key: cord-266569-cf3mfp3e authors: Senefeld, J.; Klassen, S. A.; Ford, S. K.; Wiggins, C. C.; Bostrom, B. C.; Thompson, M. A.; Baker, S. E.; Nicholson, W. T.; Johnson, P. W.; Carter, R. E.; Henderson, J. P.; Hartman, W. R.; Pirofski, L.-a.; Wright, R. S.; Fairweather, D.; Bruno, K. A.; Paneth, N. S.; Casadevall, A.; Joyner, M. J. title: Therapeutic use of convalescent plasma in COVID-19 patients with immunodeficiency: A systematic review date: 2020-11-10 journal: nan DOI: 10.1101/2020.11.08.20224790 sha: doc_id: 266569 cord_uid: cf3mfp3e In the absence of effective countermeasures, human convalescent plasma has been widely used to treat severe acute respiratory syndrome coronavirus 2 including among patients with innate or acquired immunodeficiency. However, the association between COVID-19-associated mortality in patients with immunodeficiency and therapeutic use of convalescent plasma is unknown. We review clinical features and treatment protocols of COVID-19 patients with immunodeficiency after treatment with human convalescent plasma. We also discuss the time course and clinical features of recovery. These insights provide evidence for the need to develop a clear treatment protocol for COVID-19 patients with immunodeficiency and support the efficacy of convalescent plasma in patients with primary or secondary immunodeficiency. Convalescent plasma represents a passive antibody therapy that has been used to prevent or treat infectious diseases for more than a century. 1,2 In the context of the novel coronavirus disease 2019 (COVID-19) pandemic, convalescent plasma has received full or conditional regulatory authorization in the United States for therapeutic use in adults and children hospitalized with suspected or laboratory confirmed SARS-CoV-2 positive COVID-19. [3] [4] [5] Although early signals for efficacy and optimal use of convalescent plasma have emerged, 6-10 additional large randomized controlled trials are needed to garner clinical consensus regarding the therapeutic effectiveness of convalescent plasma. Inasmuch as convalescent plasma confers antiviral properties for the recipient, evidence of therapeutic effectiveness may be confounded by endogenous anti-SARS-CoV-2 antibody responses, particularly when convalescent plasma transfusion occurs late in the disease course. 11 Hence, evaluation of the clinical responses to convalescent plasma transfusion in immunosuppressed patients who cannot generate innate immune responses may provide an optimal opportunity to assess the effect of convalescent plasma per se. 12 Thus, herein we summarize the literature detailing the clinical experiences of patients with primary and secondary immunosuppression who were transfused with COVID-19 convalescent plasma. We hypothesize that patients with immunodeficiency syndromes, or patients with diseases associated with blunted endogenous antibody responses to COVID-19, may provide evidence of improved clinical status when given plasma containing anti-SARS-CoV-2 antibodies, with improvements over and above expectation in light of their underlying clinical conditions and the severity of COVID-19. This review highlights 40 reports including 104 COVID-19 patients with primary immunosuppression due to Agammaglobulinemia (X-linked or autosomal) or Common Variable Immunodeficiency, and secondary immunodeficiencies related to hematological malignancies and solid organ transplants who were transfused with convalescent plasma. We also highlight additional cases of patients with COVID-19, including but not limited to patients with other forms of immunosuppression, transfused with convalescent plasma. We provide a summary overview of patient characteristics, COVID-19 therapies used, including convalescent plasma, and clinical symptomology (table) . References for this Review were identified through searches of PubMed for articles published from Jan 1, 2020 to Nov 1, 2020, using the Medical Subject Headings terms "COVID-19", "convalescent plasma", "convalescent serum", "immunosuppression", "cancer", "transplant", "agammaglobulinemia", "malignancy", and any relevant entry terms and supplementary concepts (figure). Relevant articles and data were also identified through searches in Google Scholar, medR Χ iv, and other websites. Articles resulting from these searches and relevant references cited in those articles were reviewed. Articles published in English were identified and included. All procedures accessed public information and did not require ethical review as determined by the Mayo Clinic Institutional Review Board in accordance with the Code of Federal Regulations, 45 CFR 46.102, and the Declaration of Helsinki. This narrative includes one patient with Autosomal Agammaglobulinemia and six patients with X-linked Agammaglobulinemia (XLA), six of whom were reported in peer-reviewed articles and one patient who was identified in a media report. 13-16 Patients with Agammaglobulinemia do not produce endogenous antibodies and require regular intravenous infusions (monthly) or subcutaneous injections (bi-weekly) of immunoglobulins to avoid serial infections from various common pathogens. 17 However, immunoglobulin replacement therapy cannot protect patients against pathogens for which antibodies are uncommon or absent in the immunoglobulin donor pool, such as the SARS-CoV-2 virus. 17 The clinical narratives describing patients with Agammaglobulinemias all demonstrate a prolonged course of disease and absent antibody response to COVID-19. However, all patients with Agammaglobulinemia demonstrated clinical improvement and symptom resolution following convalescent plasma transfusion, with three patients improving rapidly and demonstrating SARS-CoV-2 serum antibodies after transfusion. In addition to immunoglobulin therapy, some patients also received the experimental COVID-19 therapies remdesivir and hydroxychloroquine. We identified four patients with Common Variable Immunodeficiency transfused with convalescent plasma for COVID-19 therapy. 16 Common Variable Immunodeficiency represents a heterogeneous collection of immunodeficiencies commonly characterized by intrinsic B-cell defects and suppressed antibody production. 18 Patients with Common Variable Immunodeficiency often present with inflammatory and autoimmune disorders, which are suspected to elevate these patients risk for progression to severe COVID-19. 16, 18 The four patients described here were all antibody deficient and diagnosed with severe or life-threatening COVID-19. Notably, three of these patients survived following convalescent plasma transfusion, including two patients whose clinical symptomatology required mechanical ventilation or extracorporeal membrane oxygenation. We identified 54 patients with hematological malignancies transfused with convalescent plasma in 18 peer-reviewed reports. 19,20,28,29,29-36,21-24,24-27 The largest cohort of patients with hematological malignancies was a group of 17 patients with B-cell depletion whose immunodeficiency was secondary to therapies for various types of lymphoma or leukemia. 19 Among nine peer-reviewed articles and two media reports we identified a total of 29 COVID-19 patients transfused with convalescent plasma whom were receiving immunosuppressive therapies for previous solid organ transplants. 37-47 In a cohort of 13 transplant recipients transfused with convalescent plasma concomitant to hydroxychloroquine, steroids and anticoagulants therapies for COVID-19, eight patients demonstrated improved oxygen requirements and were promptly discharged 37 . In the other nine reports, a majority of the 17 patients with COVID-19 demonstrated improved clinical symptomatology following convalescent plasma transfusion. Improvement was even seen in a liver transplant patient discharged home after a convalescent plasma transfusion that occurred during a seventeen day medically-induced coma due to COVID-19 complications. 44 These data provide evidence and encouraging anecdotal statements (panel) supporting the efficacy of convalescent plasma in patients with primary or secondary immunodeficiency, and are consistent with the historical evidence demonstrating that passive antibody therapies for infectious diseases are especially effective when given early in the course of disease prior to an endogenous antibody response. 2, 48, 49 In contrast to ongoing studies of convalescent plasma efficacy in clinical trials where the majority of patients are not immunosuppressed and thus mount their own protective antibody responses, 6,11,50 convalescent plasma use in these immunosuppressed patients represents a situation where exogenous antibody is provided in the setting of an immune deficit. 17 This is particularly true in the case for patients with Agammaglobulinemia, who represent in effect a natural 'immunological knockout' providing the opportunity to evaluate the value of adding specific antibody to a host unable to make antibody to SARS- The results for patients with Agammaglobulinemia are striking for the beneficial effects of convalescent plasma, and even though the reports lack a control group, the rapid time course of clinical improvement following administration of specific antibody in a situation where no endogenous antibody was present is impressive. Convalescent plasma was also found to be safe and efficacious in COVID-19 patients with common variable immunodeficiency, myasthenia gravis, and Sjögren's syndrome, in addition to COVID-19 patients with heart rhythm abnormalities and gravida. [51] [52] [53] [54] [55] [56] [57] Hence, from the viewpoint of establishing the efficacy of convalescent plasma administration in COVID-19 therapy, the experience with this patient set provides the important criterion that addition of specific antibody to a host with no antibodies resulted in a favorable therapeutic effect. All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this this version posted November 10, 2020. ; MJJ is the guarantor. SAK, JWS, SKF, AC and MJJ conceptualised the paper, extracted the data and established the writing consortium. All authors contributed to the reviewing and editing of the report and approved the final version. We declare no competing interests. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this this version posted November 10, 2020. ; Data are presented as mean (range) or count (n), mean (%). *Data were not reported for all patients, please see Supplement 1 for additional information. a Other includes pediatric patients, patients with congenital heart disease, gravida patients, and patients with Sjögren's syndrome Table: Summary of each patient's hospital course and disposition after transfusion of COVID-19 convalescent plasma. All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this this version posted November 10, 2020. • In the present case, the rapid clinical improvement followed by viral clearance after administration of hyperimmune plasma argue that passively transferred antibodies played a key role in COVID-19 recovery. 23 • One day later [after convalescent plasma transfusion], the patient was afebrile for the first time in 3 weeks and had improved energy. 13 • On day 122 (of illness), due to worsening symptoms, the patient was given convalescent plasma. He defervesced within 24 hours and was discharged nine days later. 31 • …she was transferred to the intensive care unit for intubation. In the meantime…the patient received convalescent therapy instead and did not undergo intubation following the immediate improvement after plasma therapy infusion. 52 • Based on the lack of clinical improvement…we transfused 1 unit of convalescent plasma…Importantly, the patient did not receive any other treatment potentially having an effect on the course of COVID-19…After transfusion of the convalescent plasma, the patient showed a dramatic clinical improvement, became asymptomatic, and was discharged home only 2 days later. 36 • The patient was discharged after 2 weeks [convalescent plasma transfusion] with a dramatic response to therapy. • …received 217 mL of convalescent plasma…24 hours later, his heart rate had improved to 60-70 bpm with less frequent premature atrial contractions and premature ventricular contractions and he was breathing comfortably on room air…36 hours after transfusion the patient was discharged from the hospital… 53 • Stagnancy in the patient's evolution, as represented by the lack of response to any of the treatments dispensed....we administered on day 23 COVID-19 convalescent plasma...after 24 hours of infusion, fever ceased without subsequent reappearance and with progressive improvement of asthenia. 14 All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this this version posted November 10, 2020. ; preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this this version posted November 10, 2020. ; This appendix has been provided by the authors to give readers additional information about their work. All rights reserved. No reuse allowed without permission. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this this version posted November 10, 2020. ; https://doi.org/10.1101/2020.11.08.20224790 doi: medRxiv preprint Plasma donation helps save Indiana man diagnosed with COVID-19 article_540bc9b2-ac1d-11ea-958d-abf6e203c27a.html. 44 NHS Blood and Transplant. One of the first COVID-19 convalescent plasma recipients supports donor appeal. Give Blood Lung transplant patient with COVID-19 recovers following plasma clinical trial. Univ COVID-19 in Liver Transplant Recipients-A Series with Successful Recovery Coronavirus Disease 2019 Viremia, Serologies, and Clinical Course in a Case Series of Transplant Recipients Use of convalescent plasma therapy in SARS patients in Hong Kong Convalescent plasma treatment reduced mortality in patients with severe pandemic influenza A (H1N1) 2009 virus infection Convalescent Plasma for COVID-19. A randomized clinical trial Convalescent plasma for pediatric patients with SARS CoV 2 associated acute respiratory distress syndrome COVID-19 presentation in association with myasthenia gravis: a case report and review of the literature Hospitalized COVID-19 patients treated with Convalescent Plasma in a mid-size city in the midwest Convalescent plasma therapy in a pregnant COVID-19 patient with a dramatic clinical and imaging response: A case report Severe COVID-19 in Third Trimester Pregnancy: Multidisciplinary Approach COVID-19 convalescent plasma clears SARS-CoV-2 refractory to remdesivir in an infant with congenital heart disease Treatment with convalescent plasma for COVID 19 patients in Wuhan We thank the members of the National COVID-19 Convalescent Plasma Project (http://ccpp19.org) for their support and collation of key scientific papers. This study was supported in part by National Heart, Lung, and Blood Institute (NHLBI) grant 5R35HL139854 (to MJJ), grant F32HL154320 (to JWS), and grant RO1 HL059842 (to AC); Natural Sciences and Engineering Research Council of Canada (NSERC) PDF-532926-2019 (to SAK); National Institute of Allergy and Infectious Disease (NIAID) grants R21 AI145356, R21 AI152318 and R21 AI154927 (to DF), and grant R01 AI152078 9 (to AC); and National Institute on Aging (NIA) U54AG044170 (to SEB).