Cytokine Storm in COVID-19-Immunopathological Mechanisms, Clinical Considerations, and Therapeutic Approaches: The REPROGRAM Consortium Position Paper

Abstract

Cytokine storm is an acute hyperinflammatory response that may be responsible for critical illness in many conditions including viral infections, cancer, sepsis, and multi-organ failure. The phenomenon has been implicated in critically ill patients infected with SARS-CoV-2, the novel coronavirus implicated in COVID-19. Critically ill COVID-19 patients experiencing cytokine storm are believed to have a worse prognosis and increased fatality rate. In SARS-CoV-2 infected patients, cytokine storm appears important to the pathogenesis of several severe manifestations of COVID-19: acute respiratory distress syndrome, thromboembolic diseases such as acute ischemic strokes caused by large vessel occlusion and myocardial infarction, encephalitis, acute kidney injury, and vasculitis (Kawasaki-like syndrome in children and renal vasculitis in adult). Understanding the pathogenesis of cytokine storm will help unravel not only risk factors for the condition but also therapeutic strategies to modulate the immune response and deliver improved outcomes in COVID-19 patients at high risk for severe disease. In this article, we present an overview of the cytokine storm and its implications in COVID-19 settings and identify potential pathways or biomarkers that could be targeted for therapy. Leveraging expert opinion, emerging evidence, and a case-based approach, this position paper provides critical insights on cytokine storm from both a prognostic and therapeutic standpoint.

Keywords: COVID-19; autoimmunity; critical care; cytokine storm; guidelines; immunological mechanisms; immunotherapies; neuroimmunology.

Figure 1

Mechanisms of SARS-CoV-2 associated cytokine storm and associated damages. Infection with SARS-CoV 2 can stimulate a hyperinflammatory immune response wherein epithelial-cell-mediated production of reactive oxygen species (ROS) can cause cell death. ROS can also stimulate the synthesis of NLRP3 and NF-κB which contribute to increased cytokine levels, and thus, the cytokine storm. This essentially causes immune invasion which can lead to clinically relevant conditions such as ARDS, sepsis, MODS and potentially even death. The organs affected as a result of MODS, and their associated symptoms, have been shown. Lower gastrointestinal (GI) is rich in ACE2 receptors and hence at higher risk of infection due to COVID-19. Twenty percent of COVID-19 patients have diarrhea as symptoms. SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; COVID-19, coronavirus disease 2019; ROS, reactive oxygen species; NLRP3, (NOD)-like receptor protein 3 inflammasome; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; IL, interleukin; TNF, tumor necrosis factor; IFN, interferon; PAMPs, pathogen-associated molecular patterns; DAMPs, damage-associated molecular patterns; PRR, pattern recognition receptors; AST, aspartate aminotransferase; MODS, multiple organ dysfunction syndrome.

Figure 2

Crosstalk between immune system and CNS system cytokine networks. There is a supposed link between the immune system cytokine network and the CNS system cytokine network. Peripheral cytokines can cross the blood brain barrier to enter the CNS. Alternatively, microglia and astrocytes can also produce cytokines. Potential involvement of neurons in regulation of cytokines for example brain-derived neurotrophic factor (BDNF) and interleukin-6 levels is also plausible (51). SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; COVID-19, coronavirus disease 2019; CNS, central nervous system; IL, interleukin; TNF, tumor necrosis factor; IFN, interferon.

Figure 3

Various therapeutic strategies for targeting cytokine storm. Different stages of the hyperinflammatory immune response can be targeted for therapeutic purposes, with the final aim of modulating and inhibiting cytokine influx in order to restore immune homeostasis. HMGB, high-mobility group protein 1; DAMP, damage-associated molecular pattern; COX, cyclooxygenase.

Figure 4

Targeting cytokine storm via the JAK-STAT pathway. During a cytokine storm, there are increased levels of IL-6 which can form a complex with mIL-6R to act on gp130. Gp130 regulates levels of IL-6, MCP-1, and GM-CSF via the JAK-STAT pathway. This could facilitate the cytokine storm. Inhibition of the JAK-STAT pathway, potentially using IL-6 inhibitors or direct inhibition of signaling, can be a therapeutic strategy (depending on the timing—indicated preferably at later stages of illness, not in early phase, or at clinical signs of cytokine storm). SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; COVID-19, coronavirus disease 2019; IL, interleukin; mIL-6R, membrane bound interleukin-6 receptor; gp 130, glycoprotein 130; MCP-1, monocytes chemoattractant protein-1; GM-CSF, granulocyte-macrophage colony-stimulating factor; JAK-STAT, janus kinase/signal transducer and activator of transcription.

Figure 5

REPROGRAM consortium pathway for targeting cytokine storm in severe or critically ill COVID-19 patients. Diagnostic panel for risk factor assessment of cytokine storm associated prognosis of COVID-19 patients could include (Panel A: on top right) (99): older age, dyspnoea, higher SOFA score, IL-6, lymphocyte count; cardiac troponin; BNP/NT-proBNP (if clinical suspicion of heart failure); one marker of inflammation (Ferritin > 1,000 mg/mL, CRP > 25 mg/L, and Il-6 elevation); presence of severe respiratory failure, bilateral infiltration on imaging and progressive non-invasive ventilation requirement, D-dimer > 1,000 mg/mL; LDH > 300 U/L; absolute lymphocyte count < 0.8 billion/L; PCT level (>0.5 ng/mL), and AST > 40 U/liter (, –119). In low-resourced settings, cytokine release syndrome clinical symptoms could be used in the absence or limited availability of diagnostic panels. Fondaparinux is a synthetic pentasaccharide factor Xa inhibitor. Fondaparinux binds antithrombin and accelerates its inhibition of factor Xa. It is chemically related to low molecular weight heparins. Patients with CNS involvement should have cerebral CT or MRI scan and in the if a stroke is suspected also a CT angiography or MRI angiography, in case of epileptic seizures or status epilepticus an EEG and in case of suspected encephalitis a lumbar puncture for cerebro-spinal fluid assessment. Also, bedside neuropsychological assessments are of value. In addition, assessment of CK and myoglobin are of value (neurophysiology as well, but this is not so important acutely). Treatments should include: antiepileptics (for example, levetiracetam 2x1000 mg) and depending on disease condition. SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; COVID-19, coronavirus disease 2019; IV, intravenous; PT, prothrombin time; PTT, partial thromboplastic time; LDH, lactate dehydrogenase; CK, creatine kinase; CBC, complete blood count; BNP, brain natriuretic peptide; NT-proBNP, N-terminal pro hormone brain natriuretic peptide; CRP, c-reactive protein; IL, interleukin; AST, aspartate aminotransferase; SOFA, sequential organ failure assessment score; LMW, low molecular weight; VTE, venous thromboembolism; PE, pulmonary embolism; DVT, deep vein thrombosis; DIC, disseminated intravascular coagulation; CT, computed tomography; NMR, nuclear magnetic resonance; EEG, electroencephalogram; CSF, cerebrospinal fluid; IVIg, intravenous immunoglobulin; DCR, direct current cardioversion; CNS, central nervous system; Mg, magnesium; K, potassium; C, complement component; PCT, procalcitonin.