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.

Risk Factors for Fungal Co-Infections in Critically Ill COVID-19 Patients, with a Focus on Immunosuppressants

“…Further, in a multilocation retrospective cohort conducted in France, Dellière et al [ 88 ] reported that treatment with azithromycin for up to 3 days significantly correlated with the incidence of probable invasive pulmonary aspergillosis in COVID-19 patients. Such observation was attributed to the immunomodulatory properties of azithromycin that may weaken the host’s immune response and subsequent susceptibility to aspergillosis [ 88 , 89 ].…”

Azithromycin for treatment of hospitalised COVID-19 patients: a randomised, multicentre, open-label clinical trial (DAWn-AZITHRO)

“…While the lack of effect of azithromycin on short-term outcomes like 15- and 28-day clinical status and mortality have been extensively published, few have reported on longer term and functional outcomes. It has been hypothesized that Azithromycin-treatment in COVID-19 may promote tissue repair and reduce post-COVID fibrosis by modulation of macrophage and myofibroblast function [ 19 ]. At our five-to-seven-week follow-up visit, the proportion of patients with complete resolution of COVID-related radiological abnormalities was similar in treated and untreated patients.…”

High Levels of the Cleaved Form of Galectin-9 and Osteopontin in the Plasma Are Associated with Inflammatory Markers That Reflect the Severity of COVID-19 Pneumonia

“…The optimal time to prescribe TCZ was reported to be the early stages of inflammation and the initial reduction in O 2 saturation [ 75 ]. All patients survived in this study, probably due to early administration of TCZ and other possibly effective agents such as azithromycin [ 76 ], ciclesonide [ 77 ], nafamostat mesilate [ 78 ], and FAV. It is better to follow the new guideline of TCZ therapy in the future [ 79 ].…”