Immunomodulation Through Low-Dose Radiation for Severe COVID-19: Lessons From the Past and New Developments

Abstract

Low-dose radiation therapy (LD-RT) has historically been a successful treatment for pneumonia and is clinically established as an immunomodulating therapy for inflammatory diseases. The ongoing COVID-19 pandemic has elicited renewed scientific interest in LD-RT and multiple small clinical trials have recently corroborated the historical LD-RT findings and demonstrated preliminary efficacy and immunomodulation for the treatment of severe COVID-19 pneumonia. The present review explicates archival medical research data of LD-RT and attempts to translate this into modernized evidence, relevant for the COVID-19 crisis. Additionally, we explore the putative mechanisms of LD-RT immunomodulation, revealing specific downregulation of proinflammatory cytokines that are integral to the development of the COVID-19 cytokine storm induced hyperinflammatory state. Radiation exposure in LD-RT is minimal compared to radiotherapy dosing standards in oncology care and direct toxicity and long-term risk for secondary disease are expected to be low. The recent clinical trials investigating LD-RT for COVID-19 confirm initial treatment safety. Based on our findings we conclude that LD-RT could be an important treatment option for COVID-19 patients that are likely to progress to severity. We advocate the further use of LD-RT in carefully monitored experimental environments to validate its effectiveness, risks and mechanisms of LD-RT.

COVID-19: The Disease, the Immunological Challenges, the Treatment with Pharmaceuticals and Low-Dose Ionizing Radiation

“…Low-dose radiotherapy, in which the total dose applied is significantly less than the dose used in cancer treatments, was historically a successful option for pneumonia before the discovery of penicillin [ 182 , 183 ]. Reports have suggested that an absorbed dose of 1 Gy, which is 50 to 100 times lower than the total doses used by oncologists, has anti-inflammatory effects [ 183 , 184 ].…”

“…Low-dose radiotherapy, in which the total dose applied is significantly less than the dose used in cancer treatments, was historically a successful option for pneumonia before the discovery of penicillin [ 182 , 183 ]. Reports have suggested that an absorbed dose of 1 Gy, which is 50 to 100 times lower than the total doses used by oncologists, has anti-inflammatory effects [ 183 , 184 ]. As early as 1905, Musser and Edsall reported on their X-ray treatment of five patients with unresolved pneumonia, which shed the first light on the potential benefit of radiation in treating respiratory diseases [ 185 ].…”

“…In 1936, Powell applied low-dose radiotherapy in a clinical study with 231 patients after his first success on a patient with a complete recovery from lobar pneumonia [ 188 ]. A concern is that Powell did not randomize his patients as his staff recognized near-immediate relief from respiratory distress and circulatory distress after treatment [ 183 , 187 , 188 ]. In a study that appeared soon after, Scott noted that the patients experienced initial relief of symptoms, followed by a reduction of fever [ 189 ].…”

COVID-19-Associated Pneumonia: Radiobiological Insights

“…In spite of these limitations, several prospective trials are currently being carried out in the context of the COVID-19 pandemic, encouraged by the lack of effective alternative and the high mortality probability in most severe cases of COVID-19 pneumonia ( Cosset et al, 2020 ; Wilson et al, 2020 ). In addition, the probability that such doses would result in any deterministic toxicity to healthy tissue is very low ( Hanekamp et al, 2020 ). Most often, these studies are designed to assess the possibility to reduce the need for non-invasive or invasive ventilation by administering a very low dose of X-rays in cases of severe lung infection.…”

Nrf2 activation putatively mediates clinical benefits of low-dose radiotherapy in COVID-19 pneumonia and acute respiratory distress syndrome (ARDS): Novel mechanistic considerations

“…As an initial default strategy, current anti-viral and anti-inflammatory treatments have been identified that may be repurposed for use against COVID-19. One such treatment involves low-dose radiation therapy (LDRT), which was previously used (circa 1930-1950) prior to the “age of antibiotics” in the treatment of critically ill patients with bacterial and/or viral pneumonia [1] , [2] , [3] , [4] . Based on the historically successful clinical use of LDRT, approximately 10 clinical trials are currently underway worldwide to test the safety and effectiveness of LDRT against COVID-19 [5] .…”