convalescent plasma
221038390
Convalescent plasma for COVID 19: Promising, not proven
While promising, convalescent plasma remains experimental and is not proven effective for COVID 19. In addition, many questions remain regarding the accuracy and predictive value of antibody testing of donors and patients, optimal donor selection, optimal timing, and selection of patients most likely to benefit. Until these questions are answered, convalescent plasma should ideally be used in the context of well designed clinical trials. The evidence is suggestive but weak. Trials are ongoing.
Cleveland Clinic Journal of Medicine
Simon R Mucha NurJehan Quraishy
220966321
Antibody based immunotherapeutics and use of convalescent plasma to counter COVID 19: advances and prospects
ABSTRACT Introduction Coronavirus disease 2019 (COVID 19) has spread to several countries globally. Currently, there is no specific drug or vaccine available for managing COVID 19. Antibody based immunotherapeutic strategies using convalescent plasma, monoclonal antibodies (mAbs) neutralizing antibodies (NAbs) and intravenous immunoglobulins have therapeutic potential. Areas covered This review provides the current status of the development of various antibody based immunotherapeutics such as convalescent plasma, mAbs, NAbs, and intravenous immunoglobulins against COVID 19. The review also highlights their advantages, disadvantages, and clinical utility for the treatment of COVID 19 patients. Expert opinion In a pandemic situation such as COVID 19, the development of new drugs should focus on and expedite the strategies where safety and efficacy are proven. Antibody based immunotherapeutic approaches such as convalescent plasma, intravenous immunoglobulins, and mAbs have a proven record of safety and efficacy and are in use for decades. Some of them are already being used to manage COVID 19 patients and found to be useful. However, the mAbs with virus neutralization potential is the need of the hour during this COVID 19 pandemic to be more specific and virus targeted. The research and investment need to be accelerated to bring them into clinical use for prophylactic and therapeutic purposes against COVID 19.
Expert opinion on biological therapy
Khan Sharun Ruchi Tiwari Mohd Iqbal Yatoo Shailesh Kumar Patel Senthil Natesan Jaideep Dhama Yashpal Singh Malik Harapan Harapan Raj Kumar Singh Kuldeep Dhama
215801115
COVID 19 convalescent plasma transfusion
The pandemic caused by the novel coronavirus, called SARSCoV 2, affected more than one million people around the world. The COVID 19, the acronym derived from the coronavirus disease 2019, was first reported in December 2019 in the province of Hubei (China) and disseminated to other parts of that country and has now become a global threat, in Brazil as well. The clinical spectrum of COVID 19 varies from asymptomatic in a high percentage of infected people to severe acute respiratory syndrome (SARS) the main cause of death. No specific treatment has been found to be completely effective against the virus and no vaccine is available yet to prevent the infection. Therefore, all therapeutic options for the potentially lethal COVID 19 infection must be discussed ethically and scientifically. Historically, convalescent plasma (CP) a passive immunotherapy, has been used as a possible therapeutic option when no proven specific vaccine or drug is available for emerging infections.1,2 The administration of convalescent plasma or immunoglobulins has been shown to shorten the hospital stay and reduce the mortality rate in patients with SARS who did not respond to methylprednisolone in uncontrolled non randomized clinical trials.3,4 Cheng et al. investigated 1775 SARS patients and found that 80 patients transfused with SARS convalescent plasma had a lower mortality rate, compared to non transfused patients (12.5% vs. 17%.4 Hung and colleagues conducted a prospective cohort study offering treatment with H1N1 convalescent plasma (antibody titer >1:160) to infected patients in intensive care. They found that the relative risk of mortality by an H1N1 infection was significantly reduced in patients transfused with convalescent
Hematology, Transfusion and Cell Therapy
Dante Mario Langhi Gil C De Santis Jose Orlando Bordin
220717268
Convalescent plasma treatment for SARS CoV 2 infection: analysis of the first 436 donors in England, 22 April to 12 May 2020
Serological reactivity was analysed in plasma from 436 individuals with a history of disease compatible with COVID 19, including 256 who had been laboratory confirmed with SARS CoV 2 infection. Over 99% of laboratory confirmed cases developed a measurable antibody response (254/256) and 88% harboured neutralising antibodies (226/256) Antibody levels declined over 3 months following diagnosis, emphasising the importance of the timing of convalescent plasma collections. Binding antibody measurements can inform selection of convalescent plasma donors with high neutralising antibody levels.
Euro surveillance bulletin Europeen sur les maladies transmissibles European communicable disease bulletin
Heli Harvala Jenny Mehew Matthew Robb Samreen Ijaz Steve Dicks Monika Patel Nicholas Watkins Peter Simmonds Tim Brooks Rachel J Johnson Robin Gopal David J Roberts Maria Zambon Stephen Thomas Sheila Maclennan Lise J Estcourt Susan R Brailsford Hatice Baklan Kate I Tettmar Jeremy Kellington Joanna Sell Gail Miflin
220365150
A severe refractory COVID 19 patient responding to convalescent plasma; A case series
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.
Annals of Medicine and Surgery
Hadi Mohammed Abdullah Hersh H Hama-Ali Sabah Nasraddin Ahmed Kosar Muhammad Ali Kamaran Amin Omer Karadakhy Safeen Othman Mahmood Zana H Mahmood Karmand Qadir Hamad Amin Peshnyar Muhammad Atta Bryar E Nuradeen Shvan Hussein Mohammed Rawezh Q Salih Hiwa O Baba Fahmi Hussein Kakamad
218534054
COVID 19 convalescent plasma: phase 2
A s transfusion medicine specialists we understood the potential that convalescent plasma (CCP) could play early in the management of patients with COVID 19. However, with no guidance from the US Food and Drug Administration (FDA) we could not begin to establish a program for coronavirus disease 2019 (COVID 19) CCP. That changed on March 24, 2020, when the FDA issued its first guidance on this topic. The rules were clear: identify subjects with molecularly confirmed COVID 19, and after they have been asymptomatic for 14 days, test them to confirm they are no longer infectious and that they are eligible to donate CCP. With a small hospital based donor center, an academic medical center that had implemented molecular testing for COVID 19, and an established clinical research unit, we realized we were set to establish and implement a program quickly. In addition, Iowa City, Iowa, was an initial "hot spot" for patients, as a number of local people had been infected on an Egyptian cruise the first week of March. The purpose of this commentary is to briefly summarize our initial experience establishing the CCP program and propose ideas for how to move this treatment forward to the next phase. With the FDA guidance document on March 24, 2020, we put together an institutional review board (IRB) application to screen subjects for eligibility, obtain their consent to participate in our "study," and test them to confirm they were negative and likely eligible to donate. This application was submitted to the IRB on Friday, March 27, and was approved on April 1. By April 6, we had screened our first donor, who had been asymptomatic for 14 days (this 14 day period delayed screening for many subjects we were following) and the donor was confirmed to be negative for the virus and donated on April 9. Meanwhile, we worked with our infectious disease specialist to adopt the "Mayo" protocol, which is likely being widely used across the country as the Biomedical Advanced Research and Development Authority (BARDA) supported expanded access protocol. This protocol became available to us on Saturday, April 4, and was approved by our IRB on April 10. We treated our first patient on April 13, 20 days after the FDA guidance document was released. As we all now realize, processes that typically take months have been compressed to weeks or even days to get CCP treatment to patients with COVID 19. As it is now more than 1 month since the original FDA guidance document was released, we can begin to review the results to date and consider implementing plans that may improve on this therapy and eventually help us determine whether the therapy has been effective. We have treated 20 patients to date with CCP and screened more than 50 subjects to be CCP donors. On the donor side, we have tested 36 subjects who had previously tested positive for COVID 19. Of these, four patients tested viral positive, most near the 14 day window for resolution of symptoms. This finding suggests the FDA was wise to confirm that subjects in this window are tested before donation to ensure the safety of donor personnel. We also have severe acute respiratory syndrome coronavirus 2 (SARS CoV 2) antibody results back on 31 of our subjects. There is no standard for testing for antibodies, and we anticipate that a wide array of tests will be used at least initially. For us, we worked with our state hygienic lab to validate an enzyme linked immunoassay (EUROIMMUN) that detects IgG antibodies against SARSCoV 2. They are testing samples from our subjects to determine their IgG levels. The cutoff for a positive test with this assay is greater than 1.1 (ratio of optical density of patient sample to optical density of comparator) and found that 5 of our 31 (16% subjects with molecularly confirmed COVID 19 had antibody levels below the cutoff. While the plasma from these subjects may still contain protective antibodies (IgA, IgM, neutralizing antibodies) we have made the decision to not use plasma from these donors for our patients at this time. Of the 26 remaining subjects with positive antibody results, the SARS CoV 2 IgG ratio ranged from 1.3 to 10.7 with a mean of 5.6 and a median of 5.2. At this stage, we have
Transfusion
C Michael Knudson J Brooks Jackson
218856253
Efficacy and safety of convalescent plasma for severe COVID 19 based on evidence in other severe respiratory viral infections: a systematic review and meta analysis
BACKGROUND: The safety and efficacy of convalescent plasma in severe coronavirus disease 2019 (COVID 19) remain uncertain. To support a guideline on COVID 19 management, we conducted a systematic review and meta analysis of convalescent plasma in COVID 19 and other severe respiratory viral infections. METHODS: In March 2020, we searched international and Chinese biomedical literature databases, clinical trial registries and prepublication sources for randomized controlled trials (RCTs) and nonrandomized studies comparing patients receiving and not receiving convalescent plasma. We included patients with acute coronavirus, influenza and Ebola virus infections. We conducted a meta analysis using random effects models and assessed the quality of evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. RESULTS: Of 1099 unique records, 6 studies were eligible, and none of these included patients with COVID 19. One nonrandomized study (n 40) on convalescent plasma in severe acute respiratory syndrome coronavirus (SARS CoV) provided uninformative results regarding mortality (relative risk [RR] 0.10, 95% confidence interval [CI] CI 0.01 to 1.70) Pooled estimates from 4 RCTs on influenza (n 572) showed no convincing effects on deaths (4 RCTs, RR 0.94, 95% CI 0.49 to 1.81) complete recovery (2 RCTs, odds ratio 1.04, 95% CI 0.69 to 1.64) or length of stay (3 RCTs, mean difference 1.62, 95% CI 3.82 to 0.58, d) The quality of evidence was very low for all efficacy outcomes. Convalescent plasma caused few or no serious adverse events in influenza RCTs (RR 0.85, 95% CI 0.56 to 1.29, low quality evidence) INTERPRETATION: Studies of non COVID 19 severe respiratory viral infections provide indirect, very low quality evidence that raises the possibility that convalescent plasma has minimal or no benefit in the treatment of COVID 19 and low quality evidence that it does not cause serious adverse events.
Canadian Medical Association Journal
Niveditha Devasenapathy Zhikang Ye Mark Loeb Fang Fang Borna Tadayon Najafabadi Yingqi Xiao Rachel J Couban Philippe Begin Gordon H Guyatt
218618593
Convalescent plasma for patients with COVID 19
The ongoing worldwide pandemic of coronavirus disease 2019 (COVID 19) (1) caused by severe acute respiratory syndrome coronavirus 2 (SARS CoV 2) has posed a huge threat to global public health, while no specific treatment is recommended for therapy (2) In Duan et al.'s study (3) they observed a large clinical improvement in 10 severe COVID 19 patients treated with convalescent plasma transfusion. Despite some limitations, this traditional therapy sheds light on the therapy for severe and critical COVID 19 patients (3, 4) However, some doubts were generated during the process of reading their study that we would like to highlight and [1]1To whom correspondence may be addressed. Email: dengguangtong{at}outlook.com or chenxiangck{at}126.com. [1] #xref corresp 1 1
Proceedings of the National Academy of Sciences
Furong Zeng Xiang Chen Guangtong Deng
221626220
Convalescent plasma anti SARS CoV 2 spike protein ectodomain and receptor binding domain IgG correlate with virus neutralization.
The newly emerged severe acute respiratory syndrome coronavirus 2 (SARS CoV 2) highlights the urgent need for assays that detect protective levels of neutralizing antibodies. We studied the relationship between anti spike ectodomain (ECD) anti receptor binding domain (RBD) IgG titers, and SARS CoV 2 virus neutralization (VN) titers generated by two in vitro assays using convalescent plasma samples from 68 COVID 19 patients. We report a strong positive correlation between both plasma anti RBD and anti ECD IgG titers and in vitro VN titer. The probability of a VN titer =160, the FDA recommended level for convalescent plasma used for COVID 19 treatment, was =80% when anti RBD or anti ECD titers were =1:1350. Of all donors, 37% lacked VN titers =160. Dyspnea, hospitalization, and disease severity were significantly associated with higher VN titer. Frequent donation of convalescent plasma did not significantly decrease VN or IgG titers. Analysis of 2,814 asymptomatic adults found 73 individuals with anti ECD IgG titers of =1:50 and strong positive correlation with anti RBD and VN titers. Fourteen of these individuals had VN titers =1:160, all of which had anti RBD titer =1:1350. 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 titers of =1:1350 may provide critical information about protection against COVID 19 disease.
The Journal of clinical investigation
Eric Salazar Suresh V Kuchipudi Paul A Christensen Todd N Eagar Xin Yi Picheng Zhao Zhicheng Jin S Wesley Long Randall J Olsen Jian Chen Brian Castillo Christopher M Leveque Dalton M Towers Jason J Lavinder Jimmy D Gollihar Jose A Cardona Gregory C Ippolito Ruth H Nissly Ian M Bird Denver Greenawalt Randall Rossi Abhinay Gontu Sreenidhi Srinivasan Indira B Poojary Isabella M Cattadori Peter J Hudson Nicole M Josleyn Laura I Prugar Kathleen E Huie Andrew S Herbert David W Bernard John M Dye Vivek Kapur James M Musser
219978911
Clinical predictors of donor antibody titer and correlation with recipient antibody response in a COVID 19 convalescent plasma clinical trial
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.
medRxiv
Maria Lucia L Madariaga Jenna J Guthmiller Stephen J Schrantz Maud O Jansen Chance Christensen Micah T Prochaska Geoffrey D Wool Amy Durkin-Celauro Won Hee Oh Laura Trockman Janani Vigneswaran Robert C Keskey Haley L Dugan Nai-Ying Zheng Mari Cobb Henry A Utset Olivia Stovicek Cindy Bethel Scott M Matushek Mihai C Giurcanu Kathleen G Beavis Diego di Sabato David Meltzer Mark K Ferguson John P Kress Kumaran Shanmugarajah John Fung John C Alverdy Jessica Scott Donington