14 and CD16 by flow cytometry. FVC% and DLCO% were used as measures of disease severity. Collectively, monocyte percentages in the BAL were associated with lower FVC% (Rs=-0.53,p=0.02). Importantly, patients with DLCO% below 60 showed higher monocyte infiltration (p=0.015). CD14 positivity on monocytes was more pronounced in patients with DLCO% below 60, while CD16 and CD11c were not associated with DLCO. Increased Osteopontin expression in airway macrophages was also linked with lower DLCO% levels (Rs=-0.661, p=0.019), in contrast to CD163 macrophage expression which tended to be higher in patients with higher DLCO%. Neutrophils were negatively associated with DLCO% in Post-COVID-19 patients (Rs=-0.62,p=0.01). Airway immune cell populations from BAL were associated with Post-COVID-19 induced altered respiratory function.
ABSTRACT
Introduction. The continuing circulation of influenza A (H1N1)pdm2009 virus poses a threat of a new epidemic rise. It is known that influenza A (H1N1)pdm2009 is characterized by a severe course, development of life-threatening complications, and high mortality, which is associated not only with the biological features of the pathogen, but also with the induction of deep immunosuppression, especially the interferon system and the cellular-type immune response. The role of influenza in the development of severe forms of the new coronavirus infection COVID-19 has been revealed. The increase of the number of virus strains resistant to various classes of antiviral drugs is of unfavorable importance. This requires the development of new approaches to the treatment of influenza A (H1N1)pdm2009 with the combined use of drugs with complex antiviral and immunocorrective activity. Purpose. To substantiate the combination therapy of influenza A (H1N1)pdm2009 in children using oseltamivir (Tamiflu) and recombinant interferon-alpha2b (Viferon). Materials and methods. Clinical and laboratory examination of 85 children aged from 3 to 5 years with moderate (43) and severe forms (42) of influenza A (H1N1)pdm2009 was carried out. Results and discussion. In patients with severe forms of A(H1N1)pdm2009 influenza, a higher frequency of anamnestic risk groups (85.7%), frequent development of febrile fever (100%), severe intoxication symptoms (100%), symptoms of laryngitis (28.6%), tracheitis (57.1%), bronchitis (76.2%), dyspeptic (42.9%) and cerebral syndromes (62.9%), other complications (80.9%) were revealed. In these patients, more significant changes of the indicators of the cellular type of the immune response were found - the decrease of CD3, CD4, CD8, the humoral type of immune response - the increase of CD20, IgM, circulating immune complexes, the decrease of IgA and IgG, innate immunity factors - the decrease of the metabolic activity of neutrophils, moderate increase of CD16. The combined administration of recombinant interferon-alpha2b (Viferon) and oseltamivir (tamiflu) compared with oseltamivir (tamiflu) monotherapy reduced the duration of fever (Me 2, IQI 1-4 days and Me 3, IQI 2-4 days), intoxication (Me 3, IQI 2-4.5 days and Me 4.5, IQI 3-7 days), symptoms of rhinitis (Me 5, IQI 4-7 days and Me 6.5, IQI 4.5-7.5 days), pharyngitis (Me 5, IQI 4-7 days and Me 6.5, IQI 4.5-7.5 days), tracheitis (Me 2, IQI 1-3 days and Me 3.5, IQI 2-4 days), bronchitis (Me 3, IQI 2-5 days and Me 5, IQI 4-6 days). In this group, the complications developed less frequently (4.5% and 33.3%);there was the decrease of hospitalization time (Me 5, IQI 4-7 days and Me 6.5, IQI 5-7 days). There was the increase of the number of children, who (after 10 days from the start of therapy) had sanitation of the nasopharynx from the virus (90.9% and 61.9%). Conclusion. The high frequency of anamnestic risk groups and the induction of deep immunosuppression, especially the cellular component of immunity, are the cause of the formation of severe forms of influenza A (H1N1)pdm2009. This justified the appointment of combination therapy using the neuraminidase inhibitor oseltamivir (Tamiflu) and recombinant interferon-alpha2b (Viferon), which not only inhibits virus replication, but also has immunocorrective activity against the interferon system and cellular immunity. The high efficiency of the combined administration of recombinant interferon-alpha2b (Viferon) and oseltamivir (Tamiflu) lets to recommend the inclusion of these drugs in the treatment of severe forms of influenza A(H1N1)pdm2009 in children.Copyright © 2020, Professionalnye Izdaniya. All rights reserved.
ABSTRACT
Introduction. The continuing circulation of influenza A (H1N1)pdm2009 virus poses a threat of a new epidemic rise. It is known that influenza A (H1N1)pdm2009 is characterized by a severe course, development of life-threatening complications, and high mortality, which is associated not only with the biological features of the pathogen, but also with the induction of deep immunosuppression, especially the interferon system and the cellular-type immune response. The role of influenza in the development of severe forms of the new coronavirus infection COVID-19 has been revealed. The increase of the number of virus strains resistant to various classes of antiviral drugs is of unfavorable importance. This requires the development of new approaches to the treatment of influenza A (H1N1)pdm2009 with the combined use of drugs with complex antiviral and immunocorrective activity. Purpose. To substantiate the combination therapy of influenza A (H1N1)pdm2009 in children using oseltamivir (Tamiflu) and recombinant interferon-alpha2b (Viferon). Materials and methods. Clinical and laboratory examination of 85 children aged from 3 to 5 years with moderate (43) and severe forms (42) of influenza A (H1N1)pdm2009 was carried out. Results and discussion. In patients with severe forms of A(H1N1)pdm2009 influenza, a higher frequency of anamnestic risk groups (85.7%), frequent development of febrile fever (100%), severe intoxication symptoms (100%), symptoms of laryngitis (28.6%), tracheitis (57.1%), bronchitis (76.2%), dyspeptic (42.9%) and cerebral syndromes (62.9%), other complications (80.9%) were revealed. In these patients, more significant changes of the indicators of the cellular type of the immune response were found - the decrease of CD3, CD4, CD8, the humoral type of immune response - the increase of CD20, IgM, circulating immune complexes, the decrease of IgA and IgG, innate immunity factors - the decrease of the metabolic activity of neutrophils, moderate increase of CD16. The combined administration of recombinant interferon-alpha2b (Viferon) and oseltamivir (tamiflu) compared with oseltamivir (tamiflu) monotherapy reduced the duration of fever (Me 2, IQI 1-4 days and Me 3, IQI 2-4 days), intoxication (Me 3, IQI 2-4.5 days and Me 4.5, IQI 3-7 days), symptoms of rhinitis (Me 5, IQI 4-7 days and Me 6.5, IQI 4.5-7.5 days), pharyngitis (Me 5, IQI 4-7 days and Me 6.5, IQI 4.5-7.5 days), tracheitis (Me 2, IQI 1-3 days and Me 3.5, IQI 2-4 days), bronchitis (Me 3, IQI 2-5 days and Me 5, IQI 4-6 days). In this group, the complications developed less frequently (4.5% and 33.3%);there was the decrease of hospitalization time (Me 5, IQI 4-7 days and Me 6.5, IQI 5-7 days). There was the increase of the number of children, who (after 10 days from the start of therapy) had sanitation of the nasopharynx from the virus (90.9% and 61.9%). Conclusion. The high frequency of anamnestic risk groups and the induction of deep immunosuppression, especially the cellular component of immunity, are the cause of the formation of severe forms of influenza A (H1N1)pdm2009. This justified the appointment of combination therapy using the neuraminidase inhibitor oseltamivir (Tamiflu) and recombinant interferon-alpha2b (Viferon), which not only inhibits virus replication, but also has immunocorrective activity against the interferon system and cellular immunity. The high efficiency of the combined administration of recombinant interferon-alpha2b (Viferon) and oseltamivir (Tamiflu) lets to recommend the inclusion of these drugs in the treatment of severe forms of influenza A(H1N1)pdm2009 in children.Copyright © 2020, Professionalnye Izdaniya. All rights reserved.
ABSTRACT
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.
ABSTRACT
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.
ABSTRACT
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.
ABSTRACT
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: 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. © 2022, SPb RAACI.
ABSTRACT
A resposta imune a infeccao por SARS-CoV-2 durante o periodo gravidico puerperal e as alteracoes que podem aumentar o risco de complicacoes maternas, fetais e neonatais ainda nao sao bem caracterizadas. Para isso, foram determinados, atraves de citometria de fluxo, niveis perifericos de linfocitos T-totais (CD3+), T-auxiliar (CD3+/CD4+), T-citotoxico (CD3+/CD8+), linfocitos B (CD19+), celulas NK (CD16+/56+) e NKT (CD3+/CD16-56+) em gestantes e puerperas com suspeita de COVID-19 com o objetivo de identificar potenciais alteracoes imunologicas induzidas pelo coronavirus. Foram utilizadas amostras de sangue periferico de mulheres que realizaram RT-PCR para COVID-19 entre maio de 2021 e marco de 2022. As amostras foram coletadas em tres maternidades publicas do Rio Grande do Norte na admissao para parto e no puerperio imediato nos casos suspeitos. O sangue foi coletado em tubos contendo EDTA para a realizacao da citometria de fluxo, utilizando o analisador de fluorescencia celular ativado (FACScan) e o software Cell Quest. Os linfocitos foram identificados por alta expressao de CD45 e baixa dispersao lateral, utilizando as seguintes combinacoes de 3 cores de anticorpo monoclonal: isotiocianato de uoresceina (FITC), ficoeritrina (PE) e Proteina Clorofila Piridina (PerCP). Cinquenta mulheres precisaram realizar o RT-PCR e 32 (64%) testaram positivo para COVID-19. Gestantes e puerperas infectadas pelo SARS-CoV-2 apresentaram niveis elevados de celulas T citotoxicas, mediana (ME) = 495,0;intervalo interquartil (IIQ) = 391,5, quando comparadas com pacientes nao infectadas, ME=356,2;IIQ=297,8;p=0.032. Com relacao a quantidade das celulas NK, ME=159,1;IIQ=220,4, e dos linfocitos B, ME=126,7;IIQ=186.4, as contagens foram significativamente mais baixas no grupo com menos de 30 dias de infeccao, em comparacao com o grupo em que o RT-PCR foi negativo, ME=280,8;IIQ=214,9;p=0,021 e ME=323,9;IIQ=365,5;p=0,045, respectivamente. Gestantes e puerperas com COVID-19 apresentam maior numero de linfocitos T citotoxicos no sangue periferico e menor numero de celulas NK e linfocitos B. Considerando que gravidez e pos-parto alteram fisiologicamente o sistema imunologico e que esse estudo transversal nao permite analisar causalidade entre infeccao e alteracoes celulares, mais estudos sao necessarios para elucidar as alteracoes causadas pela COVID-19 no sistema imunologico durante o periodo gravidico puerperal, para confirmar se a infeccao viral compromete a imunidade, aumentando o risco de complicacoes para o binomio mae-feto. Declaramos que nao houve apoio financeiro e (ou) material recebido para o desenvolvimento deste trabalho. Copyright © 2022
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SESSION TITLE: Long COVID: It Can Take Your Breath Away SESSION TYPE: Original Investigations PRESENTED ON: 10/16/2022 10:30 am - 11:30 am PURPOSE: Nearly one third of patients who recover from acute SARS-CoV2 infection will experience persistent symptoms known as Post-Acute Sequelae of SARS-CoV2 infection (PASC). Among individuals with PASC, pulmonary complications are common. Patients with severe COVID-19 have observed high systemic levels of cytokines and profound immune dysregulation. During acute SARS-CoV-2 infection, CD169, a type I interferon-inducible receptor, is overexpressed on monocytes. CD169+ macrophages are involved in hyperinflammation, viral spread, and immune regulatory function. Although monocytes/macrophage play a pivotal role in inflammation during acute SARS-CoV2 infection, less is known about how these cells contribute to lung sequelae and immunopathology in PPASC. METHODS: Cross section study conducted comparing three groups: participants with PPASC with a reduced predicted diffusing capacity for carbon monoxide (DLCOc, <80%) on pulmonary function test;participants who fully recovered (RC) from SARS-CoV-2 with no residual symptoms;and healthy participants (HC) negative for SARS-CoV-2. These groups were age and gender matched from similar community settings. Among the groups, we compared the numbers of monocyte subsets (classical, intermediate and non-classical monocytes) and monocyte activation by assessing CD169 expression using flow cytometry analysis of peripheral blood mononuclear cells. RESULTS: Ten participants enrolled in each group with median age 53 years, 38.7% males. We found that PPASC and RC had higher median levels of total circulating monocytes than in HC, 59374 (IQR: 43161-91523), 65661 (40049-89490) and 2689 (1378-28125), respectively (p<0.01, p<0.01). Regarding monocyte subsets based on CD14+CD16+ expression, we observed significant increase in the number of classical (CD14+CD16-), intermediate (CD14+CD16+), and non-classical (CD14-CD16+) monocytes in PPASC and RC, compared to HC (p<0.01, p=0.01, respectively). There was no difference in the number of monocytes and in the proportion of each subset between PPASC and RC. We observed increased CD169+ monocyte counts in PPASC and RC compared to HC 56.8 (23.0-92.5), 66.75 (4.3-968.7), and 2.095 (0-16.9), respectively (p<0.01, p<0.01). Furthermore, a rising trend of CD169 expression was observed in intermediate and non-classical monocytes from PPASC compared to HC. In addition, CD169+ non-classical monocytes were positively correlated with D-dimer levels in PPASC (ρ=0.72, p=0.03). CONCLUSIONS: This study present evidence that patients with COVID infection exhibit persistent alterations in monocytes even after the acute COVID infection period. Correlation of D-dimer level with CD169+ non-classical monocytes in patients with PPASC provides a further rational for determining if a specific monocyte subset contributes to the pathogenesis of PPASC. CLINICAL IMPLICATIONS: Further studies are required for understanding of the development and progression of PPASC. DISCLOSURES: No relevant relationships by Dominic Chow No relevant relationships by Logan Dean No relevant relationships by Gehan Devendra No relevant relationships by FRITZIE IGNO No relevant relationships by Boonyanudh Jiyarom No relevant relationships by Juwon Park No relevant relationships by Parthav Shah No relevant relationships by Cecilia Shikuma No relevant relationships by Chathura Siriwardhana
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Introduction The COVID-19 pandemic had a significant impact on morbidity and mortality in Germany challenging intensive care unit (ICU) capacities across the country. To delineate the high variability in disease severity, clinical presentation and outcome, we focused on cellular regulators of inflammation and resolution on a single cell level to gain a deeper understanding of the patient's individual inflammatory response and their impact on survival. Methods Written informed consent was obtained from all patients and healthy controls. The study was approved by the local ethical review board (Az249/20 S-EB). To characterize the peripheral immune landscape, we performed a 14 parameter flow cytometric analysis of PBMCs of 32 critically ill CoV2 patients and a targeted HPLC-MS/MS of previously sorted PBMCs. All data was analyzed and correlated to clinical parameters and patients' outcomes (Fig. 4). Results As known [1], computational analysis of flow cytometry revealed a strong decrease of B Cell and CD8+ T Cell ratios and an increase of monocytes in critically ill CoV19 patients compared to control (Fig. 1A). Interestingly, non-survivors displayed an increased ratio of CD16+ monocytes and proinflammatory IL- 1beta in monocytes, B and T cells, while HLADR receptors were downregulated correlating with clinical outcome (Fig. 1B). Not unexpectedly, we saw a major increase in proinflammatory lipidmediators, such as PGJ2, PGF2, TxB2 (Fig. 1C). Additionally, our analysis revealed that not only the amount, but also the source of those mediators was shifted from CD16 to classical CD14 monocytes, even more pronounced in non-survivors. CD16 monocytes of CoV2 patients, however, lost the ability to generate proresolving lipidmediators depending on cytochrome p450 (Cyp450) or soluble epoxide hydrolase (sEH) TxB2 (Fig. 1D). Conclusions Even though a lot of insight into CoV2 has been gained over the last 2 years, relatively little is known about the impact of immune changes in critically ill patients. With this study, we are the first to attribute lipid mediators to specific cell types. Our findings show that TxB2 in critically ill CoV2 patients, which correlates with mortality in CoV2 [2], is produced mainly in CD14 monocytes. We further report that specifically non-survivors display increased ratios of non-classical CD16 monocytes, which are impaired to generate a major class of lipidmediators depending on Cyp450. In conclusion, these data provide evidence that not only the absolute amount of pro- and anti-inflammatory mediators, but also the cellular source of these mediators remains key to fully understand their role in critically ill CoV2 patients. (Figure Presented).
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Background: Several studies have demonstrated immunogenicity after COVID-19 vaccination in patients with autoimmune rheumatic diseases (AIRD) [1], but the differences between mRNA-based and vector vaccines and the cellular responses to COVID-19 vaccines according to distinct immunogenicity in AIRD patients are still unclear. Objectives: To investigate the differences in efficacy and safety between the vector vaccine ChAdOx1 nCoV-19/AZD1222 (Oxford-AstraZeneca) and mRNA-based vaccine mRNA-1273 (Moderna) in patients with AIRD, and to explore the cell-cell interactions between high and low anti-SARS-CoV-2 IgG levels in patients with rheumatic arthritis (RA) by single-cell RNA sequencing (scRNA-seq). Methods: From September 16 to November 15, 2021, we consecutively enrolled 243 participants aged ≥20 years with AIRD who received COVID-19 vaccination, of whom 113 were immunized with AZD1222 and 130 with mRNA-1273. The level of serum IgG antibodies to the SARS-CoV-2 receptor-binding domain on the spike protein S1 subunit was quantifed by electrochemiluminescence immuno-assay at 4-6 weeks after vaccination. Moreover, peripheral blood mononuclear cells were isolated from two RA patient with high anti-SARS-CoV-2 IgG level and four RA patients with low level for scRNA-seq and cell-cell communication signal was analyzed by CellChat. Results: The anti-SARS-CoV-2 IgG seropositivity rate was 78.8% (89/113) for AZD1222 and 83.1% (108/130) for mRNA-1273. The level of anti-SARS-CoV-2 IgG was higher in patients who received mRNA-1273 than in those who received AZD1222 (β: 30.15, 95% CI: 11.67-48.63, p=0.002) (Table 1). Prednisolone-equivalent dose >5 mg/day and methotrexate (MTX) use in AIRD patients, and non-anti-tumor necrosis factor (TNF)-α biologics and Janus kinase (JAK) inhibitor use in RA patients were associated with inferior immunogenicity. ScRNA-seq revealed CD16-monocytes were predominant in RA patients with high anti-SARS-CoV2-IgG antibody level, and enriched pathways related to antigen presentation via major histocompatibility complex class II (MHC class II) were found (Figure 1). HLA-DRA and CD4 interaction was vigorous among all identifed MHC-II pathway and was enhanced in high anti-SARS-CoV2-IgG antibody group. Conclusion: mRNA-1273 and AZD1222 vaccines exhibited differential immunogenicity in patients with AIRD. Enriched pathways related to antigen presentation via MHC class II in CD16-monocytes might be associated with higher anti-SARS-CoV2-IgG level in RA patients and further study is warranted.
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SARS-CoV-2 can cause a decrease in the number of lymphocytes and their functional activity. In patients with COVID-19, especially with a severe course of the disease, a decrease in the quantitative composition of the main populations of lymphocytes is recorded. These indicators do not recover for a long time after recovery. However, it is still not known how long the quantitative and qualitative changes in the composition of lymphocytes will last and whether the severity of the infection affects this process. The aim of our study was to assess the quantitative and qualitative composition of the main populations and subpopulations of lymphocytes in patients with a new coronavirus infection of varying severity. 65 patients with a new coronavirus infection were examined. The average age of the subjects was 47.3±14.5 years. The volunteers were divided into three groups according to the severity of the infection: asymptomatic (n = 21);moderate (n = 32);severe (n = 12). The relative and absolute number of T-lymphocytes (CD3+), T-helper cells (CD3+CD4+), cytotoxic lymphocytes (CD3+CD8+), natural killers (CD3–CD16+CD56+), TNK-lymphocytes (CD3+CD16–CD56+) and B-lymphocytes (CD45+CD19+) were determined. To calculate the percentage of lymphocytes, whole blood was lysed with OPTILYSE C solution (Beckman Coulter, USA) and stained with monoclonal antibodies CD3+-FITC/CD8+-ECD/CD4+PC5/CD16+CD56+PE and CD45+-Pacific Blue/CD19+-PC5 (Beckman Coulter, USA). Cytofluorometry was performed on a flow cytofluorometer “Navios™” (Beckman Coulter, USA). The results of our studies showed that there were no statistically significant changes in the relative and absolute number of immunocompetent cells in asymptomatic patients with a new coronavirus infection, compared with the control group. With an average severity of the disease, a decrease in the relative and absolute content of CD3+ and CD8+ lymphocytes was revealed, these indicators were restored to control values six months after recovery. In patients with severe infection, there was a decrease in the relative and absolute number of T cells and cytotoxic lymphocytes. These values remained significantly below normal for six months and returned to normal only seven to eight months after recovery. Also, the volunteers of this group were found to have a decrease in the number of natural killers and TNK cells. Thus, the data obtained by us indicate that pathological changes concerning the relative and absolute number of the main populations and subpopulations of lymphocytes in patients with COVID-19 depend on the severity of the disease. The number of T-lymphocytes, cytotoxic lymphocytes, natural killer cells, that is, populations of cells that play a crucial role in effective antiviral protection, has been reduced in those who have undergone a new coronavirus infection in moderate and severe form. This information can be useful for expanding methodological approaches to the diagnosis, treatment of a new coronavirus infection, as well as measures for the rehabilitation of those who have suffered it.
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Background: Although respiratory failure is the hallmark of severe disease, it is increasingly clear that Coronavirus Disease 2019 (COVID-19) is a multi-system disorder. The presence of gastrointestinal (GI) involvement by Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has been suggested by epidemiological, clinical, non-human primate, in-vitro (enteroid) and ex-vivo (human biopsy) studies. Having recently documented persistence of SARS-CoV-2 within the intestinal epithelium 7 months after infection, here we aimed to study mucosal immune cell abnormalities in individuals with prior history of COVID-19. Methods: Individuals with previous COVID-19 diagnosis (by either RT–PCR or seroconversion) and controls (without RT-PCR or serological evidence of prior COVID-19 infection) undergoing endoscopic evaluation were recruited into the study (Table 1). Colonic and small intestinal (duodenal and ileal) biopsies were analyzed by multiparameter flow cytometry for mucosal immune cell populations including myeloid cells (classical and non-classical monocytes, dendritic cell subsets), T cells (subsets and activation state), B cells (including plasma cells) and NK cells. Persistence of viral antigens was determined by immunofluorescence microscopy (n=30) using a previously published anti-nucleocapsid (NP) antibody. Results: Thirty subjects with a previous history of COVID-19 (post-COVID), median of 4 months from diagnosis (range 1-10 months), were recruited and compared with 40 normal volunteer (NV) controls. Relative to controls, post-COVID subjects displayed higher frequencies of classical (CD14+) monocytes in both, the colon and the small bowel, while significantly higher frequencies of conventional dendritic cells (cDC)1 (lin-HLA-DRhiCD14- CD11c+CD141+) and cDC2 (lin-HLA-DRhiCD14-CD11c+CD1c+) were noted in the colon. Among NK subsets, CD56bright CD16- NK cells were significantly higher in the colon of post-COVID subjects. Among T cell subsets, CD8+ tissue resident memory T cells (CD8+CD69+CD103+) were significantly increased in colon of post-COVID subjects compared to NV. Among B cell subsets, plasma cells (CD3-CD27+CD38hi) trended higher (p= 0.06), while mucosal B cells (CD3-CD19+) were significantly lower in the terminal ileum of post-COVID subjects compared to NV. Finally, with IF, we detected SARS-CoV-2 NP in 10 out of 30 (33%) of post-COVID subjects (Figure 1). Conclusion: Innate and adaptive immune cell abnormalities persist in the intestinal mucosa of post-COVID subjects for up to 10 months and may reflect viral persistence or immune cell dysregulation in the intestines. These findings have major implications for understanding the pathogenesis of long-term sequelae of COVID-19, including long-haul COVID.(Table Presented)(Figure Presented)