RESUMO
BACKGROUND: There is a need to understand the relationship between COVID-19 Convalescent Plasma (CCP) anti-SARS-CoV-2 IgG levels and clinical outcomes to optimize CCP use. This study aims to evaluate the relationship between recipient baseline clinical status, clinical outcomes, and CCP antibody levels. METHODS: The study analyzed data from the COMPILE study, a meta-analysis of pooled individual patient data from 8 randomized clinical trials (RCTs) assessing the efficacy of CCP vs. control, in adults hospitalized for COVID-19 who were not receiving mechanical ventilation at randomization. SARS-CoV-2 IgG levels, referred to as 'dose' of CCP treatment, were retrospectively measured in donor sera or the administered CCP, semi-quantitatively using the VITROS Anti-SARS-CoV-2 IgG chemiluminescent immunoassay (Ortho-Clinical Diagnostics) with a signal-to-cutoff ratio (S/Co). The association between CCP dose and outcomes was investigated, treating dose as either continuous or categorized (higher vs. lower vs. control), stratified by recipient oxygen supplementation status at presentation. RESULTS: A total of 1714 participants were included in the study, 1138 control- and 576 CCP-treated patients for whom donor CCP anti-SARS-CoV2 antibody levels were available from the COMPILE study. For participants not receiving oxygen supplementation at baseline, higher-dose CCP (/control) was associated with a reduced risk of ventilation or death at day 14 (OR = 0.19, 95% CrI: [0.02, 1.70], posterior probability Pr(OR < 1) = 0.93) and day 28 mortality (OR = 0.27 [0.02, 2.53], Pr(OR < 1) = 0.87), compared to lower-dose CCP (/control) (ventilation or death at day 14 OR = 0.79 [0.07, 6.87], Pr(OR < 1) = 0.58; and day 28 mortality OR = 1.11 [0.10, 10.49], Pr(OR < 1) = 0.46), exhibiting a consistently positive CCP dose effect on clinical outcomes. For participants receiving oxygen at baseline, the dose-outcome relationship was less clear, although a potential benefit for day 28 mortality was observed with higher-dose CCP (/control) (OR = 0.66 [0.36, 1.13], Pr(OR < 1) = 0.93) compared to lower-dose CCP (/control) (OR = 1.14 [0.73, 1.78], Pr(OR < 1) = 0.28). CONCLUSION: Higher-dose CCP is associated with its effectiveness in patients not initially receiving oxygen supplementation, however, further research is needed to understand the interplay between CCP anti-SARS-CoV-2 IgG levels and clinical outcome in COVID-19 patients initially receiving oxygen supplementation.
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Anticorpos Antivirais , Soroterapia para COVID-19 , COVID-19 , Imunização Passiva , Imunoglobulina G , SARS-CoV-2 , Humanos , COVID-19/terapia , COVID-19/imunologia , COVID-19/mortalidade , Anticorpos Antivirais/sangue , SARS-CoV-2/imunologia , Masculino , Pessoa de Meia-Idade , Feminino , Imunoglobulina G/sangue , Idoso , Resultado do Tratamento , Adulto , Estudos Retrospectivos , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
INTRODUCTION: When a new disease occurs, one of the most affordable remedies is drugs containing specific antibodies to this infectious agent. The use of such drugs is aimed at reducing the amount of the pathogen in the macroorganism and the associated reduction in the severity of the symptoms of the disease or recovery. The purpose of this review is to analyze the experience of using immunoglobulins and monoclonal antibodies in the treatment of COVID-19 patients during the pandemic. RESULTS AND CONCLUSION: The two main groups of medical protective agents that block the penetration of the SARS-CoV-2 virus into permissive cells are drugs obtained from blood plasma of convalescents (immunoglobulin) and human monoclonal antibodies. The first group of drugs in the treatment of COVID-19 includes blood plasma of convalescents, which can be successfully used for emergency prevention. The main disadvantage of using blood plasma convalescents is the difficulty of standardization due to the different content of specific antibodies in donors. Another disadvantage is the undesirable side effects in recipients that occur after plasma administration. An alternative approach to COVID-19 therapy is the use of humanized and genetically engineered human monoclonal antibodies against certain epitopes of the SARS-CoV-2 virus. For example, monoclonal antibodies against receptor-binding domain of the S-protein, which prevents the virus from entering permissive cells and interrupts the development of infection. The advantages of these drugs are their safety, high specific activity, and the possibility of standardization. However, the complexity of their production and high cost make them inaccessible for mass use in practical medicine.
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Anticorpos Monoclonais , COVID-19 , SARS-CoV-2 , Humanos , SARS-CoV-2/imunologia , SARS-CoV-2/efeitos dos fármacos , COVID-19/imunologia , COVID-19/terapia , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais/imunologia , Anticorpos Antivirais/imunologia , Anticorpos Antivirais/uso terapêutico , Imunoglobulinas/uso terapêutico , Imunoglobulinas/imunologia , Tratamento Farmacológico da COVID-19 , Soroterapia para COVID-19 , Imunização Passiva , Pandemias , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/imunologia , Antivirais/uso terapêuticoRESUMO
Primary humoral deficiency and secondary B-cell depletion may lead to prolonged Sars-Cov-2 infection due to a decreased viral clearance. Prolonged infection is mainly driven by the lack of anti-Sars-Cov-2 immunoglobulin (IVIg) especially in patients with no vaccine response. Anti-spike immunoglobulin can be provided by infusion of convalescent patients' plasma: recent studies highlighted that commercial immunoglobulin show high titers of neutralizing IgG. We conducted a single center retrospective cohort. We included 9 patients (6 males, median age 74 years old): one patient with X-linked agammaglobulinemia and 8 patients treated with rituximab (2 granulomatosis with polyangiitis, 1 neuromyelitis optica, 4 low grade B-cell lymphoma and 1 EBV post-transplant lymphoproliferative disorder). Mean serum globulin was 4 ± 1.6 g/L. 7/8 had received at least 3 doses of mRNA anti-Sars-Cov-2 vaccine (median 4) with no response (anti-Spike IgG 0 for 6 patients). In this specific population requiring oxygen therapy but no intensive care support, the administration of IVIg was well tolerated and provided a swift improvement of clinical status, a significant decrease of inflammation associated to the an improvement of radiological patterns. Our results suggest that immunoglobulin could be used as a salvage therapy as an alternative to convalescent plasma but highly stringent patient selection is required due to the worldwide shortage of IVIg.
Assuntos
COVID-19 , Hospedeiro Imunocomprometido , Imunoglobulinas Intravenosas , SARS-CoV-2 , Humanos , Masculino , Idoso , Feminino , Imunoglobulinas Intravenosas/uso terapêutico , Imunoglobulinas Intravenosas/administração & dosagem , COVID-19/imunologia , COVID-19/terapia , SARS-CoV-2/imunologia , Estudos Retrospectivos , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Resultado do Tratamento , Imunização Passiva , Soroterapia para COVID-19 , Tratamento Farmacológico da COVID-19RESUMO
BACKGROUND AND OBJECTIVES: Initial therapeutic efforts to treat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) included the use of plasma from convalescent donors containing anti-SARS-CoV-2 antibodies. High-neutralizing antibody titres are required for therapeutic efficacy. This study aims to show that immunoadsorption followed by tangential flow filtration can be used to obtain antibody concentrates with high-neutralizing capacities. MATERIALS AND METHODS: Eligible donors (n = 10, five males and three females) underwent immunoadsorption using adsorber columns specific for human antibodies. Glycine-washed out eluates of 1.5 L volume were further concentrated by tangential flow filtration using 30 kDa ultrafiltration membranes. The same membranes were applied for diafiltrations to exchange residual glycine for 0.9% normal saline. RESULTS: Antibody concentrates were obtained within 8 h from the start of donation and had 4.58 ± 1.95, 3.28 ± 1.28 and 2.02 ± 0.92 times higher total IgG, IgA and IgM concentrations, 3.29 ± 1.62 and 3.74 ± 0.6 times higher SARS-CoV-2 N and S antibody concentrations and 3.85 ± 1.71 times higher SARS-CoV-2 S-specific IgG concentrations compared to the donors' peripheral blood. The specific SARS-CoV-2 virus neutralization capacities increased in all but one concentrate. All antibody concentrates (50-70 mL final volume) passed microbiological tests, were free of hazardous glycine levels and could be stored at -80°C and 4°C for 1 year with 20 ± 3% antibody loss. CONCLUSION: Immunoadsorption followed by tangential flow filtration is a feasible procedure to collect IgG, IgA and IgM as well as SARS-CoV-2 N- and S-specific antibody concentrates of low volume, free of albumin and coagulation factors. Whether these concentrates can be used as passive immunisation in infected patients remains to be elucidated.
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Anticorpos Neutralizantes , Anticorpos Antivirais , COVID-19 , SARS-CoV-2 , Humanos , COVID-19/terapia , COVID-19/imunologia , COVID-19/sangue , Masculino , SARS-CoV-2/imunologia , Feminino , Anticorpos Antivirais/sangue , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Adulto , Técnicas de Imunoadsorção , Pessoa de Meia-Idade , Doadores de Sangue , Pandemias , Imunoglobulina G/sangue , Soroterapia para COVID-19 , Imunoglobulina M/sangue , Imunização PassivaRESUMO
As an antibody-based therapy, plasma therapy has been used as an emergency therapeutic strategy against severe acute respiratory syndrome coronavirus type 2 infection. Due to the critical role of macrophages in coronavirus disease-19 (COVID-19)-associated hyperinflammation, the main objective of this study was to assess the effect of plasma transfusion on the expression levels of the inflammatory biomarkers involved in activation and pulmonary infiltration of macrophages. The target population included 50 severe hospitalized COVID-19 patients who were randomly assigned into 2 groups, including intervention and control. Serum levels of chemokine (C-C motif) ligand (CCL)-2, CCL-3, tumor necrosis factor (TNF)-α, and interleukin (IL)-6 were measured by enzyme-linked immunosorbent assay. Moreover, quantitative real-time polymerase chain reaction (PCR) was carried out to assess the relative expression of nuclear factor (NF)-κB1, NF-κB2, nuclear factor erythroid 2 p45-related factor 2 (NRF-2), and thioredoxin-interacting protein genes. Sampling was done at baseline and 72 h after receiving plasma. The intervention group demonstrated significantly lower serum levels of IL-6, TNF-α, and CCL-3. In addition, real-time PCR data analyses showed that the relative expression of NF-κB2 was significantly declined in the patients who received plasma. The use of convalescent plasma probably has a significant inhibitory effect on the cytokines, chemokines, and inflammatory genes related to macrophage activation, which are closely associated with the worsening of clinical outcomes in severe COVID-19.
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Biomarcadores , Soroterapia para COVID-19 , COVID-19 , Imunização Passiva , Macrófagos , SARS-CoV-2 , Humanos , COVID-19/terapia , COVID-19/sangue , COVID-19/imunologia , Masculino , Pessoa de Meia-Idade , Feminino , Biomarcadores/sangue , Macrófagos/imunologia , Macrófagos/metabolismo , SARS-CoV-2/imunologia , Adulto , Inflamação/sangue , Inflamação/terapia , Inflamação/imunologia , Idoso , Citocinas/sangue , Índice de Gravidade de DoençaRESUMO
Interventional clinical studies of convalescent plasma to treat COVID-19 were predominantly funded and led by public sector actors, including blood services operators. We aimed to analyze the processes of clinical studies of convalescent plasma to understand alternatives to pharmaceutical industry biopharmaceutical research and development, particularly where public sector actors play a dominant role. We conducted a qualitative, critical case study of purposively sampled prominent and impactful clinical studies of convalescent plasma during 2020-2021.
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Soroterapia para COVID-19 , COVID-19 , Imunização Passiva , Setor Público , SARS-CoV-2 , Humanos , COVID-19/terapia , Desenvolvimento de Medicamentos , Pandemias , Ensaios Clínicos como AssuntoRESUMO
Immunocompromised patients are at high risk to fail clearance of SARS-CoV-2. Prolonged COVID-19 constitutes a health risk and a management problem as cancer treatments often have to be disrupted. As SARS-CoV-2 evolves, new variants of concern have emerged that evade available monoclonal antibodies. Moreover, antiviral therapy promotes SARS-CoV-2 escape mutations, particularly in immunocompromised patients. These patients frequently suffer from prolonged infection. No successful treatment has been established for persistent COVID-19 infection. Here, we report on a series of 21 immunocompromised patients with COVID-19-most of them hematologic malignancies-treated with plasma obtained from recently convalescent or vaccinated donors or a combination thereof. Repeated dosing of SARS-CoV-2-antibody-containing plasma could clear SARS-CoV-2 infection in 16 out of 21 immunocompromised patients even if COVID-19-specific treatments failed to induce sustained viral clearance or to improve clinical course of SARS-CoV-2 infection. Ten patients were major responders defined as an increase delta(d)Ct of > = 5 after the first administration of convalescent and/or vaccinated plasma (C/VP). On average, SARS-CoV-2 PCR Ct values increased from a median value of 22.55 (IQR = 19.10-24.25) to a median value of 29.57 (IQR = 27.55-34.63; p = <.0001) in the major response subgroup. Furthermore, when treated a second time with C/VP, even 4 out of 5 of the initial nonresponders showed an increase in Ct-values from a median value of 23.13 (IQR = 17.75-28.05) to a median value of 32.79 (IQR = 31.75-33.75; p = .013). Our results suggest that C/VP could be a feasible treatment of COVID-19 infection in patients with hematologic malignancies who did not respond to antiviral treatment.
Assuntos
Soroterapia para COVID-19 , COVID-19 , Neoplasias Hematológicas , Imunização Passiva , Hospedeiro Imunocomprometido , SARS-CoV-2 , Humanos , COVID-19/imunologia , COVID-19/virologia , COVID-19/prevenção & controle , COVID-19/terapia , Neoplasias Hematológicas/terapia , Neoplasias Hematológicas/imunologia , Neoplasias Hematológicas/virologia , Feminino , Pessoa de Meia-Idade , Masculino , Idoso , SARS-CoV-2/imunologia , Imunização Passiva/métodos , Hospedeiro Imunocomprometido/imunologia , Adulto , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Vacinas contra COVID-19/imunologia , Vacinas contra COVID-19/administração & dosagem , Doença Crônica , Resultado do TratamentoRESUMO
The case of clinical trials for convalescent plasma during COVID-19 illustrates important lessons for realizing public sector approaches to biomedical research and development. These lessons, centering on mission, transparency, and spillover effects, can be translated to wider efforts to develop a "public option" for clinical trials.
Assuntos
Soroterapia para COVID-19 , COVID-19 , Ensaios Clínicos como Assunto , Imunização Passiva , SARS-CoV-2 , Humanos , COVID-19/prevenção & controle , Setor Público , Estados UnidosRESUMO
This study aims to assess the safety, virological, and clinical outcomes of convalescent plasma transfusion (CPT) in immunocompromised patients hospitalized for coronavirus disease 2019 (COVID-19). We conducted a retrospective multicenter cohort study that included all immunosuppressed patients with COVID-19 and RNAemia from May 2020 to March 2023 treated with CPT. We included 81 patients with hematological malignancies (HM), transplants, or autoimmune diseases (69% treated with anti-CD20). Sixty patients (74%) were vaccinated, and 14 had pre-CPT serology >264 BAU/mL. The median delay between symptom onset and CPT was 23 days [13-31]. At D7 post-CPT, plasma PCR was negative in 43/64 patients (67.2%), and serology became positive in 25/30 patients (82%). Post-CPT positive serology was associated with RNAemia negativity (p < 0.001). The overall mortality rate at D28 was 26%, being higher in patients with non-B-cell HM (62%) than with B-cell HM (25%) or with no HM (11%) (p = 0.02). Patients receiving anti-CD20 without chemotherapy had the lowest mortality rate (8%). Positive RNAemia at D7 was associated with mortality at D28 in univariate analysis (HR: 3.05 [1.14-8.19]). Eight patients had adverse events, two of which were severe but transient. Our findings suggest that CPT can abolish RNAemia and ameliorate the clinical course in immunocompromised patients with COVID-19.
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COVID-19 , Neoplasias Hematológicas , Humanos , COVID-19/terapia , Transfusão de Componentes Sanguíneos , Soroterapia para COVID-19 , Estudos de Coortes , Plasma , Neoplasias Hematológicas/complicações , Neoplasias Hematológicas/terapia , Hospedeiro Imunocomprometido , ViremiaRESUMO
Although severe coronavirus disease 2019 (COVID-19) and hospitalization associated with COVID-19 are generally preventable among healthy vaccine recipients, patients with immunosuppression have poor immunogenic responses to COVID-19 vaccines and remain at high risk of infection with SARS-CoV-2 and hospitalization. In addition, monoclonal antibody therapy is limited by the emergence of novel SARS-CoV-2 variants that have serially escaped neutralization. In this context, there is interest in understanding the clinical benefit associated with COVID-19 convalescent plasma collected from persons who have been both naturally infected with SARS-CoV-2 and vaccinated against SARS-CoV-2 ("vax-plasma"). Thus, we report the clinical outcome of 386 immunocompromised outpatients who were diagnosed with COVID-19 and who received contemporary COVID-19-specific therapeutics (standard-of-care group) and a subgroup who also received concomitant treatment with very high titer COVID-19 convalescent plasma (vax-plasma group) with a specific focus on hospitalization rates. The overall hospitalization rate was 2.2% (5 of 225 patients) in the vax-plasma group and 6.2% (10 of 161 patients) in the standard-of-care group, which corresponded to a relative risk reduction of 65% (P = 0.046). Evidence of efficacy in nonvaccinated patients cannot be inferred from these data because 94% (361 of 386 patients) of patients were vaccinated. In vaccinated patients with immunosuppression and COVID-19, the addition of vax-plasma or very high titer COVID-19 convalescent plasma to COVID-19-specific therapies reduced the risk of disease progression leading to hospitalization.IMPORTANCEAs SARS-CoV-2 evolves, new variants of concern (VOCs) have emerged that evade available anti-spike monoclonal antibodies, particularly among immunosuppressed patients. However, high-titer COVID-19 convalescent plasma continues to be effective against VOCs because of its broad-spectrum immunomodulatory properties. Thus, we report clinical outcomes of 386 immunocompromised outpatients who were treated with COVID-19-specific therapeutics and a subgroup also treated with vaccine-boosted convalescent plasma. We found that the administration of vaccine-boosted convalescent plasma was associated with a significantly decreased incidence of hospitalization among immunocompromised COVID-19 outpatients. Our data add to the contemporary data providing evidence to support the clinical utility of high-titer convalescent plasma as antibody replacement therapy in immunocompromised patients.
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Soroterapia para COVID-19 , Vacinas contra COVID-19 , COVID-19 , Hospitalização , Imunização Passiva , Hospedeiro Imunocomprometido , SARS-CoV-2 , Humanos , COVID-19/imunologia , COVID-19/terapia , COVID-19/prevenção & controle , Imunização Passiva/métodos , Feminino , Masculino , Pessoa de Meia-Idade , SARS-CoV-2/imunologia , Vacinas contra COVID-19/imunologia , Vacinas contra COVID-19/administração & dosagem , Idoso , Hospitalização/estatística & dados numéricos , Adulto , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Terapia de Imunossupressão , Pacientes Ambulatoriais , Resultado do TratamentoRESUMO
BACKGROUND: Surrogates of antiviral efficacy are needed for COVID-19. We aimed to investigate the relationship between the virological effect of treatment and clinical efficacy as measured by progression to severe disease in outpatients treated for mild-to-moderate COVID-19. METHODS: In this systematic review and meta-analysis, we searched PubMed, Scopus, and medRxiv from database inception to Aug 16, 2023, for randomised placebo-controlled trials that tested virus-directed treatments (ie, any monoclonal antibodies, convalescent plasma, or antivirals) in non-hospitalised individuals with COVID-19. We only included studies that reported both clinical outcomes (ie, rate of disease progression to hospitalisation or death) and virological outcomes (ie, viral load within the first 7 days of treatment). We extracted summary data from eligible reports, with discrepancies resolved through discussion. We used an established meta-regression model with random effects to assess the association between clinical efficacy and virological treatment effect, and calculated I2 to quantify residual study heterogeneity. FINDINGS: We identified 1718 unique studies, of which 22 (with a total of 16 684 participants) met the inclusion criteria, and were in primarily unvaccinated individuals. Risk of bias was assessed as low in 19 of 22 studies for clinical outcomes, whereas for virological outcomes, a high risk of bias was assessed in 11 studies, some risk in ten studies, and a low risk in one study. The unadjusted relative risk of disease progression for each extra log10 copies per mL reduction in viral load in treated compared with placebo groups was 0·12 (95% CI 0·04-0·34; p<0·0001) on day 3, 0·20 (0·08-0·50; p=0·0006) on day 5, and 0·53 (0·30-0·94; p=0·030) on day 7. The residual heterogeneity in our meta-regression was estimated as low (I2=0% [0-53] on day 3, 0% [0-71] on day 5, and 0% [0-43] on day 7). INTERPRETATION: Despite the aggregation of studies with differing designs, and evidence of risk of bias in some virological outcomes, this review provides evidence that treatment-induced acceleration of viral clearance within the first 5 days after treatment is a potential surrogate of clinical efficacy to prevent hospitalisation with COVID-19. This work supports the use of viral clearance as an early phase clinical trial endpoint of therapeutic efficacy. FUNDING: Australian Government Department of Health, Medical Research Future Fund, and Australian National Health and Medical Research Council.
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Antivirais , COVID-19 , SARS-CoV-2 , Carga Viral , Humanos , COVID-19/terapia , COVID-19/imunologia , Antivirais/uso terapêutico , Carga Viral/efeitos dos fármacos , Resultado do Tratamento , Tratamento Farmacológico da COVID-19 , Pacientes Ambulatoriais , Imunização Passiva , Ensaios Clínicos Controlados Aleatórios como Assunto , Soroterapia para COVID-19 , Progressão da Doença , Hospitalização/estatística & dados numéricosRESUMO
BACKGROUND: Immunocompromised patients with impaired humoral immunity are at risk for persistent COVID-19 (pCOVID), a protracted symptomatic disease with active viral replication. OBJECTIVES: To establish a national consensus statement on the diagnosis, treatment, management, isolation, and prevention of pCOVID in adults. SOURCES: We base our suggestions on the available literature, our own experience, and clinical reasoning. CONTENT: Literature on the treatment of pCOVID is scarce and consists of few case reports and case series. The available studies provide low-quality evidence for monoclonal antibodies, convalescent plasma, antiviral drugs, and immunomodulators. Different combination therapies are described. Continuous viral replication and antiviral treatment may lead to the development of mutations that confer resistance to therapy. IMPLICATIONS: To reduce the risk of resistance and improve outcomes, we suggest treating pCOVID with a combination of antibody-based therapy and two antiviral drugs for duration of 5-10 days. Immunomodulatory therapy can be added in patients with an inflammatory clinical picture. In cases of treatment failure or relapse, prolonged antiviral treatment can be considered. For the prevention of pCOVID, we suggest active and passive vaccination and early initiation of treatment for acute COVID-19. Additional research on pCOVID treatment is urgently needed.
Assuntos
Antivirais , COVID-19 , Hospedeiro Imunocomprometido , SARS-CoV-2 , Humanos , COVID-19/diagnóstico , COVID-19/terapia , Antivirais/uso terapêutico , SARS-CoV-2/imunologia , SARS-CoV-2/genética , Consenso , Imunização Passiva/métodos , Soroterapia para COVID-19 , Anticorpos Monoclonais/uso terapêuticoRESUMO
BACKGROUND AND OBJECTIVES: Chronic systemic inflammation has been hypothesized to be a mechanistic factor leading to post-acute cognitive dysfunction after COVID-19. However, little data exist evaluating longitudinal inflammatory markers. METHODS: We conducted a secondary analysis of data collected from the CONTAIN randomized trial of convalescent plasma in patients hospitalized for COVID-19, including patients who completed an 18-month assessment of cognitive symptoms and PROMIS Global Health questionnaires. Patients with pre-COVID-19 dementia/cognitive abnormalities were excluded. Trajectories of serum cytokine panels, D-dimer, fibrinogen, C-reactive peptide (CRP), ferritin, lactate dehydrogenase (LDH), and absolute neutrophil counts (ANCs) were evaluated over 18 months using repeated measures and Friedman nonparametric tests. The relationships between the area under the curve (AUC) for each inflammatory marker and 18-month cognitive and global health outcomes were assessed. RESULTS: A total of 279 patients (N = 140 received plasma, N = 139 received placebo) were included. At 18 months, 76/279 (27%) reported cognitive abnormalities and 78/279 (28%) reported fair or poor overall health. PROMIS Global Mental and Physical Health T-scores were 0.5 standard deviations below normal in 24% and 51% of patients, respectively. Inflammatory marker levels declined significantly from hospitalization to 18 months for all markers (IL-2, IL-2R, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IL-13, INFγ, TNFα, D-dimer, fibrinogen, ferritin, LDH, CRP, neutrophils; all p < 0.05), with the exception of IL-1ß, which remained stable over time. There were no significant associations between the AUC for any inflammatory marker and 18-month cognitive symptoms, any neurologic symptom, or PROMIS Global Physical or Mental health T-scores. Receipt of convalescent plasma was not associated with any outcome measure. DISCUSSION: At 18 months posthospitalization for COVID-19, cognitive abnormalities were reported in 27% of patients, and below average PROMIS Global Mental and Physical Health scores occurred in 24% and 51%, respectively. However, there were no associations with measured inflammatory markers, which decreased over time.
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COVID-19 , Humanos , COVID-19/complicações , SARS-CoV-2 , Soroterapia para COVID-19 , Inflamação , Fibrinogênio , Ferritinas , CogniçãoRESUMO
BACKGROUND: Limited studies have explored the association between clinical symptoms and titers of SARS-CoV-2 antibodies. STUDY DESIGN AND METHODS: In this cross-sectional study, whole-blood donors who had experienced a confirmed or suspected COVID-19 infection completed questionnaires at the time of blood donation. Plasma SARS-CoV-2 immunoglobulin G (IgG) titers were measured using an enzyme-linked immunosorbent assay. Logistic regression models were used to calculate odds ratios (ORs) for high-titer COVID-19 convalescent plasma (CCP) for each variable. RESULTS: Among the total 386 donors, 120 (31%) donors with IgG titers ≥1:160 were classified as high-titer donors. The multivariable ORs (95% confidence intervals [CIs]) for high titers were 2.33 (1.45-3.75), 2.11 (1.29-3.43), 1.10 (1.01-1.21), 1.19 (1.00-1.43), and 1.97 (1.05-3.71) for sore throat, cough, symptom count, fever duration, and low fever (compared with non-fever), respectively. No significant association was observed between other symptoms and medical visits and the odds of high-titer CCP. The association between high-titer CCP and fever duration was restricted to confirmed COVID-19-infected donors, while associations with sore throat and cough remained significant in suspected infected donors. In addition, medical visit was positively associated with high-titer CCP in suspected donors, but not in confirmed donors. In bootstrapped logistic regression models, the associations remained significant and reproducible for medical visit in suspected donors and for sore throat and cough in both suspected donors and total donors. DISCUSSION: Experiencing a sore throat and cough were associated with high-titer CCP in overall donors. We also identified sore throat, cough, and medical visits as potential predictors of high-titer CCP for suspected donors during the pandemic.
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Anticorpos Antivirais , Doadores de Sangue , Soroterapia para COVID-19 , COVID-19 , Imunoglobulina G , SARS-CoV-2 , Humanos , COVID-19/sangue , COVID-19/imunologia , COVID-19/epidemiologia , Doadores de Sangue/estatística & dados numéricos , Masculino , Feminino , SARS-CoV-2/imunologia , Adulto , Imunoglobulina G/sangue , Estudos Transversais , Anticorpos Antivirais/sangue , China/epidemiologia , Pessoa de Meia-Idade , Imunização Passiva , Adulto Jovem , TosseRESUMO
COVID-19 is a global pandemic caused by the highly infectious SARS-CoV-2 virus. Efforts to combat SARS-CoV-2 infection include mass vaccination and development of monoclonal and convalescent plasma therapeutics that require precise measurements of correlative, functional neutralizing antibodies that prevent virus infection. Developing rapid, safe, easy-to-use, and high-quality neutralization assays are essential for the success of the massive effort. Here, we developed a vesicular stomatitis virus-based neutralization assay that was capable of quantifying varying degrees of neutralization in patient serum samples. This assay has two detection readouts, flow cytometry and live cell imaging. The two readout methods produced consistent values of all 50% neutralization titers, further enhancing measurement confidence on the assay. Moreover, the use of available reference standards such as the World Health Organization International Standard (NIBSC code 20/136) enables quantification and standardization of the pseudovirus neutralization assay with neutralizing antibody titers measured in International Units/mL. Quantitative and standardized neutralization assays are critical for reliable efficacy evaluation and comparison of numerous vaccines and therapeutics.
Assuntos
COVID-19 , Humanos , SARS-CoV-2 , Soroterapia para COVID-19 , Testes Imunológicos , Citometria de Fluxo , Anticorpos Neutralizantes , Anticorpos Antivirais , Testes de Neutralização , Glicoproteína da Espícula de CoronavírusRESUMO
Neutralizing antibodies (NAbs) are elicited after infection and vaccination and have been well studied. However, their antibody-dependent cellular cytotoxicity (ADCC) functionality is still poorly characterized. Here, we investigated ADCC activity in convalescent sera from infected patients with wild-type (WT) severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) or omicron variant compared with three coronavirus disease 2019 (COVID-19) vaccine platforms and postvaccination breakthrough infection (BTI). We analyzed ADCC activity targeting SARS-CoV-2 spike (S) and nucleocapsid (N) proteins in convalescent sera following WT SARS-CoV-2-infection (n = 91), including symptomatic and asymptomatic infections, omicron-infection (n = 8), COVID-19 vaccination with messenger RNA- (mRNA)- (BNT162b2 or mRNA-1273, n = 77), adenovirus vector- (n = 41), and inactivated virus- (n = 46) based vaccines, as well as post-mRNA vaccination BTI caused by omicron (n = 28). Correlations between ADCC, binding, and NAb titers were reported. ADCC was elicited within the first month postinfection and -vaccination and remained detectable for ≥3 months. WT-infected symptomatic patients had higher S-specific ADCC levels than asymptomatic and vaccinated individuals. Also, no difference in N-specific ADCC activity was seen between symptomatic and asymptomatic patients, but the levels were higher than the inactivated vaccine. Notably, omicron infection showed reduced overall ADCC activity compared to WT SARS-CoV-2 infection. Although post-mRNA vaccination BTI elicited high levels of binding and NAbs, ADCC activity was significantly reduced. Also, there was no difference in ADCC levels across the four vaccines, although NAbs and binding antibody titers were significantly higher in mRNA-vaccinated individuals. All evaluated vaccine platforms are inferior in inducing ADCC compared to natural infection with WT SARS-CoV-2. The inactivated virus-based vaccine can induce N-specific ADCC activity, but its relevance to clinical outcomes requires further investigation. Our data suggest that ADCC could be used to estimate the extra-neutralization level against COVID-19 and provides evidence that vaccination should focus on other Fc-effector functions besides NAbs. Also, the decreased susceptibility of the omicron variant to ADCC offers valuable guidance for forthcoming efforts to identify the specific targets of antibodies facilitating ADCC.
Assuntos
Vacinas contra COVID-19 , COVID-19 , Humanos , COVID-19/prevenção & controle , Vacina BNT162 , SARS-CoV-2 , Soroterapia para COVID-19 , Anticorpos Neutralizantes , Citotoxicidade Celular Dependente de Anticorpos , Anticorpos Antivirais , VacinaçãoRESUMO
BACKGROUND: The CONvalescent Plasma for Hospitalized Adults With COVID-19 Respiratory Illness (CONCOR-1) trial was a multicenter randomized controlled trial assessing convalescent plasma in hospitalized COVID-19 patients. This study evaluates the cost-effectiveness of convalescent plasma and its impact on quality-of-life to provide insight into its potential as an alternative treatment in resource-constrained settings. METHODS: Individual patient data on health outcomes and resource utilization from the CONCOR-1 trial were used to conduct the analysis from the Canadian public payer's perspective with a time horizon of 30 days post-randomization. Baseline and 30-day EQ-5D-5L were measured to calculate quality-adjusted survival. All costs are presented in 2021 Canadian dollars. The base case assessed the EQ-5D-5L scores of hospitalized inpatients reporting at both timepoints, and a utility score of 0 was assigned for patients who died within 30 days. Costs for all patients enrolled were used. The sensitivity analysis utilizes EQ-5D-5L scores from the same population but only uses costs from this population. RESULTS: 940 patients were randomized: 627 received CCP and 313 received standard care. The total costs were $28,716 (standard deviation, $25,380) and $24,258 ($22,939) for the convalescent plasma and standard care arms respectively. EQ-5D-5L scores were 0.61 in both arms (p = .85) at baseline. At 30 days, EQ-5D-5L scores were 0.63 and 0.64 for patients in the convalescent plasma and standard care arms, respectively (p = .46). The incremental cost was $4458 and the incremental quality-adjusted life day was -0.078. DISCUSSION: Convalescent plasma was less effective and more costly than standard care in treating hospitalized COVID-19.
Assuntos
COVID-19 , Adulto , Humanos , COVID-19/terapia , Qualidade de Vida , Bisoprolol , Análise Custo-Benefício , Soroterapia para COVID-19 , Canadá/epidemiologiaRESUMO
The emergence of SARS-CoV-2 Omicron variant has led to a complete reconfiguration of the therapeutic landscape, with all monoclonal antibodies having lost any neutralization activity. We report here a case series of 75 immunocompromised patients infected by the Omicron variant who benefited from COVID-19 convalescent plasma (CCP). At Day 28, the overall survival was 76% (95% CI 67-86) with no significant difference in the clinical outcome between patients with hematological malignancies, solid organ transplantation or autoimmune diseases. No safety concern was reported during the course of the study. These results showed that CCP is well tolerated and represents a treatment option for immunocompromised patients who remain highly impacted by the COVID19 epidemic.
Assuntos
COVID-19 , Humanos , COVID-19/terapia , Soroterapia para COVID-19 , SARS-CoV-2 , Imunização Passiva , Hospedeiro Imunocomprometido , Anticorpos Antivirais/uso terapêutico , Anticorpos NeutralizantesRESUMO
Blood transfusions from convalescent Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infected patients could be used to treat patients with severe infections or immunocompromised patients. However, it is necessary to select the optimal donors to maximize the utilization of resources. In this study, we investigated the associations among body mass index (BMI), tobacco smoking, exercise frequency and duration, and alcohol consumption with the SARS-CoV-2 immunoglobulin-G (IgG) antibody titer levels with in the Chinese convalescent blood donor population. Here we show that BMI, smoking habits, and exercise frequency appear to be predictive factors for IgG levels in convalescent male blood donors. However, these variables were not observed as predictive of IgG levels in female convalescent blood donors. The findings could be used to optimize the screening for potential blood donors to treat immunocompromised or severely ill COVID-19 patients.
Assuntos
COVID-19 , Humanos , Masculino , Feminino , SARS-CoV-2 , Doadores de Sangue , Estudos Transversais , Imunização Passiva , Soroterapia para COVID-19 , Anticorpos Antivirais , Imunoglobulina G , ChinaRESUMO
Throughout the SARS-CoV-2 pandemic, several variants of concern (VOCs) have been identified, many of which share recurrent mutations in the spike glycoprotein's receptor-binding domain (RBD). This region coincides with known epitopes and can therefore have an impact on immune escape. Protracted infections in immunosuppressed patients have been hypothesized to lead to an enrichment of such mutations and therefore drive evolution towards VOCs. Here, we present the case of an immunosuppressed patient that developed distinct populations with immune escape mutations throughout the course of their infection. Notably, by investigating the co-occurrence of substitutions on individual sequencing reads in the RBD, we found quasispecies harboring mutations that confer resistance to known monoclonal antibodies (mAbs) such as S:E484K and S:E484A. These mutations were acquired without the patient being treated with mAbs nor convalescent sera and without them developing a detectable immune response to the virus. We also provide additional evidence for a viral reservoir based on intra-host phylogenetics, which led to a viral substrain that evolved elsewhere in the patient's body, colonizing their upper respiratory tract (URT). The presence of SARS-CoV-2 viral reservoirs can shed light on protracted infections interspersed with periods where the virus is undetectable, and potential explanations for long-COVID cases.