Therapeutic blockade of granulocyte macrophage colony-stimulating factor in COVID-19-associated hyperinflammation: challenges and opportunities

Abstract

The COVID-19 pandemic is a global public health crisis, with considerable mortality and morbidity exerting pressure on health-care resources, including critical care. An excessive host inflammatory response in a subgroup of patients with severe COVID-19 might contribute to the development of acute respiratory distress syndrome (ARDS) and multiorgan failure. Timely therapeutic intervention with immunomodulation in patients with hyperinflammation could prevent disease progression to ARDS and obviate the need for invasive ventilation. Granulocyte macrophage colony-stimulating factor (GM-CSF) is an immunoregulatory cytokine with a pivotal role in initiation and perpetuation of inflammatory diseases. GM-CSF could link T-cell-driven acute pulmonary inflammation with an autocrine, self-amplifying cytokine loop leading to monocyte and macrophage activation. This axis has been targeted in cytokine storm syndromes and chronic inflammatory disorders. Here, we consider the scientific rationale for therapeutic targeting of GM-CSF in COVID-19-associated hyperinflammation. Since GM-CSF also has a key role in homoeostasis and host defence, we discuss potential risks associated with inhibition of GM-CSF in the context of viral infection and the challenges of doing clinical trials in this setting, highlighting in particular the need for a patient risk-stratification algorithm.

Trial registration: ClinicalTrials.gov NCT04326920.

Figure 1

Role of GM-CSF in homoeostasis, viral response, and inflammation GM-CSF has an important homoeostatic role in the maturation and function of alveolar macrophages, which clear and catabolise surfactant, and in host defence. In response to viral insults (eg, with SARS-CoV-2), alveolar type II epithelial cells secrete GM-CSF, improving the innate immune response of myeloid cells, particularly alveolar macrophages. In severe inflammatory states, GM-CSF production is upregulated by alveolar type II epithelial cells and monocyte-derived M1-like macrophages, thereby stimulating IL-6 production from CD14⁺ and CD16⁺ inflammatory monocytes, increasing Th1 and Th17 T cells and driving the recruitment and priming of neutrophils. The resulting autocrine, positive feedback loop of GM-CSF production further perpetuates the inflammatory milieu. GM-CSF=granulocyte macrophage colony-stimulating factor. IL=interleukin. SARS-CoV-2=severe acute respiratory syndrome coronavirus 2. Th=T helper.

Figure 2

A window of opportunity in hyperinflammation for optimum treatment intervention Hyperinflammation can be initiated by an inciting trigger (eg, SARS-CoV-2 infection) and can progress from an early indolent state to a fulminant and fatal hypercytokinaemia. Withholding potentially lifesaving immunomodulatory treatment until a patient is intubated could result in a missed window of opportunity for optimum therapeutic intervention. SARS-CoV-2=severe acute respiratory syndrome coronavirus 2.