|Year : 2020 | Volume
| Issue : 1 | Page : 37-41
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
|Date of Submission||20-Apr-2020|
|Date of Acceptance||26-Apr-2020|
|Date of Web Publication||2-Jun-2020|
Professor and Head, Department of Medicine, All India Institute of Medical Sciences, New Delhi 110 029
Source of Support: None, Conflict of Interest: None
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
|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
|How to cite this URL:|
Praveen T, Desai D, Soneja M, Wig N. Immune dysregulation in COVID-19 and its therapeutic implications. J Clin Sci Res [serial online] 2020 [cited 2020 Jul 11];9:37-41. Available from: http://www.jcsr.co.in/text.asp?2020/9/1/37/285713
| 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%. Besides the direct cytopathic effects of the virus, immune dysregulation associated with viral infection also contributes to mortality. 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. 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. This phenomenon has been demonstrated in animal models of Middle East respiratory syndrome (MERS) virus infection and substantiated by the limited success of IFN therapy in patients who had already developed acute respiratory distress syndrome (ARDS). Besides destroying viral-infected cells, NK-cells and CD8+ T-cells are also important in inhibiting activated macrophages. SARS-CoV-2 is associated with decrease in both number and function of NK-cells and CD8 T-cells, leading to delay in viral clearance as well as immune dysregulation. Uninhibited activated macrophages can lead to secondary haemophagocytic–lymphohistiocytosis (HLH) syndrome. 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), HET-E (incompatibility locus protein from Podosporaanserine) and telomerase-associated protein (TP1) (NACHT); leucine-rich repeat; pyrin [PYD]) containing protein-3 (NLRP-3) inflammasome response is one of the proposed reasons for this. 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 pro-inflammatory cytokines interleukin (IL)-1-beta and IL-18 and pyroptosis by activation of caspase-1. Vitamin C dampens the NLRP3 pathway indirectly by reducing oxidative stress and, thus, has the potential to mitigate tissue damage.
| Immune Dysregulation in Severe Acute Respiratory Coronavirus-2 Infection|| |
Immune dysregulation in SARS-CoV-2 infection is characterised by lymphopenia, increased neutrophil–lymphocyte ratio, decreased NK-cells and CD8+
T-cell activity, decreased regulatory T-cells and increased CD4+ to CD8+ ratio. Failure to eliminate virus due to inappropriate IFN response and decreased number and function of CD8+ and NK-cells lead to virus induced tissue damage. The virus enters cells using the angiotensin-converting enzyme-2 (ACE-2) receptors. This subsequently leads to downregulation of ACE-2 receptor expression on the infected cells. This tilts the homeostatic balance towards angiotensin-2-mediated effects, causing more inflammation and capillary leak. Further release of antigens from damaged cells (DAMPS) promotes transcription of type-1 IFNs, release of inflammatory cytokines (IL-1-beta, IL-6, IL-18, tumour necrosis factor-alpha [TNF-alpha] and IL-12) and activation of inflammasomes leading to tissue damage.
T-helper cell 17 response
Transforming growth factor-beta and IL-1-beta lead to increased differentiation of naïve T-cells into T-helper cell 17 ( Th17) cells. Th17 cell differentiation is associated with increased release of IL-23 and IL-17. IL-23 is an essential cytokine for Th17 survival and proliferation, whereas IL-17 is a pleomorphic cytokine with multiple actions on different targets. IL-17 receptors are present on epithelial cells, endothelial cells, macrophages and chondrocytes. Stimulation of IL-17 receptors leads to further production of IL-6, IL-1-beta, metalloproteinases, TNF-alpha, nitric oxide and granulocyte colony-stimulating factor (G-CSF). This leads to recruitment of more neutrophils into the lung, capillary leak and subsequent lung damage.
Increased Th1 response
IL-12 released by dendritic cells leads to increased differentiation of naïve T-cells into T helper 1 (Th1) cells. IL-2 and IFN-gamma released by Th1 cells stimulate macrophages. Loss of inhibition of activated macrophages by NK-cells and CD8+ T-cells leads to persistent activation of macrophages and subsequent HLH.
IL-6 acts through membrane-bound receptors (on hepatocytes, macrophages and T-cells) and through soluble IL-6 receptors (trans-signalling). During inflammation, A disintegrin and metalloproteinase 17 (ADAM17) enzyme cleaves cell-bound IL-6 receptors and releases them into the circulation. These soluble IL-6 receptors bind to IL-6 and amplify the inflammatory response by acting on multiple cell types via membrane-bound glycoprotein 130 (GP130). This results in increased recruitment of mononuclear cells, inhibition of T-cell apoptosis and decreased Treg differentiation and ultimately leads to a cytokine storm.
After a prolonged hyper-inflammatory phase, T-cells switch to suppressor phenotype with increased expression of programmed cell death protein 1 (PD-1), cytotoxic T-lymphocyte-associated protein-1 (CTLA-1), B- and T-lymphocyte attenuator as well as increased differentiation into Treg cells and increased IL-10. 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.
The key pathogenetic concepts underlying immune dysregulation in SARS-COV-2 infection are summarised in [Figure 1], [Figure 2], [Figure 3].
|Figure 1: Pathophysiology of tissue damage due to direct viral cytopathic and hyper-inflammatory response. |
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|Figure 2: Differentiation of T naïve cells into different subsets DC = Dendritic cell; IL = Interleukin; Treg = Regulatory T-cells; TH = Helper T-cells; TGF-β = Transforming growth factor-beta|
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| Immunomodulating Agents in the Treatment of Severe Acute Respiratory Coronavirus-2 Infection|| |
The immune response to SARS-CoV-2 occurs in two phases ([Table 1]). The initial immune response is important in eliminating the virus. 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 hyper-inflammatory phase.
|Table 1: Phases of immune response in severe acute respiratory syndrome coronavirus-2 infection|
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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 COVID-19 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. 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. Methylprednisolone given at doses of 1–2 mg/kg body weight for 5–7 days has shown clinical benefit in early ARDS due to COVID-19.,
Tocilizumab, IL-6 receptor blocker, has been used in COVID-19 with some success. Blocking IL-6 receptors can increase the IL-6 levels initially as soluble IL-6 receptors are blocked. Even though the half-life of tocilizumab is 10 days, repeated doses of tocilizumab may be required if soluble IL-6R is very high., Patients should be monitored for the development of neutropenia and for hospital-acquired extracellular bacterial and fungal infections.
Granulocyte–monocyte colony-stimulating factor blockers
Granulocyte–monocyte CSF (GM-CSF) acts both upstream and downstream of IL-6 by increasing production of IL-6 from cells and recruitment of neutrophils and macrophages. GM-CSF blockers in hyper-inflammatory phase can be useful, but this can lead to increased differentiation to plasmacytoid dendritic cells and excessive type 1 IFNs.
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. Their immunomodulatory action is mediated by decreased dendritic cell activity, dampened Th1 and Th17 immunity as well as increased Treg cells and IL-10 levels. MSCs have been used with significant benefits in a small group of patients with ARDS due to H7N9. Initial reports of their use in COVID-19 have been promising.
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. The oXiris membrane is an AN-69 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 (AN-69 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. 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 hyper-sensitivity (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.,, These details are shown in [Table 2].
|Table 2: Comparison of different methods of extracorporeal cytokine removal|
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The combination of effective antiviral drugs early in the course of the disease with immunomodulatory therapy in the hyper-immune phase of the disease may be a suitable approach in the management of COVID-19 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 hyper-immune phase and immunoparalysis. Studies on T cell subsets, cytokine profiling and expression of immune checkpoints (programmed cell PD-1, programmed cell death protein ligand-1 and CTLA-4) help in optimisation of treatment.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
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;382:1708-20.
Qin C, Zhou L, Hu Z, Zhang S, Yang S, Tao Y, et al
. Dysregulation of immune response in patients with COVID-19 in Wuhan, China. Clin Infect Dis 2020. pii: ciaa248. doi: 10.1093/cid/ciaa248. [Epub ahead of print].
Schmidt ME, Varga SM. The CD8 T cell response to respiratory virus infections. Front Immunol 2018;9:678.
Channappanavar R, Fehr AR, Zheng J, Wohlford-Lenane C, Abrahante JE, Mack M,et al
. IFN-I response timing relative to virus replication determines MERS coronavirus infection outcomes. J Clin Invest 2019;130:3625-39.
Ranieri VM, Pettilä V, Karvonen MK, Jalkanen J, Nightingale P, Brealey D, et al
. Effect of intravenous interferon β-1a on death and days free from mechanical ventilation among patients with moderate to severe acute respiratory distress syndrome: A randomized clinical trial. JAMA 2020;323:725-33.
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;44:465-8.
Popko K, Górska E. The role of natural killer cells in pathogenesis of autoimmune diseases. Cent-Eur J Immunol 2015;40:470-6.
Ahn M, Anderson DE, Zhang Q, Tan CW, Lim BL, Luko K, et al
. Dampened NLRP3-mediated inflammation in bats and implications for a special viral reservoir host. Nat Microbiol 2019;4:789-99.
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;2:13-9.
Shi Y, Wang Y, Shao C, Huang J, Gan J, Huang X, et al
. COVID-19 infection: The perspectives on immune responses. Cell Death Differ 2020;27:1451-4.
Rico-Mesa JS, White A, Anderson AS. Outcomes inpPatients with COVID-19 infection taking ACEI/ARB. Curr Cardiol Rep 2020;22:31.
Land WG. The role of damage-associated molecular patterns in human diseases. Sultan Qaboos Univ Med J 2015;15:e9-21.
Wu D, Yang XO. TH17 responses in cytokine storm of COVID-19: An emerging target of JAK2 inhibitor Fedratinib. Microbiol Immunol Infect 2020. pii: S1684-1182 (20) 30065-7.
Hamers L, Kox M, Pickkers P. Sepsis-induced immunoparalysis: Mechanisms, markers, and treatment options. Minerva Anestesiol 2015;81:426-39.
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;197:700-1.
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;8:267-76.
Zha L, Li S, Pan L, Tefsen B, Li Y, French N, et al
. Corticosteroid treatment of patients with coronavirus disease 2019 (COVID-19). Med J Aust 2020. [Epub ahead of print].
Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al
. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA 2020;323:1061-9.
Xu X, Han M, Li T, Sun W, Wang D, Fu B, et al
. Effective treatment of severe COVID-19 patients with tocilizumab. Proc Natl Acad Sci U S A 2020. pii: 202005615. doi: 10.1073/pnas.2005615117. [Epub ahead of print].
Conti L, Gessani S. GM-CSF in the generation of dendritic cells from human blood monocyte precursors: Recent advances. Immunobiology 2008;213:859-70.
Matthay MA. Therapeutic potential of mesenchymal stromal cells for acute respiratory distress syndrome. Ann Am Thorac Soc 2015;12 Suppl 1:S54-7.
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 COVID-19 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].
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 COVID-19 pneumonia. Aging Dis 2020;11:216-28.
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.
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 3:1-7.
Knaup H, Stahl K, Schmidt BMW, Idowu TO, 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 2018;22:285.
Rimmer E, Houston BL, Kumar A, Abou-Setta 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 meta-analysis. Crit Care 2014;18:699.
Patel P, Nandwani V, Vanchiere J, Conrad SA, Scott LK. Use of therapeutic plasma exchange as a rescue therapy in 2009 pH 1N1 influenza A-an associated respiratory failure and hemodynamic shock. Pediatr Crit Care Med 2011;12:e87-9.
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2]