Low-Dose Radiation Therapy for COVID-19: Promises and Pitfalls

Abstract

The coronavirus disease-2019 (COVID-19) pandemic caused by SARS-CoV-2 has exacted an enormous toll on healthcare systems worldwide. The cytokine storm that follows pulmonary infection is causally linked to respiratory compromise and mortality in the majority of patients. The sparsity of viable treatment options for this viral infection and the sequelae of pulmonary complications have fueled the quest for new therapeutic considerations. One such option, the long-forgotten idea of using low-dose radiation therapy, has recently found renewed interest in many academic centers. We outline the scientific and logistical rationale for consideration of this option and the mechanistic underpinnings of any potential therapeutic value, particularly as viewed from an immunological perspective. We also discuss the preliminary and/or published results of prospective trials examining low-dose radiation therapy for COVID-19.

Figure 1.

Schematic representation of viral infection, replication, and immune effects of Severe Acute Respiratory Syndrome-coronavirus-2 (SARS-CoV-2) infection and the possible mechanisms of low-dose radiation therapy. Depicted on the top are cartoons of lung epithelial cells in blue, endothelial cells in green, and resident macrophages in orange. The cartoon on the left illustrates early infection by the virus (red circle with spikes), internalization, replication, reformation, and release. In the middle is a depiction of release of pathogen-associated molecular pattern (PAMP) hallmarks, including ATP, viral RNA, and interleukin-1 (among others); destruction of the infected cell (now gray); and recruitment of peripheral blood mononuclear cells (PBMCs), adherence to endothelial cells during this chemotaxis, and elaboration of host of proinflammatory cytokines (green arrows). On the right is a depiction of potential consequences of low-dose radiation of this immune-dysregulated lung microenvironment where there is less PBMC recruitment, less chemotaxis, less endothelial adherence because of downregulation of E/L-selectins, more apoptosis and less proliferation of recruited PBMCs, and a shift in the proinflammatory cytokine milieu towards more of an anti-inflammatory one. Also depicted on the bottom panel are features of COVID as the severity of disease increases (from left to right): clinical manifestations, interventional approaches, and viral and immune responses. ACE2 = angiotensin converting enzyme 2; ARDS = acute respiratory distress syndrome; BiPAP = bilevel positive airway pressure; CPAP = continuous positive airway pressure; ECMO = extracorporeal membrane oxygenation; MOF = multi-organ failure; SaO₂ = oxygen saturation.