Should we stimulate or suppress immune responses in COVID-19? Cytokine and anti-cytokine interventions

Abstract

The coronavirus disease-19 pandemic (COVID-19), which appeared in China in December 2019 and rapidly spread throughout the world, has forced clinicians and scientists to take up extraordinary challenges. This unprecedented situation led to the inception of numerous fundamental research protocols and many clinical trials. It quickly became apparent that although COVID-19, in the vast majority of cases, was a benign disease, it could also develop a severe form with sometimes fatal outcomes. Cytokines are central to the pathophysiology of COVID-19; while some of them are beneficial (type-I interferon, interleukin-7), others appear detrimental (interleukin-1β, -6, and TNF-α) particularly in the context of the so-called cytokine storm. Yet another characteristic of the disease has emerged: concomitant immunodeficiency, notably involving impaired type-I interferon response, and lymphopenia. This review provides an overview of current knowledge on COVID-19 immunopathology. We discuss the defective type-I IFN response, the theoretical role of IL-7 to restore lymphocyte repertoire, as well as we mention the two patterns observed in severe COVID-19 (i.e. interleukin-1β-driven macrophage activation syndrome vs. interleukin-6-driven immune dysregulation). Next, reviewing current evidence drawn from clinical trials, we examine a number of cytokine and anti-cytokine therapies, including interleukin-1, -6, and TNF inhibitors, as well as less targeted therapies, such as corticosteroids, chloroquine, or JAK inhibitors.

Keywords: Anakinra; COVID-19; Cytokine storm; IL-1; IL-6; Sars-CoV2; Tocilizumab; Type-I interferon.

Fig. 1

Kinetics and intensity of the antiviral response are decisive in COVID-19 outcome. In mild to moderate COVID-19, the early antiviral response, mostly type-I interferon (IFN), allows the rapid reduction of viral load and prevents T-cell depletion and hypercytokinemia. In severe COVID-19, delayed (solid green line) or low (dotted green line) antiviral response results in elevated lung cytokine/chemokine levels, impaired virus-specific T-cell responses, and acute clinical deterioration. Optimal times for therapeutic interventions are proposed. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 2

The immunopathology of COVID-19. The entry of SARS-CoV-2 in epithelial/endothelial cells, via binding to ACE2 (and CD147), induces apoptotic and necroptotic pathways resulting in lung injury and release of numerous chemokines driving the recruitment of large amounts of immune cells within the lungs. Dendritic cells (DCs) and plasmacytoid DCs (pDCs, the main source of type-I interferon (IFN)), along with alveolar macrophages and neutrophils, promote the innate immune response by secreting alarmins and antiviral or proinflammatory cytokines, plus presenting the antigen to adaptive immune cells. SARS-CoV-2 may have evolved strategies to downregulate the type-I IFN response and induce T cell apoptosis. The recognition of molecular patterns (viral RNA, particles, or danger signals) by various Toll-like receptors (TLRs), NOD-like receptors (NLRs) or RIG-I like receptors (RLRs) activates the transcription and release of proinflammatory mediators, such as interleukin (IL)-1β, -6, -18, and tumor necrosis factor (TNF)-α. These mediators further skew naïve T-cells to Th1 or cytotoxic lymphocytes (CTLs or CD8+), which in turn secrete amounts of cytokines. A pro-inflammatory feedforward loop of cytokines on innate immune cells results in cytokine storm, coagulopathy, and acute respiratory distress syndrome (ARDS). COVID-19 cytokine storm may intertwine two mechanisms; one highly suggestive of macrophage activation syndrome (hemophagocytic lymphohistiocytosis, HLH) driven by IL-1β, and another pattern characterized by immune dysregulation driven by IL-6, which triggers immunoparalysis (decreased HLA-DR on CD14 monocytes) and global lymphopenia.