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).

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.

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.

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.

References

ALIJOTAS-REIG, J., ESTEVE-VALVERDE, E., RUIZ-HIDALGO, D., LOPEZ-SANCHEZ, G., MARTINEZ-VALLE, F., TRAPE-PUJOL, J. AND MIRO-MUR, F. (2020) Anakinra as rescue therapy to treat patients with severe COVID-19 refractory to tocilizumab. Archives of Clinical and Biomedical Research. 5, 959–970.

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