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Cytokine Storm of COVID-19 and Its Impact on Patients with and without Chronic Liver Disease

  • Madhumita Premkumar1  and
  • Chandan Kumar Kedarisetty2,* 
 Author information
Journal of Clinical and Translational Hepatology 2021;():-

DOI: 10.14218/JCTH.2021.00055

Abstract

The coronavirus pandemic has resulted in increased rates of hepatic decompensation, morbidity and mortality in patients suffering from existing liver disease, and deranged liver biochemistries in those without liver disease. In patients with cirrhosis with coronavirus disease 2019 (COVID-19), new onset organ failures manifesting as acute-on-chronic liver failure have also been reported. The severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) also directly binds to enterocytes and cholangiocytes via the angiotensin converting enzyme receptor 2, although the lung remains the portal of entry. Superadded with the COVID-19 related bystander hepatitis, a systemic inflammatory response is noted due to unregulated macrophage activation syndrome and cytokine storm. However, the exact definition and diagnostic criteria of the ‘cytokine storm’ in COVID-19 are yet unclear. In addition, inflammatory markers like C-reactive protein, ferritin, D-dimer and procalcitonin are frequently elevated. This in turn leads to disease progression, activation of the coagulation cascade, vascular microthrombi and immune-mediated injury in different organ systems. Deranged liver chemistries are also noted due to the cytokine storm, and synergistic hypoxic or ischemic liver injury, drug-induced liver injury, and use of hepatotoxic antiviral agents all contribute to deranged liver chemistry. Control of an unregulated cytokine storm at an early stage may avert disease morbidity and mortality. Several immunomodulator drugs and repurposed immunosuppressive agents have been used in COVID-19 with varying degrees of success.

Keywords

Chronic liver disease, COVID-19, Cytokines, Hepatitis, Gut-liver axis

Introduction

The novel coronavirus 2019 (COVID-19) disease, caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has resulted in a devastating global pandemic, with 113,989,973 confirmed COVID-19 cases, which include 2,531,542 deaths reported by the World Health Organization1 as of March 2, 2021. COVID-19 has been reported as an air- and surface-borne contagious disease with features of viral pneumonia (fever, cough, lymphopenia, prothrombotic tendency, ground glass opacities on chest radiology) and hypoxemia.2,3 In addition, alterations in liver chemistries have been reported in patients with and without liver disease, with some reports of increasing severity, complication, and new decompensation, while others refute this possibility. Liver chemistry changes are more likely in those with severe disease and those who have received multiple therapies, requiring high flow oxygen or invasive ventilation.4 This presents an interesting clinical conundrum, as we need to assess the immunological injury, alteration in liver chemistries and varied clinical course in such patients.5 We require predictive models of severity of disease, which enable us to prognosticate patients with cirrhosis during the COVID-19 pandemic.6 In addition, the association between liver chemistries, need for invasive ventilation and COVID-19-associated hospital deaths remains controversial and despite availability of breakthrough vaccines, the pandemic is likely to continue claiming more lives.7 Given the heterogenous clinical presentation, the spectrum of liver involvement varies from altered liver chemistry in patients without underlying liver disease to progressive decompensation in patients with cirrhosis.8

In this review, we have summarized relevant information related to the cytokine storm and pathophysiological basis of liver injury in COVID-19 in those with or without chronic liver disease. The mechanisms of liver injury in COVID-19 are crucial to planning strategies to ameliorate the direct viral, immunological or drug-related liver injury.

Cytokine storm and immune activation in COVID-19

The body’s immune system can identify epitopes of the viral antigens of the SARS-CoV-2 via the antigen presenting cells (APCs), like dendritic cells and macrophages, that process the viral antigens and present them to the natural killer (referred to as NK) cells, CD4+ T helper cells and other lymphocytes, which in turn activate CD8+ cytotoxic T cells and B cells. The presentation of viral antigens using the major histocompatibility complex ensures activation of both the innate and acquired immunity, resulting in proinflammatory cytokines, chemokines, and coagulation enzymes.9,10 These inflammatory pathways, if dysregulated result in massive activation and ‘cytokine storm’, a prothrombotic tendency culminating into multiple organ failures and likely death. Pyroptosis is a form of programmed cell death which is an inflammatory caspase-1 dependent type, that occurs in response to infection with intracellular pathogens, such as SARS-CoV-2. Rapid viral replication can result in increased pyroptosis, which can be a precursor for massive release of inflammatory mediators.10

In COVID-19, uncontrolled immune response can lead to secondary hemophagocytic lympho-histiocytosis or macrophage activation syndrome, which presents as a life-threatening condition, in the form of persistent fever and pancytopenia quickly progressing into multi-organ failure and increased mortality.11,12 Macrophage activation syndrome is diagnosed on the basis of clinical and laboratory diagnostic criteria which include fever, increased ferritin, triglyceride levels, pancytopenia, consumptive coagulopathy with hypofibrinogenemia, and splenomegaly.13,14 Hemophagocytosis is defined as the engulfment of red blood cells, leucocytes, and platelets by macrophages (detected on histology).13 Besides these features, low or absent NK cell activity and serum CD25 ≥2,400 units/mL is noted.14 The cytokine storm refers to elevated interferon-alpha, interleukin (IL)-6, IL-1, CCL-5, CXCL8, and CXCL-10. In addition, inflammatory markers like C-reactive protein (CRP) and procalcitonin are frequently elevated.15,16 Viral features, low interferon levels, increased neutrophil extracellular traps (NETs), and increased pyroptosis lead to impaired SARS-CoV-2 clearance and create the setting for macrophage activation syndrome and cytokine storm. Certain genetic mutations predispose to this condition.1719 Once the inflammation sets in, anti-viral treatment will be insufficient to control the disease severity and anti-inflammatory or immunomodulatory drugs are required. Normal antiviral response requires activation of controlled inflammatory syndrome but it is usually overtaken by systemic inflammatory response syndrome (commonly known as SIRS) due to uncontrolled inflammation. Cytokines are the signaling molecules of this response, which are produced by a multitude of immune cells, like dendritic cells, macrophages, neutrophils, NK cells, and adaptive T and B cells.20 Binding of the COVID-19-associated damage-associated molecular patterns or pathogen-associated molecular patterns to pattern recognition receptors on the immune cells, like lymphocytes and antigen presenting cells, trigger signaling pathways that lead to the cytokine storm.21,22 Various signaling pathways, including the mitogen-activated protein kinase (MAPK) pathway with Jun NH2-terminal kinase, extracellular signal-regulated kinase, p65 and p38 MAPK, lead to elution of transcription factors and induce gene expression of several immune regulatory genes encoding proinflammatory cytokines.23 The MAPK pathways modulate apoptosis and cross-talk between the p38 MAPK pathway and other pathways that can induce cell death.

Other downstream signaling pathways involve JAK1 and 2, Tyk2, and STAT3. Activation of the PI3 kinase/Akt pathway is essential to establish persistent infection with SARS-CoV2.24

The major triggered transcription factors are interferon response factors 3 and 7, nuclear factor KB, activation protein 1, and so on.25 These in turn lead to expression of chemokines, cytokines, and adhesion molecules. The cascade of signaling events leads to recruitment of leucocytes, plasma cells and T cells to the site of infection, where they assist the innate response by macrophages to perform effector function and clear SARS-CoV-2. A counterbalancing mechanism for immune modulation is the negative feedback by the cytokines IL-10 and IL-4, which is often down-regulated in severe COVID-19. This leads to an unregulated and excessive cytokine storm resulting in secondary organ failures (Fig. 1).26

COVID-19, cytokine storm and immune-mediated organ failure.
Fig. 1  COVID-19, cytokine storm and immune-mediated organ failure.

COVID-19, cell entry and angiotensin converting enzyme receptor

Although the spread of the SARS-CoV-2 infection is by droplet infection and the primary entrance is the respiratory tract, it also infects the gastrointestinal tract directly. The angiotensin converting enzyme 2 (ACE2) receptor is present on type II alveolar cells in the lung, esophageal epithelium, enterocytes of the ileum and colon, pancreas, hepatocytes and cholangiocytes, myocardium, proximal tubular cells of the nephron, and the pancreas.27,28 The resultant inflammatory response may lead to viral clearance but when uncontrolled (in the form of cytokine storm), it can lead to vascular barrier damage, alveolar membrane integrity damage, multiorgan failure, and ultimately death.29,30 Although the primary site affected is the lung, with acute lung injury and acute respiratory distress syndrome (ARDS), the liver is also affected by a similar mechanism (Fig. 1).

The ACE2 receptor is highly expressed on well-differentiated enterocytes, and this explains why fecal shedding of the virus is detected and diarrhea is a symptom of COVID-19. Gastrointestinal manifestations are noted in up to 61% of COVID patients. ACE2 receptors are present at various gastrointestinal sites, like gastric and duodenal glands and distal enterocytes. COVID-19 can present as malabsorption, altered intestinal permeability, and activation of the enteric nervous system. SARS-CoV-2 is a systemic infection and the intracellular vesicles containing the virus remain in situ for long after apparent recovery from the disease. Pathological examination of patients with liver disease shows the liver histology has microvesicular steatosis, as well as areas of focal necrosis with lymphocyte infiltration like reports of bystander hepatitis caused by immunological injury attributable to influenza virus. SARS-CoV-2 could also cause direct cytopathic injury to the liver, other than hypoxic, or free radical-mediated injury. The virus has also been detected in up to 41% of autopsied livers with a viral load of 1.6×106 copies per gram of liver tissue.31,32 Down-regulation of the negative feedback counterregulatory IL-10 and IL-4 mechanism results in a hyperinflammatory cytokine storm.9

ACE2 expression in cell clusters is higher in cholangiocytes than in hepatocytes (59.7% vs. 2.6%), but immune-mediated hepatitis is more likely to be the explanation for deranged liver chemistries, as with other respiratory tract viruses.33,34 With such a broad infection footprint, many drugs affecting the immune cascade have been tried. Use of the anti-IL-6 agent tocilizumab, hydroxychloroquine and steroids are examples, which have shown a varied efficacy.

Viral kinetics of SARS-CoV2 in cirrhosis

Cirrhosis is an immunocompromised state, and it appears there is impaired viral clearance of the SARS-CoV-2. The virus resides in double membrane vesicles, which prevent creation of pattern recognition receptors, and even after the PCR test being negative, the lung alveolar cells and macrophages can show tell-tale signs of these viral vesicles, even after 2 weeks of apparent resolution of disease.2,21

In cirrhosis, there is also a lower level of type I interferon, which results in impaired viral response. Neutrophils also contribute to viral clearance by release of free radicals, degranulation of vesicles, and secretion of antimicrobials through the formation of unique NETs.35 Neutrophils are activated by IL-8, CXCL8, leukotriene B4 or lipopolysaccharide, and generate a programmed cell death with a chromatin reticular framework covered with neutrophil granule-derived peptides and proteolytic enzymes. This generates a net-like structure, in which pathogens get trapped, aptly called NETs. The positively charged histones of the chromatin network of NETs can bind to and immobilize negatively charged viral envelope of the SARS-CoV-2 particles.36,37

COVID-19 and hepatic involvement in people without liver disease

COVID-19 results in liver injury, transaminitis and even impending liver failure in patients without liver disease, especially those with moderate to severe illness. Hypoxemia, impaired cardiac function, and reduced tissue perfusion in severely ill COVID-19 patients can lead to increased vulnerability of an apparently healthy liver. The mechanisms of liver injury in a native ‘healthy’ liver are multifactorial. Direct viral cytopathic effects, hypoxic injury, hepatotoxicity from therapeutic drugs, and secondary damage due to multiple organ dysfunction are the most likely underlying mechanisms for liver injury. On histopathology, a mild increase in sinusoidal lymphocytic infiltration, sinusoidal dilatation, mild steatosis, and multifocal hepatic necrosis are noted. Direct cytopathic effects of the SARS-CoV-2 are multiple foci of necrosis in the periportal area (zone 1) and adjacent to terminal hepatic veins (zone 3), with minimum inflammation. The described histology is like non-viral related acute liver injury. Conspicuous absence of dense inflammation, widespread necrosis, ballooning, Mallory hyaline, or pericellular fibrosis, cholestasis or lack immune mediated damage differentiates it from viral hepatitis.38,39

Biochemically, abnormal liver chemistries in COVID-19 include elevation of aspartate transaminase (AST), alanine aminotransferase (ALT), and gamma-glutamyl transpeptidase, but bilirubin and alkaline phosphatase changes are seen rarely. In absence of liver disease, liver failure is rare. A recent meta-analysis5 showed that the liver chemistries per se did not affect outcomes in patients with mild and moderate COVID-19 infection.

Table 1 shows the list of studies which provided data on liver injury in patients without underlying liver disease.4042

Table 1

List of studies which provided data on liver injury in patients without underlying liver disease

No.ReferenceStudy typeNo. of patients with COVID-19Pre-existing liver diseasesHepatobiliary function markersInflammatory markers and other relevant blood testsProposed possible theories of hepatic injury
1Xie H40Retrospective case series79Patients with previous liver diseases were excluded31.6%, 35.4% and 5.1% of patients had elevated ALT, AST and TBIL, respectively. Median (range) values were 36.5 (17.5–71.5) U/L, 34.5 (25.3–55.3) U/L and 12.7 (8.1–15.4) mmol/L, respectivelyCRP (max.,79.6 µmol/L) and ESR (max., 58 mm/h) increased; while LYM reduced (min., 0.9×109/L)Overall disease exacerbation; disease severity. Males were more likely to have liver injury when infected with COVID-19 (p<0.05); compared with patients without liver injury, patients with liver injury had increased levels of white blood cell counts, neutrophils, CRP and CT score (p<0.05) and had a longer length of stay (p<0.05)
2Zhang Y41Retrospective case series115Two patients had chronic hepatitis B (excluded)ALT and AST increased in 9.57% and 14.78% patients, respectively on admission. TBIL elevation was rarely observed. Mean levels higher in severe cases54.78% had reduced ALB, significantly lower in severe cases. 57.39% had increased CRP, higher in severe cases (80.75+69.18). LDH level (mean+SD:346.10+ 257.26) significantly elevated in severe casesDysfunction of immune system. Levels of ALT, AST, TBIL, LDH and INR showed statistically significant elevation in severe COVID-19 cases compared with that in mild cases
3Huang C3Prospective case series41Chronic liver disease in one patientAST (max., 48.0 U/L) increased in 37%, more in the ICU group73% had LDH >245 U/L (max., 408 U/L). 37% had LYM >1.0×109/L (max., 1.1×109/L)Overall disease exacerbation: cytokine storm. Compared with non-ICU patients, ICU patients had higher plasma levels of IL2, IL7, IL10, GSCF, MCP1, MIP1A, and TNF-α
4Fan Z42Retrospective case series148None described55 patients (37.2%) had abnormal liver function at hospital admission. Elevated ALT (n=27; 41–115 U/L), AST (n=32; 37–107 U/L), γ-glutamyl transferase (n=26; 48–159 U/L), ALP (n=6; 102–144 U/L), and total bilirubin (n=9; 21–46.6 µmol/L)PCT and CRP elevated in those with abnormal liver functionMore patients with abnormal liver function (57.8%) received treatment with lopinavir/ritonavir compared with those with normal liver function (31.3%; p=0.01)

COVID-19, inflammation, coagulation, and liver disease

The cytokine storm triggered by COVID-19 has several implications in those with liver disease. Firstly, patients with cirrhosis are already in a procoagulant rebalanced state and are predisposed to pulmonary microthrombosis.43 The systemic inflammatory state is difficult to diagnose, as patients frequently have an elevated CRP and a preexisting cytopenia and splenomegaly attributable to portal hypertension. Due to the hyperdynamic circulation, patients with decompensated cirrhosis already have endothelial inflammation, elevated baseline norepinephrine, and are at increased risk of thromboembolism and ARDS.44,45 The procoagulant tendency of COVID-19 is due to systemic endothelial activation, or damage mediated by viral binding to the ACE2 receptor on the endothelium and other organs. In addition, presence of comorbidities, mechanical ventilation, and bedridden state favor venous thromboembolism.42

The resultant influx of inflammatory mediators raises blood viscosity, and in presence of venous catheters or dialysis access, there is possibility of deep vein thromboses in cirrhosis and liver failure. Patients with predisposing risk factors like coronary artery disease and stroke are also affected by the cytokine storm and have increased risk for cardiac or cerebrovascular events when they have metabolic liver disease. Patients with liver disease often fare poorly in an intensive care setting during for viral pneumonia with respiratory failure, like COVID-19 and H1N1 influenza infections.42,4648 Although patients with cirrhosis are likely to benefit from prophylactic anticoagulation with low molecular weight heparin, they are also at increased risk of variceal bleeding due to increased portal pressure triggered by new onset bystander hepatitis. (Fig. 2). Also, endogenous heparinoids are produced in patients with liver failure with cytokine storm or cirrhosis with systemic inflammation, which affect coagulation and predispose to bleeding. Therefore, using balancing anticoagulants in patients with cirrhosis with COVID-19 with a cytokine storm harbors inherent bleeding risk on one hand and pulmonary microthrombosis on the other.49 The terminal events in these patients with cirrhosis with COVID-19 have been progressive respiratory failure, with secondary organ failures like cardiac or renal failure requiring inotropic support, secondary sepsis, variceal bleeding, or sometimes sudden cardiac events.50,51 In the multicentric APCOLIS study52 of 288 patients, 43% of patients with liver disease presented as acute liver injury, 20% presented as acute-on-chronic liver failure (commonly referred to as ACLF) or acute decompensation (9%). A Child Turcotte Pugh score >9 predicted mortality with hazard ratio of 19.2 (95% confidence interval: 2.3–163.3), with sensitivity of 85.7% and specificity of 94.4%. Patients with liver disease have poor outcomes in the setting of invasive ventilation. Improved intensive care, timely interventions and monitoring altered liver chemistries can improve outcomes.53

Etiopathogenesis of liver injury in COVID-19.
Fig. 2  Etiopathogenesis of liver injury in COVID-19.

Other associations, such as presence of chronic hepatitis B, did not increase the mortality risk. Therefore, it appears that the cytokine storm is one of the important defining factors contributing to morbidity and mortality in those with liver disease.54 A raised AST and direct bilirubin at baseline were independent predictors of COVID-19 mortality.

When acute liver injury and ACLF were reported in patients with liver disease, it was typically seen in the setting of multiple organ failures, severe pneumonia or ARDS. After propensity matching, the baseline and peak values of liver function tests, the trajectory of COVID-19 and severity of liver scores and outcomes are often equivalent in those with compensated cirrhosis.54,55 In contrast, in decompensated liver disease, there is a marked risk of COVID-19-associated liver and coagulation failure. Particularly, studies have reported such events in patients with Child-Turcotte-Pugh B and C cirrhosis with increased decompensation events like ascites, coagulopathy, and hepatic encephalopathy and in-hospital mortality. In view of the increased morbidity and mortality, it is essential to protect patients with decompensated cirrhosis and provide guidance to better manage and evaluate patients with COVID-19 and its complications.56

Table 2 shows the list of studies which included patients with underlying liver disease, and significant findings.5763

Table 2

List of studies which included patients with underlying liver disease, and significant findings6167

No.ReferenceStudy typeNo. of patients with COVID-19Pre-existing liver diseasesHepatobiliary function markersInflammatory markers and other relevant blood testsProposed possible theories of hepatic injury
1Wang D57Retrospective case series138Chronic liver disease in 2.9% of patientsNo significant liver abnormalitiesLYM (median: 0.8×109/L) reduced in 70.3% of cases, and LDH (median: 261 U/L) increased in 39.9% of patientsOverall disease exacerbation
2Cai Q58Retrospective case series2982.7% had liver disease. CHB (1.7%). NAFLD (4.7%). ALD (3%)14.8% experienced liver injury, with ALT max., 59.5 U/L and AST max., 65 U/L: 8.7%, respectivelyCRP (max., 47.13 mg/dL) increased in 70% casesOverall disease exacerbation. Liver injury mainly occurred in severe patients (36.2% vs. 9.6%, p<0.001)
3Xu XW59Retrospective case series6212% had underlying liver diseaseAST (max., 32 U/L) increased in 16% of patients42% showed LYM reductionNone described
4Shi H60Retrospective case series81Hepatitis or liver cirrhosis in 9% of casesAST (>40 U/L) increased in 53% of patients, lower in asymptomatic patientsCT imaging describedNone described
5Zhang B61Retrospective case series with the data of non-survivors82Liver diseases in 2.4% cases. Patients who died had comorbidities (76.8%), including hypertension (56.1%), heart disease (20.7%), diabetes (18.3%), cerebrovascular disease (12.2%), and cancer (7.3%)ALT (>40 U/L), AST (>40 U/L), and TBIL (> 20.5 mmol/L)LYM (<1.0×109/L), ALB (<40 g/L) and CD8+ cells (<220×109/L). CRP (100%), lactate dehydrogenase (93.2%), and D-dimer (97.1%). IL-6 >10 pg/mL used as cut-off
6Guan WJ62Retrospective case series1,099Hepatitis B in 2.1% of patientsAST >40 IU/L (22.2%). ALT >40 IU/L (21.3%)PCT >0.5 ng/mL (5.5%)
7Li L63Retrospective case series85Hepatitis B, alcoholic liver disease, and fatty liver disease (n=2 in each category)24.7% had ALT elevation at admissionCRP ≥20 mg/L and LYM count <1.1×109/L were independent risk factors for hepatic injury. ALB (mean: 33.4 g/L) in the ALT-elevated group was significantly lowerInflammatory cytokine storm. Deterioration of the disease with a dynamic process. Limitation: 6 in the elevated-ALT group (n=33) had a history of liver disease (i.e. HBV infection, alcoholic liver disease, fatty liver)

COVID-19, obesity and fatty liver disease

A recent paper by Bramante et al.64 showed that presence of nonalcoholic fatty liver disease (NAFLD) is associated with increased risk of hospital admission [odds ratio: 2.04 (1.55, 2.96, p<0.01)]. In another study65 on 202 NAFLD patients with COVID-19, altered liver chemistries were noted in 75% during hospital stay. About a third of patients with NAFLD continued to have raised transaminases even on follow up, suggesting a long-lasting superadded insult to the fatty liver. Male sex, age >60 years, high body mass index, presence of comorbidities and NAFLD were associated with progression to severe COVID-19 disease. On logistic regression, NAFLD was an independent risk factor for COVID-19 progression, high likelihood of ongoing liver injury and raised liver chemistries during hospital stay, and prolonged duration of viral shedding. It appears that presence of obesity, NAFLD and metabolic syndrome are associated with an increased risk of COVID-19 progression.66

Drugs targeting the cytokine storm

Several drugs have been tested in COVID-19 based on the assumption that dysregulated immune responses need to be curbed. One of the main therapies includes the use of steroids, either prednisolone or methylprednisolone or intravenous hydrocortisone, which act through the glucocorticoid receptor and effector genes. As per the World Health Organization guidelines, systemic corticosteroid therapy is not for routine use. It should only be given to those with cytokine storm, ARDS, acute heart failure, acute kidney injury, and high serum levels of D-dimer.67 Anti-rheumatic drugs, hydroxychloroquine, chloroquine, JAK inhibitors, IL-1 and IL-6 inhibitors, anti-tumor necrosis factor-alpha (commonly referred to as TNF-α) drugs, corticosteroids, colchicine, and intravenous immunoglobulin. The use of chloroquine and hydroxychloroquine was reported to reduce COVID-19-mediated injury, by arresting the cytokine storm or the activation of CD8+ cells, or by preventing endocytosis-mediated uptake of the virus. Chloroquine and hydroxychloroquine act by accumulating in lysosomes, increasing the pH of the endosome, thereby interfering with viral entry or exit from the cells. Also, these drugs interfere with the ACE2 receptor, preventing entry of the SARS-CoV-2. Chloroquine and hydroxychloroquine may reduce glycosylation of the ACE2 receptor which prevents the virus binding to and entering the new cells. However, major trials have found no putative benefit for prophylaxis of COVID-19, and gradually these drugs have been disregarded.68 Similarly, other direct antivirals like remdesivir and favipiravir also failed to show significant efficacy or survival benefit.69,70 Tocilizumab, a humanized IgG1 monoclonal antibody to the IL-6 receptor, has been used with limited success in COVID-19. The recommended dose of tocilizumab is 8 mg/kg intravenous as single or two divided doses at 12 to 24 h intervals, with a maximum dose of 800 mg. However, the adverse events include increased propensity of infection, hypertriglyceridemia, diverticulitis, and hepatotoxicity.71

Several repurposed drugs have been adopted from rheumatology practice to assess amelioration of the cytokine storm in COVID-19. Colchicine has been recommended as potential therapy for complications of COVID-19, as an IL-1 inhibitor.72 Other drugs include a recombinant humanized anti-IL6 receptor antibody called sarilumab, a recombinant human mouse chimeric monoclonal antibody called siltuximab, and an IL-1 blocker called anakinra.73,74 Anakinra, an anti-rheumatic drug, was studied in the trial setting to inhibit pathological effects of IL-1 alpha and IL-1 beta.75 Other than drugs that directly inhibit the immune response, cytokine dialysis has also been tried, using blood ultrafiltration, diffusion, and adsorption circuits in dialysis machines. Restoration of the immune IL-6/IL-1 levels and other proinflammatory molecules theoretically protects against organ failures but clinical efficacy is still unclear, and the immune dysregulation is only one problem of many. A novel treatment approach for preventing and managing the cytokine storm using mesenchymal stem cell-based immunomodulators has been proposed. Intravenous transplantation of mesenchymal stem cells was shown to be effective in COVID-19 in a trial.76

Relevance of the cytokine storm in COVID-19

After describing the various aspects of the cytokine storm, it is important to emphasize that the condition has no definition. In most studies on COVID-19, it is described as a hyperimmune response characterized by the release of ILs, interferon, TNF, chemokines, and other mediators. These represent a normal response to a variety of pathogens, and the term ‘cytokine storm’ implies that these released cytokines are injurious to the host; furthermore, there is no consensus yet as to the levels of permissible cytokines that distinguish a well-conserved innate immune response from a dysregulated hyperinflammatory immune response. In addition, all the signaling pathways described have regulatory and counterregulatory responses and pleiotropic downstream mediators that may be acting in complex dependent activities that cannot be easily predicted. To complicate matters, it is unclear if the cytokine storm is pathogenic or protective in an individual patient.77 The abject failure of some drugs like tocilizumab, anakinra, etc. is a case in point and should dampen the enthusiasm displayed globally for applying drugs for one condition without much success in another. It is time to reinterpret and define the cytokine storm. The role of T cells that exert protective functions by reigning in on overactive innate immunity is important, as lymphopenia is associated with ARDS.78 The important role of microthrombosis in the pathogenesis of severe pneumonia and outcomes related to hypoxemia with secondary organ failures is often under-played. The failure of the use of immunomodulators used in rheumatological conditions should make us reassess the degree of cytokine storm and possibly use therapy in patients with demonstrated high levels of cytokines. The cytokine release syndrome was described by Maude et al.79 in recipients of chimeric antigen receptor T cell therapy, where the peak plasma IL-6 level was approximately 10,000 pg/mL, which was almost 1,000-times higher than the level reported in severe COVID-19. Hence, a consensus definition and diagnostic criteria for the cytokine storm is the need of the day.80

Summary

The COVID-19 crisis has presented an enormous challenge to the medical community, as it is a multisystem disease with high mortality and secondary attack rate in predisposed individuals, requiring a multidisciplinary approach for diagnosis, prognostication, and management decision plans. Several therapeutic agents have been tried to manage the hyperinflammatory cytokine storm which leads to immune-mediated organ damage. The trial and failure of several agents like hydroxychloroquine, remdesivir, chloroquine, etc. underlines the fact the evidence-based practice is still unable to provide an answer for controlling the cytokine storm. Strategic vaccination is now a reality, but the story of COVID-19 suggests that we need to be prepared to provide treatments which can manage and control the deleterious effects of our immune reaction, while retaining the viral clearance and disease-controlling immune mechanisms.

Abbreviations

ACE2: 

angiotensin converting enzyme 2

ACLF: 

acute-on chronic liver failure

ALT: 

alanine transaminase

ARDS: 

acute respiratory distress syndrome

AST: 

aspartate transaminase

COVID-19: 

coronavirus disease-19

CRP: 

C-reactive protein

IL: 

interleukin

MAPK: 

mitogen-activated protein kinase

NAFLD: 

nonalcoholic fatty liver disease

NET: 

neutrophil extracellular trap

NK: 

natural killer

SARS-CoV-2: 

severe acute respiratory syndrome coronavirus-2

SIRS: 

systemic inflammatory response syndrome

TNF-α: 

tumor necrosis factor-alpha

Declarations

Funding

None to declare.

Conflict of interest

The authors have no conflict of interests related to this publication.

Authors’ contributions

Conceptualization and original draft preparation (MP), conceptualization, reviewing and editing of the manuscript (CKK). Both authors approved the final version of the manuscript.

References

  1. WHO Coronavirus Disease (COVID-19) Dashboard. Available from https://covid19.who.int/ Last accessed March 2, 2021
  2. Xu Z, Shi L, Wang Y, Zhang J, Huang L, Zhang C, et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med 2020;8(4):420-422 View Article
  3. 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(10223):497-506 View Article
  4. Zhang C, Shi L, Wang FS. Liver injury in COVID-19: management and challenges. Lancet Gastroenterol Hepatol 2020;5(5):428-430 View Article
  5. Kulkarni AV, Kumar P, Tevethia HV, Premkumar M, Arab JP, Candia R, et al. Systematic review with meta-analysis: liver manifestations and outcomes in COVID-19. Aliment Pharmacol Ther 2020;52(4):584-599 View Article
  6. Li Q, Guan X, Wu P, Wang X, Zhou L, Tong Y, et al. Early transmission dynamics in Wuhan, China, of novel coronavirus-infected pneumonia. N Engl J Med 2020;382(13):1199-1207 View Article
  7. Branch AD. How to survive COVID-19 even if the vaccine fails. Hepatol Commun 2020;4(12):1864-1879 View Article
  8. Xu L, Liu J, Lu M, Yang D, Zheng X. Liver injury during highly pathogenic human coronavirus infections. Liver Int 2020;40(5):998-1004 View Article
  9. Wang J, Jiang M, Chen X, Montaner LJ. Cytokine storm and leukocyte changes in mild versus severe SARS-CoV-2 infection: review of 3939 COVID-19 patients in China and emerging pathogenesis and therapy concepts. J Leukoc Biol 2020;108(1):17-41 View Article
  10. Rios CI, Cassatt DR, Hollingsworth BA, Satyamitra MM, Tadesse YS, Taliaferro LP, et al. Commonalities between COVID-19 and radiation injury. Radiat Res 2021;195(1):1-24 View Article
  11. Ragab D, Salah Eldin H, Taeimah M, Khattab R, Salem R. The COVID-19 cytokine storm; what we know so far. Front Immunol 2020;11:1446 View Article
  12. McGonagle D, Sharif K, O’Regan A, Bridgewood C. The role of cytokines including interleukin-6 in COVID-19 induced pneumonia and macrophage activation syndrome-like disease. Autoimmun Rev 2020;19(6):102537 View Article
  13. Opoka-Winiarska V, Grywalska E, Roliński J. Could hemophagocytic lymphohistiocytosis be the core issue of severe COVID-19 cases?. BMC Med 2020;18(1):214 View Article
  14. Ueland T, Heggelund L, Lind A, Holten AR, Tonby K, Michelsen AE, et al. Elevated plasma sTIM-3 levels in patients with severe COVID-19. J Allergy Clin Immunol 2021;147(1):92-98 View Article
  15. Sarzi-Puttini P, Giorgi V, Sirotti S, Marotto D, Ardizzone S, Rizzardini G, et al. COVID-19, cytokines and immunosuppression: what can we learn from severe acute respiratory syndrome?. Clin Exp Rheumatol 2020;38(2):337-342
  16. Lin L, Lu L, Cao W, Li T. Hypothesis for potential pathogenesis of SARS-CoV-2 infection-a review of immune changes in patients with viral pneumonia. Emerg Microbes Infect 2020;9(1):727-732 View Article
  17. Soy M, Keser G, Atagündüz P, Tabak F, Atagündüz I, Kayhan S. Cytokine storm in COVID-19: pathogenesis and overview of anti-inflammatory agents used in treatment. Clin Rheumatol 2020;39(7):2085-2094 View Article
  18. Min CK, Cheon S, Ha NY, Sohn KM, 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;6:25359 View Article
  19. Bergsbaken T, Fink SL, Cookson BT. Pyroptosis: host cell death and inflammation. Nat Rev Microbiol 2009;7(2):99-109 View Article
  20. Kumar V. Toll-like receptors in sepsis-associated cytokine storm and their endogenous negative regulators as future immunomodulatory targets. Int Immunopharmacol 2020;89(Pt B):107087 View Article
  21. Snijder EJ, Van Der Meer Y, Zevenhoven-Dobbe J, Onderwater JJ, van der Meulen J, Koerten HK, et al. Ultrastructure and origin of membrane vesicles associated with the severe acute respiratory syndrome coronavirus replication complex. J Virol 2006;80(12):5927-5940 View Article
  22. Wang F, Nie J, Wang H, Zhao Q, Xiong Y, Deng L, et al. Characteristics of peripheral lymphocyte subset alteration in COVID-19 pneumonia. J Infect Dis 2020;221(11):1762-1769 View Article
  23. Huang W, Berube J, McNamara M, Saksena S, Hartman M, Arshad T, et al. Lymphocyte subset counts in COVID-19 aatients: a meta-analysis. Cytometry A 2020;97(8):772-776 View Article
  24. Battagello DS, Dragunas G, Klein MO, Ayub ALP, Velloso FJ, Correa RG. Unpuzzling COVID-19: tissue-related signaling pathways associated with SARS-CoV-2 infection and transmission. Clin Sci (Lond) 2020;134(16):2137-2160 View Article
  25. Sallenave JM, Guillot L. Innate immune signaling and proteolytic pathways in the resolution or exacerbation of SARS-CoV-2 in Covid-19: key therapeutic targets?. Front Immunol 2020;11:1229 View Article
  26. Zhao Y, Qin L, Zhang P, Li K, Liang L, Sun J, et al. Longitudinal COVID-19 profiling associates IL-1RA and IL-10 with disease severity and RANTES with mild disease. JCI Insight 2020;5(13):e139834 View Article
  27. Bourgonje AR, Abdulle AE, Timens W, Hillebrands JL, Navis GJ, Gordijn SJ, et al. Angiotensin-converting enzyme 2 (ACE2), SARS-CoV-2 and the pathophysiology of coronavirus disease 2019 (COVID-19). J Pathol 2020;251(3):228-248 View Article
  28. South AM, Diz DI, Chappell MC. COVID-19, ACE2, and the cardiovascular consequences. Am J Physiol Heart Circ Physiol 2020;318(5):H1084-H1090 View Article
  29. Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet 2020;395:507-513 View Article
  30. Lai CC, Shih TP, Ko WC, Tang HJ, Hsueh PR. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease-2019 (COVID-19): the epidemic and the challenges. Int J Antimicrob Agents 2020;55(3):105924 View Article
  31. Albini A, Di Guardo G, Noonan DM, Lombardo M. The SARS-CoV-2 receptor, ACE-2, is expressed on many different cell types: implications for ACE-inhibitor- and angiotensin II receptor blocker-based cardiovascular therapies. Intern Emerg Med 2020;15(5):759-766 View Article
  32. Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 2020;181(2):271-280.e8 View Article
  33. Liu F, Long X, Zhang B, Zhang W, Chen X, Zhang Z. ACE2 expression in pancreas may cause pancreatic damage after SARS-CoV-2 infection. Clin Gastroenterol Hepatol 2020;18(9):2128-2130.e2 View Article
  34. Kumar P, Sharma M, Kulkarni A, Rao PN. Pathogenesis of liver injury in coronavirus disease 2019. J Clin Exp Hepatol 2020;10(6):641-642 View Article
  35. Vorobjeva NV, Chernyak BV. NETosis: molecular mechanisms, role in physiology and pathology. Biochemistry (Mosc) 2020;85(10):1178-1190 View Article
  36. Arcanjo A, Logullo J, Menezes CCB, de Souza Carvalho Giangiarulo TC, Dos Reis MC, de Castro GMM, et al. The emerging role of neutrophil extracellular traps in severe acute respiratory syndrome coronavirus 2 (COVID-19). Sci Rep 2020;10(1):19630 View Article
  37. Thierry AR, Roch B. Neutrophil extracellular traps and by-products play a key role in COVID-19: pathogenesis, risk factors, and therapy. J Clin Med 2020;9(9):2942 View Article
  38. Li Y, Xiao SY. Hepatic involvement in COVID-19 patients: pathology, pathogenesis, and clinical implications. J Med Virol 2020;92(9):1491-1494 View Article
  39. Yao XH, Li TY, He ZC, Ping YF, Liu HW, Yu SC, et al. A pathological report of three COVID-19 cases by minimal invasive autopsies. Zhonghua Bing Li Xue Za Zhi 2020;49(5):411-417 View Article
  40. Xie H, Zhao J, Lian N, Lin S, Xie Q, Zhuo H. Clinical characteristics of non-ICU hospitalized patients with coronavirus disease 2019 and liver injury: a retrospective study. Liver Int 2020;40(6):1321-1326 View Article
  41. Zhang Y, Zheng L, Liu L, Zhao M, Xiao J, Zhao Q. Liver impairment in COVID-19 patients: a retrospective analysis of 115 cases from a single centre in Wuhan city, China. Liver Int 2020;40(9):2095-2103 View Article
  42. Fan Z, Chen L, Li J, Cheng X, Yang J, Tian C, et al. Clinical features of COVID-19-related liver functional abnormality. Clin Gastroenterol Hepatol 2020;18(7):1561-1566 View Article
  43. Jayarangaiah A, Kariyanna PT, Chen X, Jayarangaiah A, Kumar A. COVID-19-associated coagulopathy: an exacerbated immunothrombosis response. Clin Appl Thromb Hemost 2020;26:1076029620943293 View Article
  44. Skendros P, Mitsios A, Chrysanthopoulou A, Mastellos DC, Metallidis S, Rafailidis P, et al. Complement and tissue factor-enriched neutrophil extracellular traps are key drivers in COVID-19 immuno-thrombosis. J Clin Invest 2020;130(11):6151-6157 View Article
  45. Premkumar M, Sarin SK. Current concepts in coagulation profile in cirrhosis and acute-on-chronic liver failure. Clin Liver Dis (Hoboken) 2020;16(4):158-167 View Article
  46. Vespa E, Pugliese N, Piovani D, Capogreco A, Danese S, Aghemo A, et al. Liver tests abnormalities in COVID-19: trick or treat?. J Hepatol 2020;73(5):1275-1276 View Article
  47. Piano S, Dalbeni A, Vettore E, Benfaremo D, Mattioli M, Gambino CG, et al. Abnormal liver function tests predict transfer to intensive care unit and death in COVID-19. Liver Int 2020;40(10):2394-2406 View Article
  48. Premkumar M, Devurgowda D, Dudha S, Maiwall R, Bihari C, Grover S, et al. A/H1N1/09 influenza is associated with high mortality in liver cirrhosis. J Clin Exp Hepatol 2019;9(2):162-170 View Article
  49. Premkumar M, Bihari C, Saxena P, Devurgowda D, Vyas T, Mirza R, et al. Heparin-like effect associated with risk of bleeding, sepsis, and death in patients with severe alcohol-associated hepatitis. Clin Gastroenterol Hepatol 2020;18(2):486-495.e3 View Article
  50. Moon AM, Webb GJ, Aloman C, Armstrong MJ, Cargill T, Dhanasekaran R, et al. High mortality rates for SARS-CoV-2 infection in patients with pre-existing chronic liver disease and cirrhosis: preliminary results from an international registry. J Hepatol 2020;73(3):705-708 View Article
  51. Marjot T, Moon AM, Cook JA, Abd-Elsalam S, Aloman C, Armstrong MJ, et al. Outcomes following SARS-CoV-2 infection in patients with chronic liver disease: an international registry study. J Hepatol 2021;74(3):567-577 View Article
  52. Sarin SK, Choudhury A, Lau GK, Zheng MH, Ji D, Abd-Elsalam S, et al. Pre-existing liver disease is associated with poor outcome in patients with SARS CoV2 infection; the APCOLIS study (APASL COVID-19 liver injury spectrum study). Hepatol Int 2020;14(5):690-700 View Article
  53. Premkumar M, Kajal K, Kulkarni AV, Gupta A, Divyaveer S. Point-of-care echocardiography and hemodynamic monitoring in cirrhosis and acute-on-chronic liver failure in the COVID-19 era. J Intensive Care Med 2021;13:885066620988281 View Article
  54. Ding ZY, Li GX, Chen L, Shu C, Song J, Wang W, et al. Association of liver abnormalities with in-hospital mortality in patients with COVID-19. J Hepatol 2020 View Article
  55. 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;71(15):762-768 View Article
  56. Boettler T, Newsome PN, Mondelli MU, Maticic M, Cordero E, Cornberg M, et al. Care of patients with liver disease during the COVID-19 pandemic: EASL-ESCMID position paper. JHEP Rep 2020;2(3):100113 View Article
  57. 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(11):1061-1069 View Article
  58. Cai Q, Huang D, Ou P, Yu H, Zhu Z, Xia Z, et al. COVID-19 in a designated infectious diseases hospital outside Hubei Province, China. Allergy 2020;75(7):1742-1752 View Article
  59. Xu XW, Wu XX, Jiang XG, Xu KJ, Ying LJ, Ma CL, et al. Clinical findings in a group of patients infected with the 2019 novel coronavirus (SARS-Cov-2) outside of Wuhan, China: retrospective case series. BMJ 2020;368:m606 View Article
  60. Shi H, Han X, Jiang N, Cao Y, Alwalid O, Gu J, et al. Radiological findings from 81 patients with COVID-19 pneumonia in Wuhan, China: a descriptive study. Lancet Infect Dis 2020;20(4):425-434 View Article
  61. Zhang B, Zhou X, Qiu Y, Song Y, Feng F, Feng J, et al. Clinical characteristics of 82 cases of death from COVID-19. PLoS One 2020;15(7):e0235458 View Article
  62. 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(18):1708-1720 View Article
  63. Li L, Li S, Xu M, Yu P, Zheng S, Duan Z, et al. Risk factors related to hepatic injury in patients with corona virus disease 2019. medRxiv 2020:2020.02.28.20028514 View Article
  64. Bramante C, Tignanelli CJ, Dutta N, Jones E, Tamariz L, Clark JM, et al. Non-alcoholic fatty liver disease (NAFLD) and risk of hospitalization for Covid-19. medRxiv 2020:2020.09.01.20185850 View Article
  65. Ji D, Qin E, Xu J, Zhang D, Cheng G, Wang Y, et al. Non-alcoholic fatty liver diseases in patients with COVID-19: a retrospective study. J Hepatol 2020;73(2):451-453 View Article
  66. Zheng KI, Gao F, Wang XB, Sun QF, Pan KH, Wang TY, et al. Obesity as a risk factor for greater severity of COVID-19 in patients with metabolic associated fatty liver disease. Metabolism 2020;108:154244 View Article
  67. World Health Organization. (‎2020)‎. Clinical management of severe acute respiratory infection when novel coronavirus (‎‎‎‎‎‎2019-nCoV)‎‎‎‎‎‎ infection is suspected: interim guidance, 28 January 2020. World Health Organization. https://apps.who.int/iris/handle/10665/330893
  68. Gao J, Tian Z, Yang X. Breakthrough: chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. Biosci Trends 2020;14(1):72-73 View Article
  69. Wang Y, Zhang D, Du G, Zhao J, Jin Y, Fu S, et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet 2020;395(10236):1569-1578 View Article
  70. Stawicki SP, Jeanmonod R, Miller AC, Paladino L, Gaieski DF, Yaffee AQ, et al. The 2019-2020 novel coronavirus (severe acute respiratory syndrome coronavirus 2) pandemic: a joint American college of academic international medicine-world academic council of emergency medicine multidisciplinary COVID-19 working group consensus paper. J Glob Infect Dis 2020;12(2):47-93 View Article
  71. Quartuccio L, Sonaglia A, McGonagle D, Fabris M, Peghin M, Pecori D, et al. Profiling COVID-19 pneumonia progressing into the cytokine storm syndrome: results from a single Italian Centre study on tocilizumab versus standard of care. J Clin Virol 2020;129:104444 View Article
  72. Dupuis J, Sirois MG, Rhéaume E, Nguyen QT, Clavet-Lanthier ME, Brand G, et al. Colchicine reduces lung injury in experimental acute respiratory distress syndrome. PLoS One 2020;15(12):e0242318 View Article
  73. Montesarchio V, Parrela R, Iommelli C, Bianco A, Manzillo E, Fraganza F, et al. Outcomes and biomarker analyses among patients with COVID-19 treated with interleukin 6 (IL-6) receptor antagonist sarilumab at a single institution in Italy. J Immunother Cancer 2020;8(2):e001089 View Article
  74. Hashizume M. Outlook of IL-6 signaling blockade for COVID-19 pneumonia. Inflamm Regen 2020;40:24 View Article
  75. Navarro-Millán I, Sattui SE, Lakhanpal A, Zisa D, Siegel CH, Crow MK. Use of anakinra to prevent mechanical ventilation in severe COVID-19: a case series. Arthritis Rheumatol 2020;72(12):1990-1997 View Article
  76. 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(2):216-228 View Article
  77. Wu C, Chen X, Cai Y, Xia J, Zhou X, Xu S, et al. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China. JAMA Intern Med 2020;180(7):934-943 View Article
  78. Calfee CS, Delucchi K, Parsons PE, Thompson BT, Ware LB, Matthay MA, et al. Subphenotypes in acute respiratory distress syndrome: latent class analysis of data from two randomised controlled trials. Lancet Respir Med 2014;2(8):611-620 View Article
  79. Maude S, Barrett DM. Current status of chimeric antigen receptor therapy for haematological malignancies. Br J Haematol 2016;172(1):11-22 View Article
  80. Sinha P, Matthay MA, Calfee CS. Is a “cytokine storm” relevant to COVID-19?. JAMA Intern Med 2020;180(9):1152-1154 View Article
  • Journal of Clinical and Translational Hepatology
  • pISSN 2225-0719
  • eISSN 2310-8819

Cytokine Storm of COVID-19 and Its Impact on Patients with and without Chronic Liver Disease

Madhumita Premkumar, Chandan Kumar Kedarisetty
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