Plasma exchange and COVID 19

Abstract

Coronaviruses (CoVs) were first described in the 1960s as a broad subfamily of RNA viruses affecting both human and animals. In humans, infections caused by members of this family primarily involve respiratory and/or gastrointestinal system, with a wide range of clinical manifestations [[1]Su S. Wong G. Shi W. Liu J. Lai A.C.K. Zhou J. et al.Epidemiology, genetic recombination, and pathogenesis of coronaviruses.Trends Microbiol. 2016; 24: 490-502Abstract Full Text Full Text PDF PubMed Scopus (1684) Google Scholar]. Since the beginning of the 21st century, there have emerged two highly pathogenic and, at times, fatal in humans, members of the corona-family: Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) that was the etiological agent of a severe respiratory endemic disease in China during 2002–2003 and Middle East Respiratory Syndrome Coronavirus (MERS-CoV) that was responsible for a similar outbreak in the Middle East during 2012-today [[2]Zhu Z. Lian X. Su X. Wu W. Marraro G.A. Zeng Y. From SARS and MERS to COVID-19: a brief summary and comparison of severe acute respiratory infections caused by three highly pathogenic human coronaviruses.Respir Res. 2020; 21: 224Crossref PubMed Scopus (249) Google Scholar]. By November 2019 a novel viral infection appeared in Wuhan China, caused by a new variant of coronaviruses. The infection was first reported on December 31, 2019, and has since spread rapidly worldwide, leading the World Health Organization (WHO) to officially declare it as a pandemic disease on March 11, 2020 [[3]WHO announces COVID-19 outbreak a pandemic [Internet]. [cited 2022 May 29]. Available from: 〈https://www.euro.who.int/en/health-topics/health-emergencies/coronavirus-covid-19/news/news/2020/3/who-announces-covid-19-outbreak-a-pandemic〉.Google Scholar]. The outbreak of the novel coronavirus disease had enormous impact on global health and created panic, forcing the medical community to search rapidly for answers. As of May 29, 2022, more than 525 million infections of COVID-19 have been reported, including more than 6.28 million deaths globally [[4]W.H.O. Coronavirus (COVID-19) Dashboard [Internet]. [cited 2022 May 29]. Available from: 〈https://covid19.who.int〉.Google Scholar]. These staggering numbers prove undoubtedly that the COVID-19 pandemic constitutes the toughest challenge of the century to mankind, rendering the struggle for effective therapy a global necessity of high priority for all healthcare systems and physicians. Disease is caused by a new betacoronavirus variant called Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), classified to the subfamily of Orthocoronavirinae. It is a single-stranded, positive-sense, enveloped RNA virus, spherical in shape with a diameter 80–220 nm and a crown-like appearance under the microscope [[5]Cascella M. Rajnik M. Aleem A. Dulebohn S.C. Di Napoli R. Features, evaluation, and treatment of coronavirus (COVID-19). In: StatPearls [Internet]. StatPearls Publishing, Treasure Island (FL)2022〈http://www.ncbi.nlm.nih.gov/books/NBK554776/〉Google Scholar]. A common characteristic of RNA viruses is that while adapting to their new human hosts, they are prone to genetic evolution, resulting in development of mutations over time that may differ from ancestral strains. New mutations can potentially change infectiousness and virulence, as well as the virus’ ability to evade adaptive immune responses developed by the host [[6]Walensky R.P. Walke H.T. Fauci A.S. SARS-CoV-2 Variants of Concern in the United States—Challenges and Opportunities.JAMA. 2021; 325: 1037-1038Crossref PubMed Scopus (168) Google Scholar]. Since December 2020, the World Health Organization (WHO) decided to identify in Greek letters all emerging mutations of SARS-CoV-2 and define as a variant of concern (VOC) those variants exhibiting certain features, such as increased transmissibility or virulence, change in clinical presentation and ability to overcome the body’s immune response or decrease effectiveness of current therapeutic strategies [[7]Coronavirus disease (COVID-19): Variants of SARS-COV-2 [Internet]. [cited 2022 Jun 5]. Available from: 〈https://www.who.int/news-room/questions-and-answers/item/coronavirus-disease-(covid-19)-variants-of-sars-cov-2〉.Google Scholar]. On November 2021, the Omicron variant was designated as a VOC and, since then, has rapidly spread and finally dominated across the world. The Omicron mutation is more transmissible than other variants and not susceptible to certain anti-SARS-CoV-2 antibodies used at the time for treatment and prevention of the viral infection [[8]CDC. Omicron Variant: What You Need to Know [Internet]. Centers for Disease Control and Prevention; 2022 [cited 2022 Jun 5]. Available from: 〈https://www.cdc.gov/coronavirus/2019-ncov/variants/omicron-variant.html〉.Google Scholar]. All individuals are at risk for COVID-19 infection and severe disease. However, it was evident from the outbreak of the pandemic, that the most important risk factor for serious illness was the patient’s increasing age (especially ≥ 60 years). In addition, other comorbid medical conditions, such as cardiovascular or chronic respiratory disease, diabetes mellitus, obesity or other immunocompromised conditions lead to a high probability of a serious outcome in COVID-19 infection [[9]Wingert A. Pillay J. Gates M. Guitard S. Rahman S. Beck A. et al.Risk factors for severity of COVID-19: a rapid review to inform vaccine prioritisation in Canada.BMJ Open. 2021; 11e044684Crossref PubMed Scopus (25) Google Scholar]. The median estimated incubation period of the virus infection is 4–5 days from the time of exposure and clinical manifestations vary, ranging from asymptomatic, or mild flu-like symptoms to severe or fulminant and quite often fatal disease. Most analyses of the coronavirus clinical spectrum report a rate of about 81 % for mild disease (defined as no respiratory involvement or mild pneumonia), 14 % for severe (defined as respiratory involvement with dyspnea, oxygen saturation < 93 % and/or lung infiltrations > 50 %) and 5 % for critical illness, which may require Intensive Care Unit (ICU) admission [10Wu Z. McGoogan J.M. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from the Chinese center for disease control and prevention.JAMA. 2020 7; 323: 1239-1242Crossref PubMed Scopus (10387) Google Scholar, 11Stokes E.K. Zambrano L.D. Anderson K.N. Marder E.P. Raz K.M. El Burai Felix S. et al.Coronavirus disease 2019 case surveillance - United States, January 22-May 30, 2020.MMWR Morb Mortal Wkly Rep. 2020; 69: 759-765Crossref PubMed Scopus (0) Google Scholar]. When serious life-threatening disease occurs, the risk of mortality is high and attributed mainly to an excessive immune response typically called the Cytokine Storm or Release Syndrome (CSS), that clinically may result in Acute Respiratory Distress Syndrome (ARDS), sepsis and/or Multiple Organ Failure (MOF). Cytokine Storm Syndrome is a condition of uncontrolled systemic hyper-inflammation caused by cytokine excess leading to multi-organ failure and frequently even death [[12]Review: Cytokine Storm Syndrome: Looking Toward the Precision Medicine Era. [cited 2022 Apr 27]; Available from: 〈https://onlinelibrary.wiley.com/doi/10.1002/art.40071〉.Google Scholar]. The phenomenon is not unique to COVID-19 nor is it observed for the first time. It is an umbrella term that includes pathogenetic pathways of host maladaptive response to infection, observed and described nearly two decades before [[13]Nguyen T.C. Carcillo J.A. Bench-to-bedside review: thrombocytopenia-associated multiple organ failure – a newly appreciated syndrome in the critically ill.Crit Care. 2006; 10: 235Crossref PubMed Scopus (86) Google Scholar]. It was initially recognized in the process of hematopoietic stem cell transplantation as an acute graft-versus-host disease and, subsequently, researchers revealed that it may also occur in various diseases [[14]Favalli E.G. Ingegnoli F. De Lucia O. Cincinelli G. Cimaz R. Caporali R. COVID-19 infection and rheumatoid arthritis: faraway, so close!.Autoimmun Rev. 2020; 19102523Crossref Scopus (288) Google Scholar]. Since the recognition of the syndrome, research on autoimmune disorders, malignancies, sepsis syndrome and specific iatrogenic causes established the concept that an excessive immune response can seriously damage the body, leading rapidly to clinical deterioration, multi-organ failure, and finally, death. Major progress in understanding pathogenetic mechanisms of the Cytokine Storm has been made by studying Hemophagocytic Lymphohistiocytosis (HLH) Familial or Secondary by specific viral infections, typical diseases accompanied by a deficiency in cytotoxic cell function [[15]Esteban Y.M. de Jong J.L.O. Tesher M.S. An overview of hemophagocytic lymphohistiocytosis.Pedia Ann. 2017; 46: e309-e313Crossref PubMed Scopus (48) Google Scholar]. Research has yet to reveal whether the syndrome results from abnormalities in innate or adaptive immunity, although there are clues that suggest problems in both branches [[12]Review: Cytokine Storm Syndrome: Looking Toward the Precision Medicine Era. [cited 2022 Apr 27]; Available from: 〈https://onlinelibrary.wiley.com/doi/10.1002/art.40071〉.Google Scholar]. This overly systemic reactive response is a condition of uncontrolled systemic hyper-inflammation caused by cytokine excess. It involves multiple inciting events mediated by complex interactions of cytokine storm, inflammation, endothelial dysfunction and pathologic coagulation system [16Gyawali B. Ramakrishna K. Dhamoon A.S. Sepsis: the evolution in definition, pathophysiology, and management.SAGE Open Med. 2019; 7 (2050312119835043)Crossref PubMed Google Scholar, 17Chang J.C. Sepsis and septic shock: endothelial molecular pathogenesis associated with vascular microthrombotic disease.Thromb J. 2019; 17: 10Crossref PubMed Scopus (85) Google Scholar]. However, evidence demonstrates, that in the development of Cytokine Storm Syndrome a variety of cytokines are involved, including interleukin 1 (IL-1) family, IL-6, IL-8, IL-10, TNF-α and interferon (IFN-γ). The key pathogenic substance appears to differ depending on the underlying disease. For example, IFN-γ plays the key role in Primary HLH, IL-1β is the key cytokine in Systemic Juvenile Idiopathic Arthritis, whereas in sepsis multiple factors are involved [[16]Gyawali B. Ramakrishna K. Dhamoon A.S. Sepsis: the evolution in definition, pathophysiology, and management.SAGE Open Med. 2019; 7 (2050312119835043)Crossref PubMed Google Scholar]. Therefore, even if the clinical symptoms caused by Cytokine Storm Syndrome exhibit a common pattern, treatment must be individualized. Soon after the onset of the pandemic, it became apparent that critically ill COVID-19 patients died mostly because of the pathological inflammatory response following infection rather than infection itself. This group of patients exhibited elevated levels of a wide range of cytokines, including multiple interleukins (IL-1β, IL-2, IL-6, IL-7, IL-8, IL-10), granulocyte colony-stimulating factor, monocyte chemoattractant protein-1, interferon γ-induced protein 10, tumor necrosis factor-α, macrophage inflammatory protein-1 α and a variety of chemokines [[18]Song P. Li W. Xie J. Hou Y. You C. Cytokine storm induced by SARS-CoV-2.Clin Chim ActaInt J Clin Chem. 2020; 509: 280-287Crossref PubMed Scopus (290) Google Scholar]. This hyperinflammatory condition can induce complement activation, endothelial damage, increased vascular permeability and pathological activation of the coagulation system [[19]Yuki K. Fujiogi M. Koutsogiannaki S. COVID-19 pathophysiology: a review.Clin Immunol Orlando Fla. 2020; 215108427Google Scholar]. Many researchers tried to identify certain biomarkers to differentiate, early in the course of COVID-19 infection, between patients with or without severe disease. According to systematic revisions high levels of C-Reactive protein (CRP), Lactate Dehydrogenase (LDH) and D-dimer, along with decreased T-lymphocyte cells may help physicians predict the progression of coronavirus disease to a critical illness [[20]Yue-liang X. Jiang-lin W. Hui-qin Y. Ge Z. Hongyu D. Wei-jin F. et al.The risk factors for severe patients with COVID-19 in China: a systematic review and meta-analysis.Eur J Inflamm. 2021; 19 (20587392211000890)Crossref Scopus (3) Google Scholar]. In addition, other trials reveal interleukins and in particular high levels of IL-6, IL-8 and IL-10 to be independent risk factors for the severity of COVID-19 pneumonia and correlate with disease progression, ARDS and mortality [21Liu X.Q. Xue S. Xu J.B. Ge H. Mao Q. Xu X.H. et al.Clinical characteristics and related risk factors of disease severity in 101 COVID-19 patients hospitalized in Wuhan, China.Acta Pharm Sin. 2022; 43: 64-75Crossref PubMed Scopus (11) Google Scholar, 22Nagant C. Ponthieux F. Smet J. Dauby N. Doyen V. Besse-Hammer T. et al.A score combining early detection of cytokines accurately predicts COVID-19 severity and intensive care unit transfer.Int J Infect Dis. 2020; 101: 342-345Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar]. Similar phenomena were described during the previous SARS and MERS epidemics, when respiratory involvement correlated with significant high levels of serum cytokines [23Chien J. Hsueh P. Cheng W. Yu C. Yang P. Temporal changes in cytokine/chemokine profiles and pulmonary involvement in severe acute respiratory syndrome.Respirol Carlton Vic. 2006; 11: 715-722Crossref PubMed Scopus (175) Google Scholar, 24Min C.K. Cheon S. Ha N.Y. Sohn K.M. Kim Y. Aigerim A. et al.Comparative and kinetic analysis of viral shedding and immunological responses in MERS patients representing a broad spectrum of disease severity.Sci Rep. 2016; 6: 25359Crossref PubMed Scopus (260) Google Scholar]. Despite the fact that the international medical and political community came together against a threatening enemy and the substantial progress that has been made to better understanding of the pathophysiology of SARS-CoV-2, COVID-19 disease continues to concern mankind having enormous impact of every aspect on everyday living. Worldwide political authorities primarily had to take public health measures, in an effort to prevent and contain the infection from spreading. Subsequently, there was a significant struggle to develop, with unprecedented speed, a preventive anti-viral vaccine. When this happened, the global community rallied on performing a robust vaccination effort worldwide. During this effort and to date, direct treatment for the virus itself was certainly desired and various therapeutic agents were researched. Nowadays, there are a number of anti-viral agents on the market (e.g. molnupiravir, paxlovid, remdesivir) showing some level of effectiveness, as well as anti-SARS-CoV-2 monoclonal antibodies (e.g. bamlanivimab/etesevimab, casirivimab/imdevimab). Nevertheless, currently there is still no specific effective treatment against COVID-19 disease. In addition, due to the above mentioned characteristics of severe COVID-19 infection, coronavirus disease should be defined, understood and consequently managed as a systemic disease. Therefore in severe COVID-19 cases it is essential, in addition to targeting virus activity with existing antiviral agents, to effectively modulate the innate and restore the adaptive immune response, breaking the cycle of coronavirus infection. Consequently, besides antiviral agents and supportive care, management of severe COVID-19 patients might also include efforts to timely control CSS in order to prevent disease deterioration and reduce mortality [18Song P. Li W. Xie J. Hou Y. You C. Cytokine storm induced by SARS-CoV-2.Clin Chim ActaInt J Clin Chem. 2020; 509: 280-287Crossref PubMed Scopus (290) Google Scholar, 25Ye Q. Wang B. Mao J. The pathogenesis and treatment of the `Cytokine Storm’ in COVID-19.J Infect. 2020; 80: 607-613Abstract Full Text Full Text PDF PubMed Scopus (1611) Google Scholar]. In this regard, a variety of therapeutic options were tested and are still available, such as anti-inflammatory drugs (e.g. dexamethasone), immunomodulators agents (e.g. baricitinib, tocilizumab) and cytokine antagonists [25Ye Q. Wang B. Mao J. The pathogenesis and treatment of the `Cytokine Storm’ in COVID-19.J Infect. 2020; 80: 607-613Abstract Full Text Full Text PDF PubMed Scopus (1611) Google Scholar, 26Reeves H.M. Winters J.L. The mechanisms of action of plasma exchange.Br J Haematol. 2014; 164: 342-351Crossref PubMed Scopus (141) Google Scholar]. Most of these potential complementary therapeutic options often need time (days or weeks), in order to remove pro-inflammatory factors and exhibit their beneficial action which, in critically ill patients, is always difficult to obtain. Blood purification methods and notably therapeutic plasma exchange have been included as possible therapeutic options targeting this systemic hyperinflammation status, since they are unique treatment approaches that act instantly at multiple levels of this cascade phenomenon [[27]Busund R. Koukline V. Utrobin U. Nedashkovsky E. Plasma exchange in severe sepsis and septic shock: a prospective, randomised, controlled trial.Intensive Care Med. 2002 1; 28: 1434-1439Crossref PubMed Scopus (225) Google Scholar]. Therapeutic Plasma Exchange, is an extracorporeal blood purification method designed for the removal of large-molecular weight substances (MW > 15000 Da), reversing pathological processes related to their presence [[28]Kaplan A.A. Therapeutic plasma exchange: a technical and operational review: therapeutic Plasma exchange.J Clin Apher. 2013; 28: 3-10Crossref PubMed Scopus (80) Google Scholar]. It’s defined as “a therapeutic procedure in which the blood of the patient is passed through a medical device which separates out plasma from other blood components. Plasma is removed and replaced with a replacement solution potentially a colloid solution (e.g. human albumin and/or plasma) or a combination of crystalloid/colloid” [[29]Padmanabhan A. Connelly-Smith L. Aqui N. Balogun R.A. Klingel R. Meyer E. et al.Guidelines on the use of therapeutic apheresis in clinical practice - evidence-based approach from the writing committee of the american society for apheresis: the eighth special issue.J Clin Apher. 2019; 34: 171-354Crossref PubMed Scopus (544) Google Scholar]. The method was developed by Dr Dau in the 1970s and was first used to control severe hyperviscosity related to multiple myeloma. Nowadays, it is often used as a primary or adjunct therapy to treat severe and critical diseases mediated by pathogenic antibodies, immune complexes, cryoglobulins, paraproteins, endotoxins, lipoproteins and inflammatory mediators like cytokines. Consequently, TPE is usually applied to manage critical diseases such as Thrombotic Microangiopathies, Thrombotic Thrombocytopenic Purpura, Guillain-Barre Syndrome, Myasthenia Gravis, Glomerulonephritis and others [[29]Padmanabhan A. Connelly-Smith L. Aqui N. Balogun R.A. Klingel R. Meyer E. et al.Guidelines on the use of therapeutic apheresis in clinical practice - evidence-based approach from the writing committee of the american society for apheresis: the eighth special issue.J Clin Apher. 2019; 34: 171-354Crossref PubMed Scopus (544) Google Scholar]. The American Society for Apheresis (ASFA) regularly publishes updated evidence-based guidelines, the most recent edition in 2019, supporting indications for applying TPE [[29]Padmanabhan A. Connelly-Smith L. Aqui N. Balogun R.A. Klingel R. Meyer E. et al.Guidelines on the use of therapeutic apheresis in clinical practice - evidence-based approach from the writing committee of the american society for apheresis: the eighth special issue.J Clin Apher. 2019; 34: 171-354Crossref PubMed Scopus (544) Google Scholar]. These guidelines contain all the diseases for which there are adequate evidence in the literature to support or refute the use of apheresis procedures. For plasma exchange to be a rational treatment of choice, at least one of the three following conditions concerning the substance to be removed should be fulfilled: sufficiently large substance mostly dissolved in the intravascular compartment, with a comparatively prolonged half-life and acutely toxic and/or resistant to conventional therapy [[28]Kaplan A.A. Therapeutic plasma exchange: a technical and operational review: therapeutic Plasma exchange.J Clin Apher. 2013; 28: 3-10Crossref PubMed Scopus (80) Google Scholar]. TPE is one of the most common therapeutic apheresis procedures performed globally [[30]Stegmayr B. Mörtzell Henriksson M. Newman E. Witt V. Derfler K. Leitner G. et al.Distribution of indications and procedures within the framework of centers participating in the WAA apheresis registry.Transfus Apher Sci J World Apher Assoc J Eur Soc Haemapheresis. 2017; 56: 71-74Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar] by either centrifugation or membrane filtration methods. The type of anticoagulant selected to achieve the extracorporeal circuit depends on the apheresis device, with citrate solutions most commonly used. According to numerous studies, exchange of 1–1.5-plasma volume is considered sufficient to achieve adequate substance removal without high risk for procedural complications. Most frequently the replacement fluids used for the method are 5 % albumin, normal saline, a combination of the above or Fresh Frozen Plasma (FFP). The time interval between sessions and the number of sessions required are generally based on the underlying disease and its clinical course. Most of the procedure’s adverse effects are mild and easily resolved, rendering the method relatively safe [[31]Winters J.L. Plasma exchange: concepts, mechanisms, and an overview of the American Society for Apheresis guidelines.Hematol Am Soc Hematol Educ Program. 2012; 2012: 7-12Crossref PubMed Google Scholar]. In the course of using TPE, the procedure was applied in diseases with similarities to COVID-19 infection, such as sepsis due to various causes, influenza infection and Secondary Hemophagocytic Lymphohistiocytosis (HLH). Therapeutic plasma exchange has been used as an alternative treatment in severe sepsis for several decades, with conflicting results. Although there is no clear evidence to recommend plasma exchange in severe sepsis, there are a few studies supporting the role of TPE in this entity, suggesting improvement in hemodynamic stability and coagulation disbalance in septic patients receiving the treatment [32Rimmer E. Houston B.L. Kumar A. Abou-Setta A.M. Friesen C. Marshall J.C. et al.The efficacy and safety of plasma exchange in patients with sepsis and septic shock: a systematic review and meta-analysis.Crit Care. 2014; 18: 699Crossref PubMed Scopus (102) Google Scholar, 33Knaup H. Stahl K. Schmidt B.M.W. Idowu T.O. Busch M. Wiesner O. 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 Lond Engl. 2018; 22: 285Crossref PubMed Scopus (77) Google Scholar, 34Stahl K. Schmidt J.J. Seeliger B. Schmidt B.M.W. Welte T. Haller H. et al.Effect of therapeutic plasma exchange on endothelial activation and coagulation-related parameters in septic shock.Crit Care Lond Engl. 2020; 24: 71Crossref PubMed Scopus (24) Google Scholar]. Based on this growing evidence and currently available clinical data, the American Society for Apheresis (ASFA) in the eight special issue offers plasma exchange a category III, 2B recommendation for sepsis with multiple organ failure (MOF). This is an overall weak recommendation, meaning that currently the peer-reviewed evidence does not establish the optimum role of plasma exchange in these patients [[29]Padmanabhan A. Connelly-Smith L. Aqui N. Balogun R.A. Klingel R. Meyer E. et al.Guidelines on the use of therapeutic apheresis in clinical practice - evidence-based approach from the writing committee of the american society for apheresis: the eighth special issue.J Clin Apher. 2019; 34: 171-354Crossref PubMed Scopus (544) Google Scholar]. Therefore, decision-making for patients with infection and MOF should be individualized and it remains a challenge for every clinician to identify those patients most likely to benefit from the method and apply it on a case-to-case basis as an adjunct therapy. Furthermore, there are several studies that support the helpful role of therapeutic plasma exchange in severe cases of influenza infection [35Patel P. Nandwani V. Vanchiere J. Conrad S.A. Scott L.K. Use of therapeutic plasma exchange as a rescue therapy in 2009 pH1N1 influenza A--an associated respiratory failure and hemodynamic shock.Pedia Crit Care Med J Soc Crit Care Med World Fed Pedia Intensive Crit Care Soc. 2011; 12: e87-e89Crossref PubMed Scopus (49) Google Scholar, 36Kawashima H. Togashi T. Yamanaka G. Nakajima M. Nagai M. Aritaki K. et al.Efficacy of plasma exchange and methylprednisolone pulse therapy on influenza-associated encephalopathy.J Infect. 2005; 51: E53-E56Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar]. For example, during the H1N1 influenza pandemic, TPE was performed as a rescue therapy on three pediatric patients with ARDS on mechanical ventilation and hemodynamic instability. All of them received three TPE sessions on consecutive days, with no reported side effects and after that dramatically improved the organ dysfunction score and survived with good functional recovery [[35]Patel P. Nandwani V. Vanchiere J. Conrad S.A. Scott L.K. Use of therapeutic plasma exchange as a rescue therapy in 2009 pH1N1 influenza A--an associated respiratory failure and hemodynamic shock.Pedia Crit Care Med J Soc Crit Care Med World Fed Pedia Intensive Crit Care Soc. 2011; 12: e87-e89Crossref PubMed Scopus (49) Google Scholar]. Finally, Hemophagocytic Lymphohistiocytosis constitutes a typical disease accompanied by an hypercytokinemic status, characterized by excessive elaboration of IL-2, IL-7, TNF and macrophage inflammatory protein 1-alpha, at times fatal. Although HLH is not included in the indications for applying TPE, a few studies have suggested a promising role for the method [37Demirkol D. Yildizdas D. Bayrakci B. Karapinar B. Kendirli T. Koroglu T.F. et al.Hyperferritinemia in the critically ill child with secondary hemophagocytic lymphohistiocytosis/sepsis/multiple organ dysfunction syndrome/macrophage activation syndrome: what is the treatment?.Crit Care. 2012; 16: R52Crossref PubMed Scopus (122) Google Scholar, 38Bosnak M. Erdogan S. Aktekin E.H. Bay A. Therapeutic plasma exchange in primary hemophagocytic lymphohistiocytosis: Reports of two cases and a review of the literature.Transfus Apher Sci. 2016; 55: 353-356Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar, 39Lorenz G. Schul L. Schraml F. Riedhammer K.M. Einwächter H. Verbeek M. et al.Adult macrophage activation syndrome-haemophagocytic lymphohistiocytosis: ‘of plasma exchange and immunosuppressive escalation strategies’ - a single centre reflection.Lupus. 2020; 29: 324-333Crossref PubMed Scopus (10) Google Scholar]. The scientific community eagerly awaits the discovery of effective and specific antiviruses agents. Until then, a variety of immunosuppressive measures on the cytokine storm syndrome and coagulopathy which accompany serious COVID-19 cases, are under investigation, in order to reduce the likelihood of progressive organ damage. Although currently used anti-inflammatory and immunomodulator agents have shown some therapeutic benefit, complementary approaches for critically ill COVID-19 patients with ARDS and MOF are needed in order to save more lives. Despite the lack of solid evidence for the usefulness of plasma exchange in severe infectious conditions including sepsis, practical experience with the application of the method in various clinical diseases provides clues for using TPE as an alternative treatment in serious covid-19 cases. Several researchers considered TPE not only as a rescue therapy, but also as an alternative treatment option highly justified to apply earlier in the clinical course of serious coronavirus cases with signs of rapid deterioration and features of Cytokine storm Syndrome [[40]Keith P. Day M. Perkins L. Moyer L. Hewitt K. Wells A. 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: 128Crossref PubMed Scopus (97) Google Scholar]. As soon as this hyperinflammation status in severe coronavirus infections was understood, it became apparent that removing large amounts of cytokines and blocking the development of CSS before substantial endothelial or end-organ damage occurred, were potentially beneficial therapeutic options. Therapeutic plasma exchange is a procedure that can reduce plasma components, such as antibodies, proteins and inflammatory mediators, and thus act as an adjunctive therapy option for the treatment of severe COVID-19 infections. In this regard, there are various strengths that could support the rational of TPE being a non-pharmacological treatment strategy for more effective management of critically ill coronavirus patients, although to date few high-quality studies have evaluated the role of plasma exchange in severe COVID-19 management. At least four mechanisms of TPE action support the role of the method in modifying the course and outcome of coronavirus disease. First and foremost, plasma exchange has a direct clinical effect, through direct removal of inflammatory cytokines, especially in rapidly deteriorating cases of CSS, attenuating the phenomenon thus giving the required time for other possible therapeutic