What Are the Key Cytokines Produced in the Lung During Cytokine Release Syndrome in COVID-19 Patients and Is Cytokine Neutralizing Therapy Effective in Them?

The Significance of COVID-19

Since its first detection in Wuhan province of China around December 2019, the SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) has rapidly spread to every corner of the globe and forced many countries to undertake unprecedented measures to mitigate the resulting public health crisis. By the end of May 2022, the virus has infected more than 500 million individuals and caused over six million deaths worldwide (WHO, 2022). As reflected by the statistics, the clinical outcomes of the coronavirus disease 2019 (COVID-19) can be highly heterogeneous. The majority of infected individuals — approximately 81% — are likely to develop mild symptoms (Wu and McGoogan, 2020). However, despite the chance of advancing to severe or critical cases, such as acute respiratory distress syndrome (ARDS) or multiple organ dysfunction syndrome (MODS) is lower, the disease is not to be underestimated. The fatality rate of COVID-19 can reach as high as 49% among patients with serious clinical presentations (Wu and McGoogan, 2020).

Does Cytokine Release Syndrome Fuel COVID-19 Severity?

During the early phase of the pandemic, there were mixed reports on what drove the COVID-19 severity. Remy et al. (2020) argued that profound immunosuppression — and not hyperinflammatory cytokine storm — was the primary endotype of COVID-19. Similarly, failure of viral clearance was suggested to aggravate disease severity more than early hyper inflammation (Sharma et al., 2020). However, accumulating evidence has indicated that severe COVID-19 is mainly propelled by hypercytokinemia or what is more commonly referred to as “cytokine storm”. As the name suggests, “cytokine storm” reflects the systemic hyper-amplification state of immune response that is mediated by the excess production of early response pro-inflammatory cytokines by monocytes, resembling the features of Cytokine-Release Syndrome and or Macrophage Activation Syndrome. This condition is deemed more deleterious in COVID-19 than the viral infection itself, including in mild COVID-19 cases. For instance, pro-inflammatory eicosanoids in macrophages have been demonstrated to remain upregulated months after moderate SARS-CoV-2 infection, indicating persistent inflammation long after viral clearance (Bohnacker et al., 2022). In addition, in serious COVID-19 cases, Ruan et al. (2020) suggested that the disease fatality is possibly linked to cytokine storm upon finding significantly higher interleukin-6 (IL-6) in patients who died than recovered. A single-cell analysis of peripheral blood samples also revealed increased expression of hypercytokinemia-associated genes, including TNF, IL10, CCL3, and IL6 in two COVID-19 patients with severe symptoms (Guo et al., 2020). Together, the previous studies tend to support the notion that cytokine storm is indeed the predominant pathophysiologic process that underlies COVID-19 morbidity and fatality. This in turn raises another question: can neutralizing cytokines that are implicated in the hyperinflammation improve COVID-19 prognosis?

COVID-19 and the Lung

Given that the lung is the most affected body part in COVID-19, this essay will narrow the focus on key cytokines that are directly involved in severe SARS coronavirus-induced pulmonary condition. A recent study found that the hyper-elevated cytokines that are associated with acute lung injury in COVID-19 are restricted to IL-1β, IL-2, IL-6, IL-8, IL-10, and TNFα (tumour necrosis factor α) (Vaka et al, 2022). Although those cytokines are indispensable for the immunoinflammatory responses in the human body, in abundance, however, they can inflame alveoli and pulmonary tissue. This in turn may lead to immunothrombosis and hypoxemia (Shaw et al., 2021). Here, the interleukin-6 (IL-6) is of particular interest because compared to the other cytokines, its raised expression in circulation has been proposed to independently predict the degree of lung injury and mortality in COVID-19 pneumonia in a more reliable manner (Chen et al., 2020). Herold et al. (2020) reported that IL-6 and C-Reactive Protein values of above 80 pg/mL and 97 mg/L, respectively, are predictive of respiratory failure in COVID-19 patients. Thus, currently available neutralizing therapeutic treatments against IL-6 and other key cytokines will be further discussed.

IL-6 Signalling Pathway

The pathologic elevation of IL-6 in COVID-19 has been proposed to be driven by pro-inflammatory and pro-fibrotic Angiotensin II (Ang II). The SARS-CoV-2 uses a Spike protein to bind to angiotensin-converting enzyme (ACE2) receptors for entry to alveolar type II (AT2) pneumocytes. Under physiological conditions, the ACE2 is a core component of the renin-angiotensin system (RAS) which regulates the water-salt balance and blood pressure. The ACE2 enzyme can degrade Ang II to inactive metabolites, however, in COVID-19, this protective action is suppressed, leading to the accumulation of Ang II. Ang II has been reported to stimulate immune system cells and the production of inflammatory cytokines, including IL-6 and TNFα (Verdecchia et al., 2020). Furthermore, the depletion of ACE2 increases the interaction between Ang II and Angiotensin II receptor 1 (AT1R). The ACE2/Ang II/AT1 cascade can in turn activate ADAM17 protease which cleaves immunological cytokines into mature forms (Queiroz et al., 2020). Additionally, ADAM17 also plays a key role in the shedding of soluble Interleukin 6-receptor (sIL-6R), leading to more receptors available for binding and enhanced cytokine signalling (Riethmueller et al., 2016).

To exert its inflammatory actions, IL-6 must bind to its receptors that are available in both soluble (sIL-6R) and membrane-anchored (mIL-6R) forms. The binding results in the activation of gp130 and subsequently JAK (Janus kinase)/STAT (signal transducer and activator of transcription) pathway. The STAT3 is known to control the expression of inflammatory transcription factors, including NFκB, which promote the production of pro-inflammatory mediators. In COVID-19, signalling via sIL-6R (also known as the trans-signalling pathway) is more frequently observed. The trans-signalling pathways allow IL-6 to target cells with fewer IL-6Rs. Given the ubiquitous expression of gp130 membrane proteins, it is thus no surprise that the trans-signalling pathway is often observed in diverse inflammatory diseases (Su et al., 2017). Based on the aforementioned processes, several therapeutic targets to neutralize the IL-6 deleterious effects can be identified, such as acting on the cytokine itself, its receptors, or the downstream JAK/STAT pathway. However, how effective are they?

IL-6 Blockers

For anti-IL-6 monoclonal antibodies, their ability to bind strongly to IL-6 is expected to prevent the cytokine from interacting with mIL-6R or sIL-6R and block the cytokine’s biological activity. At present, the only approved anti-IL-6 antibody therapy by the FDA is siltuximab, which is traditionally used for the treatment of Castleman’s disease. The downregulation of soluble IL-6 levels through this method has been reported to improve the inflammatory burden of COVID-19. According to SISCO (Siltuximab in Serious COVID-19) trial, siltuximab reduced the need for ventilatory support in 33% of patients in the treatment group and further stabilized the conditions in another 43% of patients (Gritti et al., 2020). Similarly, therapeutic therapies targeting the JAK/STAT pathway also appear promising. A frequently used JAK inhibitor in rheumatoid arthritis, baricitinib, exerts its function by binding competitively to the kinases’ ATP-binding sites. The inhibitor has been shown to induce a significant reduction in the serum levels of inflammatory cytokines such as IL-6, IL-1β, and TNF-α; and enhanced production of antibody against the SARS-CoV-2 spike protein in the NCT04438629 trial. Those effects were linked to a steady increase in PaO2/FIO2 (P/F) ratio and decreased requirement for breathing devices (Bronte et al., 2020). A randomised placebo-controlled COV-BARRIER trial on baricitinib has also been conducted. The result revealed similar COVID-19 disease progression between the baricitinib and standard-of-care groups, although the mortality rate is reduced in the non-placebo-treated patients (Marconi et al., 2021). It is tempting to speculate that the discrepancy between the two studies may be due to age differences. The treatment and placebo groups in the NCT04438629 trial have a median age of 68 and 77.5 years old, respectively. In contrast, the patients enrolled in the COV-BARRIER trial seem younger with a mean age of 57.8 in the baricitinib group and 57.5 in the standard-of-care group.

In support of the efficacy of cytokine neutralizing therapy in COVID-19 cytokine syndrome, another type of IL-6 signalling blockade treatment, tocilizumab, has received authorization in 16 countries globally, including Emergency Use Authorization (EUA) from the U.S. FDA, for use in critical hospitalized patients (Genentech, 2022). This drug inhibits IL-6 signal transduction by binding to both mIL-6R and sIL-6R. To date, tocilizumab has been claimed to have treated over one million individuals worldwide (Genentech, 2022). For the popularity of its effectiveness, tocilizumab has become a subject of various COVID-19 clinical outcomes. In the RECOVERY (Randomised Evaluation of COVID-19 Therapy) trial that enrolled COVID-19 patients with severe systemic inflammation and hypoxia, the trial outcomes revealed that in comparison to individuals who were treated with only systemic corticosteroids, the tocilizumab-receiving group had a greater chance of being discharged from hospital and avoiding the endpoint of mechanical ventilation or mortality (RECOVERY Collaborative Group, 2021). Similarly, the EMPACTA (Evaluating Minority Patients with Actemra) trial with participants at an earlier stage of COVID-19 pneumonia who were not receiving supplemental ventilation showed that the Actemra (tocilizumab) plus standard care was able to reduce progression to assisted ventilation or death compared to dexamethasone plus standard care (Salama et al., 2020). However, despite the positive outcomes of using anti-IL-6 receptor blocker in COVID-19, controverting results have also been reported. For instance, the COVACTA trial showed that the administration of tocilizumab in hospitalized COVID-19 patients with severe pneumonia did not yield significantly different results from the placebo group in terms of mortality rates and clinical status (Rosas et al., 2021). Likewise, the REMDACTA trial found that tocilizumab provides no additional benefit over antiviral remdesivir and corticosteroids (Tatham et al., 2021).

Other Cytokines Blockers

Besides IL-6, the cytokines of IL-1 family which act upstream of IL-6 are also of great concern in the COVID-19 cytokine storm. Although IL-1 may not be as activated in COVID-19 as IL-6, however, the blockade of NLRP3/AIM2 inflammasome stimulation and subsequent IL-1 production have been argued to provide an advantage over IL-6 antagonists and dexamethasone. In COVID-19 patients with moderate to severe ARDS and hyperinflammation that showed no response to tocilizumab and other standard-of-care treatment, the administration of anakinra was found to reduce mechanical ventilation necessity and fatality (Alijotas-Reig et al., 2020). This is consistent with a finding by Aomar-Millán et al. (2021) that COVID-19 patients with severe pneumonia and moderate hyperinflammation who were irresponsive to tocilizumab and corticosteroids could benefit from supplemental anakinra.

For other cytokines blockers, TNF-alpha inhibitor such as infliximab has been demonstrated to promote recovery in severe and critical patients with hypoxic respiratory failure by inhibiting pathological inflammatory signalling in the NCT04425538 trial (Hachem et al., 2021). At present, to the best of my knowledge, there is no clinical evidence of the efficacy of IL-2, IL-8, and IL-10 inhibitors. However, an anti-IL-8 inhibitor for hospitalized COVID-19 patients was previously registered for a clinical trial (NCT04347226) although terminated early. In addition, an observational study on IL-6 inhibitor, siltuximab, suggested that the treatment also modulated IL-8 levels which was linked to systemic inflammation inhibition and enhanced clinical outcomes (Gritti et al., 2021).

Current Challenges and Future Considerations

Referring back to the main question of this essay, is cytokine antagonist effective in treating COVID-19 hyperinflammation? The positive outcomes from the various clinical trials suggest that targeted inhibition of key cytokines in COVID-19, in particular IL-6, IL-1, TNF-α, and IL-8, may be effective. Furthermore, as indicated in the previously mentioned examples, when blocking one type of cytokine such as IL-6 does not work, inhibiting the other inflammatory mediator such as IL-1 may produce the desired clinical effects. Targeting multiple pro-inflammatory cytokines simultaneously as seen in combining tocilizumab and anakinra treatment in severe COVID-19 patients also resulted in synergetic benefits (Aomar-Millán et al., 2021). Together, these findings further support that pathological pro-inflammatory cytokines are suitable targets in COVID-19.

At present, dexamethasone is a widely used standard of care for hospitalized COVID-19 patients. Although this anti-inflammatory medication has been demonstrated to lower fatality rates in patients who were receiving respiratory support (RECOVERY Collaborative Group, 2021), targeted inhibition of the key cytokines in COVID-19 hyperinflammation seems superior, as indicated in the aforementioned studies. This suggests that individual inhibition and or combinatorial targeting of multiple hyperinflammation-associated cytokines are potentially more beneficial than non-selective suppression of a broad range of NF-κB-regulated pro-inflammatory cytokines. Furthermore, the broad-spectrum medication may lead to adverse immunosuppression and secondary infections compared to targeted inhibitions.

Given that IL-6 is the most significant predictor of disease severity, IL-6 blocker, in particular tocilizumab, has been a major focus of research in COVID-19 drug repurposing. However, as reported in several clinical trials, IL-6 antagonists do not always produce the desired results. The contradicting outcomes may be due to the diversity in the background of participating patients. For example, the baricitinib study that reported a positive outcome likely enrolled older patients. The more senior patients may have a higher number of comorbidities, and hence age and underlying medical conditions potentially contribute to the dynamics of inflammatory responses. In treatment using tocilizumab, it has been suggested that the inhibitor works more effectively in severe patients than in individuals with mild COVID-19 symptoms (Cáceres et al., 2020). Furthermore, the timing of therapy administration is also crucial. The delivery of tocilizumab has been reported to be more efficacious at an earlier stage of COVID-19 pneumonia before the worsening of respiratory conditions (FiO2 < 0.5), whereas later administration after ventilatory support necessity (FiO2 > 0.5) did not lead to clinical improvement (Hernández-Mora et al., 2020). In addition, the patient’s drug history also contributes to the cytokine antagonist efficacy. In the COVACTA trial that showed comparable outcomes between treatment and control groups, only approximately 22% of patients were receiving corticosteroids at the time of enrolment. In contrast, in the RECOVERY trial that also enrolled severe patients, 82% of participants were on corticosteroids. Thus, there seem to be “prerequisites” for cytokines blockers to effectively treat COVID-19 cytokine storm. Future studies are needed to evaluate the subset of COVID-19 patients in relation to disease stage, comorbidity, and drug history that may benefit the most from targeted cytokine inhibitors.

It may also be worth investigating the extent to which improving COVID-19 hyperinflammation is preferred over improving endothelial dysfunction and hypercoagulation. For example, tocilizumab has been proposed to benefit COVID-19 patients not only for its anti-inflammatory properties, but also for the inhibitor’s ability to improve endothelial function (Ikonomidis et al., 2020). In addition, the IL-1 antagonist, anakinra, can also reduce the hypercoagulation state on top of hyperinflammation by inhibiting IL-1α-mediated thrombin activation and platelet production (Gupta, 2022). Future studies on this topic, therefore, may shed a light on other potential treatments for severe COVID-19 patients.

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