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© 2020 Journal of Clinical and Scientific Research | Published by Wolters Kluwer – Medknow for Sri Venkateswara Institute of Medical Sciences, Tirupati 37 Immune dysregulation in COVID-19 and its therapeutic implications T. Praveen, D. Desai, M. Soneja, N. Wig Department of Medicine, All India Instute of Medical Sciences, New Delhi, India Review Article INTRODUCTION The World Health Organization declared severe acute respiratory syndrome (SARS) coronavirus‑2 (SARS‑CoV‑2) disease‑2019 (COVID‑19) to be a pandemic in March 2020. Several countries have been affected by COVID‑19 since the initial outbreak in the Hubei province of China, resulting in case fatality rates of 2%–5%. [1] Besides the direct cytopathic effects of the virus, immune dysregulation associated with viral infection also contributes to mortality. [2] The elderly and patients with comorbidities are more susceptible to develop severe disease. The underlying immunological abnormalities could be the possible reason for severe disease in this population. In this review, we discuss the immune response in SARS‑CoV‑2, the mechanism of immunodysregulation as well as potential therapeutic targets for immunomodulatory therapies. OVERVIEW OF IMMUNE RESPONSE IN SEVERE ACUTE RESPIRATORY SYNDROME CORONAVIRUS‑2 INFECTION After initial entry of the virus into the host, natural killer (NK) cells, cluster of differentiation 8 (CD8+) T‑cells as well as interferons (IFNs) act to eliminate the infection. [3] Therefore, defects in cytotoxic cells or delayed IFN response (especially in elderly and with comorbidities) may predispose to severe disease. Once the infection has been established, IFNs can be detrimental by causing excessive cytokine release by the hosT‑cells. Many countries in the world are affected by severe acute respiratory syndrome (SARS) coronavirus-2 (SARS-CoV-2) disease-2019 (COVID-19) pandemic. Approximately 80% of the cases are mild symptomatic, 15% are severe and approximately 5% are critically ill. The mortality among severe and critically ill patients ranges from 17% to 78%. Elderly and patients with comorbidities have higher chances of progression to severe disease and subsequent mortality. There are no proven antiviral agents available for the management of COVID-19. Besides the viral cytopathic effects, dysregulation in immunity also contributes substantially to the pathogenesis. Treatment with immunomodulatory agents such as interleukin-6 blockers, glucocorticoids and mesenchymal stem cell therapy has been observed to be potentially beneficial. In this review, the immune response in SARS-CoV-2, the mechanism of immune dysregulation as well as potential therapeutic targets for immunomodulatory therapies are discussed. Keywords: Coronavirus disease-2019, immune dysregulation, immunomodulatory therapy, SARS-CoV-2 Access this article online Quick Response Code: Website: www.jcsr.co.in DOI: 10.4103/JCSR.JCSR_40_20 Address for correspondence: Dr N. Wig, Professor and Head, Department of Medicine, All India Instute of Medical Sciences, New Delhi 110 029, India. E-mail: [email protected] Submied: 20-Apr-2020   Accepted: 26-Apr-2020   Published: 02-Jun-2020 This is an open access journal, and arcles are distributed under the terms of the Creave Commons Aribuon-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creaons are licensed under the idencal terms. For reprints contact: [email protected] How to cite this article: Praveen T, Desai D, Soneja M, Wig N. Immune dysregulation in COVID-19 and its therapeutic implications. J Clin Sci Res 2020;9:37-41. Abstract [Downloaded free from http://www.jcsr.co.in on Friday, June 5, 2020, IP: 10.232.74.26]
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Immune dysregulation in COVID‑19 and its therapeutic implications

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© 2020 Journal of Clinical and Scientific Research | Published by Wolters Kluwer – Medknow for Sri Venkateswara Institute of Medical Sciences, Tirupati 37
Immune dysregulation in COVID-19 and its therapeutic implications
T. Praveen, D. Desai, M. Soneja, N. Wig Department of Medicine, All India Institute of Medical Sciences, New Delhi, India
Review Article
INTRODUCTION
The World Health Organization declared severe acute respiratory syndrome (SARS) coronavirus2 (SARSCoV2) disease2019 (COVID19) to be a pandemic in March 2020. Several countries have been affected by COVID19 since the initial outbreak in the Hubei province of China, resulting in case fatality rates of 2%–5%.[1] Besides the direct cytopathic effects of the virus, immune dysregulation associated with viral infection also contributes to mortality.[2] The elderly and patients with comorbidities are more susceptible to develop severe disease. The underlying immunological abnormalities could be the possible reason for severe disease in this population. In this review, we discuss the immune response in SARSCoV2, the mechanism of
immunodysregulation as well as potential therapeutic targets for immunomodulatory therapies.
OVERVIEW OF IMMUNE RESPONSE IN SEVERE ACUTE RESPIRATORY SYNDROME CORONAVIRUS2 INFECTION
After initial entry of the virus into the host, natural killer (NK) cells, cluster of differentiation 8 (CD8+) Tcells as well as interferons (IFNs) act to eliminate the infection.[3] Therefore, defects in cytotoxic cells or delayed IFN response (especially in elderly and with comorbidities) may predispose to severe disease. Once the infection has been established, IFNs can be detrimental by causing excessive cytokine release by the hosTcells.
Many countries in the world are affected by severe acute respiratory syndrome (SARS) coronavirus-2 (SARS-CoV-2) disease-2019 (COVID-19) pandemic. Approximately 80% of the cases are mild symptomatic, 15% are severe and approximately 5% are critically ill. The mortality among severe and critically ill patients ranges from 17% to 78%. Elderly and patients with comorbidities have higher chances of progression to severe disease and subsequent mortality. There are no proven antiviral agents available for the management of COVID-19. Besides the viral cytopathic effects, dysregulation in immunity also contributes substantially to the pathogenesis. Treatment with immunomodulatory agents such as interleukin-6 blockers, glucocorticoids and mesenchymal stem cell therapy has been observed to be potentially beneficial. In this review, the immune response in SARS-CoV-2, the mechanism of immune dysregulation as well as potential therapeutic targets for immunomodulatory therapies are discussed.
Keywords: Coronavirus disease-2019, immune dysregulation, immunomodulatory therapy, SARS-CoV-2
Access this article online Quick Response Code:
Website: www.jcsr.co.in
DOI: 10.4103/JCSR.JCSR_40_20
Address for correspondence: Dr N. Wig, Professor and Head, Department of Medicine, All India Institute of Medical Sciences, New Delhi 110 029, India. E-mail: [email protected] Submitted: 20-Apr-2020 Accepted: 26-Apr-2020 Published: 02-Jun-2020
This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.
For reprints contact: [email protected]
How to cite this article: Praveen T, Desai D, Soneja M, Wig N. Immune dysregulation in COVID-19 and its therapeutic implications. J Clin Sci Res 2020;9:37-41.
Abstract
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Praveen, et al.: Immune dysregulation in COVID19
38 Journal of Clinical and Scientific Research | Volume 9 | Issue 1 | January-March 2020
Thelper cell 17 response Transforming growth factorbeta and IL1beta lead to increased differentiation of naïve Tcells into Thelper cell 17 (Th17) cells. Th17 cell differentiation is associated with increased release of IL23 and IL17. IL23 is an essential cytokine for Th17 survival and proliferation, whereas IL17 is a pleomorphic cytokine with multiple actions on different targets. IL17 receptors are present on epithelial cells, endothelial cells, macrophages and chondrocytes. Stimulation of IL17 receptors leads to further production of IL6, IL1beta, metalloproteinases, TNFalpha, nitric oxide and granulocyte colonystimulating factor (GCSF). This leads to recruitment of more neutrophils into the lung, capillary leak and subsequent lung damage.[13]
Increased Th1 response IL12 released by dendritic cells leads to increased differentiation of naïve Tcells into T helper 1 (Th1) cells. IL2 and IFNgamma released by Th1 cells stimulate macrophages.[10] Loss of inhibition of activated macrophages by NKcells and CD8+ Tcells leads to persistent activation of macrophages and subsequent HLH.
Interleukin6 IL6 acts through membranebound receptors (on hepatocytes, macrophages and Tcells) and through soluble IL6 receptors (transsignalling). During inflammation, A disintegrin and metalloproteinase 17 (ADAM17) enzyme cleaves cellbound IL6 receptors and releases them into the circulation. These soluble IL6 receptors bind to IL6 and amplify the inflammatory response by acting on multiple cell types via membranebound glycoprotein 130 (GP130). This results in increased recruitment of mononuclear cells, inhibition of Tcell apoptosis and decreased Treg differentiation and ultimately leads to a cytokine storm.[14]
After a prolonged hyperinflammatory phase, Tcells switch to suppressor phenotype with increased expression of programmed cell death protein 1 (PD1), cytotoxic Tlymphocyteassociated protein1 (CTLA1), B and Tlymphocyte attenuator as well as increased differentiation into Treg cells and increased IL10. This induces a state of immune paralysis with increased susceptible to hospital acquired infections. Patients with advanced age and comorbid conditions are predisposed to immunoparalysis, which should be kept in mind before treating them with immunosuppressants.[15]
The key pathogenetic concepts underlying immune dysregulation in SARSCOV2 infection are summarised in Figures 13.
This phenomenon has been demonstrated in animal models of Middle East respiratory syndrome (MERS) virus infection[4] and substantiated by the limited success of IFN therapy in patients who had already developed acute respiratory distress syndrome (ARDS).[5] Besides destroying viralinfected cells, NKcells and CD8+ Tcells are also important in inhibiting activated macrophages. SARSCoV2 is associated with decrease in both number and function of NKcells and CD8 Tcells, leading to delay in viral clearance as well as immune dysregulation.[6] Uninhibited activated macrophages can lead to secondary haemophagocytic–lymphohistiocytosis (HLH) syndrome.[7] It is noteworthy that bats, despite being reservoirs of many deadly viruses, are seldom affected by these viruses. A dampened neuronal apoptosis inhibitory protein, CIITA (major histocompatibility complex [MHC] class II transcription activator), HETE (incompatibility locus protein from Podospora anserine) and telomeraseassociated protein (TP1) (NACHT); leucinerich repeat; pyrin [PYD]) containing protein3 (NLRP3) inflammasome response is one of the proposed reasons for this.[8] A variety of stress signals such as extracellular adenosine triphosphate, potassium efflux, reactive oxygen species, viral RNA and cathepsins can lead to the activation of NLRP3 pathway. This leads to the release of proinflammatory cytokines interleukin (IL)1beta and IL18 and pyroptosis by activation of caspase1. Vitamin C dampens the NLRP3 pathway indirectly by reducing oxidative stress and, thus, has the potential to mitigate tissue damage.[9]
IMMUNE DYSREGULATION IN SEVERE ACUTE RESPIRATORY CORONAVIRUS2 INFECTION
Immune dysregulation in SARSCoV2 infection is characterised by lymphopenia, increased neutrophil– lymphocyte ratio, decreased NKcells and CD8+ Tcell activity, decreased regulatory Tcells and increased CD4+ to CD8+ ratio.[10] Failure to eliminate virus due to inappropriate IFN response and decreased number and function of CD8+ and NKcells lead to virus induced tissue damage. The virus enters cells using the angiotensinconverting enzyme2 (ACE2) receptors. This subsequently leads to downregulation of ACE2 receptor expression on the infected cells. This tilts the homeostatic balance towards angiotensin2mediated effects, causing more inflammation and capillary leak.[11] Further release of antigens from damaged cells (DAMPS) promotes transcription of type1 IFNs, release of inflammatory cytokines (IL1beta, IL6, IL18, tumour necrosis factoralpha [TNFalpha] and IL12) and activation of inflammasomes leading to tissue damage.[12]
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Journal of Clinical and Scientific Research | Volume 9 | Issue 1 | January-March 2020 39
IMMUNOMODULATING AGENTS IN THE TREATMENT OF SEVERE ACUTE RESPIRATORY CORONAVIRUS2 INFECTION
The immune response to SARSCoV2 occurs in two phases (Table 1). The initial immune response is important in eliminating the virus.[9] However, once the infection is established, further immune response leads to tissue damage. Antiviral drug (remdesivir), hydroxychloroquine and IFN therapy can be considered early in the disease, whereas immunomodulatory therapy should be considered in the hyperinflammatory phase.
Table 1: Phases of immune response in severe acute respiratory syndrome coronavirus-2 infection Asymptomatic mild infection
Hyper-inflammatory response
Immune paralysis
Prolonged hospital stay Hospital acquired/ iatrogenic infections
HLH=Haemophagocytic lymphohistiocytosis
Corticosteroids Treatment with corticosteroids was associated with adverse events and increased mortality in SARS and MERS, thus raising concerns regarding their role in the management of COVID19 ARDS. However, the studies conducted in SARS and MERS were retrospective with significant indication bias and had used very high doses early in the disease. This resulted in significant side effects such as avascular necrosis of femur and psychosis.[16] There are data, suggesting that the use of steroids in moderate doses for short durations in early ARDS of other aetiologies may have mortality benefit.[17] Methylprednisolone given at doses of 1–2 mg/kg body weight for 5–7 days has shown clinical benefit in early ARDS due to COVID19.[18,19]
Tocilizumab Tocilizumab, IL6 receptor blocker, has been used in COVID19 with some success. Blocking IL6 receptors can increase the IL6 levels initially as soluble IL6 receptors are blocked. Even though the halflife of tocilizumab is 10 days, repeated doses of tocilizumab may be required if soluble IL6R is very high.[20,21] Patients should be monitored for the development of neutropenia and for hospitalacquired extracellular bacterial and fungal infections.
Granulocyte–monocyte colonystimulating factor blockers Granulocyte–monocyte CSF (GMCSF) acts both upstream and downstream of IL6 by increasing production of IL6 from cells and recruitment of neutrophils and macrophages. GMCSF blockers in hyperinflammatory phase can be
DC
Th2
Th1
Th17
Treg
IL-12
IL-23
IL-6
IL-17
Figure 2:  Differentiation  of  T  nave  cells  into  different  subsets  DC  = Dendritic  cell;  IL  =  Interleukin;  Treg  = Regulatory  T-cells;  TH = Helper T-cells; TGF-β = Transforming growth factorbeta
Figure 1: Pathophysiology of tissue damage due to direct viral cytopathic and hyper-inflammatory response.  IL = Interleukin; NK-cells = Natural killer cell; CD = Cluster  designation; PD1 = Programmed cell death protein ligand1; CTAL4 = Cytotoxic Tlymphocyte associated protein4
NK-cells and CD8+ T-cells
Th1 cells Tissue damage
Figure 3:  Overlap  between  cytokine  storm  and  secondary  HLH IL = Interleukin; IFN-gamma = Interferon-gamma; Th = T-helper cells; APC =  Antigen-presenting cell; HLH = Haemophagocytic-lymphohistiocytosis
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40 Journal of Clinical and Scientific Research | Volume 9 | Issue 1 | January-March 2020
useful, but this can lead to increased differentiation to plasmacytoid dendritic cells and excessive type 1 IFNs.[22]
Mesenchymal stem cell therapy Mesenchymal stem cells (MSCs) are multipotent stem cells with the ability to differentiate into multiple cell types, have a broad range of immunomodulatory actions and are able to home into areas of inflammation. Since they express only minimal MHC Class 1 and no MHC Class 2 and costimulatory molecules, these cells are not recognised as foreign by the host immune system.[23] Their immunomodulatory action is mediated by decreased dendritic cell activity, dampened Th1 and Th17 immunity as well as increased Treg cells and IL10 levels. MSCs have been used with significant benefits in a small group of patients with ARDS due to H7N9.[24] Initial reports of their use in COVID19 have been promising.[25]
Extracorporeal cytokine removal therapy CytoSorb is a filter containing beads that adsorb cytokines whose molecular weights range from 10 to 60 KDa. Thus, CytoSorb adsorbs most of the inflammatory cytokines when sparing albumin. CytoSorb does not remove bacterial endotoxins, complement proteins or antigen–antibody complexes.[26] The oXiris membrane is an AN69 membrane coated with a positively charged polycationic polymer polyethyleneimine and a layer of heparin grafting and is used in continuous venovenous haemodialysis, continuous venovenous haemodialysis and haemodiafiltration. The oXiris membrane adsorbs cytokines with molecular weights <35 KDa (AN69 membrane) as well as endotoxin (polycationic polymer polyethyleneimine). It is biologically plausible that both CytoSorb and oXiris membrane may have efficacy in the treatment of cytokine storm via cytokine removal. However, evidence with these techniques is limited to anecdotal reports and few case series in sepsis.[27] Therapeutic plasma exchange, besides removing cytokines, antigen–antibody complex and endotoxins, has an additional advantage of replacing factors such as complement, A disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13), immunoglobulins and coagulation factors. Theoretically, the centrifugal technique may be best suited for this indication due to lower blood flow rates (safer in haemodynamically unstable patients) and low risk of hypersensitivity (as no filters are used). There is extensive experience with plasma exchange for variety of indications and it has been used successfully in sepsis, cytokine storm and secondary HLH.[2830] These details are shown in Table 2.
The combination of effective antiviral drugs early in the course of the disease with immunomodulatory therapy in the hyperimmune phase of the disease may be a suitable approach in the management of COVID19 illness. Early immunosuppression may prolong viral shedding, whereas prolonged immunosuppression may cause a state of immunoparalysis and subsequent opportunistic infections. Further research should be directed to identify biological markers for early recognition of hyperimmune phase and immunoparalysis. Studies on T cell subsets, cytokine profiling and expression of immune checkpoints (programmed cell PD1, programmed cell death protein ligand1 and CTLA4) help in optimisation of treatment.
Financial support and sponsorship Nil.
Conflicts of interest There are no conflicts of interest.
REFERENCES
1. Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med 2020;382:170820.
2. Qin C, Zhou L, Hu Z, Zhang S, Yang S, Tao Y, et al. Dysregulation of immune response in patients with COVID19 in Wuhan, China. Clin Infect Dis 2020. pii: ciaa248. doi: 10.1093/cid/ciaa248. [Epub ahead of print].
3. Schmidt ME, Varga SM. The CD8 T cell response to respiratory virus infections. Front Immunol 2018;9:678.
4. Channappanavar R, Fehr AR, Zheng J, WohlfordLenane C, Abrahante JE, Mack M, et al. IFNI response timing relative to virus replication determines MERS coronavirus infection outcomes. J Clin Invest 2019;130:362539.
5. Ranieri VM, Pettilä V, Karvonen MK, Jalkanen J, Nightingale P, Brealey D, et al. Effect of intravenous interferon β1a on death and days free from mechanical ventilation among patients with moderate to severe acute respiratory distress syndrome: A randomized clinical trial. JAMA 2020;323:72533.
6. Sullivan KE, Delaat CA, Douglas SD, Filipovich AH. Defective natural killer cell function in patients with hemophagocytic lymphohistiocytosis and in first degree relatives. Pediatr Res 1998;44:4658.
7. Popko K, Górska E. The role of natural killer cells in pathogenesis of autoimmune diseases. CentEur J Immunol 2015;40:4706.
8. Ahn M, Anderson DE, Zhang Q, Tan CW, Lim BL, Luko K, et al. Dampened NLRP3mediated inflammation in bats and implications
Table 2: Comparison of different methods of extracorporeal cytokine removal Blood component
CytoSorb oXiris Plasma exchange
Not removed Not removed Removed
Cytokines Removed Removed Removed Endotoxins Not removed Removed Removed IL6 R Removed Not removed Removed ADAM17 Not removed Not removed Removed
IL=Interleukin; ADAM17=A disintegrin and metalloproteinase 17
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Praveen, et al.: Immune dysregulation in COVID19
Journal of Clinical and Scientific Research | Volume 9 | Issue 1 | January-March 2020 41
for a special viral reservoir host. Nat Microbiol 2019;4:78999. 9. Sang X, Wang H, Chen Y, Guo Q, Lu A, Zhu X. Vitamin C inhibits the
activation of the NLRP3 inflammasome by scavenging mitochondrial ROS VL 2. Inflammasome 2016;2:139.
10. Shi Y, Wang Y, Shao C, Huang J, Gan J, Huang X, et al. COVID19 infection: The perspectives on immune responses. Cell Death Differ 2020;27:14514.
11. RicoMesa JS, White A, Anderson AS. Outcomes inpPatients with COVID19 infection taking ACEI/ARB. Curr Cardiol Rep 2020;22:31.
12. Land WG. The role of damageassociated molecular patterns in human diseases. Sultan Qaboos Univ Med J 2015;15:e921.
13. Wu D, Yang XO. TH17 responses in cytokine storm of COVID19: An emerging target of JAK2 inhibitor Fedratinib. Microbiol Immunol Infect 2020. pii: S16841182 (20) 300657.
14. Cooms EA, Haghbayan H. Interleukin6 in COVID19: A Systematic Review and MetaAnalysis. Available from: https://www.medrxiv. org/content/10.1101/2020.03.30.20048058v1. [Last accessed on 2020 Apr 16].
15. Hamers L, Kox M, Pickkers P. Sepsisinduced immunoparalysis: Mechanisms, markers, and treatment options. Minerva Anestesiol 2015;81:42639.
16. Hui DS. Systemic corticosteroid therapy may delay viral clearance in patients with Middle East respiratory syndrome coronavirus infection. Am J Respir Crit Care Med 2018;197:7001.
17. Villar J, Ferrando C, Martinez D, Amobros A, Munoz T, Soler JA, et al. Dexamethasone treatment for the acute respiratory distress syndrome: A multicentre, randomised controlled trial. Lancet Respir Med 2020;8:26776.
18. Zha L, Li S, Pan L, Tefsen B, Li Y, French N, et al. Corticosteroid treatment of patients with coronavirus disease 2019 (COVID19). Med J Aust 2020. [Epub ahead of print].
19. Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirusinfected pneumonia in Wuhan, China. JAMA 2020;323:10619.
20. Xu X, Han M, Li T, Sun W, Wang D, Fu B, et al. Effective treatment of severe COVID19 patients with tocilizumab. Proc Natl Acad Sci U S A 2020. pii: 202005615. doi: 10.1073/pnas.2005615117. [Epub ahead of print].
21. FDA Approves Phase III Clinical Trial of Tocilizumab for COVID19
Pneumonia Cancer Network. Available from: https://www. cancernetwork. com/news/fdaapprovesphaseiiiclinicaltrialtocil izumabcovid19pneumonia. [Last accessed on 2020 Mar 31].
22. Conti L, Gessani S. GMCSF in the generation of dendritic cells from human blood monocyte precursors: Recent advances. Immunobiology 2008;213:85970.
23. Matthay MA. Therapeutic potential of mesenchymal stromal cells for acute respiratory distress syndrome. Ann Am Thorac Soc 2015;12 Suppl 1:S547.
24. Chen J, Hu C, Chen L, Tang L, Zhu Y, Xu X, et al. Clinical Study of Mesenchymal stem cell treatment for acute respiratory distress syndrome induced by epidemic influenza A (H7N9) Infection: A hint for COVID19 treatment. Engineering Engineering [Internet] 2020 Feb 28 [cited 2020 Apr 23]; Available from: http://www.sciencedirect. com/science/article/pii/S2095809920300370. [Last accessed on 2020 Apr 23].
25. Leng Z, Zhu R, Hou W, Feng Y, Yang Y, Han Q, et al. Transplantation of ACE2 mesenchymal stem cells improves the outcome of patients with COVID19 pneumonia. Aging Dis 2020;11:21628.
26. Singh YP, Chhabra SC, Lashkari K, Taneja A, Garg A, Chandra A, et al. Hemoadsorption by extracorporeal cytokine adsorption therapy (CytoSorb®) in the management of septic shock: A retrospective observational study. Int J Artif Organs 2019;391398819891739.
27. Schwindenhammer V, Girardot T, Chaulier K, Grégoire A, Monard C, Huriaux L, et al. Xiris® use in septic shock: Experience of two French centres. Blood Purif 2019;47 Suppl 3:17.
28. Knaup H, Stahl K, Schmidt BMW, Idowu TO, Busch M, Wiesner O, et al. Early therapeutic plasma exchange in septic shock: A prospective openlabel nonrandomized pilot study focusing on safety, hemodynamics, vascular barrier function, and biologic markers. Crit Care 2018;22:285.
29. Rimmer E, Houston BL, Kumar A, AbouSetta AM, Friesen C, Marshall JC, et al. The efficacy and safety of plasma exchange in patients with sepsis and septic shock: A systematic review and metaanalysis. Crit Care 2014;18:699.
30. Patel P, Nandwani V, Vanchiere J, Conrad SA, Scott LK. Use of therapeutic plasma exchange as a rescue therapy in 2009 pH 1N1 influenza Aan associated respiratory failure and hemodynamic shock. Pediatr Crit Care Med 2011;12:e879.