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Convalescent Plasma Therapy for COVID-19: State of the Art
Abstract
Convalescent plasma (CP) therapy has been used since the early 1900s to treat emerging infectious diseases; its efficacy was later associated with the evidence that polyclonal neutralizing antibodies can reduce the duration of viremia. Recent large outbreaks of viral diseases for which effective antivirals or vaccines are still lacking has renewed the interest in CP as a life-saving treatment. The ongoing COVID-19 pandemic has led to the scaling up of CP therapy to unprecedented levels. Compared with historical usage, pathogen reduction technologies have now added an extra layer of safety to the use of CP, and new manufacturing approaches are being explored. This review summarizes historical settings of application, with a focus on betacoronaviruses, and surveys current approaches for donor selection and CP collection, pooling technologies, pathogen inactivation systems, and banking of CP. We additionally list the ongoing registered clinical trials for CP throughout the world and discuss the trial results published thus far.
... The year 2019 marked the emergence of a formidable adversary, as a novel coronavirus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) unleashed a global pandemic we now know as coronavirus disease 2019 (COVID-19) [1][2][3][4]. Initially spread in Wuhan, Hubei Province, People's Republic of China, at the end of December 2019, COVID-19 has since spread globally [1,2]. There have been 3,751,069 confirmed cases and Life 2023, 13, 2184 2 of 11 263,346 deaths worldwide (mortality rate: 7.0%), based on numbers up to early May 2020. ...
... However, further studies are necessary to determine how to treat severe cases. One treatment being explored, apart from antivirals, is the use of plasma from recovered patients, known as convalescent plasma therapy [2][3][4]. At its core, convalescent plasma therapy hinges on the simple yet powerful concept of transferring immunity. ...
... We also demonstrated the disappearance of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA (RNAemia) in a subset of 100 donors with varying degrees of disease severity [16]. Moreover, multiple studies have evaluated the efficacy, safety, disease progression, and utility of convalescent plasma therapy, ranging from small cohorts of patients to data of thousands of patients for experimental trials and systematic review [3,[17][18][19][20][21]. These studies will aid in establishing the initial evidence regarding the usage of convalescent plasma in treatment. ...
Convalescent plasma therapy, which involves administering plasma from recovered coronavirus disease 2019 (COVID-19) patients to infected individuals, is being explored as a potential treatment for severe cases of COVID-19. This study aims to evaluate the efficacy and safety of convalescent plasma therapy in COVID-19 patients with moderate to severe illness. An open-label, single-arm intervention study was conducted without a control group. Plasma collected from recovered COVID-19 patients was administered to eligible participants. The primary endpoint was the proportion of patients who were placed on artificial ventilation or died within 14 days of transfusion. Secondary endpoints included clinical improvement, viral load measurements, and adverse event monitoring. A total of 59 cases were included in the study. The primary endpoint was evaluated by comparing the rate obtained in the study to an existing rate of 25%. The study also assessed clinical improvement, viral load changes, and safety endpoints through adverse event monitoring. Convalescent plasma therapy shows potential as a treatment option for COVID-19. This study aimed to provide evidence for the efficacy and safety of this therapy and may contribute to its future use in treating severe cases of COVID-19.
... Convalescent blood plasma (CBP) has generally been taken following the beginning of early symptoms to optimize effectiveness. Additionally, convalescent whole blood (CWB) supports the management of hemorrhagic disorders, for example in Ebola infection, provided transfusion happens within 24 hours to retain functional clotting components as well as platelets [12]. In CPT, around 200-600 mL of blood is procured from a convalescent patient, then their plasma (CP) is separated through various techniques and stored at an appropriate temperature after getting treated with necessary treatments [12]. ...
... Additionally, convalescent whole blood (CWB) supports the management of hemorrhagic disorders, for example in Ebola infection, provided transfusion happens within 24 hours to retain functional clotting components as well as platelets [12]. In CPT, around 200-600 mL of blood is procured from a convalescent patient, then their plasma (CP) is separated through various techniques and stored at an appropriate temperature after getting treated with necessary treatments [12]. Further, it is transfused to the patient having severe diseases and unable to recover [43]. ...
... Regrettably, as evident from MERS and preliminary COVID-19 recommend that patients with minor symptoms may grow low-titer antibodies, emphasizing the importance of antibody titration in population-wide and home-based strategies [12]. The convalescent COVID-19 donor may also get benefit from plasmapheresis by deleting high-molecular-weight viscous components as well as by decreasing the prothrombotic event caused by the anticoagulants based on citrate used in donation [64]. ...
The pandemic COVID-19 has spread widely throughout the globe and has been responsible for millions of deaths worldwide. Recently it has been identified that there is no specific and 100% effective treatment available to treat the infection especially for the severe cases. A significant amount of research efforts and clinical trials have been undertaken globally and many more are underway to find the potential treatment option. Earlier, convalescent plasma or hyperimmune immunoglobulin was effectively used in the treatment of many endemic or epidemic viral infections as a part of passive immunization. In this article, we have touched upon the immunopathology of COVID-19 infection, a basic understanding of convalescent plasma, it's manufacturing as well as evaluation, and have reviewed the scientific developments focussing on the potential of convalescent plasma vis-à-vis other modalities for the management of COVID-19. The article also covers various research approaches, clinical trials conducted globally, and the clinical trials which are at various stages of exploring the efficacy and safety of the convalescent plasma therapy (CPT) to predict its future perspective to manage COVID-19 infection.
... Clinicians are pursuing Convalescent Plasma Therapy (CPT) as an immunotherapeutic alternative to antiviral medication therapy [41][42][43][44] . While antiviral medications are undergoing clinical testing, CPT is emerging as a potential COVID-19 A high titer of neutralizing antibodies, which can have an antiviral impact, is present in the plasma [45] . Studies have demonstrated that CPT is effective in opposition to COVID-19 and that there have been no serious adverse responses to this treatment. ...
... Antihuman leukocyte antigen antibodies are the source of TRALI, and a similar case was noted for CPT during an Ebola virus outbreak [49] . Before beginning CPT for COVID-19, it is advised to screen for antihuman leukocyte antigen antibodies [45] . Finally, because the plasma is human-derived, it must be obtained and used under the strictest ethical standards for CPT to be successful [41] . ...
The new coronavirus (SARS-CoV-2) that caused a viral disease with a high risk of mortality (COVID-19) was found towards the end of 2019. This was a significant acute respiratory syndrome. In a brief period, this virus spread throughout the entire planet, causing tremendous loss of life and economic damage. The process of developing new treatments takes time, and there are presently no recognized specific treatments to treat this infection. The most promising participants, who subsequently developed into prospective leads, were dropped from the clinical research in their latter phases. Medication that has previously acquired permission may only be repurposed for use for various medical reasons following a thorough investigation for safety and effectiveness. Because there are now no effective treatments available, natural products are being used haphazardly as antiviral medications and immunity boosters. The fundamental statement that most natural compounds have powerful antiviral action does not apply to SARS-CoV-2. MERS-CoV and SARS-CoV infections are inhibited by natural treatments. According to in silicon study, the virus' non-structural proteins, including PLpro, Mpro, and RdRp, as well as structural proteins like the spike (S) protein, have been shown to have a strong affinity for several natural products and to be inhibited by them. The virus also suggests that it is a valid candidate for therapeutic research since it utilizes the intracellular ACE2 receptor of the host cell. In this study, interesting targets for SARS-CoV-2 medication development are explored, as well as the antiviral properties of some well-known natural compounds.
... In short, all COVID-19 patients receive antiviral treatment; severe patients receive additional antibacterial treatment, and most of them also receive antifungal treatment. Notably, 1 severe patient also receives convalescent plasma therapy (Focosi et al. 2020; National Health Commission and National Administration of Traditional Chinese Medicine 2020) on day 16 of hospitalization. The most common comorbidity in the COVID-19 patients is hypertension (4 and 6 in non-severe and severe groups, respectively), followed by type-II diabetes. ...
... As an interesting example, we investigated the severe patient who receives convalescent plasma therapy (Focosi et al. 2020; National Health Commission and National Administration of Traditional Chinese Medicine 2020) on day 16 of hospitalization. Blood samples are taken 1 day before and ~ 6 h after treatment. ...
Coronavirus 2019 (COVID-19) is a complex disease that affects billions of people worldwide. Currently, effective etiological treatment of COVID-19 is still lacking; COVID-19 also causes damages to various organs that affects therapeutics and mortality of the patients. Surveillance of the treatment responses and organ injury assessment of COVID-19 patients are of high clinical value. In this study, we investigated the characteristic fragmentation patterns and explored the potential in tissue injury assessment of plasma cell-free DNA in COVID-19 patients. Through recruitment of 37 COVID-19 patients, 32 controls and analysis of 208 blood samples upon diagnosis and during treatment, we report gross abnormalities in cfDNA of COVID-19 patients, including elevated GC content, altered molecule size and end motif patterns. More importantly, such cfDNA fragmentation characteristics reflect patient-specific physiological changes during treatment. Further analysis on cfDNA tissue-of-origin tracing reveals frequent tissue injuries in COVID-19 patients, which is supported by clinical diagnoses. Hence, our work demonstrates and extends the translational merit of cfDNA fragmentation pattern as valuable analyte for effective treatment monitoring, as well as tissue injury assessment in COVID-19.
... The most commonly used measure regarding patient safety was the implementation of protocols that ensure the quality of blood products, which include donor screening 34,53 , deferring patients that recently traveled to certain countries 61 , and following preventive safety protocols. These were complemented by the release of new blood donation guidelines by the FDA, which donors should be able to meet 61 . ...
... In April 2020, they released a document that seeks to regulate CP therapy in regards to its donation, preparation, quality assurance, safety evaluation, and efficacy 70 . The ongoing clinical trials for CP treatment among COVID-19 patients was approved by the FDA and this allowed more than 30,000 individuals to undergo the treatment 34 . Moreover, in this clinical trial, the safety and advantage of CP treatment was confirmed. ...
SARS-CoV-2 has presented many challenges ranging from health to economic issues. The healthcare sector was particularly affected, straining its performance and resources. Blood banking facilities were faced with safety issues for donors, patients and staff, as well as compromised supply and demand for blood products brought by the COVID-19 pandemic. Hence, this study aimed to determine the growing concerns as well as corresponding implemented measures of different blood banking laboratories worldwide. Based on the PRISMA framework, this study systematically searched and reviewed 50 relevant literatures from PubMed, Sciencedirect, ProQuest, and ClinicalKey to identify the concerns of blood banking facilities, and the associated measures implemented in response to the pandemic, and found that being updated and adhering to safety and security protocols, and having staff equipped with PPEs, educated and trained with safety protocols were important in addressing safety issues in blood banks. In maintaining blood supply, measures of increasing the donor recruitment by setting programs and strategies encouraging blood donation, and decreasing the utilization of blood products by canceling or postponing elective surgeries were commonly undertaken. In addressing the demand for COVID-19 Convalescent Plasma (CCP) treatment, different organizations and agencies regulate blood banking functions in order to allow CCP treatment. Lastly, to prevent blood wastage due to decreased blood demand, coordination with other blood banks was needed to balance the supply. The implications of the detailed concerns and measures may serve as a reference for other blood banking facilities to adopt in their practice and operations in dealing with similar challenges.
... CP therapy fortifies the immune system of critically ill patients passively, through transfusing antibody-rich plasma from recently recovered patients [6]. In the past, this method showed positive efficacy in the management of various infections caused by viruses including influenza viruses A, flaviviruses, respiratory beta-coronaviruses, and Ebola virus [7]. Although the exact mechanism of the therapeutic effects of CP therapy remains unclear, antibody-induced cellular cytotoxicity, complement activation, and viral neutralization have been suggested as its mechanism of action [8]. ...
Introduction: Convalescent plasma (CP) therapy is a form of passive immunization which has been used as a treatment for coronavirus disease 2019 (COVID-19). This study aims to evaluate the efficacy and safety of CP therapy in patients with severe COVID-19. Methodology: In this retrospective cohort study, 50 patients with severe COVID-19 treated with CP at Shahid Beheshti Hospital, Kashan, in 2019 were evaluated. Eligible plasma donors were COVID-19 survivors with high IgG levels and no comorbidities. Clinical and laboratory parameters, including vital signs, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and white blood cell (WBC) levels, were measured before and after CP therapy at specified intervals including 24 h and 48 h post-therapy. Results: The average age of the patients was 55.96 years, and 46% had comorbidities. No adverse effects from CP therapy were reported. Significant associations were observed between baseline ESR levels and factors such as age, comorbidities, hypertension history, and intubation status. However, there was no significant correlation between the outcomes of WBC, ESR, and CRP levels and the IgG levels in recipients. Conclusions: CP therapy appears to be a safe and potentially effective treatment for severe COVID-19, especially in patients with certain baseline characteristics. These findings add valuable insights into the management of severe COVID-19 cases, although further research is needed to fully understand the implications and optimize treatment protocols.
... The benefits from donor's antibodies have been recognized in the treatment of flavivirus infections, influenza type A, Ebola, and beta coronaviruses seasonal respiratory infections [ 12]. Nevertheless, there is insufficient evidence regarding the clinical efficacy of convalescent plasma therapy for COVID-19 [13]. ...
The total and SARS-CoV-2-specific antibody content in convalescent plasma (CP) samples from Bulgarian donors and their therapeutic potential for COVID-19 patients was subjected to characterization. CPs (n = 90) were obtained after informed consent at National Centre of Transfusion Hematology in Sofia, Bulgaria, in the period 01 June 2021 and were tested for RBD-IgG, RBD-IgA and anti-nuclear antibodies (ANA) by semi-quantitative ELISA. Concentrations of total IgG, IgG isotypes, IgA, and IgM, as well as of 25 Th1, Th2, Th17 and regulatory cytokines were determined for all samples; concentrations of Neutralizing antibodies against six SARS-CoV-2 variants were determined in Receptor-Binding Domain (RBD-positive) samples (Luminex xMAP technology). Concordant production of RBD-specific IgG and IgA was detected in 45 (50%); 12 (13.3%) were RBD-IgG single-positive, 8 (8.8%) RBD-IgA single-positive, and 25 (27.7%) – double negative. Absence of neutralizing activity was documented for 8/65 (12.3%) of RBD-positive samples. No correlation existed between the levels of RBD-IgG and RBD-IgA and the total neutralizing activity of CPs (p > 0.05). Total IgG, IgA, IgM and IgG Isotype concentrations did not differ from reference values. Increased concentrations of IL-18, IL-27, IL-1Ra, IL-21 and IL-22 were detected in most tested samples (80% respectively). The comparison between 45 RBD-double positive and 25 RBD-double negative CPs showed significant differences for the concentrations of IL-22 (2.4 vs 40, p < 0.05) and IL-10 (1 vs 15, p < 0.001). All CPs were ANA negative. Detailed characterization for SARS-CoV-2 specific antibody content and cytokine concentrations might improve the results of CPs application for in early stage treatment in resource-limited settings.
... COVID-19 convalescent plasma (CP) has been authorized for off-label emergency use and phase III studies, and researchers are attempting to create medicines. SARS-CoV-2 spike protein-neutralizing antibodies have been found in CP from recuperating patients, which may help COVID-19 patients who are critically ill by neutralizing the virus and stopping its reproduction (6)(7)(8). CP is beneficial in treating Middle East respiratory syndrome, influenza A (H1N1), avian influenza (H5N1), and Ebola (9)(10)(11)(12)(13). A recently published Mayo Clinic observational study of 20,000 patients with CP revealed a favorable safety pattern (14). ...
Objectives: Over 50 million confirmed cases and 1.5 million fatalities worldwide have been linked to the COVID-19 pandemic. Researchers have used convalescent plasma (CP) from recovered patients, which includes neutralizing antibodies, to develop therapeutics for virus neutralization and prevention. This study assessed the effectiveness of CP using several clinical and laboratory variables. Methods: The intervention group received two doses of CP on the day of hospitalization, while the control group received standard care. Clinical and analytical data were documented and evaluated before plasma therapy and on the third and fifth days after therapy. The results were measured in the patient's blood using the ELISA method. Results: The present study showed that the ICU hospitalization times for the control and CP groups were similar, with a slightly lower mortality rate in the CP group (6.2% vs. 8.2%, p > 0.05). There was no significant association between COVID-19 and clinical factors such as blood pressure, heart rate (HR), respiration rate (RR), and temperature. The blood serum urea, serum LDH, ALT, PTT, PLT, and IL-6 were significantly higher in the CP group than in the control group (p <0.05). Our results indicated that there was no difference in blood pH, PO 2 , HCO 3 , ESR, WBC counts, serum troponin, Na, AST, CRP, D-dimer, and PT between patients in the CP and control groups.
... For further research, it is hoped that researchers can provide a limitation that plasma donor candidates must come from the same area. In [36], [37], it is stated that plasma donors should preferably be selected from COVID-19 survivors living in the exact location as potential plasma recipients to allow consideration of target viral antigen mutations. ...
Convalescent Plasma Therapy (CPT) is an additional therapy to increase the chances of recovery for patients infected with COVID-19. CPT is carried out by giving blood plasma from COVID-19 survivors to COVID-19 patients. Not all survivors of COVID-19 can become plasma donors. Several criteria must be met. Therefore, selecting and sequencing potential plasma donors can be considered an act of decision-making. This research aims to provide an overview of the application of the SAW-TOPSIS combination and the Borda Count method in selecting and ranking potential plasma donor candidates. The criteria for prospective plasma donors are limited to six aspects, namely age, weight, history of blood transfusion, gender, pregnancy status, history of being infected with COVID-19, and history of previous illnesses. Data was taken from ten COVID-19 survivors to illustrate the application of the three methods. The data is taken from a questionnaire distributed via Google Forms. This research was carried out through 3 stages: applying the SAW method, the TOPSIS method, and the Borda Count method. From the calculated results, P06 was the most potential plasma donor candidate, followed by P03, P09, P02, and P04.
... The sick person benefits from the antibodies produced by the recovered person. This modality is considered effective in the treatment of infectious diseases that are caused by viruses such as flaviviruses, influenza viruses A, Ebola virus, and respiratory betacoronaviruses 9 . Nevertheless, there is insufficient evidence regarding the clinical efficacy of convalescent plasma therapy in the treatment of COVID-19. ...
Insight into the clinical potential of convalescent plasma in patients with coronavirus disease (COVID-19) is important given the severe clinical courses in unvaccinated and seronegative individuals. The aim of the study was to investigate whether there is a survival benefit of convalescent plasma therapy in COVID-19 patients. The authors independently assessed randomized controlled trials (RCTs) identified by the search strategy for inclusion, extracted data, and assessed risk of bias. The binary primary outcome was all-cause mortality. Risk ratio (RR) of the convalescent plasma treatment (vs. best standard care) and its associated standard error (effect size) were calculated. A random-effects model was employed to statistically pool the effect sizes of the selected studies. We included 19 RCTs with 17,021 patients. The random-effects model resulted in an estimated pooled RR of 0.94 (95% CI 0.81–1.08, p = 0.33), showing no statistical evidence of the benefit of convalescent plasma therapy on all-cause mortality. Convalescent plasma therapy was not found to be effective in reducing all-cause mortality in COVID-19 patients. Further studies are needed to determine in which patients convalescent plasma therapy may lead to a reduction in mortality.
... • Immunoglobulin replacement should be administered in patients with hypogammaglobulinemia (IgG < 4 g/l) [31]. (Strong recommendation) • Intravenous human COVID-19 immunoglobulin and convalescent plasma may be given to patients with a high viral load and rapid disease progression during the early stage [95,[133][134][135]. (Weak or conditional recommendation) • If patients have recurrent fever ≥ 38.0 °C, hemodynamic instability or hypoxemia, clinicians Patients with major risk factors for disease progression, high viral loads, and rapid disease development. ...
The outbreak of coronavirus disease 2019 (COVID-19) posed an unprecedented challenge on public health systems. Despite the measures put in place to contain it, COVID-19 is likely to continue experiencing sporadic outbreaks for some time, and individuals will remain susceptible to recurrent infections. Chimeric antigen receptor (CAR)-T recipients are characterized by durable B-cell aplasia, hypogammaglobulinemia and loss of T-cell diversity, which lead to an increased proportion of severe/critical cases and a high mortality rate after COVID-19 infection. Thus, treatment decisions have become much more complex and require greater caution when considering CAR T-cell immunotherapy. Hence, we reviewed the current understanding of COVID-19 and reported clinical experience in the management of COVID-19 and CAR-T therapy. After a panel discussion, we proposed a rational procedure pertaining to CAR-T recipients with the aim of maximizing the benefit of CAR-T therapy in the post COVID-19 pandemic era.
... The presence of neutralizing antibodies is considered a functional correlate of immunity and provides at least partial resistance to subsequent. Although some serological assays showed a high correlation between IgG and neutralizing antibodies [10], others have poor correlation [11]. Therefore, comparison with virus-neutralization experiments is important as part of the validation of new serological assays. ...
Neutralizing antibody titers are an important measurement of the effectiveness of vaccination against SARS-CoV-2. Our laboratory has set out to further verify the functionality of these antibodies by measuring the neutralization capacity of patient samples against infectious SARS-CoV-2. Samples from patients from Western New York who had been vaccinated with the original Moderna and Pfizer vaccines (two doses) were tested for neutralization of both Delta (B.1.617.2) and Omicron (BA.5). Strong correlation between antibody levels and neutralization of the delta variant were attained, however, antibodies from the first two vaccines did not have good neutralization coverage of the subvariant omicron BA.5. Further studies are ongoing with local patient samples to determine correlation following updated booster administration.
... Despite certain drawbacks, such as the need for dedicated collection, testing, dose standardization, and blood group testing, this therapy serves as a first line of defense (Luke et al., 2010). Despite being poorly defined and associated with some controversy, CPT is among the therapeutic strategies that are under investigation for efficacy against SARS-CoV-2 Focosi et al., 2020;Perotti et al., 2020;Focosi and Farrugia, 2021). The FDA granted permission for the emergency use of COVID-19 convalescent plasma on 23 August 2020 for the treatment of COVID-19 patients who were taking immunosuppressive medications. ...
Millions of people have died as a result of SARS-CoV-2, which was first discovered in China and has since spread globally. Patients with SARS-CoV-2 infection may show a range of symptoms, including fever, coughing, and shortness of breath, or they may show no symptoms at all. To treat COVID-19 symptoms and avoid serious infections, many medications and vaccinations have been employed. However, to entirely eradicate COVID-19 from the world, next-generation vaccine research is required because of the devastating consequences it is having for humanity and every nation’s economy. Scientists are working hard to eradicate this dangerous virus across the world. SARS-CoV-2 has also undergone significant mutation, leading to distinct viral types such as the alpha, beta, gamma, delta, and omicron variants. This has sparked discussion about the effectiveness of current vaccines for the newly formed variants. A proper comparison of these vaccinations is required to compare their efficacy as the number of people immunized against SARS-CoV-2 globally increases. Population-level statistics evaluating the capacity of these vaccines to reduce infection are therefore being developed. In this paper, we analyze the many vaccines on the market in terms of their production process, price, dosage needed, and efficacy. This article also discusses the challenges of achieving herd immunity, the likelihood of reinfection, and the importance of convalescent plasma therapy in reducing infection.
... Polyclonal antibody serum product developed in recent years shows good application prospects in various studies. Convalescent plasma is one of the most extensive therapies researched for SARS-CoV-2 and is more likely to produce specific antibodies [9]. Even so, the ability to obtain plasma depends on voluntary donations from recovered patients. ...
Therapeutic antibodies-F(ab’)2 obtained from hyperimmune equine plasma could treat emerging infectious diseases rapidly because of their high neutralization activity and high output. However, the small-sized F(ab’)2 is rapidly eliminated by blood circulation. This study explored PEGylation strategies to maximize the half-life of equine anti-SARS-CoV-2 specific F(ab’)2. Equine anti-SARS-CoV-2 specific F(ab’)2 were combined with 10 KDa MAL-PEG-MAL in optimum conditions. Specifically, there were two strategies: Fab-PEG and Fab-PEG-Fab, F(ab’)2 bind to a PEG or two PEG, respectively. A single ion exchange chromatography step accomplished the purification of the products. Finally, the affinity and neutralizing activity was evaluated by ELISA and pseudovirus neutralization assay, and ELISA detected the pharmacokinetic parameters. The results displayed that equine anti-SARS-CoV-2 specific F(ab’)2 has high specificity. Furthermore, PEGylation F(ab’)2-Fab-PEG-Fab had a longer half-life than specific F(ab’)2. The serum half-life of Fab-PEG-Fab, Fab-PEG, and specific F(ab’)2 were 71.41 h, 26.73 h, and 38.32 h, respectively. The half-life of Fab-PEG-Fab was approximately two times as long as the specific F(ab’)2. Thus far, PEGylated F(ab’)2 has been prepared with high safety, high specificity, and a longer half-life, which could be used as a potential treatment for COVID-19.
... Current antibody therapies are divided into anti-viral and anti-inflammatory treatments. Among antibody options, convalescent plasma (CP) treatment is receiving significant attention, which may provide patients with immediate passive immunity 21,22 . However, CP therapy is suboptimal and fails to reverse respiratory failure and reduce mortality 23,24 . ...
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic. Antibody resistance dampens neutralizing antibody therapy and threatens current global Coronavirus (COVID-19) vaccine campaigns. In addition to the emergence of resistant SARS-CoV-2 variants, little is known about how SARS-CoV-2 evades antibodies. Here, we report a novel mechanism of extracellular vesicle (EV)-mediated cell-to-cell transmission of SARS-CoV-2, which facilitates SARS-CoV-2 to escape from neutralizing antibodies. These EVs, initially observed in SARS-CoV-2 envelope protein-expressing cells, are secreted by various SARS-CoV-2-infected cells, including Vero E6, Calu-3, and HPAEpiC cells, undergoing infection-induced pyroptosis. Various SARS-CoV-2-infected cells produce similar EVs characterized by extra-large sizes (1.6–9.5 μm in diameter, average diameter > 4.2 μm) much larger than previously reported virus-generated vesicles. Transmission electron microscopy analysis and plaque assay reveal that these SARS-CoV-2-induced EVs contain large amounts of live virus particles. In particular, the vesicle-cloaked SARS-CoV-2 virus is resistant to neutralizing antibodies and able to reinfect naïve cells independent of the reported receptors and cofactors. Consistently, the constructed 3D images show that intact EVs could be taken up by recipient cells directly, supporting vesicle-mediated cell-to-cell transmission of SARS-CoV-2. Our findings reveal a novel mechanism of receptor-independent SARS-CoV-2 infection via cell-to-cell transmission, provide new insights into antibody resistance of SARS-CoV-2 and suggest potential targets for future antiviral therapeutics.
... CP therapy treatment has been utilized since the mid-1900s to treat irresistible infections, in the absence of antivirals and monoclonal antibodies, the CP can be treated as a life-saving treatment. 33 CP is being studied worldwide, as a treatment for COVID-19 and prevention, however, it did not reduce all-cause mortality. [34][35][36] Researchers recommend that CP treatment could be a viable alternative in the event of a COVID-19 emergency. ...
Background and Aim
The COVID‐19 pandemic has plagued our lives for more than 2 years, and the preference for convalescent plasma (CP) as a life‐saving treatment since CP has proven as a potential therapeutic option for acute COVID‐19 patients who were suffering from severe disease. It is important to identify which factors are associated with plasma donation. Therefore, this study aimed to assess the associated factors for CP donation to COVID‐19 patients.
Methods
A cross‐sectional study was conducted online from December 21, 2021 to February 15, 2022 to identify different socio‐demographic factors and knowledge related to CP donation. People who recovered from the COVID‐19 infections and those who are willing to participate were included in the study. A total of 60 participants were included in the study. The data were analyzed using descriptive statistics, correlation matrix, and factor analysis.
Results
The analysis results confirm that 41.67% (n = 25) of the participants aged 26–30 years; among the recovered patients, only about 23% (n = 14) of the participants donated plasma. Though 97% (n = 58) of the participants agreed to donate plasma when it will be needed, however, when someone asked to donate plasma then 76.67% (n = 46) of the patients declined it. Findings depict that gender had a weak positive relationship with ever decline in plasma donation at 5% level of significance and the age of the participants inversely related to plasma donation.
Conclusion
Almost all the recovered participants were willing to donate plasma, however, due to a lack of knowledge and misconception, relatively few people actually did. This study reemphasizes the importance of health education to overcome the misconception about plasma donation, which is crucial for the treatment of COVID‐19 infection.
... Additionally, passive immunotherapy could be useful in a prophylactic setting for at-risk populations. Although the efficacy of convalescent plasma against the progression of COVID-19 disease is yet to be proven in randomized clinical trials 60 , the recent meta-analysis suggests that the convalescent plasma is not an effective therapy 31 . This is likely due to treatment time and the IgG titer in plasma against the SARS-CoV-2 spike protein. ...
In late 2019 the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus emerged in China and quickly spread into a worldwide pandemic. It has caused millions of hospitalizations and deaths, despite the use of COVID-19 vaccines. Convalescent plasma and monoclonal antibodies emerged as major therapeutic options for treatment of COVID-19. We have developed an anti-SARS-CoV-2 immunoglobulin intravenous (Human) (COVID-HIGIV), a potential improvement from using convalescent plasma. In this report the efficacy of COVID-HIGIV was evaluated in hamster and mouse models of SARS-CoV-2 infection. COVID-HIGIV treatment in both mice and hamsters significantly reduced the viral load in the lungs. Among COVID-HIGIV treated animals, infection-related body weight loss was reduced and the animals regained their baseline body weight faster than the PBS controls. In hamsters, COVID-HIGIV treatment reduced infection-associated lung pathology including lung inflammation, and pneumocyte hypertrophy in the lungs. These results support ongoing trials for outpatient treatment with COVID-HIGIV for safety and efficacy evaluation (NCT04910269, NCT04546581).
... 16 TPE may help to control the circulating inflammatory cytokines and hypercoagulable conditions by replacing the ADAMTS13 enzyme, whereas CP from recovered donors may aid in inactivating the virus by neutralizing antibodies. 17 TPE can be challenging in the prone position, although it is a well-tolerated procedure by most reported studies. TPE in sepsis has been reported that both the disease severity and timing are important factors for TPE efficacy. ...
Background: Coronavirus disease 2019 (COVID-19) has emerged as a global health catastrophe since its first reported cases in late December 2019. Critically ill COVID-19 patients have been related to cytokine storms leading to acute respiratory distress syndrome and high mortality rates. Therapeutic plasma exchange (TPE) and convalescent plasma (CP) therapy improve clinically by removing inflammatory cytokines excess and using passive antibody-containing blood, respectively. This study aimed to evaluate TPE and CP treatment for moderate-to-severe COVID-19 infection.
Method: The patients were randomly divided into TPE group (n = 10), CP group (n = 11), and control group (n = 10). This 1-week quasi-experimental study with a pretest–post-test control group design was conducted in the Intensive Care Unit (ICU) of Dr. Moewardi General Hospital and Universitas Sebelas Maret (UNS) Hospital. The study comparison between groups included blood gas analysis profile (pH, base excess, PaCO2, PaO2, hematocrit, HCO3, total CO2, SaO2), FiO2, P/F ratio, COVID-19 severity, and D-dimer. The paired t-test was used to analyze every group's pretest–post-test mean difference. One-way ANOVA was performed to analyze the mean difference across the three groups. SPSS version 22.0 for Windows was used to perform statistical analyses.
Result: TPE and CP groups showed significant clinical-laboratory improvement than control (p > 0.05). Furthermore, high clinical-laboratory improvement tendency was observed in CP therapy than TPE.
Conclusion: The use of TPE and CP in moderate-to-severe COVID-19 patients has been related to improving clinical-laboratory outcomes.
... Prior research on MERS and SARS coronavirus outbreaks suggested that CP is safe and may confer clinical benefits, including faster viral clearance, particularly when administered early in the disease course [71][72][73]. In some recent studies, early use of CP has been shown to decrease progression of COVID-19 illness [72][73][74][75][76][77], however, the reports on the benefit of CP in COVID-19 have been inconsistent [78][79][80][81][82][83][84][85][86]. In this study, 19.6% of patients with moderate disease received CP early into the illness. ...
Citation: Khamis, F.; Al Awaidy, S.; Shaaibi, M.A.; Shukeili, M.A.; Chhetri, S.; Balushi, A.A.; Sulaimi, S.A.; Balushi, A.A.; Wesonga, R.
... Antibody-dependent enhancement (ADE) is a conceptual concern [34]. Specific antibodies that are found in CP can help individuals with deficient humoral immune deficits, and the clotting factors in it can support patients with bleeding diathesis [35]. ...
Coronavirus 2019 has created a big threat to the modern world. Many researchers and scientists had taken the burden of finding information about this entity, its structure, its transmission, and also about the treatment that can be given to individuals infected by it. There has been use of different medicines at different times simultaneously researching about them, starting with only symptomatic and supportive treatment, then antimalarial agents like chloroquine and hydroxychloroquine, then going to favipavir, and other antivirals, then came the use of vaccines and also convalescent plasma therapy for COVID-19. The most advanced is convalescent plasma use for the treating coronavirus. Using plasma of patients who have remitted from this disease and putting it into those individuals who are dealing with the disease or are critically ill for improvement of their health status. This treatment has been used for many other diseases too and has been proven efficacious. So, this technique is being used and studied for coronavirus 2019 as well. There have been set certain criteria for those who can donate plasma and also criteria for the recipients of this technique. Also, there can be adverse reactions or even side effects with this, like transfusion-related acute lung injury (TRALI), so they should also be kept in mind during treatment with this method. So, though there are many methods to date to treat these individuals but one of the latest ones is using plasma, which is proven to be efficacious but still many studies are under process for the same.
... For the circulation of biomarkers, plasma is seen to be one of the essential and suitable sources (Caro 2011;Mielczarek et al. 2016;Liu et al. 2021) that led to plasma separation as an important step for preparing a diagnostic test sample (Wang et al. 2012;Kersaudy-Kerhoas and Sollier 2013). Moreover, nowadays for the treatment of patients infected with COVID-19, plasma therapy is being used frequently (Duan et al. 2020;Zeng et al. 2020;Focosi et al. 2020). Thus, for a biological analysis, the separation of blood into its constituents (such as plasma and cells) is a fundamental step (Banko et al. 2019). ...
The last two decades witnessed a significant advancement in the field of diluted and whole blood plasma separation. This is one of the common procedures used to diagnose, cure and treat numerous acute and chronic diseases. For this separation purpose, various types of geometries of microfluidic devices, such as T-channel, Y-channel, trifurcation, constriction–expansion, curved/bend/spiral channels, a combination of any of the two geometries, etc., are being exploited, and this is detailed in this review article. The evaluation of the performance of such devices is based on the several parameters such as separation efficiency, flow rate, hematocrits, channel dimensions, etc. Thus, the current extensive review article endeavours to understand how particular geometry influences the separation efficiency for a given hematocrit. Additionally, a comparative analysis of various geometries is presented to demonstrate the less explored geometric configuration for the diluted and whole blood plasma separation. Also, a meta-analysis has been performed to highlight which geometry serves best to give a consistent separation efficiency. This article also presents tabulated data for various geometries with necessary details required from a designer’s perspective such as channel dimensions, targeted component, studied range of hematocrit and flow rate, separation efficiency, etc. The maximum separation efficiency that can be achieved for a given hematocrits and geometry has also been plotted. The current review highlights the critical findings relevant to this field, state of the art understanding and the future challenges.
... [12] Furthermore, it has been reported in a number of research articles that CPT seems to be one of the successful treatments for COVID-19. [13][14][15] From the outbreak of coronavirus, this treatment has been considered by many researchers in various countries around the world, as well as in Iran. In a hospital in India, for instance, plasma therapy was performed on 333 patients, of whom19 cases were admitted to intensive care unit (ICU). ...
BACKGROUND: Infection with COVID-19 has resulted in considerable mortality all around the world. This study aimed to investigate the effect of convalescent plasma on the treatment of hospitalized patients with COVID-19 in Imam Khomeini Hospital at Ardabil, Iran.
MATERIALS AND METHODS: In this quasi-experimental clinical trial, patients over 18 years of age with polymerase chain reaction-positive COVID-19 were admitted based on the clinical criteria of respiratory distress with hypoxia (O2 saturation 24) with moderate-to-severe lung involvement and in the 1st week of respiratory disease who were not intubated were nonrandomly assigned to two groups: convalescent plasma therapy (CPT) group (197 cases) and control group (200 cases). We used the Chi-square, t-test, Fisher's exact test, and Pearson's correlation coefficient for statistical analysis.
RESULTS: Analyses revealed that length of stay in hospital was significantly lower in the CPT group as compared to the control group (P = 0.001). Twenty-four cases (22.0%) in the CPT group and 85 cases (78.0%) in the control group needed intubation. Furthermore, mortality was 17 cases (18.3%) in the CPT group and 76 cases (81.7%) in the control group, the difference of which was also found to be statistically significant (P < 0.05).
CONCLUSIONS: It seems that CPT can be used as an alternative treatment at the early stages of COVID-19 to prevent the progress of the disease, reduce the need for intubation and consequently the length of stay in hospital, and finally, decrease mortality.
... The therapeutic armamentarium against COVID-19 disease primarily involves supportive therapy and oxygenation. Antiviral drugs like remdesivir and favipiravir or anti-inflammatory drugs like steroids and tocilizumab each have their own scientific rationale (21)(22)(23)(24). However, their efficacy except steroids has not been robustly documented in literature and results of many trials including the results of the recent SOLIDARITY study are discouraging vis a vis these therapies consisting of special drugs (25). ...
Background: The Coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) has led to a global health care crisis. We report profiles of cases admitted to our hospital.
Methods: We conducted this study at the pulmonology unit of a Dedicated COVID Hospital (DCH) of Western India. This is a prospective observational study which analysed the demographical data, clinical parameters, comorbidities, complications and laboratory and outcome parameters.
Results: Our study included 101 patients. The mean age was 43 years; 64 (63.3%) were men and 37 (36.7%) women. Out of 101, 6 (6%) had mild, 30 (30%) had moderate and 65 (64%) had severe COVID-19 disease. Severity increased with age and comorbidities. Ninety-four (94%) had pneumonia. Of these 94, 65 (69%) patients had acute respiratory distress syndrome (ARDS). Twenty-one (21%) were mild, 20 (31%) moderate and 24 (37%) severe ARDS. ARDS severity increased with age and in men. Thirty-six (36%) required oxygenation only and 29 (29%) required additional ventilatory management – mostly non-invasive ventilation (NIV). The laboratory values analysis revealed elevation of D-dimers level in 66 (65.3%) and IL6 in 68 (67.3%). Diabetes mellitus (DM) and hypertension (HT) were the common comorbidities. Totally three (2.97%) patients died due to COVID-19 infection. Mortality was associated with HT and myocarditis. Mean duration of hospital stay was 15 days, and it increased with increasing severity of disease and ARDS.
Conclusion: COVID-19 is common in the adult with male preponderance. The majority recovered with a good outcome. Comorbidities affected outcome adversely.
... Early models of therapy were designed to contain "the cytokine storm", as observed with varying levels of efficacy for the drugs under study. Next, attention was drawn to the possibility of using plasma from convalescents, for whom it is assumed that the active substances are neutralizing polyclonal antibodies [41,42]. Since the onset of the SARS-CoV-2 pandemic, biopharmaceutical companies and academic scientists have collaborated to extract neutralizing monoclonal antibodies from convalescents. ...
Abstract: (1) Background: The purpose of this article is to review pharmacological treatments for COVID-19 (currently approved by the EMA (European Medical Agency) and FDA (Food and Drug Administration)) and highlight their potential audio-vestibular side-effects as an ototoxic adverse reac- tion. (2) Methods: Review of the available literature in the scientific databases PubMed, ResearchGate, Scopus, and ScienceDirect, and in summaries of product data sheets. (3) Results: In accordance with EBM (evidence-based medicine) the treatment of COVID-19 by using lopinavir/ritonavir, chloroquine and hydroxychloroquine, azithromycin, favipiravir, amantadine, oseltamivir, and ivermectin is no longer recommended for patients suffering from COVID-19 due to a lack of clinical data, publications, and recommendations. There were 39 publications and 15 summaries of product characteristics (as other sources of data) which were also used in this analysis. Adverse events could be permanent or disappear over time. Following treatment for COVID-19, the most frequent adverse audio-vestibular reactions reported in clinical trials and publications in the area of audiology and otorhinolaryngology were: dizziness, blurry vision with dizziness, nasopharyngitis, dysgeusia, and tinnitus. As far as vac- cines are concerned, dizziness as an ototoxic effect was uncommon and occurs only in hypersensitive people who experience anaphylactic shock. (4) Conclusions: The ototoxicity of the drugs discussed here does not have as severe symptoms as the drugs used in the treatment of COVID-19 in 2020 (e.g., hydroxychloroquine), and relates mainly to disorders of the vestibulocochlear system. However, there is still a need to monitor ototoxic side-effects because of potential interactions with other ototoxic drugs. Many of the drugs approved by EMA and FDA are new, and not every side-effect is known.
Keywords: ototoxicity; COVID-19; vaccine; hearing loss; tinnitus; dizziness; audio-vestibular side-effects
... Several reported cases have stated the CP transfusion from already recovered persons to critically ill virusinfected patients [22,23]. The positive results have inspired global authorization to collect 'convalescent plasma' (CP) through various health care authorities. ...
To date, no accepted therapy exists for treating the emerging infectious disease nCOVID-19 in a safe and effective way. Although various types of treatment options are under the developing phase around the world, among those, several studies concerning convalescent plasma (CP) from recovered patients reported promising effects against nCOVID-19 infected critically ill patients nowadays. The therapy showed very few adverse effects, and it helps to diminish the viral load when administered at an early stage of infection. Convalescent plasma appears to be safe for critically ill nCOVID-19 patients by decreasing serum viral loads, and most cases are virus negative after CP transfusion. The convalescent plasma can be good as it has already been utilized to treat previous pandemics like Ebola, influenza, and SARS-CoV infection. In this review article, we pointed out the background, rationality, mechanisms, and safety outcomes of CP to treat nCOVID-19 infected patients.
... CPT involves the extraction of plasma containing antiviral antibodies from patients who have recovered (i.e., convalescent patients), followed by transfusion of the collected plasma into new patients suffering with the same disease. While blood typing to decrease the incidence of mismatched plasma was not practiced in the earliest examples of CPT, it has now long been the practice to match ABO blood types to ensure compatibility with the donated plasma [146]. ...
This is an extensive review on virtually all aspects of antibodies against SARS-CoV-2 and the disease it causes, COVID-19. It contains over 550 references and is completely up to date as of end of February, 2022.
... While in early 2020 most clinical use was reported in case series or small phase II clinical trials (7), beginning in late March 2020, the U.S. expanded access program (EAP) generated a large and robust treatment data set, with insights into safety and optimal use. This database provided the first clear evidence that CP is safe, which was important given that early in the pandemic there were significant concerns about antibody-dependent enhancement (8). ...
Convalescent plasma (CP) recurs as a frontline treatment in epidemics
because it is available as soon as there are survivors. The COVID-19 pandemic represented
the first large-scale opportunity to shed light on the mechanisms of action, safety, and efficacy of CP using modern evidence-based medicine approaches. Studies ranging from
observational case series to randomized controlled trials (RCTs) have reported highly variable efficacy results for COVID-19 CP (CCP), resulting in uncertainty. We analyzed variables associated with efficacy, such as clinical settings, disease severity, CCP SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) antibody levels and function, dose, timing of administration (variously defined as time from onset of symptoms, molecular diagnosis, diagnosis of pneumonia, or hospitalization, or by serostatus), outcomes (defined as hospitalization, requirement for ventilation, clinical improvement, or mortality), CCP provenance and time for collection, and criteria for efficacy. The conflicting trial results, along with both recent WHO guidelines discouraging CCP usage and the recent expansion of the FDA emergency use authorization (EUA) to include outpatient use of CCP, create confusion for both clinicians and patients about the appropriate use of CCP. A review of 30
available RCTs demonstrated that signals of efficacy (including reductions in mortality) were
more likely if the CCP neutralizing titer was .160 and the time to randomization was
less than 9 days. The emergence of the Omicron variant also reminds us of the benefits of polyclonal antibody therapies, especially as a bridge to the development and availability
of more specific therapies.
... The therapeutic armamentarium against COVID-19 disease primarily involves supportive therapy and oxygenation. Antiviral drugs like remdesivir and favipiravir or anti-inflammatory drugs like steroids and tocilizumab each have their own scientific rationale (21)(22)(23)(24). However, their efficacy except steroids has not been robustly documented in literature and results of many trials including the results of the recent SOLIDARITY study are discouraging vis a vis these therapies consisting of special drugs (25). ...
English: Background: The Coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) has led to a global health care crisis. We report profiles of cases admitted to our hospital. Methods: We conducted this study at the pulmonology unit of a Dedicated COVID Hospital (DCH) of Western India. This is a prospective observational study which analysed the demographical data, clinical parameters, comorbidities, complications and laboratory and outcome parameters. Results: Our study included 101 patients. The mean age of the study population was 43 years; 64 (63.3%) were men and 37 (36.7%) women. Out of 101, 6 (6%) had mild, 30 (30%) had moderate and 65 (64%) had severe COVID-19 disease. Severity increased with age and comorbidities. Ninety-four (93%) had pneumonia. Of these 94, 65 (69%) patients had acute respiratory distress syndrome (ARDS). Twenty-one (32%) were mild, 20 (31%) moderate and 24 (37%) severe ARDS. ARDS severity increased with age and in men. Thirty-six (36%) required oxygenation only and 29 (29%) required additional ventilatory management-mostly non-invasive ventilation (NIV). The laboratory values analysis revealed elevation of D-dimers level in 66 (65.3%) and IL6 in 68 (67.3%). Both were elevated significantly with increasing ARDS severity. Diabetes mellitus (DM) and hypertension (HT) were the common comorbidities. Totally three (2.97%) patients died due to COVID-19 infection. Mortality was associated with HT and myocarditis. Mean duration of hospital stay was 15 d, and the duration increased with increasing severity of disease and ARDS. Conclusion: COVID-19 is common in the adult age group with male preponderance. The majority of the cases recovered with a good outcome. Comorbidities affected the outcome adversely. Rezumat-Boala COVID-19 in sectia de pneumologie a unui spital dedicat COVID-19-experienta noastra Romanian: Cadru general: Pandemia COVID-19 produsa de virusul SARS-cov-2 a condus la o criza globala a sistemelor de sanatate. Articolul raporteaza profilul cazurilor internate in spitalul nostru. Metode: Studiul de fata s-a realizat in sectia de pneumologie a unui spital dedicat ingrijirii pacientilor cu COVID-19 din Vestul Indiei. Este un studiu prospectiv observational care a analizat datele demografice, parametrii clinici, comorbiditatile, complicatiile, analizele de laborator si modul de finalizare al cazurilor internate. Rezultate: Studiul a inclus 101 pacienti. Varsta medie a populatiei studiate a fost 43 ani: 64 (63.3%) barbati, 37 (36.7%) femei. Dintre cei 101, 6 (6%) au avut forma usoara de boala, 30 (30%) forma moderata, iar 65 (64%) forma severa de COVID-19. Severitatea a fost in crestere odata cu varsta si prezenta comorbiditatilor. Nouazecisipatru (93%) dintre cazuri au avut pneumonie. Dintre acesti 94 pacienti, 65 (69%) au dezvoltat sindrom de detresa respiratorie acuta (ARDS). Douazecisiunu (32%) dintre acestea au fost forme usoare, 20 (31%) moderate si 24 (37%) forme severe de ARDS. Severitatea ARDS a crescut cu varsta si la sexul masculin. Treizecisisase de cazuri (36%) au necesitat doar oxigenoterapie si 29 (29%) au avut nevoie de suport ventilator , cel mai frecvent ventilatie non-invaziva (NIV). Analizele de laborator au aratat valori crescute ale D-dimerilor la
... Hyperimmune plasma with antibodies, obtained from convalescent patients, have also been successfully employed. [13,14] However, due to a number of practical challenges, the latter strategy is unsuitable for producing the large number of doses required to immunize populations worldwide. [14,15] The SARS-Cov-2 infection can be associated, especially in severe forms, with the exaggerate activation of inflammatory processes and the development of cytokine storm. ...
At the beginning of the COVID-19 outbreak (end 2019 - 2020), therapeutic treatments based on approved drugs have been the fastest approaches to combat the new coronavirus pandemic. Nowadays several vaccines are available. However, the worldwide vaccination program is going to take a long time and its success will depend on the vaccine public's acceptance. Therefore, outside of vaccination, the repurposing of existing antiviral, anti-inflammatory and other types of drugs, have been considered an alternative medical strategy for the COVI-19 infection. Due to the broad clinical potential of the drugs, but also to their possible side effects, analytical methods are needed to monitor the drug concentrations in biological fluids and pharmaceutical products. This review deals with analytical methods developed in the period 2015 - July 2021 to detect potential drugs that, according to a literature survey, have been taken into consideration for the treatment of COVID-19. The drugs considered here have been selected on the basis of the number of articles published in the period January 2020-July 2021, using the combination of the keywords: COVID-19 and drugs or SARS-CoV-2 and drugs. A section is also devoted to monoclonal antibodies. Over the period considered, the analytical methods have been employed in a variety of real samples, such as body fluids (plasma, blood and urine), pharmaceutical products, environmental matrices and food.
Introduction
The COVID-19 pandemic presented an unprecedented challenge to the medical community, leading to numerous therapeutic interventions being explored. Convalescent plasma therapy (CPT), derived from recovered COVID-19 patients, was one such treatment used in the absence of proven therapies. However, its efficacy remained a topic of debate.
Materials and Methods
This retrospective study aimed to assess the effectiveness of CPT in patients admitted to the intensive care unit (ICU) with moderate-to-severe COVID-19 infection. Data included comorbidities, treatment regimens, partial pressure of oxygen/fraction of inspired oxygen (PaO2/FiO2) ratios, oxygen therapy duration, and outcomes. Patients were divided into groups based on CPT receipt. Statistical analysis was performed to compare the two groups.
Results
Out of 72 patients, 36 received CPT, and 36 did not. Patients who received CPT had longer ICU and hospital stays. The mortality rate was higher in the CPT group (50%) compared to the non-CPT group (22.2%). Patients with comorbidities experienced higher mortality rates. Notably, the CPT group exhibited improved PaO2/FiO2 ratios on day 2. Complications related to CPT were minimal.
Conclusion
The use of CPT in COVID-19 treatment did not impact overall survival or hospital stay duration.
To adequately prepare for potential hazards caused by emerging and reemerging infectious diseases, the WHO has issued a list of high-priority pathogens that are likely to cause future outbreaks and for which research and development (R&D) efforts are dedicated, known as paramount R&D blueprints. Within R&D efforts, the goal is to obtain effective prophylactic and therapeutic approaches, which depends on a comprehensive knowledge of the etiology, epidemiology, and pathogenesis of these diseases. In this process, the accessibility of animal models is a priority bottleneck because it plays a key role in bridging the gap between in-depth understanding and control efforts for infectious diseases. Here, we reviewed preclinical animal models for high priority disease in terms of their ability to simulate human infections, including both natural susceptibility models, artificially engineered models, and surrogate models. In addition, we have thoroughly reviewed the current landscape of vaccines, antibodies, and small molecule drugs, particularly hopeful candidates in the advanced stages of these infectious diseases. More importantly, focusing on global trends and novel technologies, several aspects of the prevention and control of infectious disease were discussed in detail, including but not limited to gaps in currently available animal models and medical responses, better immune correlates of protection established in animal models and humans, further understanding of disease mechanisms, and the role of artificial intelligence in guiding or supplementing the development of animal models, vaccines, and drugs. Overall, this review described pioneering approaches and sophisticated techniques involved in the study of the epidemiology, pathogenesis, prevention, and clinical theatment of WHO high-priority pathogens and proposed potential directions. Technological advances in these aspects would consolidate the line of defense, thus ensuring a timely response to WHO high priority pathogens.
Convalescent plasma has increasingly been used to treat various viral infections and confer post-exposure prophylactic protection during the last decade and has demonstrated favorable clinical outcomes in patients infected with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) during the recent COVID-19 pandemic. The pandemic has highlighted the need for cost-effective, accessible, and easy-to-use alternatives to conventional blood plasmapheresis techniques, allowing hospitals to become more self-sufficient in harvesting and transfusing donor plasma into recipients in a single setting. To this end, the use of a membrane-based bedside plasmapheresis device (HemoClear) was evaluated in an open-label, non-randomized prospective trial in Suriname in 2021, demonstrating its practicality and efficacy in a low-to middle-income country. This paper will review the use of this method and its potential to expedite the process of obtaining convalescent plasma, especially during pandemics and in resource-constrained settings.
After spreading worldwide, SARS-CoV-2 became a big threat to human civilization as no effective treatment is available till now. People are suffering from this COVID 19 pandemic even after the development of the vaccine which demands the development of antiviral drugs against this deadly virus. In this research, 17 biologically active quinazoline derivatives are virtually screened with the Mpro, PLpro, RdRp, and Spike proteins of SARS-CoV-2. ADMET, toxicity, and drug-likeness properties of these compounds are also checked. MD-simulation studies were performed with the most effective compound (Q_16) of the selected derivatives against SARS-CoV-2 as suggested by the molecular docking study. RMSD, RMSF, radius of gyration and solvent accessible surface area analysis also confirmed the effective binding of this compound with selected SARS-CoV-2 proteins. We believe that the inhibitory efficiency of this quinazoline derivative will help to develop the therapeutic treatment against SARS-CoV-2.
Following infection and vaccination against SARS-CoV-2, humoral components of the adaptive immune system play a key role in protecting the host. Specifically, B cells generate high-affinity antibodies against various antigens of the virus. In this review, we discuss the mechanisms of immunity initiation through both natural infection and vaccination, shedding light on the activation of B cell subsets in response to SARS-CoV-2 infection and vaccination. The innate immune system serves as the initial line of primary and nonspecific defence against viruses. However, within several days following infection or a vaccine dose, a virus-specific immune response is initiated, primarily by B cells that produce antibodies. These antibodies contribute to the resolution of the disease. Subsequently, these B cells transition into memory B cells, which play a crucial role in providing long-term immunity against the virus. CD4+ T helper cells initiate a cascade, leading to B cell somatic hypermutation, germinal center memory B cells, and the production of neutralizing antibodies. B-cell dysfunction can worsen disease severity and reduce vaccine efficacy. Notably, individuals with B cell immunodeficiency show lower IL-6 production. Furthermore, this review delves into several aspects of immune responses, such as hybrid immunity, which has shown promise in boosting broad-spectrum protection. Cross-reactive immunity is under scrutiny as well, as pre-existing antibodies can offer protection against the disease. We also decipher breakthrough infection mechanisms, especially with the novel variants of the virus. Finally, we discuss some potential therapeutic solutions regarding B cells including convalescent plasma therapy, B-1 cells, B regulatory cell (Breg) modulation, and the use of neutralizing monoclonal antibodies in combating the infection. Ongoing research is crucial to grasp population immunity trends and assess the potential need for booster doses in maintaining effective immune responses against potential viral threats.
Disease conditions arise when the body’s homeostatic environment is compromised. For centuries, natural products have been used toward the alleviation of these conditions. As a result, the research community has been influenced by folklore usage to steer the way for plant and microbe identification and selection toward the treatment of and acquiring a better understanding of certain diseases. As the pharmacognosy paradigm evolves, natural product research is no longer limited to plant-based products but also other naturally derived compounds from sources like fungi and other microbes, as well as terrestrial and marine organisms, which themselves have been used as templates for the synthesis of drugs. This chapter briefly describes the use of these products and current drugs toward treating selected infectious diseases. A brief overview of each condition is given.
The COVID-19 pandemic caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-COV-2) is one of the biggest unsolved global problems of the 21st century for which there has been no definitive cure yet. Like other respiratory viruses, SARS-COV-2 triggers the host immunity dramatically, causing dysfunction in the immune system, both innate and adaptive, which is a common feature of COVID-19 patients. Evidence shows that in the early stages of COVID-19, the immune system is suppressed while it is overactive in severe patients characterized by excessive and prolonged inflammatory responses called "Cytokine Storm". There are many elements in the immune system that undergo alterations as the disease progresses. Some significant changes in the innate immune system following infection with SARS-COV-2 include delayed or inhibited interferon type 1 production by the infected cells leading to elevated virus replication, excessive recruitment of activated monocytes and macrophages, decrease in eosinophil population (eosinopenia), consequent decrease in CD8+T lymphocyte proliferation, natural killer (NK) cell dysfunction, and increase in neutrophil infiltration (neutrophilia) and neutrophil extracellular trap (NET) formation. Moreover, hallmark alterations in the adaptive immune system in this process cause an overall decrease in the T lymphocyte number (lymphopenia) and changes in the activity of some lymphocyte subsets and a number of B cells. This review delves into the mentioned changes in the immune system following SARS-COV-2 infection and the implications thereof to guide the development of immunotherapies for patients with COVID-19.
This chapter is dedicated to what measures could have been taken to prevent COVID-19 from becoming a pandemic. Since COVID-19 shows the distribution according to the power law and exponential law in biological networks, fractional derivatives are useful to model the spread of the virus realistically. Therefore, a mathematical model, formerly originated for COVID-19, is firstly investigated with the Caputo derivative to represent the spread of the virus according to the power law. Then, a fractional optimal control problem (FOCP) is enhanced to prevent spread. Existence-proven controls representing strategies such as non-pharmaceutical and pharmaceutical interventions and plasma transfusion therapy aim to minimize the rate of infected individuals together with the cost required for treatment and prevention of the infection. After that, the necessary optimality conditions are revealed by Pontryagin’s Maximum Principle and solved numerically using Adam’s type predictor–corrector method (PCM) combined with the forward–backward sweep algorithm (FBSA). Finally, the optimal control design is studied in terms of the Atangana–Baleanu derivative in Caputo sense (ABC) to examine the spread of the virus according to the exponential law. All results are presented comparatively under various control strategies by using MATLAB.KeywordsCOVID-19 epidemic modelFractional optimal controlCaputo derivativeAtangana–Baleanu derivativeNon-pharmaceutical and pharmaceutical interventionsPlasma transfusion therapy
Vaccines and monoclonal antibody treatments to prevent severe coronavirus disease 2019 (COVID-19) illness were available within a year of the pandemic being declared but there remained an urgent need for therapeutics to treat patients who were not vaccinated, were immunocompromised or whose vaccine immunity had waned. Initial results for investigational therapies were mixed. AT-527, a repurposed nucleoside inhibitor for hepatitis C virus, enabled viral load reduction in a hospitalized cohort but did not reduce viral load in outpatients. The nucleoside inhibitor molnupiravir prevented death but failed to prevent hospitalization. Nirmatrelvir, an inhibitor of the main protease (Mpro), co-dosed with the pharmacokinetic booster ritonavir, reduced hospitalization and death. Nirmatrelvir-ritonavir and molnupiravir received an Emergency Use Authorization in the United States at the end of 2021. Immunomodulatory drugs such as baricitinib, tocilizumab and corticosteroid, which target host-driven COVID-19 symptoms, are also in use. We highlight the development of COVID-19 therapies and the challenges that remain for anticoronavirals.
N6-methyladenosine (m6A) is the most common methylation modification in mammalian messenger RNA (mRNA) and noncoding RNAs. m6A modification plays a role in the regulation of gene expression and deregulation of m6A methylation has been implicated in many human diseases. Recent publications suggest that exploitation of this methylation process may possess utility against acute lung injury (ALI). ALI and its more severe form, acute respiratory distress syndrome (ARDS) are acute, inflammatory clinical syndromes characterized by poor oxygenation and diffuse pulmonary infiltrates. This syndrome is associated with microvascular endothelial dysfunction, subsequent pulmonary hypertension and may ultimately lead to mortality without rigorous and acute clinical intervention. Over the years, many attempts have been made to detect novel therapeutic avenues for research without much success. The urgency for the discovery of novel therapeutic agents has become more pronounced recently given the current pandemic infection of coronavirus disease 2019 (COVID-2019), still ongoing at the time that this review is being written. We review the current landscape of literature regarding ALI and ARDS etiology, pathophysiology, and therapeutics and present a potential role of m6A methylation. Additionally, we will establish the axiomatic principles of m6A methylation to provide a framework. In conclusion, METTL3, or methyltransferase-like 3, the selective RNA methyltransferase for m6A, is a hub of proinflammatory gene expression regulation in ALI, and using a modern drug discovery strategy will identify new and effective ALI drug candidates targeting METTTL3.
SARS-CoV2 is a novel respiratory coronavirus and, understanding its molecular mechanism is a prerequisite to developing effective treatment for covid-19. This RNA genome-carrying virus has a protein coat with spikes (S) that attaches to the ACE2 receptor at the cell surface of human cells. Several repurposed drugs are used to treat covid-19 patients that are proven to be largely unsuccessful or have limited success in reducing mortalities. Several vaccines are in use to reduce the viral load to prevent developing symptoms. Major challenges to their efficacy include the inability of antibody molecules to enter cells but remain effective in the bloodstream to kill the virus. The efficacy of vaccines also depends on their neutralizing ability to constantly evolve new virus strains due to novel mutations and evolutionary survival dynamics. Taken together, SARS-CoV2 antibody vaccines may not be very effective and other approaches based on genetic, genomic, and protein interactome could be fruitful to identify therapeutic targets to reduce disease-related mortalities.
Current tests for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) detect either the constituent nucleic acids/proteins of the viral particles or antibodies specific to the virus, but cannot provide information about viral neutralization by an antibody and the efficacy of an antibody. Such information is important about individuals' vulnerability to severe symptoms or their likelihood of showing no symptoms. We immobilized online SARS-CoV-2 spike (S1) protein and angiotensin-converting enzyme 2 (ACE2) into separate surface plasmon resonance (SPR) channels of a tris-nitrilotriacetic acid (tris-NTA) chip to simultaneously detect the anti-S1 antibody and viral particles in serum samples. In addition, with a high-molecular-weight-cutoff filter, we separated the neutralized viral particles from the free antibody molecules and used a sensing channel immobilized with Protein G to determine antibody-neutralized viral particles. The optimal density of probe molecules in each fluidic channel can be precisely controlled through the closure and opening of the specific ports. By utilizing the high surface density of ACE2, multiple assays can be carried out without regenerations. These three species can be determined with a short analysis time (<12 min per assay) and excellent sensor-to-sensor/cycle-to-cycle reproducibility (RSD < 5%). When coupled with an autosampler, continuous assays can be performed in an unattended manner at a single chip for up to 6 days. Such a sensor capable of assaying serum samples containing the three species at different levels provides additional insights into the disease status and immunity of persons being tested, which should be helpful for containing the SARS-CoV-2 spread during the era of incessant viral mutations.
Current serological antibody tests for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) require enzyme or fluorescent labels, and the titer well plates cannot be reused. By immobilizing histidine (His)-tagged SARS-CoV-2 spike (S1) protein onto tris‒nitrilotriacetic acid (tris-NTA) sensor and using the early association phase for mass-transfer-controlled concentration determination, we developed a rapid and regenerable surface plasmon resonance (SPR) method for quantifying anti-SARS-CoV-2 antibody. On a five-channel SPR instrument and with optimized S1 protein immobilization density, each of the four analytical channels is sequentially used for multiple measurements, and all four channels can be simultaneously regenerated once they have reached a threshold value. Coupled with a programmable autosampler, each sensor can be regenerated at least 20 times, enabling uninterrupted assays of more than 800 serum samples. The accuracy and speed of our method compare well with those of the enzyme-linked immunosorbent assay (ELISA), and the detection limit (0.057 μg mL⁻¹) can easily meet the requirement for screening low antibody levels such as those in convalescent patients. In addition, our method exhibits excellent channel-to-channel (RSD = 1.9%) and sensor-to-sensor (RSD = 2.1%) reproducibility. Obviation of an enzyme label drastically reduced the assay cost, rending our method (<60 cents) much more cost effective than those of commercial ELISA kits ($4.4–11.4). Therefore, our method offers a cost-effective and high-throughput alternative to the existing methods for serological measurements of anti-SARS-CoV-2 antibody levels, holding great promise for rapid screening of clinical samples without elaborate sample pretreatments and special reagents.
The new outbreak of coronavirus disease 2019 (COVID-19) has infected and caused the death of millions of people worldwide. Intensive efforts are underway around the world to establish effective treatments. Immunoglobulin from immunized animals or plasma from convalescent patients might constitute a specific treatment to guarantee the neutralization of the virus in the early stages of infection, especially in patients with risk factors and a high probability of progressing to severe disease. Worldwide, a few clinical trials using anti-SARS-CoV-2 immunoglobulins from horses immunized with the entire spike protein or fragments of it in the treatment of patients with COVID-19 are underway. Here, we describe the development of an anti-SARS-CoV-2 equine F(ab′) 2 immunoglobulin using a newly developed SARS-CoV-2 viral antigen that was purified and inactivated by radiation. Cell-based and preclinical assays showed that the F(ab′) 2 immunoglobulin successfully neutralizes the virus, is safe in animal models, and reduces the severity of the disease in a hamster model of SARS-CoV-2 infection and disease.
The transition to personalized, predictive, preventive and participatory medicine, due, among other things, to the achievements of fundamental science, digitalization and the development of information and communication technologies, naturally demanded changes in childrens health care. New organizational, methodological and technological changes that have taken place to ensure a highly dynamic, adapted, and, at the same time, permanent provision of the medical process anywhere and at any time, have led to the need for specialists of a new formation a pluriexpert team ready to work in new conditions: how to participate in research in fundamental science, and to the introduction of innovative methods in clinical practice, medical and social support and the educational process. In these conditions, the strategic goal set for pediatrics to analyze absolutely all aspects of health: somatic, neuropsychic, emotional and psycho-social, in the process of growth and development of a child from conception/birth to adolescence / adulthood was implemented in a new direction of clinical and fundamental medicine developmental pediatrics and child health programming. 7P-pediatrics: Programming the development and health of the child, Preventive, Predictive, Personalized, Participatory, Polyprofessional (Pluriexpert), Progressive medicine for children, in which the results of scientific work based on fundamental data and ideas of neurosciences about progressive development and modern methodology of educational support of the entire medical process are fully translated into a clinical practice.
The review presents the recent data on assumed risk factors for the development of ANCA-associated vasculitis (AAV), among which environmental factors, such as climatic, chemical, etc., are of particular interest of researchers. Controversial opinions of various authors on the role of individual causative agents of infectious diseases in the development of AAV are analyzed. The review pays special attention to scientific data on the influence of variants of the structure of genes encoding various components of the immune system on the development of the pathogenetic process of AAV. Up-to-date information on the association of single-nucleotide polymorphisms (SNPs) with the course, risk of development and the likelihood of AAV recurrence is indicated, the most associated of which are genes encoding proteins of the main histocompatibility complex (HLA), a toll-like receptors (TLR`s), as well as an inhibitor of serine proteinases-alpha-antitrypsin (AAT). The analysis of scientific publications describing the molecular mechanism of the development of a pathological focus that forms the conditions for the synthesis of PR3ANCA and MPOANCA complexes characteristic of AAV has been carried out. The data of a number of foreign studies on the relationship of individual SNPs associated with the features of the course of granulomatosis with polyangiitis, microscopic polyangiitis, as well as eosinophilic granulomatosis with polyangiitis are presented and summarized. The review presents current AAV treatment regimens and promising directions for the development of medical care for patients.
The most effective means of combating the COVID-19 pandemic s the formation of herd immunity, with the formation of an immune population to infection. Vaccination rates are continuously increasing. In early February 2021, WHO announced that the number of people vaccinated against the disease for the first time exceeded the number of infected. In early June 2021 the vaccinated number exceeded 2 billion which is more than 12 times the total number infected for the entire duration of the pandemic. The high rate of vaccination leads to the formulation of a number of questions concerning the effectiveness of vaccines currently used for mass immunization the level of herd immunity, necessary to stop the spread of the disease, the actual duration of the vaccination carried out, long-term prospects of the platforms, used in the creation of vaccines. The purpose of this paper is to substantiate reasoned answers to the questions posed.
Introduction
The lack of approved specific therapeutic agents to treat coronavirus disease (COVID‐19) associated with severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection has led to the rapid implementation of convalescent plasma therapy (CPT) trials in many countries, including the United Kingdom. Effective CPT is likely to require high titres of neutralising antibody (nAb) in convalescent donations. Understanding the relationship between functional neutralising antibodies and antibody levels to specific SARS‐CoV‐2 proteins in scalable assays will be crucial for the success of a large‐scale collection. We assessed whether neutralising antibody titres correlated with reactivity in a range of enzyme‐linked immunosorbent assays (ELISA) targeting the spike (S) protein, the main target for human immune response.
Methods
Blood samples were collected from 52 individuals with a previous laboratory‐confirmed SARS‐CoV‐2 infection. These were assayed for SARS‐CoV‐2 nAbs by microneutralisation and pseudo‐type assays and for antibodies by four different ELISAs. Receiver operating characteristic (ROC) analysis was used to further identify sensitivity and specificity of selected assays to identify samples containing high nAb levels.
Results
All samples contained SARS‐CoV‐2 antibodies, whereas neutralising antibody titres of greater than 1:20 were detected in 43 samples (83% of those tested) and >1:100 in 22 samples (42%). The best correlations were observed with EUROimmun immunoglobulin G (IgG) reactivity (Spearman Rho correlation coefficient 0.88; p < 0.001). Based on ROC analysis, EUROimmun would detect 60% of samples with titres of >1:100 with 100% specificity using a reactivity index of 9.1 (13/22).
Discussion
Robust associations between nAb titres and reactivity in several ELISA‐based antibody tests demonstrate their possible utility for scaled‐up production of convalescent plasma containing potentially therapeutic levels of anti‐SARS‐CoV‐2 nAbs.
Humoral immune responses are typically characterized by primary IgM antibody responses followed by secondary antibody responses associated with immune memory and comprised of of IgG, IgA and IgE. Here we measured acute humoral responses to SARS-CoV-2, including the frequency of antibody-secreting cells and the presence of SARS-CoV-2-specific neutralizing antibodies in the serum, saliva and broncho-alveolar fluid of 159 patients with COVID-19. Early SARS-CoV-2-specific humoral responses were dominated by IgA antibodies. Peripheral expansion of IgA plasmablasts with mucosal-homing potential was detected shortly after the onset of symptoms and peaked during the third week of the disease. The virus-specific antibody responses included IgG, IgM and IgA, but IgA contributed to virus neutralization to a greater extent compared with IgG. Specific IgA serum concentrations decreased notably one month after the onset of symptoms, but neutralizing IgA remained detectable in saliva for a longer time (days 49 to 73 post symptoms). These results represent a critical observation given the emerging information as to the types of antibodies associated with optimal protection against re-infection, and whether vaccine regimens should consider targeting a potent but potentially short-lived IgA response.
BackgroundSARS-CoV-2 and its associated disease, COVID-19, has infected over seven million people world-wide, including two million people in the United States. While many people recover from the virus uneventfully, a subset of patients will require hospital admission, some with intensive care needs including intubation, and mechanical ventilation. To date there is no cure and no vaccine is available. Passive immunotherapy by the transfusion of convalescent plasma donated by COVID-19 recovered patients might be an effective option to combat the virus, especially if used early in the course of disease. Here we report our experience of using convalescent plasma at a tertiary care center in a mid-size, midwestern city that did not experience an overwhelming patient surge. Methods Hospitalized COVID-19 patients categorized as having Severe or Life-Threatening disease according to the Mayo Clinic Emergency Access Protocol were screened, consented, and treated with convalescent plasma collected from local donors recovered from COVID-19 infection. Clinical data and outcomes were collected retrospectively. Results 31 patients were treated, 16 severe patients and 15 life-threatened patients. Overall mortality was 27% (4/31) but only patients with life-threatening disease died. 94% of transfused patients with severe disease avoided escalation to ICU care and mechanical ventilation. 67% of patients with life-threatening disease were able to be extubated. Most transfused patients had a rapid decrease in their respiratory support requirements on or about day 7 following convalescent plasma transfusion. Conclusion
Our results demonstrate that convalescent plasma is associated with reducing ventilatory requirements in patients with both severe and life-threatening disease, but appears to be most beneficial when administered early in the course of disease when patients meet the criteria for severe illness.
The rapid global spread of the novel coronavirus SARS-CoV-2 has strained healthcare and testing resources, making the identification and prioritization of individuals most at-risk a critical challenge. Recent evidence suggests blood type may affect risk of severe COVID-19. Here, we use observational healthcare data on 14,112 individuals tested for SARS-CoV-2 with known blood type in the New York Presbyterian (NYP) hospital system to assess the association between ABO and Rh blood types and infection, intubation, and death. We find slightly increased infection prevalence among non-O types. Risk of intubation was decreased among A and increased among AB and B types, compared with type O, while risk of death was increased for type AB and decreased for types A and B. We estimate Rh-negative blood type to have a protective effect for all three outcomes. Our results add to the growing body of evidence suggesting blood type may play a role in COVID-19.
Background
SARS-CoV-2 and its associated disease, COVID-19, has infected over seven million people world-wide, including two million people in the United States. While many people recover from the virus uneventfully, a subset of patients will require hospital admission, some with intensive care needs including intubation, and mechanical ventilation. To date there is no cure and no vaccine is available. Passive immunotherapy by the transfusion of convalescent plasma donated by COVID-19 recovered patients might be an effective option to combat the virus, especially if used early in the course of disease. Here we report our experience of using convalescent plasma at a tertiary care center in a mid-size, midwestern city that did not experience an overwhelming patient surge.
Methods
Hospitalized COVID-19 patients categorized as having Severe or Life-Threatening disease according to the Mayo Clinic Emergency Access Protocol were screened, consented, and treated with convalescent plasma collected from local donors recovered from COVID-19 infection. Clinical data and outcomes were collected retrospectively.
Results
31 patients were treated, 16 severe patients and 15 life-threatened patients. Overall mortality was 27% (4/31) but only patients with life-threatening disease died. 94% of transfused patients with severe disease avoided escalation to ICU care and mechanical ventilation. 67% of patients with life-threatening disease were able to be extubated. Most transfused patients had a rapid decrease in their respiratory support requirements on or about day 7 following convalescent plasma transfusion.
Conclusion
Our results demonstrate that convalescent plasma is associated with reducing ventilatory requirements in patients with both severe and life-threatening disease, but appears to be most beneficial when administered early in the course of disease when patients meet the criteria for severe illness.
Background: Laboratory diagnosis of SARS-CoV-2 infection (the cause of COVID-19) uses PCR to detect viral RNA (vRNA) in respiratory samples. SARS-CoV-2 RNA has also been detected in other sample types, but there is limited understanding of the clinical or laboratory significance of its detection in blood.
Methods: We undertook a systematic literature review to assimilate the evidence for the frequency of vRNA in blood, and to identify associated clinical characteristics. We performed RT-PCR in serum samples from a UK clinical cohort of acute and convalescent COVID-19 cases (n=212), together with convalescent plasma samples collected by NHS Blood and Transplant (NHSBT) (n=462 additional samples). To determine whether PCR-positive blood samples could pose an infection risk, we attempted virus isolation from a subset of RNA-positive samples.
Results: We identified 28 relevant studies, reporting SARS-CoV-2 RNA in 0-76% of blood samples; pooled estimate 10% (95%CI 5-18%). Among serum samples from our clinical cohort, 27/212 (12.7%) had SARS-CoV-2 RNA detected by RT-PCR. RNA detection occurred in samples up to day 20 post symptom onset, and was associated with more severe disease (multivariable odds ratio 7.5). Across all samples collected ≥28 days post symptom onset, 0/494 (0%, 95%CI 0-0.7%) had vRNA detected. Among our PCR-positive samples, cycle threshold (ct) values were high (range 33.5-44.8), suggesting low vRNA copy numbers. PCR-positive sera inoculated into cell culture did not produce any cytopathic effect or yield an increase in detectable SARS-CoV-2 RNA. There was a relationship between RT-PCR negativity and the presence of total SARS-CoV-2 antibody (p=0.02).
Conclusions: vRNA was detectable at low viral loads in a minority of serum samples collected in acute infection, but was not associated with infectious SARS-CoV-2 (within the limitations of the assays used). This work helps to inform biosafety precautions for handling blood products from patients with current or previous COVID-19.
Background
Convalescent plasma therapy for COVID‐19 relies on transfer of anti‐viral antibody from donors to recipients via plasma transfusion. The relationship between clinical characteristics and antibody response to COVID‐19 is not well defined. We investigated predictors of convalescent antibody production and quantified recipient antibody response in a convalescent plasma therapy clinical trial.
Methods
Multivariable analysis of clinical and serological parameters in 103 confirmed COVID‐19 convalescent plasma donors 28 days or more following symptom resolution was performed. Mixed‐effects regression models with piecewise linear trends were used to characterize serial antibody responses in 10 convalescent plasma recipients with severe COVID‐19.
Results
Donor antibody titres ranged from 0 to 1 : 3892 (anti‐receptor binding domain (RBD)) and 0 to 1 : 3289 (anti‐spike). Higher anti‐RBD and anti‐spike titres were associated with increased age, hospitalization for COVID‐19, fever and absence of myalgia (all P < 0.05). Fatigue was significantly associated with anti‐RBD (P = 0.03). In pairwise comparison amongst ABO blood types, AB donors had higher anti‐RBD and anti‐spike than O donors (P < 0.05). No toxicity was associated with plasma transfusion. Non‐ECMO recipient anti‐RBD antibody titre increased on average 31% per day during the first three days post‐transfusion (P = 0.01) and anti‐spike antibody titre by 40.3% (P = 0.02).
Conclusion
Advanced age, fever, absence of myalgia, fatigue, blood type and hospitalization were associated with higher convalescent antibody titre to COVID‐19. Despite variability in donor titre, 80% of convalescent plasma recipients showed significant increase in antibody levels post‐transfusion. A more complete understanding of the dose‐response effect of plasma transfusion amongst COVID‐19‐infected patients is needed.
Abstract
Antibodies predating infection
Immunological memory after infection with seasonal human coronaviruses (hCoVs) may potentially contribute to cross-protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Ng et al. report that in a cohort of 350 SARS-CoV-2–uninfected individuals, a small proportion had circulating immunoglobulin G (IgG) antibodies that could cross-react with the S2 subunit of the SARS-CoV-2 spike protein (see the Perspective by Guthmiller and Wilson). By contrast, COVID-19 patients generated IgA, IgG, and IgM antibodies that recognized both the S1 and S2 subunits. The anti-S2 antibodies from SARS-CoV-2–uninfected patients showed specific neutralizing activity against both SARS-CoV-2 and SARS-CoV-2 S pseudotypes. A much higher percentage of SARS-CoV-2–uninfected children and adolescents were positive for these antibodies compared with adults. This pattern may be due to the fact that children and adolescents generally have higher hCoV infection rates and a more diverse antibody repertoire, which may explain the age distribution of COVID-19 susceptibility.
Science , this issue p. 1339 ; see also p. 1272
Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a new human disease with few effective treatments1. Convalescent plasma, donated by persons who have recovered from COVID-19, is the acellular component of blood that contains antibodies, including those that specifically recognize SARS-CoV-2. These antibodies, when transfused into patients infected with SARS-CoV-2, are thought to exert an antiviral effect, suppressing virus replication before patients have mounted their own humoral immune responses2,3. Virus-specific antibodies from recovered persons are often the first available therapy for an emerging infectious disease, a stopgap treatment while new antivirals and vaccines are being developed1,2. This retrospective, propensity score–matched case–control study assessed the effectiveness of convalescent plasma therapy in 39 patients with severe or life-threatening COVID-19 at The Mount Sinai Hospital in New York City. Oxygen requirements on day 14 after transfusion worsened in 17.9% of plasma recipients versus 28.2% of propensity score–matched controls who were hospitalized with COVID-19 (adjusted odds ratio (OR), 0.86; 95% confidence interval (CI), 0.75–0.98; chi-square test P value = 0.025). Survival also improved in plasma recipients (adjusted hazard ratio (HR), 0.34; 95% CI, 0.13–0.89; chi-square test P = 0.027). Convalescent plasma is potentially effective against COVID-19, but adequately powered, randomized controlled trials are needed.
To explore any relationship between the ABO blood group and the COVID-19 susceptibility, we compared ABO blood group distributions in 2,173 COVID-19 patients with local control populations, and found that blood group A was associated with an increased risk of infection, whereas group O was associated with a decreased risk.
Hyperimmune plasma from Covid-19 convalescent is a potential treatment for severe Covid-19. We conducted a multicenter one arm proof of concept interventional study. Patients with Covid-19 disease with moderate-to-severe Acute Respiratory Distress Syndrome, elevated C-reactive Protein and need for mechanical ventilation and/or CPAP were enrolled. One to three 250-300 ml unit of hyperimmune plasma (neutralizing antibodies titer ≥1:160) were administered. Primary outcome was 7-days hospital mortality. Secondary outcomes were PaO2/FiO2, laboratory and radiologic changes, as well as weaning from mechanical ventilation and safety. The study observed 46 patients from March, 25 to April, 21 2020. Patients were aged 63, 61% male, of them, 30 were on CPAP and 7 intubated. PaO2/FiO2 was 128 (SD 47). Bilateral infiltrates on chest X-ray was present in 36 patients (84%). Symptoms and ARDS duration were 14 (SD 7) and 6 days (SD 3). Three patients (6.5%) died within 7 days as compared to an expected 15% from the National Statistics and 30% from a small concurrent cohort of 23 patients. The upper one-sided 90%CI was 13.9%, allowing to reject the null hypothesis of a 15% mortality. PaO2/FiO2 increased by 112 units (95%CI 82 to142) in survivors, the chest radiogram severity decreased in 23% (95%CI 5% to 42%); CRP, Ferritin and LDH decreased by 60, 36 and 20% respectively. Weaning from CPAP was obtained in 26/30 patients and 3/7 were extubated. Five serious adverse events occurred in 4 patients (2 likely, 2 possible treatment related). In conclusion, Hyperimmune plasma in Covid-19 shows promising benefits, to be confirmed in a randomized controlled trial. This proof of concept study could open to future developments including hyperimmune plasma banking, development of standardized pharmaceutical products and monoclonal antibodies.
Background: SARS-CoV-2 and its associated disease, COVID-19, has infected over seven million people world-wide, including two million people in the United States. While many people recover from the virus uneventfully, a subset of patients will require hospital admission, some with intensive care needs including intubation, and mechanical ventilation. To date there is no cure and no vaccine is available. Passive immunotherapy by the transfusion of convalescent plasma donated by COVID-19 recovered patients might be an effective option to combat the virus, especially if used early in the course of disease. Here we report our experience of using convalescent plasma at a tertiary care center in a mid-size, midwestern city that did not experience an overwhelming patient surge.
Methods: Hospitalized COVID-19 patients categorized as having Severe or Life-Threatening disease according to the Mayo Clinic Emergency Access Protocol were screened, consented, and treated with convalescent plasma collected from local donors recovered from COVID-19 infection. Clinical data and outcomes were collected retrospectively.
Results: 31 patients were treated, 16 severe patients and 15 life-threatened patients. Overall mortality was 27% (4/31) but only patients with life-threatening disease died. 94% of transfused patients with severe disease avoided escalation to ICU care and mechanical ventilation. 67% of patients with life-threatening disease were able to be extubated. Most transfused patients had a rapid decrease in their respiratory support requirements on or about day 7 following convalescent plasma transfusion.
Conclusion: Our results demonstrate that convalescent plasma is associated with reducing ventilatory requirements in patients with both severe and life-threatening disease, but appears to be most beneficial when administered early in the course of disease when patients meet the criteria for severe illness.
Abstract Remdesivir is a nucleoside antiviral recently studied in several randomized trials for treatment of COVID-19. The available observational and prospective data are conflicting, requiring clinicians to critically evaluate and reconcile results to determine patient populations that may optimally benefit from remdesivir therapy, especially while drug supply is scarce. In this review, we analyze pertinent clinical remdesivir data for patients with COVID-19 from January 1, 2020, through May 31, 2020.
Introduction: A recently emerging respiratory disease named coronavirus disease 2019 (COVID-19) has quickly spread across the world. This disease is initiated by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and uncontrolled cytokine storm, but it remains unknown as to whether a robust antibody response is related to clinical deterioration and poor outcome in COVID-19 patients. Methods: Anti-SARS-CoV-2 IgG and IgM antibodies were determined by chemiluminescence analysis (CLIA) in COVID-19 patients at a single center in Wuhan. Median IgG and IgM levels in acute and convalescent-phase sera (within 35 days) for all included patients were calculated and compared between severe and non-severe patients. Immune response phenotyping based on the late IgG levels and neutrophil-to-lymphocyte ratio (NLR) was characterized to stratified patients into different disease severities and outcomes. Results: A total of 222 patients were included in this study. IgG was first detected on day 4 of illness, and its peak levels occurred in the fourth week. Severe cases were more frequently found in patients with high IgG levels, compared to those with low IgG levels (51.8 vs. 32.3%; p = 0.008). Severity rates for patients with NLRhiIgGhi, NLRhiIgGlo, NLRloIgGhi, and NLRloIgGlo phenotype were 72.3, 48.5, 33.3, and 15.6%, respectively (p < 0.0001). Furthermore, severe patients with NLRhiIgGhi, NLRhiIgGlo had higher inflammatory cytokines levels including IL-2, IL-6 and IL-10, and decreased CD4+ T cell count compared to those with NLRloIgGlo phenotype (p < 0.05). Recovery rates for severe patients with NLRhiIgGhi, NLRhiIgGlo, NLRloIgGhi, and NLRloIgGlo phenotype were 58.8% (20/34), 68.8% (11/16), 80.0% (4/5), and 100% (12/12), respectively (p = 0.0592). Dead cases only occurred in NLRhiIgGhi and NLRhiIgGlo phenotypes. Conclusions: COVID-19 severity is associated with increased IgG response, and an immune response phenotyping based on the late IgG response and NLR could act as a simple complementary tool to discriminate between severe and non-severe COVID-19 patients, and further predict their clinical outcome.
We present the case of a six-year-old girl with severe COVID-19, in whom SARS-CoV-2 was successfully eliminated after convalescent plasma transfusion. Children show a variable clinical course of COVID-19, from asymptomatic to critical. In our patient, we diagnosed COVID-19-associated aplastic anemia with severe pancytopenia. The correlation between SARS-CoV-2 infection with aplastic anemia remains unclear. At the beginning of the disease, we used antiviral drugs and immune modulators as therapy but without any positive results. After providing a transfusion of convalescent plasma, the elimination of SARS-CoV-2 was observed. We did not observe any adverse events of this treatment. The girl still has a diagnosis of aplastic anemia and requires specialist therapy.
Coronavirus disease 2019 (COVID-19) is rapidly spreading around the world, causing much morbidity and mortality everywhere. However, effective treatments or vaccines are still not available. Although convalescent plasma (CP) therapy can be useful in the treatment of COVID-19, it has not been widely used in Korea because of the concerns about adverse effects and the difficulty in matching patients to donors. The use of ABO-incompatible plasma is not contraindicated in treatment, but can be hesitated due to the lack of experience of physicians. Here, we describe a 68-year old man with COVID-19 who was treated ABO-incompatible plasma therapy; additionally, we comment on the acute side effects associated with ABO mismatch transfusion. To overcome the obstacles of donor-recipient connections (schedule and distance), we propose the storage of frozen plasma, modification of the current Blood Management Law, and the establishment of a CP bank. We suggest that experience gained in CP therapy will be useful for not only the treatment of COVID-19, but also for coping with new emerging infectious diseases.
Convalescent plasma is currently one of the leading treatments for COVID-19, but there is a paucity of data identifying therapeutic efficacy. A comprehensive analysis of the antibody responses in potential plasma donors and an understanding of the clinical and demographic factors that drive variant antibody responses is needed. Among 126 potential convalescent plasma donors, the humoral immune response was evaluated by a SARS-CoV-2 virus neutralization assay using Vero-E6-TMPRSS2 cells, commercial IgG and IgA ELISA to Spike (S) protein S1 domain (Euroimmun), IgA, IgG and IgM indirect ELISAs to the full-length S or S-receptor binding domain (S-RBD), and an IgG avidity assay. Multiple linear regression and predictive models were utilized to assess the correlations between antibody responses with demographic and clinical characteristics. IgG titers were greater than either IgM or IgA for S1, full length S, and S-RBD in the overall population. Of the 126 plasma samples, 101 (80%) had detectable neutralizing titers. Using neutralization titer as the reference, the sensitivity of the IgG ELISAs ranged between 95-98%, but specificity was only 20-32%. Male sex, older age, and hospitalization with COVID-19 were all consistently associated with increased antibody responses across the serological assays. Neutralizing antibody titers were reduced over time in contrast to overall antibody responses. There was substantial heterogeneity in the antibody response among potential convalescent plasma donors, but sex, age and hospitalization emerged as factors that can be used to identify individuals with a high likelihood of having strong antiviral antibody levels.
One Sentence Summary
There is substantial heterogeneity in the antibody response to SARS-CoV-2 infection, with greater antibody responses being associated with male sex, advancing age, and hospitalization with COVID-19.
Aim
Convalescent Plasma (CP) therapy is of interest as no vaccine or specific treatment is available for emerging viruses such as severe acute respiratory syndrome coronavirus 2 causing Covid-19. It was aimed to report the results of our patients who underwent CP in the treatment of Covid-19.
Methods
CP treatment was applied to 26 Covid-19 patients in intensive care unit who had quantitative reverse transcriptase–polymerase chain reaction positive Sars-Cov-2 infection. Plasma was collected at least 14 days after complete recovery from patients who had mild or moderate infection with Sars-Cov-2 infection. The collected CP (200cc) were applied to severe Covid-19 patients. Laboratory values of patients just before CP and after 7 days were compared.
Results
There were no statistically significant differences in leukocyte, neutrophil, lymphocyte, platelet, CRP, ferritin, LDH, ALT, AST, sO2 and total bilirubin values just before and after 1 week of CP. A statistically significant difference was found between age and lymphocyte values of living and dying patients. The patients who died were determined to have older age (74,6 vs 61,85, p = 0,018) and more severe lymphopenia (0,47 vs 1,18, p = 0,001).
Conclusion
CP therapy has the potential to provide immediate and promising treatment options before specific vaccines and treatments are developed. In early stage Covid-19 patients who do not need mechanical ventilation, CP treatment may be a curative treatment option.
We read with deep interest the report by Tepasse and colleagues¹ , concerning two cases of persisting viremia in Covid‐19 with fatal outcome. Whilst SARS‐CoV‐2 infection in the early stages of infection has been well described, less is known about the development of antibodies to SARS‐CoV‐2, clearance of RNA shedding and clinical outcome of COVID‐19.
Introduction
Although some medicines are under research, currently, no specific antiviral drug has been approved to target 2019 novel coronavirus. In this report two severe cases of 2019 novel coronavirus disease (COVID-19) patients have been described who received convalescent plasma (CP).
Case report
Two male cases (a 46-year-old and a 56-year-old) after being diagnosed with severe COVID-19, they deteriorated despite supportive care and antiviral therapy. They started to improve with CP infusion both clinically and radiologically. Finally they were discharged in a very well condition with negative virology tests.
Conclusion
CP might be an effective therapy for severe COVID-19 patients.
Coronavirus disease 2019 (COVID-19) is causing worldwide pandemic with no specific therapeutic agents, especially for severe or critical patients. To comprehensively evaluate the effectiveness, safety, and indications of convalescent plasma transfusion (CPT) therapy for severe or critical COVID-19 patients, we analyzed the clinical, laboratory, and radiologic characteristics of 1,568 patients from a single center, in which 138 patients received ABO-compatible CPT. The median time from the first symptom to CPT was 45 days. 2.2% and 4.1% of cases died in the CPT group and in the standard-treatment group, respectively. 2.4% and 5.1% of patients in the CPT and the standard-treatment group have been admitted to ICU eventually. 70% of the patients who had severe respiratory symptoms got improved and removed oxygen supports within 7 days after CPT. The viral loads and C-reactive protein (CRP) concentration significantly decreased (P<0.001), and the percentage of lymphocytes increased (P=0.006), 76.8% of cases received radiological improvements within 14 days after CPT. Patients with a higher percentage of lymphocytes and a lower percentage of neutrophils and CRP concentration respond better to CPT (P<0.05). Notably, for the patients who received CPT within 7 weeks after symptom onset, the median time from CPT to clinical improvements was approximately 10 days. But the time to clinical improvements was significantly prolonged for patients who received CPT later than 7 weeks after onset. Our study will provide important information for the clinical practice in COVID-19 treatment, as well as provide real-world observations and clinical data for the development of monoclonal antibodies.
Background: Convalescent plasma therapy for COVID-19 relies on the transfer of anti-viral antibody from donors to recipients via plasma transfusion. The relationship between clinical characteristics and antibody response to COVID-19 is not well defined. We investigated predictors of convalescent antibody production and quantified recipient antibody response in a convalescent plasma therapy clinical trial.
Methods: Multivariable analysis of clinical and serological parameters in 103 confirmed COVID-19 convalescent plasma donors 28 days or more following symptom resolution was performed. Mixed effects regression models with piecewise linear trends were used to characterize serial antibody responses in 10 convalescent plasma recipients with severe COVID-19.
Results: Mean symptom duration of plasma donors was 11.9 and 7.8% (8/103) had been hospitalized. Antibody titers ranged from 0 to 1:3,892 (anti-receptor binding domain (RBD)) and 0 to 1:3,289 (anti-spike). Multivariable analysis demonstrated that higher anti-RBD and anti-spike titer were associated with increased age, hospitalization for COVID-19, fever, and absence of myalgia (all p<0.05). Fatigue was significantly associated with anti-RBD (p=0.03) but not anti-spike antibody titer (p=0.11). In pairwise comparison among ABO blood types, AB donors had higher anti-RBD titer than O negative donors (p=0.048) and higher anti-spike titer than O negative (p=0.015) or O positive (p=0.037) donors. Eight of the ten recipients were discharged, one remains on ECMO and one died on ECMO. No toxicity was associated with plasma transfusion. After excluding two ECMO patients and adjusting for donor antibody titer, recipient anti-RBD antibody titer increased on average 31% per day during the first three days post-transfusion (p=0.01) and anti-spike antibody titer by 40.3% (p=0.02).
Conclusion: Advanced age, fever, absence of myalgia, fatigue, blood type and hospitalization were associated with higher convalescent antibody titer to COVID-19. Despite variability in donor titer, 80% of convalescent plasma recipients showed significant increase in antibody levels post-transfusion. A more complete understanding of the dose-response effect of plasma transfusion among COVID-19 patients is needed to determine the clinical efficacy of this therapy.
The COVID-19 pandemic has brought about an urgent need for effective treatment, while conserving vital resources such as intensive care unit beds and ventilators. Antivirals, convalescent plasma, and biologics have been used with mixed results. The profound “cytokine storm” induced endotheliopathy and microthrombotic disease in patients with COVID-19 may lead to acute respiratory distress syndrome, sepsis, and multi-organ failure. We present a case of SARS-COV2 pneumonia with septic shock and multi-organ failure that demonstrated significant clinical improvement after therapeutic plasma exchange. A 65-year-old female with multiple comorbidities presented with progressive dyspnea and dry cough. She was found to be COVID-19 positive with pneumonia, and developed progressive hypoxemia and shock requiring vasopressors, cardioversion, and non-invasive positive pressure ventilation. Given her worsening sepsis with multi-organ failure, she underwent therapeutic plasma exchange with rapid clinical improvement. Her case supports the theory that plasma exchange may help abate the “cytokine storm” induced endotheliopathy and microthrombosis associated with COVID-19. Further studies are needed to identify markers of this pathway and the potential role of plasma exchange in these critically ill patients.
During the COVID-19 pandemic, SARS-CoV-2 infected millions of people and claimed hundreds of thousands of lives. Virus entry into cells depends on the receptor binding domain (RBD) of the SARS-CoV-2 spike protein (S). Although there is no vaccine, it is likely that antibodies will be essential for protection. However, little is known about the human antibody response to SARS-CoV-21–5. Here we report on 149 COVID-19 convalescent individuals. Plasmas collected an average of 39 days after the onset of symptoms had variable half-maximal pseudovirus neutralizing titres: less than 1:50 in 33% and below 1:1,000 in 79%, while only 1% showed titres above 1:5,000. Antibody sequencing revealed expanded clones of RBD-specific memory B cells expressing closely related antibodies in different individuals. Despite low plasma titres, antibodies to three distinct epitopes on RBD neutralized at half-maximal inhibitory concentrations (IC50 values) as low as single digit nanograms per millitre. Thus, most convalescent plasmas obtained from individuals who recover from COVID-19 do not contain high levels of neutralizing activity. Nevertheless, rare but recurring RBD-specific antibodies with potent antiviral activity were found in all individuals tested, suggesting that a vaccine designed to elicit such antibodies could be broadly effective.
Background
There is considerable variation in disease behavior among patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (Covid-19). Genomewide association analysis may allow for the identification of potential genetic factors involved in the development of Covid-19.
Methods
We conducted a genomewide association study involving 1980 patients with Covid-19 and severe disease (defined as respiratory failure) at seven hospitals in the Italian and Spanish epicenters of the SARS-CoV-2 pandemic in Europe. After quality control and the exclusion of population outliers, 835 patients and 1255 control participants from Italy and 775 patients and 950 control participants from Spain were included in the final analysis. In total, we analyzed 8,582,968 single-nucleotide polymorphisms and conducted a meta-analysis of the two case–control panels.
Results
We detected cross-replicating associations with rs11385942 at locus 3p21.31 and with rs657152 at locus 9q34.2, which were significant at the genomewide level (P<5×10⁻⁸) in the meta-analysis of the two case–control panels (odds ratio, 1.77; 95% confidence interval [CI], 1.48 to 2.11; P=1.15×10⁻¹⁰; and odds ratio, 1.32; 95% CI, 1.20 to 1.47; P=4.95×10⁻⁸, respectively). At locus 3p21.31, the association signal spanned the genes SLC6A20, LZTFL1, CCR9, FYCO1, CXCR6 and XCR1. The association signal at locus 9q34.2 coincided with the ABO blood group locus; in this cohort, a blood-group–specific analysis showed a higher risk in blood group A than in other blood groups (odds ratio, 1.45; 95% CI, 1.20 to 1.75; P=1.48×10⁻⁴) and a protective effect in blood group O as compared with other blood groups (odds ratio, 0.65; 95% CI, 0.53 to 0.79; P=1.06×10⁻⁵).
Conclusions
We identified a 3p21.31 gene cluster as a genetic susceptibility locus in patients with Covid-19 with respiratory failure and confirmed a potential involvement of the ABO blood-group system. (Funded by Stein Erik Hagen and others.)
Background:
The ideal treatment of coronavirus disease (COVID)-19 has yet to be defined, but convalescent plasma (CoPla) has been successfully employed.
Objective:
The objective of the study was to study the safety and outcomes of the administration of CoPla to individuals with severe COVID-19 in an academic medical center.
Methods:
Ten patients were prospectively treated with plasma from COVID-19 convalescent donors.
Results:
Over 8 days, the sequential organ failure assessment score dropped significantly in all patients, from 3 to 1.5 (p = 0.014); the Kirby index (PaO2/FiO2) score increased from 124 to 255, (p < 0.0001), body temperature decreased significantly from 38.1 to 36.9°C (p = 0.0058), and ferritin levels also dropped significantly from 1736.6 to 1061.8 ng/ml (p = 0.0001). Chest X-rays improved in 7/10 cases and in 6/10, computerized tomography scans also revealed improvement of the lung injury. Decreases in C-reactive protein and D-dimer levels were also observed. Three of five patients on mechanical ventilation support could be extubated, nine were transferred to conventional hospital floors, and six were sent home; two patients died. The administration of CoPla had no side effects and the 24-day overall survival was 77%.
Conclusions:
Although other treatments were also administered to the patients and as a result data are difficult to interpret, it seems that the addition of CoPla improved pulmonary function.
SARS coronavirus 2 (SARS-CoV-2) isolates encoding a D614G mutation in the viral spike (S) protein predominate over time in locales where it is found, implying that this change enhances viral transmission. We therefore compared the functional properties of the S proteins with aspartic acid (SD614) and glycine (SG614) at residue 614. We observed that retroviruses pseudotyped with SG614 infected ACE2-expressing cells markedly more efficiently than those with SD614. This greater infectivity was correlated with less S1 shedding and greater incorporation of the S protein into the pseudovirion. Similar results were obtained using the virus-like particles produced with SARS-CoV-2 M, N, E, and S proteins. However, SG614 did not bind ACE2 more efficiently than SD614, and the pseudoviruses containing these S proteins were neutralized with comparable efficiencies by convalescent plasma. These results show SG614 is more stable than SD614, consistent with epidemiological data suggesting that viruses with SG614 transmit more efficiently.
Sars-CoV-2 complications include pneumonia and acute respiratory distress syndrome (ARDS), which require intensive care unit admission. These conditions have rapidly overwhelmed healthcare systems, with detrimental effects on the quality of care and increased mortality. Social isolation strategies have been implemented worldwide with the aim of reducing hospital pressure. Among therapeutic strategies, the use of immunomodulating drugs, to improve prognosis, seems promising. Particularly, since pneumonia and ARDS are associated with a cytokine storm, drugs belonging to therapeutic classes as anti-IL-6, anti-TNF, and JAK inhibitors are currently studied. In this article, we discuss the potential advantages of the most promising pharmacological approaches.
A major dogma in immunology has it that the IgM antibody response precedes secondary memory responses built on the production of IgG, IgA and, occasionaly, IgE. Here, we measured acute humoral responses to SARS-CoV-2, including the frequency of antibody-secreting cells and the presence of specific, neutralizing, antibodies in serum and broncho-alveolar fluid of 145 patients with COVID-19. Surprisingly, early SARS-CoV-2-specific humoral responses were found to be typically dominated by antibodies of the IgA isotype. Peripheral expansion of IgA-plasmablasts with mucosal-homing potential was detected shortly after the onset of symptoms and peaked during the third week of the disease. While the specific antibody response included IgG, IgM and IgA, the latter contributed to a much larger extent to virus neutralization, as compared to IgG. However, specific IgA serum levels notably decrease after one month of evolution. These results represent a challenging observation given the present uncertainty as to which kind of humoral response would optimally protect against re-infection, and whether vaccine regimens should consider boosting a potent, although, at least in blood, fading IgA response.
One sentence Summary
While early specific antibody response included IgG, IgM and IgA, the latter contributed to a much larger extent to virus neutralization.
Newly emerged pathogens such as SARS-CoV-2 highlight the urgent need for assays that detect levels of neutralizing antibodies that may be protective. We studied the relationship between anti-spike ectodomain (ECD) and anti-receptor binding domain (RBD) IgG titers, and SARS-CoV-2 virus neutralization (VN) titers generated by two different in vitro assays using convalescent plasma samples obtained from 68 COVID-19 patients, including 13 who donated plasma multiple times. Only 23% (16/68) of donors had been hospitalized. We also studied 16 samples from subjects found to have anti-spike protein IgG during surveillance screening of asymptomatic individuals. We report a strong positive correlation between both plasma anti-RBD and anti-ECD IgG titers, and in vitro VN titer. Anti-RBD plasma IgG correlated slightly better than anti-ECD IgG titer with VN titer. The probability of a VN titer ≥160 was 80% or greater with anti-RBD or anti-ECD titers of ≥1:1350. Thirty-seven percent (25/68) of convalescent plasma donors lacked VN titers ≥160, the FDA-recommended level for convalescent plasma used for COVID-19 treatment. Dyspnea, hospitalization, and disease severity were significantly associated with higher VN titer. Frequent donation of convalescent plasma did not significantly decrease either VN or IgG titers. Analysis of 2,814 asymptomatic adults found 27 individuals with anti-RBD or anti-ECD IgG titers of ≥1:1350, and evidence of VN ≥1:160. Taken together, we conclude that anti-RBD or anti-ECD IgG titers can serve as a surrogate for VN titers to identify suitable plasma donors. Plasma anti-RBD or anti-ECD titer of ≥1:1350 may provide critical information about protection against COVID-19 disease.
I read with interest the recent article by Li et al (1) detailing the risk for COVID‐19 pneumonia and ABO blood group.
After demonstration that group O healthcare workers were less likely to become infected with SARS‐CoV (2), a research group proved that anti‐A blood group natural isoagglutinins inhibit SARS‐CoV entry into competent cells (3) and could opsonize viral particles leading to complement‐mediated neutralization (4). Since SARS‐CoV2 uses the same receptor as SARS‐CoV, anti‐A isoagglutinins are expected to have similar effects against SARS‐CoV2: accordingly, clusters of glycosylation sites exist proximal to the receptor‐binding motif of the SARS‐CoV and SARS‐CoV2 S protein (5).
SARS-CoV-2, the virus responsible for COVID-19, is causing a devastating global pandemic and there is a pressing need to understand the development, specificity, and neutralizing potency of humoral immune responses during acute infection. We report a cross-sectional study of antibody responses to the receptor-binding domain (RBD) of the spike protein and virus neutralization activity in a cohort of 44 hospitalized COVID-19 patients. RBD-specific IgG responses are detectable in all patients 6 days after PCR confirmation. Isotype switching to IgG occurs rapidly, primarily to IgG1 and IgG3. Using a clinical SARS-CoV-2 isolate, neutralizing antibody titers are detectable in all patients by 6 days after PCR confirmation and correlate with RBD-specific binding IgG titers. The RBD-specific binding data were further validated in a clinical setting with 231 PCR-confirmed COVID-19 patient samples. These findings have implications for understanding protective immunity against SARS-CoV-2, therapeutic use of immune plasma, and development of much-needed vaccines.
Importance
Convalescent plasma is a potential therapeutic option for patients with coronavirus disease 2019 (COVID-19), but further data from randomized clinical trials are needed.
Objective
To evaluate the efficacy and adverse effects of convalescent plasma therapy for patients with COVID-19.
Design, Setting, and Participants
Open-label, multicenter, randomized clinical trial performed in 7 medical centers in Wuhan, China, from February 14, 2020, to April 1, 2020, with final follow-up April 28, 2020. The trial included 103 participants with laboratory-confirmed COVID-19 that was severe (respiratory distress and/or hypoxemia) or life-threatening (shock, organ failure, or requiring mechanical ventilation). The trial was terminated early after 103 of a planned 200 patients were enrolled.
Intervention
Convalescent plasma in addition to standard treatment (n = 52) vs standard treatment alone (control) (n = 51), stratified by disease severity.
Main Outcomes and Measures
Primary outcome was time to clinical improvement within 28 days, defined as patient discharged alive or reduction of 2 points on a 6-point disease severity scale (ranging from 1 [discharge] to 6 [death]). Secondary outcomes included 28-day mortality, time to discharge, and the rate of viral polymerase chain reaction (PCR) results turned from positive at baseline to negative at up to 72 hours.
Results
Of 103 patients who were randomized (median age, 70 years; 60 [58.3%] male), 101 (98.1%) completed the trial. Clinical improvement occurred within 28 days in 51.9% (27/52) of the convalescent plasma group vs 43.1% (22/51) in the control group (difference, 8.8% [95% CI, −10.4% to 28.0%]; hazard ratio [HR], 1.40 [95% CI, 0.79-2.49]; P = .26). Among those with severe disease, the primary outcome occurred in 91.3% (21/23) of the convalescent plasma group vs 68.2% (15/22) of the control group (HR, 2.15 [95% CI, 1.07-4.32]; P = .03); among those with life-threatening disease the primary outcome occurred in 20.7% (6/29) of the convalescent plasma group vs 24.1% (7/29) of the control group (HR, 0.88 [95% CI, 0.30-2.63]; P = .83) (P for interaction = .17). There was no significant difference in 28-day mortality (15.7% vs 24.0%; OR, 0.65 [95% CI, 0.29-1.46]; P = .30) or time from randomization to discharge (51.0% vs 36.0% discharged by day 28; HR, 1.61 [95% CI, 0.88-2.93]; P = .12). Convalescent plasma treatment was associated with a negative conversion rate of viral PCR at 72 hours in 87.2% of the convalescent plasma group vs 37.5% of the control group (OR, 11.39 [95% CI, 3.91-33.18]; P < .001). Two patients in the convalescent plasma group experienced adverse events within hours after transfusion that improved with supportive care.
Conclusion and Relevance
Among patients with severe or life-threatening COVID-19, convalescent plasma therapy added to standard treatment, compared with standard treatment alone, did not result in a statistically significant improvement in time to clinical improvement within 28 days. Interpretation is limited by early termination of the trial, which may have been underpowered to detect a clinically important difference.
Trial Registration
Chinese Clinical Trial Registry: ChiCTR2000029757
BACKGROUND
Hyperimmune plasma from Covid-19 convalescent is a potential treatment for severe Covid-19.
METHODS
We conducted a multicenter one arm proof of concept interventional study. Patients with Covid-19 disease with moderate-to-severe Acute Respiratory Distress Syndrome, elevated C-reactive Protein and need for mechanical ventilation and/or CPAP were enrolled. One to three 250-300 ml unit of hyperimmune plasma (neutralizing antibodies titer ≥1:160) were administered. Primary outcome was 7-days hospital mortality. Secondary outcomes were PaO2/FiO2, laboratory and radiologic changes, as well as weaning from mechanical ventilation and safety.
RESULTS
The study observed 46 patients from March, 25 to April, 21 2020. Patients were aged 63, 61% male, 30 on CPAP and 7 intubated. PaO2/FiO2 was 128 (SD 47). Symptoms and ARDS duration were 14 (SD 7) and 6 days (SD 3). Three patients (6.5%) died within 7 days. The upper one-sided 90%CI was 13.9%, allowing to reject the null hypothesis of a 15% mortality. PaO2/FiO2 increased by 112 units (95%CI 82 to142) in survivors, the chest radiogram severity decreased in 23% (95%CI 5% to 42%); CRP, Ferritin and LDH decreased by 60, 36 and 20% respectively. Weaning from CPAP was obtained in 26/30 patients and 3/7 were extubated. Five serious adverse events occurred in 4 patients (2 likely, 2 possible treatment related).
CONCLUSIONS
Hyperimmune plasma in Covid-19 shows promising benefits, to be confirmed in a randomized controlled trial. This proof of concept study could open to future developments including hyperimmune plasma banking, development of standardized pharmaceutical products and monoclonal antibodies.
COVID-19 disease, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread globally, and no proven treatments are available. Convalescent plasma therapy has been used with varying degrees of success to treat severe microbial infections for more than 100 years. Patients (n = 25) with severe and/or life-threatening COVID-19 disease were enrolled at the Houston Methodist hospitals from March 28 – April 14, 2020. Patients were transfused with convalescent plasma obtained from donors with confirmed SARS-CoV-2 infection and had recovered. The primary study outcome was safety, and the secondary outcome was clinical status at day 14 post-transfusion. Clinical improvement was assessed based on a modified World Health Organization 6-point ordinal scale and laboratory parameters. Viral genome sequencing was performed on donor and recipient strains. At day 7 post-transfusion with convalescent plasma, nine patients had at least a 1-point improvement in clinical scale, and seven of those were discharged. By day 14 post-transfusion, 19 (76%) patients had at least a 1-point improvement in clinical status and 11 were discharged. No adverse events as a result of plasma transfusion were observed. Whole genome sequencing data did not identify a strain genotype-disease severity correlation. The data indicate that administration of convalescent plasma is a safe treatment option for those with severe COVID-19 disease.
Convalescent plasma is a leading treatment for COVID-19, but there is a paucity of data identifying therapeutic efficacy. Among 126 potential convalescent plasma donors, the humoral immune response was evaluated by a SARS-CoV-2 virus neutralization assay using Vero-E6-TMPRSS2 cells, commercial IgG and IgA ELISA to spike(S) protein S1 domain (Euroimmun), IgA, IgG and IgM indirect ELISAs to the full-length S or S-receptor binding domain(S-RBD), and an IgG avidity assay. Multiple linear regression and predictive models were utilized to assess the correlations between antibody responses with demographic and clinical characteristics. IgG titers were greater than either IgM or IgA for S1, full length S, and S-RBD in the overall population. Of the 126 plasma samples, 101(80%) had detectable neutralizing antibody(nAb) titers. Using nAb titers as the reference, the IgG ELISAs confirmed between 95-98% of the nAb positive, but only 20-32% of the nAb negative samples. Male sex, older age, and hospitalization with COVID-19 were associated with increased antibody responses across the serological assays. There was substantial heterogeneity in the antibody response among potential convalescent plasma donors, but sex, age, and hospitalization emerged as factors that can be used to identify individuals with a high likelihood of having strong antiviral antibody responses.
Objective
To provide an update on key safety metrics after transfusion of convalescent plasma in hospitalized COVID-19 patients, having previously demonstrated safety in 5,000 hospitalized patients.
Patients and Methods
From April 3 to June 2, 2020, the US FDA Expanded Access Program for COVID-19 convalescent plasma transfused a convenience sample of 20,000 hospitalized patients with COVID-19 convalescent plasma.
Results
The incidence of all serious adverse events was low; these included transfusion reactions (n=89; <1%), thromboembolic or thrombotic events (n=87; <1%), and cardiac events (n=680, ∼3%). Notably, the vast majority of the thromboembolic or thrombotic events (n=55) and cardiac events (n=562) were judged to be unrelated to the plasma transfusion per se. The seven-day mortality rate was 8.6% (8.2%, 9.0%), and was higher among more critically-ill patients relative to less ill counterparts, including patients admitted to the intensive care unit vs. not admitted (10.5% vs. 6.0%), mechanically ventilated vs. not ventilated (12.1% vs. 6.2%), and with septic shock or multiple organ dysfunction/failure vs. those without dysfunction/failure (14.0% vs. 7.6%).
Conclusion
These updated data provide robust evidence that transfusion of convalescent plasma is safe in hospitalized patients with COVID-19, and support the notion that earlier administration of plasma within the clinical course of COVID-19 is more likely to reduce mortality.
The latest study observed that KTRs with COVID‐19 had a higher early mortality than persons with COVID‐19 in the general population[1]. To date, there is no specific drugs. Previous studies showed convalescent plasma could help patient recovery from SARS[2, 3]. However, only a very limit evidences has been showed it is effective in COVID‐19 treatment[4, 5]. Here, we describe the first successful recovery of case of COVID‐19 in a KTR treated with convalescent plasma therapy.
In recent decades, several new diseases have emerged in different geographical areas, with pathogens including Ebola virus, Zika virus, Nipah virus, and coronaviruses (CoVs). Recently, a new type of viral infection emerged in Wuhan City, China, and initial genomic sequencing data of this virus do not match with previously sequenced CoVs, suggesting a novel CoV strain (2019-nCoV), which has now been termed severe acute respiratory syndrome CoV-2 (SARS-CoV-2). Although coronavirus disease 2019 (COVID-19) is suspected to originate from an animal host (zoonotic origin) followed by human-to-human transmission, the possibility of other routes should not be ruled out. Compared to diseases caused by previously known human CoVs, COVID-19 shows less severe pathogenesis but higher transmission competence, as is evident from the continuously increasing number of confirmed cases globally. Compared to other emerging viruses, such as Ebola virus, avian H7N9, SARS-CoV, and Middle East respiratory syndrome coronavirus (MERS-CoV), SARS-CoV-2 has shown relatively low pathogenicity and moderate transmissibility. Codon usage studies suggest that this novel virus has been transferred from an animal source, such as bats. Early diagnosis by real-time PCR and next-generation sequencing has facilitated the identification of the pathogen at an early stage. Since no antiviral drug or vaccine exists to treat or prevent SARS-CoV-2, potential therapeutic strategies that are currently being evaluated predominantly stem from previous experience with treating SARS-CoV, MERS-CoV, and other emerging viral diseases. In this review, we address epidemiological, diagnostic, clinical, and therapeutic aspects, including perspectives of vaccines and preventive measures that have already been globally recommended to counter this pandemic virus.
Two case series examining the impact of convalescent plasma on patients with COVID-19 suggest some clinical benefit from early administration and modest impact on parameters of inflammation. Further assessment of the impact of this intervention awaits controlled clinical trials.
Background:
Convalescent plasma is the only antibody based therapy currently available for COVID 19 patients. It has robust historical precedence and sound biological plausibility. Although promising, convalescent plasma has not yet been shown to be safe as a treatment for COVID-19.
Methods:
Thus, we analyzed key safety metrics after transfusion of ABO compatible human COVID-19 convalescent plasma in 5,000 hospitalized adults with severe or life threatening COVID-19, with 66% in the intensive care unit, as part of the US FDA Expanded Access Program for COVID-19 convalescent plasma.
Results:
The incidence of all serious adverse events (SAEs) in the first four hours after transfusion was <1%, including mortality rate (0.3%). Of the 36 reported SAEs, there were 25 reported incidences of related SAEs, including mortality (n = 4), transfusion-associated circulatory overload (TACO; n = 7), transfusion-related acute lung injury (TRALI; n = 11), and severe allergic transfusion reactions (n = 3). However, only 2 (of 36) SAEs were judged as definitely related to the convalescent plasma transfusion by the treating physician. The seven-day mortality rate was 14.9%.
Conclusion:
Given the deadly nature of COVID 19 and the large population of critically-ill patients included in these analyses, the mortality rate does not appear excessive. These early indicators suggest that transfusion of convalescent plasma is safe in hospitalized patients with COVID-19.
Background:
COVID-19 is a pandemic with no specific antiviral treatments or vaccines. The urgent needs for exploring the neutralizing antibodies from patients with different clinical characteristics are emerging.
Methods:
A total of 117 blood samples were collected from 70 COVID-19 inpatients and convalescent patients. Antibodies were determined with a modified cytopathogenic neutralization assay (NA) based on live SARS-CoV-2 and enzyme linked immunosorbent assay (ELISA). The dynamics of neutralizing antibody levels at different time points with different clinical characteristics were analyzed.
Results:
The seropositivity rate reached up to 100.0% within 20 days since onset, and remained 100.0% till day 41-53. The total GMT was 1:163.7 (95% CI, 128.5 to 208.6) by NA and 1:12441.7 (95% CI, 9754.5 to 15869.2) by ELISA. The antibody level by NA and ELISA peaked on day 31-40 since onset, and then decreased slightly. In multivariate GEE analysis, patients at age of 31-45, 46-60, and 61-84 had a higher neutralizing antibody level than those at age of 16-30 (β=1.0470, P=0.0125; β=1.0613, P=0.0307; β=1.3713, P=0.0020). Patients with a worse clinical classification had a higher neutralizing antibody titer (β=0.4639, P=0.0227).
Conclusions:
The neutralizing antibodies were detected even at the early stage of disease, and a significant response showed in convalescent patients.
During the ongoing COVID-19 pandemic due to the SARS-CoV-2 virus of which evidence-based medical paradigms cannot be easily applied; difficult clinical decisions shall be required particularly in the 'difficult-to-treat' cases of high risk group with associated comorbidities. Convalescent immune plasma therapy is a promising option as a sort of 'rescue' treatment in COVID-19 immune syndrome, where miraculous antiviral drugs are not available yet. In this report, we aim to convey our experience of multi-task treatment approach with convalescent immune plasma and anti-cytokine drug combination in a COVID-19 patient with extremely challenging comorbidities including active myeloid malignancy, disseminated tuberculosis and kidney failure.
Since the end of 2019, a new coronavirus strain has been reported in the Chinese province of Wuhan, indicated as 2019-nCoV or SARS-CoV-2. In February 2020, the first case of transmission on Italian soil was reported. On March 09, 2020, at the time of protocol design, the Italian Ministry of Health reported 10,149 people who had contracted the virus; of these, 8514 were positive, of which 5038 were hospitalized with symptoms (59.2%) and 877 in intensive care (10.3%), while the remaining 2599 were in home isolation; 631 were deceased (6.2%) and 1004 healed (9.9%). To date there are no studies in the literature that demonstrate its feasibility and efficacy in the context of the worldwide SARS-CoV-2 epidemic. Based upon the little existing evidence, we planned to assess the efficacy of the infusion of hyperimmune plasma in COVID-19 patients in a one-arm proof-of-concept clinical trial. The primary objective of our study is to evaluate the efficacy of the administration of plasma taken from convalescent donors of COVID-19 to critically ill patients with COVID-19 in terms of their survival. Death from any cause will be considered. The main limit of this study is its one-arm proof-of-concept design with only 43 patients enrolled. However, in the absence of previous evidence, larger and/or randomized trials did not appear to be ethically acceptable. Moreover, the results from this study, if encouraging, will allow us to plan further informed large clinical trials. Trial registration: NCT 04321421 March 23, 2020.
