Loading

Annals of Vaccines and Immunization

Combining Therapeutic Plasma Exchange with Virus Neutralizing Antibodies for Treatment of Severe COVID-19

Commentary | Open Access Volume 5 | Issue 1 |

  • 1. Department of Medical Microbiology and Immunology, UW School of Medicine and Public Health, USA
+ Show More - Show Less
Corresponding Authors
Miroslav Malkovsky, Department of Medical Microbiology and Immunology
Citation

Malkovsky M (2020) Combining Therapeutic Plasma Exchange with Virus Neutralizing Antibodies for Treatment of Severe COVID-19. Ann Vaccines Immunization 5(1): 1017.

TO THE EDITOR -

The pandemic spread of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) requires very urgently to identify effective therapies and prophylaxis. After early promise, disappointing findings have been reported with drugs repurposed for COVID-19, including hydroxychloroquine, [1] lopinavir-ritonavir [2] and remdesivir [3] Currently, there is no effective therapeutics for the treatment of severe COVID-19; as of May 25, 2020, 5,304,772 people had tested positive for COVID-19 and 342,029 people had succumbed to the disease [4].

Blanco-Melo et al. [5] studied host responses to SARS-CoV-2 and found weak innate antiviral defenses coupled with inappropriately high inflammatory cytokine levels were key entities driving the etiopathogenesis of COVID-19. They conclude their article (quote): “Because our data suggest that numerous chemokines and ILs are elevated in COVID-19 patients, future efforts should focus on U.S. Food and Drug Administration (FDA)-approved drugs that can be rapidly deployed and have immunomodulating properties.” Indeed, many COVID-19 patients develop sepsis-like syndromes and recent clinical observations [6,7] further validate the inferred role of virallydriven hyper inflammation with fulminant hypercytokinemia in severe COVID-19.

Given the potential key pathogenic role of the host response to SARS-CoV-2 in severe COVID-19 rather than the viral replication in host cells per se provides the rationale for targeting this response by therapeutic plasma exchange (TPE). The purpose here is to remove the excess of cytokines in the plasma causing the clinical signs and symptoms. This concept of potential extracorporeal removal of pathogenic substances and its relative safety and efficacy have a long history [8-11] and currently, TPE is an effective treatment in many clinical situations [12,13]. During a typical TPE procedure, which takes about 2 hours, the patient’s blood is passed through an apheresis machine (on the order of 1 to 1.5 blood volumes) and the separated plasma is collected by the instrument and eventually discarded. The cellular blood components are mixed with a replacement fluid (typically an isotonic solution of ~5% human albumin) and returned to the patient.

The recent COVID-19 studies in Italy suggested that no individual anti-inflammatory treatment targeting a single cytokine molecule had any substantial therapeutic effects (Giuseppe Ippolito, personal communication). This is not very surprising, because in comparison with healthy adults, COVID-19 patients display elevated plasma concentrations of many cytokines, including interleukin (IL)-1β, IL-1 receptor antagonist, IL-7, IL-8, IL-9, IL-10, basic fibroblast growth factor, granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, interferon-γ, interferon-γ inducible protein 10, monocyte chemoattractant protein-1, macrophage inflammatory protein 1-α, macrophage inflammatory protein 1-β, platelet-derived growth factor, tumor necrosis factor-α and vascular endothelial growth factor [14]. Performing single or repeated TPE treatments in severe COVID-19 would eliminate a significant proportion of all of these elevated plasma cytokines. In fact, a recent pilot study in septic shock demonstrated that the key proinflammatory cytokines and permeability factors (e.g., IL-1β, IL-6, and angiopoietin-2) were significantly reduced after TPE, while the levels of protective antipermeability factor angiopoietin-1 were unaffected [15] This TPE part of the proposed combination therapy may have beneficial effects in all severe COVID-19 patients, [16] particularly in those with acute respiratory distress syndrome (ARDS).

An important feature of coronaviruses such as SARS-CoV-2 is the presence of 3’-5’ exoribonuclease (ExoN) enzymatic activity. ExoN can excise incorporated nucleotide analogs typically targeting viral RNA-dependent RNA polymerases, rendering resistance to these types of antivirals. On the other hand, the proofreading capability of ExoN diminishes the accumulation of mutations, which is favorable for effectiveness of virus-neutralizing (VNAbs) antibodies and vaccines. Similar to the concept of extracorporeal removal of pathogenic substances, the idea of using antibodies to nullify pathogenic entities [17] including viruses [18-21] has a long tradition.

Recently, Shen et al. [22] reported 5 critically ill and mechanically ventilated COVID-19 patients with severe ARDS, who received VNAbs-containing convalescent plasmas between 10 and 22 days after admission. This resulted in body temperature normalization within 3 days in 4 of 5 patients and on day 12 in the fifth patient. The Sequential Organ Failure Assessment (SOFA) score decreased similar to viral loads measured by quantitative RT-PCR. One patient became PCR-negative on post transfusion day 1, two patients became PCR-negative on day 3 and two patients became negative on day 12 after the plasma transfusion. After 53, 51, and 55 days of stay, three patients were discharged from the hospital and two patients remained in stable condition at 37 days after plasma transfusion.

These remarkable results strongly suggest that replacing 400 ml of the isotonic human albumin solution during the TPE procedure with 400 ml of ABO-matched convalescent plasma [22] containing high titers of VNAbs would effectively complement the TPE treatment of severely ill COVID-19 patients. Wu et al. [23] studied virus-neutralizing antibody (VNAb) responses in 175 COVID-19 recovered patients using pseudotyped-lentiviralvector-based neutralization assay. Ten COVID-19 patients had undetectable levels of VNAbs. Interestingly, significantly higher (P<0.0001) titers of VNAbs were present in elderly and middle-age patients than in young patients and the VNAb titers corelated positively with the plasma C-reactive protein levels and negatively with the lymphocyte counts at the time of admission [23].

Many hospitals probably cannot perform the true virusneutralization assay (for measuring the presence or absence of VNAbs in convalescent plasmas), which requires a BSL-3 or 4 lab. Therefore, either a suitable BSL-2 pseudotyping-variety neutralization assay [24] or selections of convalescent plasmas with high titers of antibodies binding to the S1-RBD, S1-NTD and S2 should be performed. Testing by ELISA (or another suitable assay) can replace the virus neutralization assay, because practically all known VNAbs are binding to one of these three SARS-CoV-2 regions and interfere with binding to ACE2 or with S2-mediated membrane fusion [25]. Alternatively, VNAbscontaining allogeneic plasma could be replaced with crossneutralizing SARS-CoV RBD-specific (human or ‘humanized’) antibodies [26] or SARS-CoV-2-specific monoclonal VNAbs [27] The whole TPE-VNAbs procedure can be repeated as needed.

This combination TPE-VNAbs treatment of critically ill COVID-19 patients could be very effective and free of most toxic side effects associated with many antiviral drugs currently tested. After adjusting the used doses of VNAbs to eliminate the potential prozone-like effects [28,29] the only potential side effect could be an allergic reaction towards an unknown component in the allogeneic plasma. These reactions are known to occur but are not extremely frequent. Although one additional hypothetical risk could be a possible VNAb-mediated attenuation of humoral immunity, [30] the above-mentioned study [22] does not support this possibility, because the VNAb titers in the 5 convalescent plasma recipients ranged between 40 and 160 before the therapeutic plasma transfusions and beneficially increased to ranges of 80-320 and 160-480 on day 1 and day 7 after transfusion, respectively. While lacking any effective therapies and vaccines for COVID-19, novel treatment strategies are needed to decrease mortality. Given the relevant data briefly discussed above, the TPE-VNAbs combination therapy, ideally initiated as soon as possible after symptom onset in severe COVID-19 patients, may be considered as a therapeutic option.

REFERENCES

1. Tang W, Cao Z, Han M, Wang Z, Chen J, Sun W, et al. Hydroxychloroquine in patients with COVID-19: an open-label, randomized, controlled trial. medRxiv. 2020.

2. Cao B, Wang Y, Wen D, Wen Liu, Jingli Wang, Guohui Fan, et al. A trial of lopinavir-ritonavir in adults hospitalized with severe COVID-19. N Engl J Med. 2020; 382: 1787-1799.

3. Wang Y, Zhang D, Du G. Remdesivir in adults with severe COVID-19: a randomized, double-blind, placebo-controlled, multicenter trial. Lancet. 2020; 395:1569-1578.

4. WHO. Coronavirus disease (COVID-19). Situation Report-126.

5. Blanco-Melo D, Nilsson-Payant BE, Liu W-C, Skyler Uhl, Daisy Hoagland, Rasmus Møller, et al. Imbalanced host response to SARSCoV-2 drives development of COVID-19. Cell. 2020; 181: 1-10.

6. Ruan Q, Yang K, Wang W, Lingyu Jiang, Jianxin Song. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med. 2020; 3:1-3.

7. Mehta P, McAuley DF, Brown M, Emilie Sanchez, Rachel S Tattersall, Jessica J Manson, et al. COVID-19: Consider cytokine storm syndromes and immunosuppression. Lancet. 2020; 395: 1033-1034.

8. Abel JJ, Rowntree LG, Turner BB. On the removal of diffusible substances from the circulating blood by means of dialysis. Trans Assoc Am Phys.1913; 28: 51-54.

9. Grifols-Lucas JA. Use of plasmapheresis in blood donors. Brit Med J. 1952; 1: 854.

10. Hans R, Sharma RR, Marwaha N, Deepti Suri, Rakesh Kumar, Anju Gupta, et al. Efficacy and safety of therapeutic plasma exchange by using apheresis devices in pediatric atypical hemolytic uremic syndrome patients. J Clin Apher. 2016; 31: 381-387.

11. Dorst J, Fangerau T, Taranu D, Eichele P, Dreyhaupt J, Sebastian Michels, et al. Safety and efficacy of immunoadsorption versus plasma exchange in steroid-refractory relapse of multiple sclerosis and clinically isolated syndrome: A randomized, parallel-group, controlled trial. EClinical Medicine. 2019; 16: 98-106.

12. Fernandez-Zarzoso M, Gomez-Segui I, de la Rubia J. Therapeutic plasma exchange: Review of current indications. Transfus Apher Sci. 2019; 58: 247-253.

13. Harris ES, Meiselman HJ, Moriarty PM, Allan Metzger, Miroslav Malkovsky. Therapeutic plasma exchange for the treatment of systemic scleroderma: A comprehensive review and analysis. J Sclerod Rel Dis. 2018; 3: 132-152.

14. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020; 395: 497-506.

15. Knaup H, Stahl K, Schmidt BMW, Temitayo O Idowu, Markus Busch, Olaf Wiesner, et al. Early therapeutic plasma exchange in septic shock: a prospective open-label nonrandomized pilot study focusing on safety, hemodynamics, vascular barrier function, and biologic markers. Crit Care. 2018; 22: 285.

16. Keith P, Day M, Perkins L. A novel treatment approach to the novel coronavirus: an argument for the use of therapeutic plasma exchange for fulminant COVID-19. Crit Care. 2020; 24: 128.

17. Behring EA, Kitasato S. About the establishment of diphtheria immunity and tetanus immunity in animals. Deutch Med Woch. 1890; 49: 1113-1114.

18. Park WH, Freeman RG. The prophylactic use of measles convalescent serum. JAMA. 1926; 87: 556-558.

19. Gallagher JR. Use of convalescent measles serum to control measles in a preparatory school. Am J Public Health Nation’s Health. 1935; 25: 595-598.

20. Park WH. Therapeutic use of antipoliomyelitits serum in preparalytic cases of poliomyelitis. JAMA.1932; 99: 1050-1053.

21. Rambar AC. Mumps; use of convalescent serum in the treatment and prophylaxis of orchitis. Am J Dis Child. 1946; 71: 1-13.

22. Shen C, Wang Z, Zhao F. Treatment of 5 critically ill patients with COVID-19 with convalescent plasma. JAMA. 2020; 323: 1582-1589.

23. Wu F, Wang A, Liu M, Wang Q, Chen J, Xia S, et al. Neutralizing antibody responses to SARS-CoV-2 in a COVID-19 recovered patient cohort and their implications. medRxiv.2020.

24. Crawford KHD, Eguia R, Dingens AS, Loes AN, Malone KD, Wolf CR, et al. Protocol and reagents for pseudotypinglentiviral particles with SARS-CoV-2 spike protein for neutralization assays. Viruses. 2020; 12: 513.

25. Jiang S, Hillyer C, Du L. Neutralizing antibodies against SARS-CoV-2 and other human coronaviruses. Trends Immunol. 2020; 41: 355-359.

26. Tai W, He L, Zhang X, Pu J, Voronin D, Jiang S, Zhou Y, et al. Characterization of the receptor-binding domain (RBD) of 2019 novel coronavirus: Implication for development of RBD protein as a viral attachment inhibitor and vaccine. Cell Mol Immunol. 2020.

27. Wang C, Li W, Drabek D, Okba NMA, Haperen RV, Osterhaus ADME, et al. A human monoclonal antibody blocking SARS-CoV-2 infection. Nat Commun. 2020; 11: 2251.

28. Taborda CP, Arturo Casadevall A. Immunoglobulin M efficacy against Cryptococcus neoformans: mechanism, dose dependence, and prozone-like effects in passive protection experiments. J Immunol. 2001; 166: 2100-2107.

29. Taborda CP, Rivera J, Zaragoza O, Casadevall A. More is not necessarily better: Prozone-like effects in passive immunization with immunoglobulin G. J Immunol. 2003; 170: 3621-3630.

30. Crowe JE, Firestone CY, Murphy BR. Passively acquired antibodies suppress humoral but not cell-mediated immunity in mice immunized with live attenuated respiratory syncytial virus vaccines. J Immunol. 2001; 167: 3910-3918.

Malkovsky M (2020) Combining Therapeutic Plasma Exchange with Virus Neutralizing Antibodies for Treatment of Severe COVID-19. Ann Vaccines Immunization 5(1): 1017

Received : 11 May 2018
Accepted : 26 May 2018
Published : 29 May 2018
Journals
Annals of Otolaryngology and Rhinology
ISSN : 2379-948X
Launched : 2014
JSM Schizophrenia
Launched : 2016
Journal of Nausea
Launched : 2020
JSM Internal Medicine
Launched : 2016
JSM Hepatitis
Launched : 2016
JSM Oro Facial Surgeries
ISSN : 2578-3211
Launched : 2016
Journal of Human Nutrition and Food Science
ISSN : 2333-6706
Launched : 2013
JSM Regenerative Medicine and Bioengineering
ISSN : 2379-0490
Launched : 2013
JSM Spine
ISSN : 2578-3181
Launched : 2016
Archives of Palliative Care
ISSN : 2573-1165
Launched : 2016
JSM Nutritional Disorders
ISSN : 2578-3203
Launched : 2017
Annals of Neurodegenerative Disorders
ISSN : 2476-2032
Launched : 2016
Journal of Fever
ISSN : 2641-7782
Launched : 2017
JSM Bone Marrow Research
ISSN : 2578-3351
Launched : 2016
JSM Mathematics and Statistics
ISSN : 2578-3173
Launched : 2014
Journal of Autoimmunity and Research
ISSN : 2573-1173
Launched : 2014
JSM Arthritis
ISSN : 2475-9155
Launched : 2016
JSM Head and Neck Cancer-Cases and Reviews
ISSN : 2573-1610
Launched : 2016
JSM General Surgery Cases and Images
ISSN : 2573-1564
Launched : 2016
JSM Anatomy and Physiology
ISSN : 2573-1262
Launched : 2016
JSM Dental Surgery
ISSN : 2573-1548
Launched : 2016
Annals of Emergency Surgery
ISSN : 2573-1017
Launched : 2016
Annals of Mens Health and Wellness
ISSN : 2641-7707
Launched : 2017
Journal of Preventive Medicine and Health Care
ISSN : 2576-0084
Launched : 2018
Journal of Chronic Diseases and Management
ISSN : 2573-1300
Launched : 2016
JSM Heart Surgery Cases and Images
ISSN : 2578-3157
Launched : 2016
Annals of Reproductive Medicine and Treatment
ISSN : 2573-1092
Launched : 2016
JSM Brain Science
ISSN : 2573-1289
Launched : 2016
JSM Biomarkers
ISSN : 2578-3815
Launched : 2014
JSM Biology
ISSN : 2475-9392
Launched : 2016
Archives of Stem Cell and Research
ISSN : 2578-3580
Launched : 2014
Annals of Clinical and Medical Microbiology
ISSN : 2578-3629
Launched : 2014
JSM Pediatric Surgery
ISSN : 2578-3149
Launched : 2017
Journal of Memory Disorder and Rehabilitation
ISSN : 2578-319X
Launched : 2016
JSM Tropical Medicine and Research
ISSN : 2578-3165
Launched : 2016
JSM Head and Face Medicine
ISSN : 2578-3793
Launched : 2016
JSM Cardiothoracic Surgery
ISSN : 2573-1297
Launched : 2016
JSM Bone and Joint Diseases
ISSN : 2578-3351
Launched : 2017
JSM Bioavailability and Bioequivalence
ISSN : 2641-7812
Launched : 2017
JSM Atherosclerosis
ISSN : 2573-1270
Launched : 2016
Journal of Genitourinary Disorders
ISSN : 2641-7790
Launched : 2017
Journal of Fractures and Sprains
ISSN : 2578-3831
Launched : 2016
Journal of Autism and Epilepsy
ISSN : 2641-7774
Launched : 2016
Annals of Marine Biology and Research
ISSN : 2573-105X
Launched : 2014
JSM Health Education & Primary Health Care
ISSN : 2578-3777
Launched : 2016
JSM Communication Disorders
ISSN : 2578-3807
Launched : 2016
Annals of Musculoskeletal Disorders
ISSN : 2578-3599
Launched : 2016
Annals of Virology and Research
ISSN : 2573-1122
Launched : 2014
JSM Renal Medicine
ISSN : 2573-1637
Launched : 2016
Journal of Muscle Health
ISSN : 2578-3823
Launched : 2016
JSM Genetics and Genomics
ISSN : 2334-1823
Launched : 2013
JSM Anxiety and Depression
ISSN : 2475-9139
Launched : 2016
Clinical Journal of Heart Diseases
ISSN : 2641-7766
Launched : 2016
Annals of Medicinal Chemistry and Research
ISSN : 2378-9336
Launched : 2014
JSM Pain and Management
ISSN : 2578-3378
Launched : 2016
JSM Women's Health
ISSN : 2578-3696
Launched : 2016
Clinical Research in HIV or AIDS
ISSN : 2374-0094
Launched : 2013
Journal of Endocrinology, Diabetes and Obesity
ISSN : 2333-6692
Launched : 2013
Journal of Substance Abuse and Alcoholism
ISSN : 2373-9363
Launched : 2013
JSM Neurosurgery and Spine
ISSN : 2373-9479
Launched : 2013
Journal of Liver and Clinical Research
ISSN : 2379-0830
Launched : 2014
Journal of Drug Design and Research
ISSN : 2379-089X
Launched : 2014
JSM Clinical Oncology and Research
ISSN : 2373-938X
Launched : 2013
JSM Bioinformatics, Genomics and Proteomics
ISSN : 2576-1102
Launched : 2014
JSM Chemistry
ISSN : 2334-1831
Launched : 2013
Journal of Trauma and Care
ISSN : 2573-1246
Launched : 2014
JSM Surgical Oncology and Research
ISSN : 2578-3688
Launched : 2016
Annals of Food Processing and Preservation
ISSN : 2573-1033
Launched : 2016
Journal of Radiology and Radiation Therapy
ISSN : 2333-7095
Launched : 2013
JSM Physical Medicine and Rehabilitation
ISSN : 2578-3572
Launched : 2016
Annals of Clinical Pathology
ISSN : 2373-9282
Launched : 2013
Annals of Cardiovascular Diseases
ISSN : 2641-7731
Launched : 2016
Journal of Behavior
ISSN : 2576-0076
Launched : 2016
Annals of Clinical and Experimental Metabolism
ISSN : 2572-2492
Launched : 2016
Clinical Research in Infectious Diseases
ISSN : 2379-0636
Launched : 2013
JSM Microbiology
ISSN : 2333-6455
Launched : 2013
Journal of Urology and Research
ISSN : 2379-951X
Launched : 2014
Journal of Family Medicine and Community Health
ISSN : 2379-0547
Launched : 2013
Annals of Pregnancy and Care
ISSN : 2578-336X
Launched : 2017
JSM Cell and Developmental Biology
ISSN : 2379-061X
Launched : 2013
Annals of Aquaculture and Research
ISSN : 2379-0881
Launched : 2014
Clinical Research in Pulmonology
ISSN : 2333-6625
Launched : 2013
Journal of Immunology and Clinical Research
ISSN : 2333-6714
Launched : 2013
Annals of Forensic Research and Analysis
ISSN : 2378-9476
Launched : 2014
JSM Biochemistry and Molecular Biology
ISSN : 2333-7109
Launched : 2013
Annals of Breast Cancer Research
ISSN : 2641-7685
Launched : 2016
Annals of Gerontology and Geriatric Research
ISSN : 2378-9409
Launched : 2014
Journal of Sleep Medicine and Disorders
ISSN : 2379-0822
Launched : 2014
JSM Burns and Trauma
ISSN : 2475-9406
Launched : 2016
Chemical Engineering and Process Techniques
ISSN : 2333-6633
Launched : 2013
Annals of Clinical Cytology and Pathology
ISSN : 2475-9430
Launched : 2014
JSM Allergy and Asthma
ISSN : 2573-1254
Launched : 2016
Journal of Neurological Disorders and Stroke
ISSN : 2334-2307
Launched : 2013
Annals of Sports Medicine and Research
ISSN : 2379-0571
Launched : 2014
JSM Sexual Medicine
ISSN : 2578-3718
Launched : 2016
Annals of Vascular Medicine and Research
ISSN : 2378-9344
Launched : 2014
JSM Biotechnology and Biomedical Engineering
ISSN : 2333-7117
Launched : 2013
Journal of Hematology and Transfusion
ISSN : 2333-6684
Launched : 2013
JSM Environmental Science and Ecology
ISSN : 2333-7141
Launched : 2013
Journal of Cardiology and Clinical Research
ISSN : 2333-6676
Launched : 2013
JSM Nanotechnology and Nanomedicine
ISSN : 2334-1815
Launched : 2013
Journal of Ear, Nose and Throat Disorders
ISSN : 2475-9473
Launched : 2016
JSM Ophthalmology
ISSN : 2333-6447
Launched : 2013
Journal of Pharmacology and Clinical Toxicology
ISSN : 2333-7079
Launched : 2013
Annals of Psychiatry and Mental Health
ISSN : 2374-0124
Launched : 2013
Medical Journal of Obstetrics and Gynecology
ISSN : 2333-6439
Launched : 2013
Annals of Pediatrics and Child Health
ISSN : 2373-9312
Launched : 2013
JSM Clinical Pharmaceutics
ISSN : 2379-9498
Launched : 2014
JSM Foot and Ankle
ISSN : 2475-9112
Launched : 2016
JSM Alzheimer's Disease and Related Dementia
ISSN : 2378-9565
Launched : 2014
Journal of Addiction Medicine and Therapy
ISSN : 2333-665X
Launched : 2013
Journal of Veterinary Medicine and Research
ISSN : 2378-931X
Launched : 2013
Annals of Public Health and Research
ISSN : 2378-9328
Launched : 2014
Annals of Orthopedics and Rheumatology
ISSN : 2373-9290
Launched : 2013
Journal of Clinical Nephrology and Research
ISSN : 2379-0652
Launched : 2014
Annals of Community Medicine and Practice
ISSN : 2475-9465
Launched : 2014
Annals of Biometrics and Biostatistics
ISSN : 2374-0116
Launched : 2013
JSM Clinical Case Reports
ISSN : 2373-9819
Launched : 2013
Journal of Cancer Biology and Research
ISSN : 2373-9436
Launched : 2013
Journal of Surgery and Transplantation Science
ISSN : 2379-0911
Launched : 2013
Journal of Dermatology and Clinical Research
ISSN : 2373-9371
Launched : 2013
JSM Gastroenterology and Hepatology
ISSN : 2373-9487
Launched : 2013
Annals of Nursing and Practice
ISSN : 2379-9501
Launched : 2014
JSM Dentistry
ISSN : 2333-7133
Launched : 2013
Author Information X