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      Convalescent plasma as a potential therapy for COVID-19

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          Abstract

          The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which originated in Wuhan, China, has become a major concern all over the world. The pneumonia induced by the SARS-CoV-2 is named coronavirus disease 2019 (COVID-19). By Feb 22, 2020, this virus has affected more than 77 700 people worldwide and caused more than 2300 deaths. To date, no specific treatment has been proven to be effective for SARS-CoV-2 infection. Apart from supportive care, such as oxygen supply in mild cases and extracorporeal membrane oxygenation for the critically ill patients, specific drugs for this disease are still being researched. In the USA, the first patient infected with SARS-CoV-2 was treated by supportive care and intravenous remdesivir, before the patient recovered and was discharged. 1 However, randomised clinical trials are needed to evaluate the safety and efficacy of remdesivir in the treatment of COVID-19. Convalescent plasma or immunoglobulins have been used as a last resort to improve the survival rate of patients with SARS whose condition continued to deteriorate despite treatment with pulsed methylprednisolone. Moreover, several studies showed a shorter hospital stay and lower mortality in patients treated with convalescent plasma than those who were not treated with convalescent plasma.2, 3, 4 In 2014, the use of convalescent plasma collected from patients who had recovered from Ebola virus disease was recommended by WHO as an empirical treatment during outbreaks. 5 A protocol for the use of convalescent plasma in the treatment of Middle East respiratory syndrome coronavirus was established in 2015. 6 In terms of patients with pandemic 2009 influenza A H1N1 (H1N1pdm09) virus infection, a prospective cohort study by Hung and colleagues showed a significant reduction in the relative risk of mortality (odds ratio 0·20 [95% CI 0·06–0·69], p=0·01) for patients treated with convalescent plasma. 7 Additionally, in a subgroup analysis, viral load after convalescent plasma treatment was significantly lower on days 3, 5, and 7 after intensive care unit admission. No adverse events were observed. A multicentre, prospective, double-blind, randomised controlled trial by Hung and colleagues showed that using convalescent plasma from patients who recovered from the influenza A H1N1pdm09 virus infection to treat patients with severe influenza A H1N1 infection was associated with a lower viral load and reduced mortality within 5 days of symptom onset. 8 A meta-analysis by Mair-Jenkins and colleagues showed that the mortality was reduced after receiving various doses of convalescent plasma in patients with severe acute respiratory infections, with no adverse events or complications after treatment. 9 Another meta-analysis by Luke and colleagues identified eight studies involving 1703 patients with 1918 influenzapneumonia from 1918 to 1925 who received an infusion of influenza-convalescent human blood products, which showed a pooled absolute reduction of 21% (95% CI 15–27; p<0·001) in the overall crude case-fatality rate at low risk of bias. 10 One possible explanation for the efficacy of convalescent plasma therapy is that the antibodies from convalescent plasma might suppress viraemia. Schoofs and colleagues reported that 3BNC117-mediated immunotherapy, which is a broad neutralising antibody to HIV-1, enhances host humoral immunity to HIV-1. 11 An in vivo trial also showed that the effects of this antibody were not only limited to free viral clearance and blocking new infection, but also included acceleration of infected cell clearance. 12 Viraemia peaks in the first week of infection in most viral illnesses. The patient usually develops a primary immune response by days 10–14, which is followed by virus clearance. 4 Therefore, theoretically, it should be more effective to administer the convalescent plasma at the early stage of disease. 4 However, other treatments might have an effect on the relationship between convalescent plasma and antibody level, including antiviral drugs, steroids, and intravenous immunoglobulin. 10 According to WHO, 13 management of COVID-19 has mainly focused on infection prevention, case detection and monitoring, and supportive care. However, no specific anti-SARS-CoV-2 treatment is recommended because of the absence of evidence. Most importantly, the current guidelines emphasise that systematic corticosteroids should not be given routinely for the treatment of COVID-19, which was also the recommendation in a a Commnt in The Lancet. 14 Evidence shows that convalescent plasma from patients who have recovered from viral infections can be used as a treatment without the occurrence of severe adverse events. Therefore, it might be worthwhile to test the safety and efficacy of convalescent plasma transfusion in SARS-CoV-2-infected patients.

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          First Case of 2019 Novel Coronavirus in the United States

          Summary An outbreak of novel coronavirus (2019-nCoV) that began in Wuhan, China, has spread rapidly, with cases now confirmed in multiple countries. We report the first case of 2019-nCoV infection confirmed in the United States and describe the identification, diagnosis, clinical course, and management of the case, including the patient’s initial mild symptoms at presentation with progression to pneumonia on day 9 of illness. This case highlights the importance of close coordination between clinicians and public health authorities at the local, state, and federal levels, as well as the need for rapid dissemination of clinical information related to the care of patients with this emerging infection.
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            Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury

            The 2019 novel coronavirus (2019-nCoV) outbreak is a major challenge for clinicians. The clinical course of patients remains to be fully characterised, little data are available that describe the disease pathogenesis, and no pharmacological therapies of proven efficacy yet exist. Corticosteroids were widely used during the outbreaks of severe acute respiratory syndrome (SARS)-CoV 1 and Middle East respiratory syndrome (MERS)-CoV, 2 and are being used in patients with 2019-nCoV in addition to other therapeutics. 3 However, current interim guidance from WHO on clinical management of severe acute respiratory infection when novel coronavirus (2019-nCoV) infection is suspected (released Jan 28, 2020) advises against the use of corticosteroids unless indicated for another reason. 4 Understanding the evidence for harm or benefit from corticosteroids in 2019-nCoV is of immediate clinical importance. Here we discuss the clinical outcomes of corticosteroid use in coronavirus and similar outbreaks (table ). Table Summary of clinical evidence to date Outcomes of corticosteroid therapy * Comment MERS-CoV Delayed clearance of viral RNA from respiratory tract 2 Adjusted hazard ratio 0·4 (95% CI 0·2–0·7) SARS-CoV Delayed clearance of viral RNA from blood 5 Significant difference but effect size not quantified SARS-CoV Complication: psychosis 6 Associated with higher cumulative dose, 10 975 mg vs 6780 mg hydrocortisone equivalent SARS-CoV Complication: diabetes 7 33 (35%) of 95 patients treated with corticosteroid developed corticosteroid-induced diabetes SARS-CoV Complication: avascular necrosis in survivors 8 Among 40 patients who survived after corticosteroid treatment, 12 (30%) had avascular necrosis and 30 (75%) had osteoporosis Influenza Increased mortality 9 Risk ratio for mortality 1·75 (95% CI 1·3–2·4) in a meta-analysis of 6548 patients from ten studies RSV No clinical benefit in children10, 11 No effect in largest randomised controlled trial of 600 children, of whom 305 (51%) had been treated with corticosteroids CoV=coronavirus. MERS=Middle East respiratory syndrome. RSV=respiratory syncytial virus. SARS=severe acute respiratory syndrome. * Hydrocortisone, methylprednisolone, dexamethasone, and prednisolone. Acute lung injury and acute respiratory distress syndrome are partly caused by host immune responses. Corticosteroids suppress lung inflammation but also inhibit immune responses and pathogen clearance. In SARS-CoV infection, as with influenza, systemic inflammation is associated with adverse outcomes. 12 In SARS, inflammation persists after viral clearance.13, 14 Pulmonary histology in both SARS and MERS infections reveals inflammation and diffuse alveolar damage, 15 with one report suggesting haemophagocytosis. 16 Theoretically, corticosteroid treatment could have a role to suppress lung inflammation. In a retrospective observational study reporting on 309 adults who were critically ill with MERS, 2 almost half of patients (151 [49%]) were given corticosteroids (median hydrocortisone equivalent dose [ie, methylprednisolone 1:5, dexamethasone 1:25, prednisolone 1:4] of 300 mg/day). Patients who were given corticosteroids were more likely to require mechanical ventilation, vasopressors, and renal replacement therapy. After statistical adjustment for immortal time and indication biases, the authors concluded that administration of corticosteroids was not associated with a difference in 90-day mortality (adjusted odds ratio 0·8, 95% CI 0·5–1·1; p=0·12) but was associated with delayed clearance of viral RNA from respiratory tract secretions (adjusted hazard ratio 0·4, 95% CI 0·2–0·7; p=0·0005). However, these effect estimates have a high risk of error due to the probable presence of unmeasured confounders. In a meta-analysis of corticosteroid use in patients with SARS, only four studies provided conclusive data, all indicating harm. 1 The first was a case-control study of SARS patients with (n=15) and without (n=30) SARS-related psychosis; all were given corticosteroid treatment, but those who developed psychosis were given a higher cumulative dose than those who did not (10 975 mg hydrocortisone equivalent vs 6780 mg; p=0·017). 6 The second was a randomised controlled trial of 16 patients with SARS who were not critically ill; the nine patients who were given hydrocortisone (mean 4·8 days [95% CI 4·1–5·5] since fever onset) had greater viraemia in the second and third weeks after infection than those who were given 0·9% saline control. 5 The remaining two studies reported diabetes and avascular necrosis as complications associated with corticosteroid treatment.7, 8 A 2019 systematic review and meta-analysis 9 identified ten observational studies in influenza, with a total of 6548 patients. The investigators found increased mortality in patients who were given corticosteroids (risk ratio [RR] 1·75, 95% CI 1·3–2·4; p=0·0002). Among other outcomes, length of stay in an intensive care unit was increased (mean difference 2·1, 95% CI 1·2–3·1; p<0·0001), as was the rate of secondary bacterial or fungal infection (RR 2·0, 95% CI 1·0–3·8; p=0·04). Corticosteroids have been investigated for respiratory syncytial virus (RSV) in clinical trials in children, with no conclusive evidence of benefit and are therefore not recommended. 10 An observational study of 50 adults with RSV infection, in which 33 (66%) were given corticosteroids, suggested impaired antibody responses at 28 days in those given corticosteroids. 17 Life-threatening acute respiratory distress syndrome occurs in 2019-nCoV infection. 18 However, generalising evidence from acute respiratory distress syndrome studies to viral lung injury is problematic because these trials typically include a majority of patients with acute respiratory distress syndrome of non-pulmonary or sterile cause. A review of treatments for acute respiratory distress syndrome of any cause, based on six studies with a total of 574 patients, 19 concluded that insufficient evidence exists to recommend corticosteroid treatment. 20 Septic shock has been reported in seven (5%) of 140 patients with 2019-nCoV included in published reports as of Jan 29, 2020.3, 18 Corticosteroids are widely used in septic shock despite uncertainty over their efficacy. Most patients in septic shock trials have bacterial infection, leading to vasoplegic shock and myocardial insufficiency.21, 22 In this group, there is potential that net benefit might be derived from steroid treatment in severe shock.21, 22 However, shock in severe hypoxaemic respiratory failure is often a consequence of increased intrathoracic pressure (during invasive ventilation) impeding cardiac filling, and not vasoplegia. 23 In this context, steroid treatment is unlikely to provide a benefit. No clinical data exist to indicate that net benefit is derived from corticosteroids in the treatment of respiratory infection due to RSV, influenza, SARS-CoV, or MERS-CoV. The available observational data suggest increased mortality and secondary infection rates in influenza, impaired clearance of SARS-CoV and MERS-CoV, and complications of corticosteroid therapy in survivors. If it is present, the effect of steroids on mortality in those with septic shock is small, and is unlikely to be generalisable to shock in the context of severe respiratory failure due to 2019-nCoV. Overall, no unique reason exists to expect that patients with 2019-nCoV infection will benefit from corticosteroids, and they might be more likely to be harmed with such treatment. We conclude that corticosteroid treatment should not be used for the treatment of 2019-nCoV-induced lung injury or shock outside of a clinical trial.
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              Feasibility, safety, clinical, and laboratory effects of convalescent plasma therapy for patients with Middle East respiratory syndrome coronavirus infection: a study protocol

              As of September 30, 2015, a total of 1589 laboratory-confirmed cases of infection with the Middle East respiratory syndrome coronavirus (MERS-CoV) have been reported to the World Health Organization (WHO). At present there is no effective specific therapy against MERS-CoV. The use of convalescent plasma (CP) has been suggested as a potential therapy based on existing evidence from other viral infections. We aim to study the feasibility of CP therapy as well as its safety and clinical and laboratory effects in critically ill patients with MERS-CoV infection. We will also examine the pharmacokinetics of the MERS-CoV antibody response and viral load over the course of MERS-CoV infection. This study will inform a future randomized controlled trial that will examine the efficacy of CP therapy for MERS-CoV infection. In the CP collection phase, potential donors will be tested by the enzyme linked immunosorbent assay (ELISA) and the indirect fluorescent antibody (IFA) techniques for the presence of anti-MERS-CoV antibodies. Subjects with anti-MERS-CoV IFA titer of ≥1:160 and no clinical or laboratory evidence of MERS-CoV infection will be screened for eligibility for plasma donation according to standard donation criteria. In the CP therapy phase, 20 consecutive critically ill patients admitted to intensive care unit with laboratory-confirmed MERS-CoV infection will be enrolled and each will receive 2 units of CP. Post enrollment, patients will be followed for clinical and laboratory outcomes that include anti-MERS-CoV antibodies and viral load. This protocol was developed collaboratively by King Abdullah International Medical Research Center (KAIMRC), Gulf Cooperation Council (GCC) Infection Control Center Group and the World Health Organization—International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC-WHO) MERS-CoV Working Group. It was approved in June 2014 by the Ministry of the National Guard Health Affairs Institutional Review Board (IRB). A data safety monitoring board (DSMB) was formulated. The study is registered at http://www.clinicaltrials.gov (NCT02190799).
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                Author and article information

                Contributors
                Journal
                Lancet Infect Dis
                Lancet Infect Dis
                The Lancet. Infectious Diseases
                Elsevier Ltd.
                1473-3099
                1474-4457
                27 February 2020
                April 2020
                27 February 2020
                : 20
                : 4
                : 398-400
                Affiliations
                [a ]Department of Neonatology, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, 400014, China
                [b ]National Clinical Research Center for Child Health and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, 400014, China
                [c ]China International Science and Technology Cooperation base of Child development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, 400014, China
                [d ]Children's Hospital of Chongqing Medical University; Chongqing Key Laboratory of Pediatrics, Chongqing, 400014, China
                Article
                S1473-3099(20)30141-9
                10.1016/S1473-3099(20)30141-9
                7128218
                32113510
                3c8ccf37-3eb5-46a0-8edd-928f454c8b09
                © 2020 Elsevier Ltd. All rights reserved.

                Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

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