Immunomodulatory Effects of Azithromycin Revisited: Potential Applications to COVID-19

Abstract

The rapid advancement of the COVID-19 pandemic has prompted an accelerated pursuit to identify effective therapeutics. Stages of the disease course have been defined by viral burden, lung pathology, and progression through phases of the immune response. Immunological factors including inflammatory cell infiltration and cytokine storm have been associated with severe disease and death. Many immunomodulatory therapies for COVID-19 are currently being investigated, and preliminary results support the premise of targeting the immune response. However, because suppressing immune mechanisms could also impact the clearance of the virus in the early stages of infection, therapeutic success is likely to depend on timing with respect to the disease course. Azithromycin is an immunomodulatory drug that has been shown to have antiviral effects and potential benefit in patients with COVID-19. Multiple immunomodulatory effects have been defined for azithromycin which could provide efficacy during the late stages of the disease, including inhibition of pro-inflammatory cytokine production, inhibition of neutrophil influx, induction of regulatory functions of macrophages, and alterations in autophagy. Here we review the published evidence of these mechanisms along with the current clinical use of azithromycin as an immunomodulatory therapeutic. We then discuss the potential impact of azithromycin on the immune response to COVID-19, as well as caution against immunosuppressive and off-target effects including cardiotoxicity in these patients. While azithromycin has the potential to contribute efficacy, its impact on the COVID-19 immune response requires additional characterization so as to better define its role in individualized therapy.

Keywords: COVID-19; azithromycin; immunomodulation; inflammation; therapeutic.

Figure 1

Stages of response and progression of SARS-CoV-2 infection and the potential impact of azithromycin therapy. A hypothetical timeline of viral burden kinetics and the associated immune response mechanisms are depicted for patients with (A) mild disease and (B) severe disease that is associated with organ damage, hypercoagulation, and death. (A) Antiviral responses coordinated through the detection of virus via pattern recognition receptors triggers IRF signaling and interferon production, along with pro-inflammatory signaling through NF-κB and ERK pathways. This initiates innate and adaptive immune mechanisms that limit viral spread and leads to mild symptoms and recovery. Autophagy plays a role in pathogen elimination, but can be inhibited by the virus. (B) In some patients, viral burden persists, possibly due to SARS-CoV-2 inhibition of IRF signaling pathways. Severe disease progresses through Stage 2 (lung damage) and Stage 3 consisting of hyperinflammation, cytokine storm, and hypercoagulation represented here by excessive NF-κB and other inflammatory pathway activity. Rampant inflammation that includes macrophage, neutrophil, and T lymphocyte driven pathology persists independent of viral control in Stage 3. The potential beneficial (black arrows), detrimental (white arrows), or unknown (gray arrows) impacts of azithromycin (AZM) are depicted as defined by evidence generated in other disease models suggesting that the drug could: increase type I/III interferon production; induce regulatory function of macrophages, blunt neutrophil influx, and decrease inflammatory cytokine production through inhibition of NF-κB signaling and other inflammatory pathways; and impact autophagy through blocking the degradation of autophagosomes that can impact virus infectivity, elimination, and the regulation of inflammation.

Figure 2

Potential effects of azithromycin on immune cells that contribute to hyperinflammation in COVID-19. The response to pulmonary infection with SARS-CoV-2 is characterized by a blunted Type I/II IFN response, which could possibly be improved by azithromycin (AZM). Macrophages are implicated in the coordination of the exaggerated inflammatory response that can lead to lung damage, cytokine storm, and increased morbidity. Azithromycin has been demonstrated in other models to inhibit signaling mechanisms in inflammatory macrophages including NF-κB nuclear translocation, STAT1 phosphorylation, and inflammasome activation that all contribute to pro-inflammatory mediator production including iNOS, cytokines, and chemokines. Neutrophil influx is inhibited by azithromycin, likely through impacting chemokine production and through direct inhibition of AP-1 signaling, leading to decreases in NET formation and production of IL-1β. Proliferation of activated T lymphocytes can be blunted by azithromycin through inhibition of mTOR signaling, as well as through increased macrophage production of arginase-1 (which thereby depletes arginine which is required for T cell proliferation). Consequently, T cell and NK cell production of inflammatory cytokines including GM-CSF, IFNγ, TNFα, and IL-17 would be decreased. Therefore, within this theoretical model lies the potential for azithromycin to enhance antiviral effects, blunt harmful hyperinflammation that leads to cytokine storm, or conversely inhibit desirable immunologic effects, depending on the phase of the antiviral response. Red inhibitory lines depict possible targets of azithromycin during COVID-19, and red arrows indicate resultant increases or decreases in the production of mediators of inflammation. Figure was created using https://biorender.com/.