The Role of Cytokines including Interleukin-6 in COVID-19 induced Pneumonia and Macrophage Activation Syndrome-Like Disease

Abstract

Severe COVID-19 associated pneumonia patients may exhibit features of systemic hyper-inflammation designated under the umbrella term of macrophage activation syndrome (MAS) or cytokine storm, also known as secondary haemophagocytic lymphohistocytosis (sHLH). This is distinct from HLH associated with immunodeficiency states termed primary HLH -with radically different therapy strategies in both situations. COVID-19 infection with MAS typically occurs in subjects with adult respiratory distress syndrome (ARDS) and historically, non-survival in ARDS was linked to sustained IL-6 and IL-1 elevation. We provide a model for the classification of MAS to stratify the MAS-like presentation in COVID-19 pneumonia and explore the complexities of discerning ARDS from MAS. We discuss the potential impact of timing of anti-cytokine therapy on viral clearance and the impact of such therapy on intra-pulmonary macrophage activation and emergent pulmonary vascular disease.

Fig. 1

Classical MAS Organ Pattern versus COVID-19 Related Picture. Panel A). The MAS/sHLH picture is associated with viral and other infections that does not have a special tropism for pulmonary tissues. The hyper-activation of T-cells is associated with lymphoid organ hyperplasia with hepatosplenomegaly and adenopathy. The resulting excessive reticuloendothelial system activity manifests as bone marrow haemophagocytosis and deranged liver function tests, deranged lipid profiles as a result of liver Kupffer cell dysfunction. Systemically circulating activated macrophages contribute to disseminated intravascular coagulation (DIC). A similar picture can develop in primary HLH that represents a rare group of immunodeficiency, linked to impaired cytolytic activity due to perforin pathway loss of function, with expansion of immune cells and the lymphoid organs that house them. In primary HLH, cytokine antagonism used with anti-microbial therapy may temporarily help prior to definitive bone marrow transplantation. Pulmonary involvement may be a feature of both pHLH and sHLH. Panel B). There is evidence for MAS/sHLH emerging in the COVID-19 setting that is supported by the abnormal laboratory parameters without reporting of the classical organomegaly pattern described in Fig. 1A. Hyperactivation and over-zealous immune activity appears to be more confined to the lung parenchyma and immediately adjacent bronchial alveolar lymphoid tissue and is associated with ARDS development. Pulmonary haemophagocytosis has has been occasionally reported in human coronavirus infection but not yet been reported in COVID-19 associated pneumonia [56]. .It is proposed that severe widespread alveolar and interstitial inflammation extends to the closely juxtaposed pulmonary vasculature. The normal circulatory fibrinogen levels and regional fibrinolysis with elevated D-dimer formation seen in early COVID-19 pneumonia is not a feature of typical acute onset MAS/HLH. This MAS-like intra-pulmonary inflammation might influence a propensity towards severe local vascular dysfunction including micro-thrombosis and haemorrhage resulting in a lung centric pulmonary intravascular coagulopathy (PIC) presentation rather than a DIC presentation

Fig. 2

Hyper-cytokinaemic Overlaps Between ARDS and MAS. Elevated cytokine levels or hypercytokinaemia are associated with the current COVID-19 infection [20] and independently found in the MAS spectrum and many other settings including sepsis [17]. Cytokines including IL-6 may be substantially elevated in isolated ARDS. The magnitude of cytokine level changes may not be reliable in the differentiation from other cause of elevated cytokine levels including severe infection or tissue destruction and dependable cut-off values do not exist. Superimposed second viral or bacterial infections in either setting may further drive systemic cytokine responses. Therefore, phase 3 studies based on elevated IL-6 levels may encompass a group of ARDS cases without the bone fide MAS phenotype [57].

Fig. 3

Relative Innate and Adaptive Immune Mechanisms in HLH Spectrum Pathology. Immunodeficiency State (Primary HLH) Vs Immunocompetency State (MAS/sHLH. COVID-19 Immunodeficiency State Vs Immunocompetency State. The HLH responses can occur in the setting of both immunodeficiency states and in immunocompetence settings and following adaptive immune system engineering (Panel A and B in blue). In humans with defects in NK and CD8+ T-cells, the inability to kill virally infected cells results in primary HLH with hyper-cytokinaemia that can't be cured with anti-cytokine strategies as genetic defect typically in perforin pathway machinery makes pathogen elimination impossible [58] (Panel A). In CAR-T cell therapy hyper proliferating engineered T-cells may drive MAS/sHLH that only lasts for the duration of the presence of detectable tumour antigen (Panel B). Similar mechanisms may occur in sJIA or autoimmune diseases, but this remains to be fully defined. This model is based on the immunological disease continuum modified for gain or loss of function in innate or adaptive immunity (Reference 43). When COVID-19 hyper-inflammatory or cytokine storm reactions are viewed through the lens of primary and secondary HLH, it is noteworthy that virally induced immunosuppression may play a key role (Panel C). Coronavirus family members including COVID-19 pneumonia is associated with robust interferon suppression, blood lymphopenia including NK cell abnormalities. Such scenarios likely drive macrophage infiltration and the “second wave” of non-type-1 interferon pathway cytokines including IL-6, IL-1, IL-18, INFγ, GM-CSF and others that lead to a blood hyper-cytokinaemic picture (Panel B). It remains to be seen how many cases of COVID-19 related fatalities have mutations in genes associated with the primary HLH disorders and thus closely resemble primary HLH (Panel A). Based on persistent viral shedding from the respiratory tract during CORVID-19 related disease, then an exaggerated immune response including IFN driven and T-cell driven responses that clears the virus but induces pulmonary immune system collateral damage and ARDS offers an explanation for the more typical MAS/sHLH phenotype. Viral clearance in the face of marked hyper-inflammation would be expected in the face of brisk anti-viral antigen responses.

Fig. 4

IL-6 in Viral Pneumoia and Potential Role in Type II Pneumocyte COVID-19 infection. Panel A). Some experimental models of viral pulmonary infection triggering ARDS show that IL-6 may have a protective role with its blockade increasing mortality including reduction and phagocytosis and increased fibrosis depending on model. Panel B). Bacterial, rather than viral infections, originating outside the lung that also trigger ARDS but in this setting IL-6 blockade may be beneficial. The latter is more akin to classical MAS/sHLH where pulmonary pathology, when present, may be due to exogenous factors. However, the fact that IL-6 is detrimental in murine virally induced ARDS cannot be extrapolated to the novel COVID-19 virus infection that shows a tropism for type 2 pneumocytes (Panel C). The COVID-19 suppression of first line interferon responses and abrogation of T-cell responses suggests a role for type 2 pneunocyte gp130 receptor expression and IL-6 in pulmonary pathology [59]. Also in experimental models, IL-6 may either suppress or facilitate viral replication depending on the virus [49], so data on COVID-19 related disease is eagerly awaited.