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1.
BMC Infect Dis ; 22(1): 575, 2022 Jun 27.
Article in English | MEDLINE | ID: covidwho-1910278

ABSTRACT

BACKGROUND: Convalescent plasma (CP) has been widely used to treat COVID-19 and is under study. However, the variability in the current clinical trials has averted its wide use in the current pandemic. We aimed to evaluate the safety and efficacy of CP in severe coronavirus disease 2019 (COVID-19) in the early stages of the disease. METHODS: A randomized controlled clinical study was conducted on 101 patients admitted to the hospital with confirmed severe COVID-19. Most participants had less than 14 days from symptoms onset and less than seven days from hospitalization. Fifty patients were assigned to receive CP plus standard therapy (ST), and 51 were assigned to receive ST alone. Participants in the CP arm received two doses of 250 mL each, transfused 24 h apart. All transfused plasma was obtained from "super donors" that fulfilled the following criteria: titers of anti-SARS-CoV-2 S1 IgG ≥ 1:3200 and IgA ≥ 1:800 antibodies. The effect of transfused anti-IFN antibodies and the SARS-CoV-2 variants at the entry of the study on the overall CP efficacy was evaluated. The primary outcomes were the reduction in viral load and the increase in IgG and IgA antibodies at 28 days of follow-up. The per-protocol analysis included 91 patients. RESULTS: An early but transient increase in IgG anti-S1-SARS-CoV-2 antibody levels at day 4 post-transfusion was observed (Estimated difference [ED], - 1.36; 95% CI, - 2.33 to - 0.39; P = 0.04). However, CP was not associated with viral load reduction in any of the points evaluated. Analysis of secondary outcomes revealed that those patients in the CP arm disclosed a shorter time to discharge (ED adjusted for mortality, 3.1 days; 95% CI, 0.20 to 5.94; P = 0.0361) or a reduction of 2 points on the WHO scale when compared with the ST group (HR adjusted for mortality, 1.6; 95% CI, 1.03 to 2.5; P = 0.0376). There were no benefits from CP on the rates of intensive care unit admission (HR, 0.82; 95% CI, 0.35 to 1.9; P = 0.6399), mechanical ventilation (HR, 0.66; 95% CI, 0.25 to 1.7; P = 0.4039), or mortality (HR, 3.2; 95% CI, 0.64 to 16; P = 0.1584). Anti-IFN antibodies and SARS-CoV-2 variants did not influence these results. CONCLUSION: CP was not associated with viral load reduction, despite the early increase in IgG anti-SARS-CoV-2 antibodies. However, CP is safe and could be a therapeutic option to reduce the hospital length of stay. Trial registration NCT04332835.


Subject(s)
COVID-19 , Coronavirus Infections , Pneumonia, Viral , Antibodies, Viral , Betacoronavirus , COVID-19/therapy , Humans , Immunization, Passive , Immunoglobulin A , Immunoglobulin G/therapeutic use , SARS-CoV-2 , Treatment Outcome
2.
J Infect Dis ; 2022 Mar 21.
Article in English | MEDLINE | ID: covidwho-1816124
3.
J Transl Med ; 20(1): 129, 2022 03 16.
Article in English | MEDLINE | ID: covidwho-1745447

ABSTRACT

Autoimmunity has emerged as a characteristic of the post-COVID syndrome (PCS), which may be related to sex. In order to further investigate the relationship between SARS-CoV-2 and autoimmunity in PCS, a clinical and serological assessment on 100 patients was done. Serum antibody profiles against self-antigens and infectious agents were evaluated by an antigen array chip for 116 IgG and 104 IgM antibodies. Thirty pre-pandemic healthy individuals were included as a control group. The median age of patients was 49 years (IQR: 37.8 to 55.3). There were 47 males. The median post-COVID time was 219 (IQR: 143 to 258) days. Latent autoimmunity and polyautoimmunity were found in 83% and 62% of patients, respectively. Three patients developed an overt autoimmune disease. IgG antibodies against IL-2, CD8B, and thyroglobulin were found in more than 10% of the patients. Other IgG autoantibodies, such as anti-interferons, were positive in 5-10% of patients. Anti-SARS-CoV-2 IgG antibodies were found in > 85% of patients and were positively correlated with autoantibodies, age, and body mass index (BMI). Few autoantibodies were influenced by age and BMI. There was no effect of gender on the over- or under-expression of autoantibodies. IgG anti-IFN-λ antibodies were associated with the persistence of respiratory symptoms. In summary, autoimmunity is characteristic of PCS, and latent autoimmunity correlates with humoral response to SARS-CoV-2.


Subject(s)
Autoimmunity , COVID-19 , Adult , Antibodies, Viral/blood , Humans , Immunoglobulin M/blood , Male , Middle Aged , SARS-CoV-2
4.
J Infect Dis ; 225(12): 2155-2162, 2022 06 15.
Article in English | MEDLINE | ID: covidwho-1713676

ABSTRACT

BACKGROUND: The immunopathological pathways enabling post-coronavirus disease 2019 (COVID-19) syndrome (PCS) development are not entirely known. We underwent a longitudinal analysis of patients with COVID-19 who developed PCS aiming to evaluate the autoimmune and immunological status associated with this condition. METHODS: Thirty-three patients were included for longitudinal clinical and autoantibody analyses, 12 of whom were assessed for cytokines and lymphocyte populations. Patients were followed for 7-11 months after acute COVID-19. Autoimmune profile and immunological statuses were evaluated mainly by enzyme-linked-immunosorbent assays and flow cytometry. RESULTS: Latent autoimmunity and overt autoimmunity persisted over time. A proinflammatory state was observed in patients with PCS characterized by up-regulated interferon-α, tumor necrosis factor-α, granulocyte colony-stimulating factor (G-CSF), interleukin (IL)-17A, IL-6, IL-1ß, and IL-13, whereas interferon-γ-induced protein 10 (IP-10) was decreased. In addition, PCS was characterized by increased levels of Th9, CD8+ effector T cells, naive B cells, and CD4+ effector memory T cells. Total levels of immunoglobulin G S1-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies remained elevated over time. CONCLUSIONS: The clinical manifestations of PCS are associated with the persistence of a proinflammatory and effector phenotype induced by SARS-CoV-2 infection. This long-term persistent immune activation may contribute to the development of latent and overt autoimmunity. Results suggest the need to evaluate the role of immunomodulation in the treatment of PCS.


Subject(s)
Autoimmunity , COVID-19 , COVID-19/complications , Cytokines , Humans , Inflammation , Interferon-gamma , SARS-CoV-2
5.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-292820

ABSTRACT

Background: The immunopathological pathways enabling post-COVID syndrome (PCS) development are not entirely known. We underwent a longitudinal analysis of patients with COVID-19 who developed PCS aiming to evaluate the autoimmune and immunological status associated with this condition. Methods Thirty-three patients were included for longitudinal clinical and autoantibody analyses of whom 12 patients were assessed for cytokines and lymphocyte populations. Patients were followed during 7-11 months after acute COVID-19. Autoimmune profile and immunological status were evaluated mainly by enzyme-linked-immunosorbent assays and flow cytometry. Results Latent autoimmunity and overt autoimmunity persisted over time. A proinflammatory state was observed in patients with PCS characterized by upregulated IFN-α, TNF-α, G-CSF, IL-17A, IL-6, IL-1β, and IL-13, whereas IP-10 was decreased. In addition, PCS was characterized by increased levels of Th9, CD8+ effector T cells, naive B cells, and CD4+ effector memory T cells. Total levels of IgG S1-SARS-CoV-2 antibodies remained elevated over time. Discussion The clinical manifestations of PCS are associated with the persistence of a proinflammatory, and effector phenotype induced by SARS-CoV-2 infection. This long-term persistent immune activation may contribute to the development of latent and overt autoimmunity. Results suggest the need to evaluate the role of immunomodulation in the treatment of PCS.

6.
BMC Infect Dis ; 21(1): 1170, 2021 Nov 20.
Article in English | MEDLINE | ID: covidwho-1526605

ABSTRACT

BACKGROUND: Convalescent plasma has been widely used to treat COVID-19 and is under investigation in numerous randomized clinical trials, but results are publicly available only for a small number of trials. The objective of this study was to assess the benefits of convalescent plasma treatment compared to placebo or no treatment and all-cause mortality in patients with COVID-19, using data from all available randomized clinical trials, including unpublished and ongoing trials (Open Science Framework, https://doi.org/10.17605/OSF.IO/GEHFX ). METHODS: In this collaborative systematic review and meta-analysis, clinical trial registries (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform), the Cochrane COVID-19 register, the LOVE database, and PubMed were searched until April 8, 2021. Investigators of trials registered by March 1, 2021, without published results were contacted via email. Eligible were ongoing, discontinued and completed randomized clinical trials that compared convalescent plasma with placebo or no treatment in COVID-19 patients, regardless of setting or treatment schedule. Aggregated mortality data were extracted from publications or provided by investigators of unpublished trials and combined using the Hartung-Knapp-Sidik-Jonkman random effects model. We investigated the contribution of unpublished trials to the overall evidence. RESULTS: A total of 16,477 patients were included in 33 trials (20 unpublished with 3190 patients, 13 published with 13,287 patients). 32 trials enrolled only hospitalized patients (including 3 with only intensive care unit patients). Risk of bias was low for 29/33 trials. Of 8495 patients who received convalescent plasma, 1997 died (23%), and of 7982 control patients, 1952 died (24%). The combined risk ratio for all-cause mortality was 0.97 (95% confidence interval: 0.92; 1.02) with between-study heterogeneity not beyond chance (I2 = 0%). The RECOVERY trial had 69.8% and the unpublished evidence 25.3% of the weight in the meta-analysis. CONCLUSIONS: Convalescent plasma treatment of patients with COVID-19 did not reduce all-cause mortality. These results provide strong evidence that convalescent plasma treatment for patients with COVID-19 should not be used outside of randomized trials. Evidence synthesis from collaborations among trial investigators can inform both evidence generation and evidence application in patient care.


Subject(s)
COVID-19 , COVID-19/therapy , Humans , Immunization, Passive , Randomized Controlled Trials as Topic , SARS-CoV-2 , Treatment Outcome
7.
Autoimmun Rev ; 20(11): 102947, 2021 Nov.
Article in English | MEDLINE | ID: covidwho-1401230

ABSTRACT

The existence of a variety of symptoms with a duration beyond the acute phase of COVID-19, is referred to as post-COVID syndrome (PCS). We aimed to report a series of patients with PCS attending a Post-COVID Unit and offer a comprehensive review on the topic. Adult patients with previously confirmed SARS-CoV-2 infection and PCS were systematically assessed through a semi-structured and validated survey. Total IgG, IgA and IgM serum antibodies to SARS-CoV-2 were evaluated by an electrochemiluminescence immunoassay. A systematic review of the literature and meta-analysis were conducted, following PRISMA guidelines. Univariate and multivariate methods were used to analyze data. Out of a total of 100 consecutive patients, 53 were women, the median of age was 49 years (IQR: 37.8-55.3), the median of post-COVID time after the first symptoms was 219 days (IQR: 143-258), and 65 patients were hospitalized during acute COVID-19. Musculoskeletal, digestive (i.e., diarrhea) and neurological symptoms including depression (by Zung scale) were the most frequent observed in PCS patients. A previous hospitalization was not associated with PCS manifestation. Arthralgia and diarrhea persisted in more than 40% of PCS patients. The median of anti-SARS-CoV-2 antibodies was 866.2 U/mL (IQR: 238.2-1681). Despite this variability, 98 patients were seropositive. Based on autonomic symptoms (by COMPASS 31) two clusters were obtained with different clinical characteristics. Levels of anti-SARS-CoV-2 antibodies were not different between clusters. A total of 40 articles (11,196 patients) were included in the meta-analysis. Fatigue/muscle weakness, dyspnea, pain and discomfort, anxiety/depression and impaired concentration were presented in more than 20% of patients reported. In conclusion, PCS is mainly characterized by musculoskeletal, pulmonary, digestive and neurological involvement including depression. PCS is independent of severity of acute illness and humoral response. Long-term antibody responses to SARS-CoV-2 infection and a high inter-individual variability were confirmed. Future studies should evaluate the mechanisms by which SARS-CoV-2 may cause PCS and the best therapeutic options.


Subject(s)
Antibodies, Viral , COVID-19 , Adult , Female , Humans , Immunoglobulin G , Lung , Middle Aged , SARS-CoV-2
9.
J Transl Autoimmun ; 4: 100091, 2021.
Article in English | MEDLINE | ID: covidwho-1117210

ABSTRACT

Autoimmune responses mediated by autoantibodies have been observed in SARS-CoV-2 infection. Herein, we evaluate the presence of rheumatic, thyroid and phospholipid autoantibodies in sera samples from 120 adult hospitalized patients with COVID-19 in comparison to pre-pandemic samples from 100 healthy individuals. In addition, to estimate the frequency of these autoantibodies in COVID-19, a meta-analysis of selected articles was conducted. Hospitalized patients with COVID-19 had latent autoimmunity characterized by a high frequency of anti-thyroid peroxidase antibodies, rheumatoid factor (RF), anti-cyclic citrullinated peptide third generation antibodies, antinuclear antibodies (ANAs), IgM anti-ß2-glycoprotein I (ß2GP1) and IgM anti-cardiolipin antibodies. The meta-analysis confirmed our results, with RF and ANAs being the most common autoantibodies. In addition, cluster analysis revealed that those patients with high frequency of RF, IgM anti-ß2GP1 antibodies and ANAs had a longer hospital stay, required more vasopressors during hospitalization, and were more likely to develop critical disease. These data suggest that latent autoimmunity influences the severity of COVID-19, and support further post-COVID studies in order to evaluate the development of overt autoimmunity.

10.
J Autoimmun ; 118: 102598, 2021 03.
Article in English | MEDLINE | ID: covidwho-1065282

ABSTRACT

Convalescent plasma (CP) has emerged as a treatment for COVID-19. However, the composition and mechanism of action are not fully known. Therefore, we undertook a two-phase controlled study in which, first the immunological and metabolomic status of recovered and severe patients were evaluated. Secondly, the 28-day effect of CP on the immune response in severe patients was assessed. Nineteen recovered COVID-19 patients, 18 hospitalized patients with severe disease, and 16 pre-pandemic controls were included. Patients with severe disease were treated with CP transfusion and standard therapy (i.e., plasma recipients, n = 9) or standard therapy alone (n = 9). Clinical and biological assessments were done on day 0 and during follow-up on days 4, 7, 14, and 28. Clinical parameters, viral load, total immunoglobulin (Ig) G and IgA anti-S1-SARS-CoV-2 antibodies, neutralizing antibodies (NAbs), autoantibodies, cytokines, T and B cells, and metabolomic and lipidomic profiles were examined. Total IgG and IgA anti-S1-SARS-CoV-2 antibodies were key factors for CP selection and correlated with NAbs. In severe COVID-19 patients, mostly interleukin (IL)-6 (P = <0.0001), IL-10 (P = <0.0001), IP-10 (P = <0.0001), fatty acyls and glycerophospholipids were higher than in recovered patients. Latent autoimmunity and anti-IFN-α antibodies were observed in both recovered and severe patients. COVID-19 CP induced an early but transient cytokine profile modification and increases IgG anti-S1-SARS-CoV-2 antibodies. At day 28 post-transfusion, a decrease in activated, effector and effector memory CD4+ (P < 0.05) and activated and effector CD8+ (P < 0.01) T cells and naïve B cells (P = 0.001), and an increase in non-classical memory B cells (P=<0.0001) and central memory CD4+ T cells (P = 0.0252) were observed. Moreover, IL-6/IFN-γ (P = 0.0089) and IL-6/IL-10 (P = 0.0180) ratios decreased in plasma recipients compared to those who received standard therapy alone. These results may have therapeutic implications and justify further post-COVID-19 studies.


Subject(s)
Antibodies, Neutralizing/blood , Antibodies, Viral/blood , COVID-19/therapy , Interleukin-10/blood , Interleukin-6/blood , SARS-CoV-2 , Adult , B-Lymphocytes/metabolism , CD4-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/metabolism , COVID-19/blood , Female , Humans , Immunization, Passive , Male , Middle Aged , Severity of Illness Index
12.
J Autoimmun ; 114: 102506, 2020 11.
Article in English | MEDLINE | ID: covidwho-599328

ABSTRACT

Coronavirus disease 2019 (COVID-19) has been categorized as evolving in overlapping phases. First, there is a viral phase that may well be asymptomatic or mild in the majority, perhaps 80% of patients. The pathophysiological mechanisms resulting in minimal disease in this initial phase are not well known. In the remaining 20% of cases, the disease may become severe and/or critical. In most patients of this latter group, there is a phase characterized by the hyperresponsiveness of the immune system. A third phase corresponds to a state of hypercoagulability. Finally, in the fourth stage organ injury and failure occur. Appearance of autoinflammatory/autoimmune phenomena in patients with COVID-19 calls attention for the development of new strategies for the management of life-threatening conditions in critically ill patients. Antiphospholipid syndrome, autoimmune cytopenia, Guillain-Barré syndrome and Kawasaki disease have each been reported in patients with COVID-19. Here we present a scoping review of the relevant immunological findings in COVID-19 as well as the current reports about autoinflammatory/autoimmune conditions associated with the disease. These observations have crucial therapeutic implications since immunomodulatory drugs are at present the most likely best candidates for COVID-19 therapy. Clinicians should be aware of these conditions in patients with COVID-19, and these observations should be considered in the current development of vaccines.


Subject(s)
Autoimmune Diseases/immunology , Betacoronavirus/immunology , Coronavirus Infections/immunology , Cytokine Release Syndrome/immunology , Pneumonia, Viral/immunology , Adaptive Immunity/genetics , Autoimmune Diseases/diagnosis , Autoimmune Diseases/therapy , Autoimmune Diseases/virology , Betacoronavirus/isolation & purification , COVID-19 , COVID-19 Testing , Clinical Laboratory Techniques , Coronavirus Infections/diagnosis , Coronavirus Infections/epidemiology , Coronavirus Infections/therapy , Critical Illness , Cytokine Release Syndrome/diagnosis , Cytokine Release Syndrome/therapy , Cytokine Release Syndrome/virology , Female , Genetic Predisposition to Disease , Humans , Immunity, Innate/genetics , Immunization, Passive/methods , Inflammation Mediators/blood , Inflammation Mediators/immunology , Macrophage Activation/genetics , Macrophage Activation/immunology , Male , Pandemics , Pneumonia, Viral/diagnosis , Pneumonia, Viral/epidemiology , Pneumonia, Viral/therapy , Risk Factors , SARS-CoV-2 , Severity of Illness Index , Sex Factors
13.
Autoimmun Rev ; 19(7): 102554, 2020 Jul.
Article in English | MEDLINE | ID: covidwho-176092

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible of the coronavirus disease 2019 (COVID-19) pandemic. Therapeutic options including antimalarials, antivirals, and vaccines are under study. Meanwhile the current pandemic has called attention over old therapeutic tools to treat infectious diseases. Convalescent plasma (CP) constitutes the first option in the current situation, since it has been successfully used in other coronaviruses outbreaks. Herein, we discuss the possible mechanisms of action of CP and their repercussion in COVID-19 pathogenesis, including direct neutralization of the virus, control of an overactive immune system (i.e., cytokine storm, Th1/Th17 ratio, complement activation) and immunomodulation of a hypercoagulable state. All these benefits of CP are expected to be better achieved if used in non-critically hospitalized patients, in the hope of reducing morbidity and mortality.


Subject(s)
Antibodies, Neutralizing/therapeutic use , Coronavirus Infections/therapy , Pneumonia, Viral/therapy , Betacoronavirus , COVID-19 , Clinical Trials as Topic , Coronavirus Infections/immunology , Humans , Immunization, Passive , Lymphocytes/immunology , Pandemics , Pneumonia, Viral/immunology , Retrospective Studies , SARS-CoV-2
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