Cytokine-targeted therapy in severely ill COVID-19 patients: Options and cautions

Abstract

Dear Editor, The understanding of the cytokine storm mechanism(s) and its profile are crucial to developing effective therapeutic interventions in COVID-19. In this line, cytokine storm blockers and immune-host modulators are currently being applied in severely ill COVID-19 patients to cope with the overwhelming inflammation. However, most of the current reports highlighted different elevated cytokine patterns among severely ill COVID-19 patients, suggesting that more care should be taken before immunosuppressive therapy by cytokine blockers in COVID-19. Here, we summarize the more common cytokine profiles and cytokine-targeted therapy approaches that have been reported for severe COVID-19 patients. Finally, we underscore the urgent need to identify a precise cytokine panel before the administration of selective immunosuppressive therapy. Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS?CoV-2) with the symptoms including fever, dry cough and shortness of breath [1, 2]. Most COVID-19 patients will develop mild to moderate symptoms, while some infected people may face to hyper-inflammation induced by massive cytokines/chemokines production, called as cytokine storm, which may lead to fatal pneumonia and acute respiratory distress syndrome [1, 2]. Although, there is no specific antiviral therapy for COVID-19, understanding of cytokine storm mechanism in this disease can help to speculate possible therapeutic interventions [3]. Current reports have presented different cytokine profiles in patients with severe COVID-19 [1, 4-9]. For example, the higher levels of interleukin (IL)-2, IL-7, IL-10, tumor necrosis factor (TNF), granulocyte-colony stimulating factor (G-CSF), interferon gamma-induced protein 10 (IP-10; CXCL10), MCP-1 (CCL2) and MIP-1A (CCL3), but not IL-6, have been first shown in intensive care unit (ICU) patients compared to non-ICU patients [1]. Subsequent studies revealed the contribution of other cytokines, including IL-1?, IL-1ra, IL-2R, IL-6, IL-8 (CXCL8), IL-17, interferon (IFN)-? and GM-CSF (granulocyte-macrophage colony-stimulating factor), during severe COVID-19 infections [4, 5, 8, 9]. Figure 1 displays the protein-protein interaction between these cytokines/chemokines. In most existing reports, the elevated levels of several cytokines/chemokine (ie., IL-6, IL-10, IFN-?, TNF and IP-10), have been greater emphasized in severely ill (ICU) COVID-19 patients than mild to moderate (non-ICU) group [1, 4-7]. Involvement of the T helper 2 cytokine IL-10, that suppresses inflammation, is a prominent feature of all reports, and an imbalance and/or exhaustion of T cells may be also involved. [1, 10]. Several approaches, including global targeting of the inflammation or neutralizing a single key inflammatory mediator, are being employed to cope with cytokine storm in COVID-19. Among key cytokines, IL-6 has attracted high levels of interest and antibodies that block the IL-6 receptor (tocilizumab and sarilumab) are currently under phase 2/3 clinical trials for the potential treatment of COVID-19 [2]. Targeting IFN-? is another promising approach, which has been highlighted by launching a clinical trial for JAK–STAT inhibitor (ruxolitinib) for controlling COVID-19 severity. [11] TNF acts upstream of IL-6 and anti-TNF therapies previously revealed protective effects in lethal SARS-CoV infection [12]. Several TNF-blocking antibodies (eg., adalimumab, etanercept, and golimumab) are successfully used to treat inflammatory diseases, and these therapies have been urgently recommended for the hospitalized COVID-19 patients [13]. IL-10 is likely upregulated to counter overwhelming infection during SARS-CoV-2 infection, but it may be also involved in the infiltration of inflammatory cells and lung fibrosis [14]. IL-10 blocking, alone or in combination with programmed cell death protein 1 (PD-1), is promising for reinvigorating exhausted T cells and may control COVID-19 pathogenesis [10]. Despite the benefits, there are still disadvantages, such as the development of chronic inflammatory disorders, thus more experimental studies should be done to clarify whether overactivation or ablation of IL-10 could be helpful for severe COVID-19. In some countries, including Iran and Turkey, tocilizumab is a recommended therapeutic strategy for ICU patients with severe COVID-19 [15]. However, it should be note that the elevated IL-6 levels, in common with other cytokines such as TNF, have no specific pattern in all severe COVID-19 patients, so that their levels were not associated with the disease severity in some patients [1, 4, 5]. Therefore, as patients with severe COVID-19 represent the differential cytokine patterns, more care should be taken before immunosuppressive therapy by cytokine blockers in COVID-19. This is important that the doctors evaluate a cytokine panel, at least including IL-6, IFN-?, and TNF-?, to precisely identify the needs of each patient before administration of selective immunosuppressive therapy. Obviously, a combination of immunosuppressive therapy with antiviral therapies that diminish virus titer should be also into account. Declaration of interests The authors declare no conflict of interest. Keywords: Covid-19 , SARS-CoV-2 , cytokine storm