Anti-inflammatory therapy for COVID-19 infection: the case for colchicine

Abstract

The search for effective COVID-19 management strategies continues to evolve. Current understanding of SARS-CoV-2 mechanisms suggests a central role for exaggerated activation of the innate immune system as an important contributor to COVID-19 adverse outcomes. The actions of colchicine, one of the oldest anti-inflammatory therapeutics, target multiple mechanisms associated with COVID-19 excessive inflammation. While many COVID-19 trials have sought to manipulate SARS-CoV-2 or dampen the inflammatory response once patients are hospitalised, few examine therapeutics to prevent the need for hospitalisation. Colchicine is easily administered, generally well tolerated and inexpensive, and holds particular promise to reduce the risk of hospitalisation and mortality due to COVID-19 in the outpatient setting. Successful outpatient treatment of COVID-19 could greatly reduce morbidity, mortality and the demand for rare or expensive care resources (front-line healthcare workers, hospital beds, ventilators, biological therapies), to the benefit of both resource-replete and resource-poor regions.

Keywords: chemokines; cytokines; immune system diseases; inflammation; therapeutics.

Figure 1

Model of COVID-19 severity. IL, interleukin.

Figure 2

Proposed pathophysiology of acute vascular inflammation in SARS-CoV-2 viral illness and potential therapeutic targets of colchicine. (A) Macrophage-driven inflammation leads to inflammasome activity, cytokine production and endothelial and neutrophil activation, with surface expression of selectins, integrins and intercellular adhesion molecules promoting neutrophil adhesion to the vasculature. Colchicine inhibits E-selectin and L-selectin expression on neutrophil and endothelial surfaces. (B) Neutrophils migrate through the endothelium following chemoattractant gradients. Colchicine impairs the rheologic properties of the neutrophil cytoskeleton, limiting theirability to transmigrate. (C) Inflammasome-generated cytokines, including IL-1β and IL-6, drive additional macrophage activation and cytokine production, in an accelerating pattern known as a cytokine storm. Colchicine inhibits the NLRP3 inflammasome, with the potential to prevent the development of cytokine storm. (D) Neutrophil activation releases neutrophil elastase, which inhibits tissue factor pathway inhibitor. Diminished tissue factor pathway inhibitor activity, along with endothelial injury, promote thrombin generation and platelet activation. In addition, neutrophils release α-defensin, associated with larger and more extensive thrombi. Colchicine inhibits neutrophil elastase and α-defensin release. (E) Neutrophils interact with platelets to form aggregates that are a feature of thrombosis. Colchicine decreases neutrophil-platelet aggregation. CRP, C reactive protein; IL, interleukin; NLRP3, nod-like receptor protein 3; TNF, tumour necrosis factor.

Figure 3

Markers of inflammation and thrombosis in patients admitted to the hospital for COVID-19. Admission inflammatory markers were obtained for all patients admitted to the regular (non-ICU) floors of NYU Langone Hospital for the first weeks (March–April 2020) of the COVID-19 pandemic surge in New York City. Among patients admitted to the regular floors, those who were subsequently transferred to the intensive care unit (ICU) had higher C reactive protein (CRP) levels than the group overall; among those transferred to the ICU, both CRP and D-dimer levels in the ICU were increased compared with prior to transfer, indicating that a worsening inflammatory state is a feature of more severe disease. Not shown in the figure: individuals admitted to the regular floors who were subsequently transferred to directly to the ICU also had higher ferritin levels than the non-ICU group overall (1452 vs 1178 mg/dL), and their mean ferritin level was found to be increased further on transfer to the ICU (1876 mg/dL).

Figure 4

Neutrophil metabolism in the presence of colchicine. Neutrophils were purified from healthy volunteer whole blood using the MACSxpress whole blood neutrophil isolation kit (Miltenyi Biotec, Bergisch Gladbach, Germany) and separated into four aliquots. Neutrophils were coincubated with and without lipopolysaccharide (LPS) and with and without colchicine. In vitro quantification of neutrophil metabolism, measured as extracellular acidification rate (ECAR) (mpH/min), was evaluated using a glycolysis stress test using a Seahorse XFe24 analyzer (Agilent Technologies, Santa Clara, California, USA). Using a modified assay, cells were first incubated with activators (LPS 10 ng/mL with or without colchicine 15 nM) for 10 min.

Figure 5

Colchicine inhibits inflammasome action and reduces supernatant levels of IL-1β. THP1 cells (macrophage cell line) were stimulated with monosodium urate (MSU) or calcium pyrophosphate dihydrate (CPPD) crystals in the presence or absence of colchicine. Supernatants were analysed for IL-1β by Western blot. For the purposes of this figure, the original published blot was quantified using Image J. Adapted from Martinon et al.