3.2  Indirect inflammatory response - cytokine storm
Inflammation plays an important role in the development of cardiovascular impairment in the setting of COVID-19. Similar to SARS-CoV and MERS-CoV infection, SARS-CoV-2 infection can also trigger excessive host immune responses, leading to extensive and uncontrolled release of proinflammatory cytokines termed as cytokine storm (Restrepo & Reyes, 2018; Zumla, Hui, Azhar, Memish, & Maeurer, 2020). Cytokines play a pivotal role in the immune response to defend against different bacterial and viral infections. However, it has also been established that dysregulated, amplified and uncontrolled immune responses may cause immunopathology leading to systematic self-attack contributing to multiple organ damage and cardiovascular injury secondary to SARS-CoV-2 infection (Zhang et al., 2020). A plethora of studies have shown increased amounts of cytokines, such as interleukin-6 (IL-6), IL-7, IL-8, IL-9, IL-10, IL-1β, IL-1RA, tumor necrosis factor-alpha (TNF-α), granulocyte-macrophage colony-stimulating factor, fibroblast growth factor, macrophage inflammatory protein 1 alpha, platelet-derived growth factor, monocyte chemoattractant protein and vascular endothelial growth factor in the serum of COVID-19 patients, especially in ICU patients (Chen, Zhou, et al., 2020; Conti et al., 2020; Huang et al., 2020; Wang, Hu, et al., 2020; Zhang, Zhao, Zhang, et al., 2020). Importantly, there is a strong correlation between serum cytokine levels and mortality rates in patients with COVID-19. The amplified and uncontrolled inflammatory response induces cellular apoptosis or necrosis of the affected cells. This is followed by increased permeability of blood vessels leading to the accumulation of inflammatory monocytes, macrophages and neutrophils in different body organs fueling the inflammatory cascade (Channappanavar et al., 2016). The vicious circle intensifies the situation as the cytokine storm is further stimulated and the regulation of immune response is lost resulting in severe consequences. Collectively, this indicates the uncontrolled inflammatory response is a major factor in the adverse response observed in COVID-19 patients. In that sense, it would seem reasonable that ameliorating the exaggerated immune response would improve the clinical outcomes in patients with COVID-19 (Table 3 ).
Table 3 Overview of the pharmacological approaches under investigation for ameliorating cytokine storm, hyperinflammatory state and the associated secondary organ complications in COVID-19 patients.
Pharmacological intervention Sample size and criteria Treatment protocol Key findings Conclusion Reference
• Tocilizumab for IL-6 cytokine release syndrome • Multicenter Randomized controlled trial (RCT)
• Severe COVID-19 infections
• 18–85 years of age
• Elevated serum IL-6
•  N = 94 standard therapy + tocilizumab
•  N = 94 standard therapy • 4–8 mg/kg tocilizumab i.v. once
• Additional dose if fever persists in 24 h after first dose • First phase showed normalization of fever within 24 h of tocilizumab
• Improved respiratory function, oxygenation, and pulmonary lesions • Phase 4 study completed in May 2020
• Results pending
• Tocilizumab may be a promising investigative therapy to reduce cytokine release syndrome and associated multi-organ damage (ChiCTR2000029765, 2020)
• Tocilizumab to mitigate cytokine storm and associated complications • Retrospective cohort study
• >18 years of age
• Intensive care unit (ICU) COVID-19 hospitalization
• Primary endpoint of hospital-related mortality
•  N = 210 standard care + tocilizumab
•  N = 420 standard care • 400 mg single dose or 8 mg/kg tocilizumab
• 88% required 1 infusion, 12% received a second infusion • Hazard ratio (HR) 0.71 for hospital related mortality (95% confidence interval (CI) 0.56–0.89)
• Treatment was more effective in patients with C-reactive protein (CRP) >15 mg/dL
• HR 0.48 (95% CI 0.30–0.77) than those with CRP <15 mg/dL HR 0.92 (95% CI 0.57–1.48) • Tocilizumab treatment is associated with a lower rate of mortality, particularly in those with enhanced inflammatory state
• Double blind RCT recently completed with results pending NCT04320615 (Biran et al., 2020)
• Tocilizumab to mitigate cytokine storm • Prospective observational study
• Severe or critical COVID-19 infection
• 25 to 88 years of age
•  N = 21 tocilizumab + standard therapy
• 42.9% had CVD • 4–8 mg/kg or 400 mg tocilizumab i.v. once
• 85.7% received single dose of tocilizumab, 14.3% required second dose within 12 h of first dose • Fever normalized within 24 h
• Reduced O2 therapy requirements
• Minimal improvement in IL-6 levels
• CT lung lesion improvement
• All patients discharged • Limited sample size and no control group
• Tocilizumab treatment in severe COVID-19 cases may improve clinical symptoms in hyperinflammatory state (Xu et al., 2020)
• Intensive methylprednisolone regimen +/− tocilizumab for management of cytokine storm • Prospective observational study
• O2 sat ≤ 94% OR tachypnea, elevated CRP, high D-dimer
• Primary outcome of hospital discharge or clinical improvement
•  N = 86 methylprednisolone +/− tocilizumab
• N = 86 standard care • Stage 1: Immediate methylprednisolone 250 mg i.v. on day 1, then 80 mg on days 2–5
• Stage 2 (lack of clinical improvement or worsening respiratory status): Add tocilizumab 8 mg/kg i.v. once between days 2–5 • Improvement in respiratory status HR 1.79 (95% CI 1.20–2.67)
• Improvement reached in a shorter time vs. control
• Reduced hospital mortality and need for mechanical ventilation • Short duration of intensive immunosuppressive therapy is associated with improved clinical outcomes in patients with hyperinflammaory state (Ramiro et al., 2020)
• Ruxolitinib treatment for elevated cytokine levels and inflammatory response • Prospective RCT
• 18 to 75 years of age with severe infection
• Primary outcome of time to clinical improvement
•  N = 20 ruxolitinib + standard care
•  N = 21 placebo + standard care • Ruxolitinib 5 mg twice daily
• Placebo vitamin C 100 mg twice daily • No difference in primary endpoint HR 1.669 (95% CI 0.836–3.335)
• Improvement in lung computerized tomography (CT) scans
• Significantly reduced cytokine levels and CRP by day 3 • Ruxolitinib may hasten time of chest CT scan improvement and mitigate systemic inflammation (Cao et al., 2020)
• Anakinra for targeting the cytokine inflammatory cascade through IL-1 blockade • Open label case series
• Elevated CRP N = 9
• 6/9 with CVD risk factors (diabetes, obesity)
• 3/9 with hypertension • Anakinra 100 mg every 12 h s.c. on days 1–3
• Anakinra 100 mg once daily s.c. on days 4–10 • Fever subsided by day 3
• CRP normalized in 5 patients by day 11
• Halted progression of CT lung lesions
• 100% survival • Small case series, potential for confounding factors
• Potential therapy to target inflammatory cascade
• Positive results in patients with hypertension and other CVD risk factors (Aouba et al., 2020)
• Ana-COVID study
• Anakinra for COVID-19 hyperinflammatory state • Prospective/retrospective cohort study
• Hospitalized adults with critical lung function
• Cohort with CVD (hypertension, stroke, cardiopathy)
• Primary outcome of ICU admission with mechanical ventilation or death
•  N = 52 anakinra + standard care
•  N = 44 standard care • Anakinra 100 mg s.c. twice daily for 3 days
• Then anakinra 100 mg s.c. once daily for 7 days • Significantly reduced need for mechanical ventilation or death HR 0.22 (0.11–0.41) • Anakinra may be associated with improved outcomes in patients with severe COVID-19 infection, including those with CVD and history of cardiovascular events
• May be due to mitigation of inflammatory cascade (Huet et al., 2020)
The innate immune system detects viral infections by using pattern recognition receptors, particularly Toll-like receptors (TLR), to recognize pathogen-associated molecular patterns of the virus including lipids, lipoproteins, proteins and nucleic acids (Li et al., 2020). Activation of the TLR increases the expression of the transcription factors nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), interferon (IFN) regulatory factor 3 and mitogen-activated protein kinases, which subsequently induce the expression of a myriad of inflammatory factors (Akira, 2009). For example, the binding of SARS-CoV-2 to TLR activates the NF-κB inflammatory pathway triggering the transcription of the different components of the NLRP3 (NOD-, LRR-, and pyrin domain-containing 3) inflammasome (Chen, Moriyama, Chang, & Ichinohe, 2019; Siu et al., 2019). The NLRP3 inflammasome is a large multiple protein platform consisting of main 3 components, the NLRP3 scaffold, the adapter component apoptosis-associated speck-like protein carrying a caspase activation and recruitment domain and the inactive zymogen procaspase-1 (Elliott & Sutterwala, 2015; Latz, Xiao, & Stutz, 2013). Upon activation of the NLRP3 inflammasome and once assembled, procaspase-1 is converted into the active effector protease caspase-1, which then causes cleavage and maturation of proinflammatory cytokines pro-interleukin-1β (pro-IL-1β) and pro-IL-18 into their corresponding active forms, inflammatory IL-1β and IL-18. This, in turn, triggers a cascade of other downstream mediators of inflammation such as TNF-α, IL-6, prostaglandins and leukotrienes which induces more tissue damage, fever, and fibrosis (Conti et al., 2020; Yue et al., 2018). Based on the robust inflammatory response triggered by the NLRP3 inflammasome cascade, targeting the pathway has potential therapeutic value, which can reduce the detrimental consequences of uncontrolled inflammation from SARS-CoVs infections.
Inflammation is well known to participate in various CVDs, such as atherosclerosis, coagulopathy, coronary artery disease and HF (Libby, Ridker, & Maseri, 2002). In the majority of severe cases of COVID-19, the cytokine storm has been coupled with elevated levels of erythematosus sedimentation rate and C-reactive protein (CRP). Subsequently, hypercoagulation and disseminated intravascular coagulation would present as thrombosis, thrombocytopenia and gangrene of the limbs (Siddiqi & Mehra, 2020; Zhang, Zhao, Zhang, et al., 2020). The identification of key cytokines such as TNFα in patients with HF demonstrated a strong positive correlation between cytokines and the severity of left ventricular dilation/hypertrophy and left ventricular dysfunction (Dibbs et al., 2003; Janczewski et al., 2003). Other evidence indicates increased IL-1β and IL-6 levels detected in patients with acute myocarditis and acute MI (Xu, Shi, et al., 2020). Increased IL-6 levels have been associated with long QT-syndrome in patients with systemic inflammation, leading to higher risks for arrhythmias such as torsade de pointes (Aromolaran et al., 2018). As well, the level of IL-6 can be used as a predictor of adverse cardiovascular events after acute coronary syndrome and chronic HF (Fanola et al., 2017; Held et al., 2017). The serum levels of IL-8 are increased in patients with acute MI and is associated with higher mortality rates (Cavusoglu et al., 2015). Collectively, we can conclude there is a strong correlation between elevated inflammatory markers and the adverse cardiovascular outcomes observed in patients with COVID-19 suggesting the potential role of an inflammatory storm in the development and progression of cardiac injury.
Importantly, it has been reported that populations at high risk to develop the more severe forms of cardiac complications secondary to COVID-19 are patients with advanced age, obesity, metabolic syndrome, hypertension and diabetes. These conditions share a common feature where immune changes favour a hyperinflammatory state and compromised inflammatory resolution (Bruunsgaard & Pedersen, 2003; Goldstein, 2010; Lawrence & Gilroy, 2007; Rius et al., 2012). Therefore, traditional cardiovascular treatment plus anti-inflammatory therapy targeting key steps and components of the cytokine storm could be hypothesized as a therapeutic strategy and management of cardiovascular impairment in severe cases of COVID-19. As the inflammatory response in different organs share common pathways, ameliorating the systematic inflammatory response will benefit the cardiovascular system and have potential advantages for other organs.