COVID-19-Associated Pneumonia: Radiobiological Insights

Abstract

The evolution of SARS-CoV-2 pneumonia to acute respiratory distress syndrome is linked to a virus-induced "cytokine storm", associated with systemic inflammation, coagulopathies, endothelial damage, thrombo-inflammation, immune system deregulation and disruption of angiotensin converting enzyme signaling pathways. To date, the most promising therapeutic approaches in COVID-19 pandemic are linked to the development of vaccines. However, the fight against COVID-19 pandemic in the short and mid-term cannot only rely on vaccines strategies, in particular given the growing proportion of more contagious and more lethal variants among exposed population (the English, South African and Brazilian variants). As long as collective immunity is still not acquired, some patients will have severe forms of the disease. Therapeutic perspectives also rely on the implementation of strategies for the prevention of secondary complications resulting from vascular endothelial damage and from immune system deregulation, which contributes to acute respiratory distress and potentially to long term irreversible tissue damage. While the anti-inflammatory effects of low dose irradiation have been exploited for a long time in the clinics, few recent physiopathological and experimental data suggested the possibility to modulate the inflammatory storm related to COVID-19 pulmonary infection by exposing patients to ionizing radiation at very low doses. Despite level of evidence is only preliminary, these preclinical findings open therapeutic perspectives and are discussed in this article.

Keywords: SARS-CoV-2 pneumonia; immune system; radiation therapy; radiation-induced cancers; radiobiology.

FIGURE 1

Chest computed tomography images of patients with COVID-19 pneumonia (A) shows Ground-glass opacities (blue arrows) (B) shows confluent crazy-paving pattern and consolidation opacities: secondary appearance of intralobular reticulations (blue arrows).

FIGURE 2

Chest computed tomography images of patients with COVID-19 pneumonia: shows extensive abnormalities and a proportion of pulmonary condensation (blue arrows) vs. higher Ground-glass, with possible progression to pulmonary fibrosis.

FIGURE 3

Beneficial effect of low-dose irradiation to reprogram macrophages in anti-inflammatory M2 promoting tissue repair or slowing the progression of severe lung damage induced by covid 19 disease. Balance of M1/M2 macrophage is necessary to achieve proper tissue repair. Hyperinflammation and the severity of the lesions alter this balance (illustrated above each of the lungs A and B). (A): Illustrations and details of M1 macrophage stimulation in COVID19 in the lung and their pro-inflammatory potential with very little macrophage reprogramming into anti-inflammatory M2. Depending on severity and duration inflammation (M1 persistent activation) this leads to severe lung damage by covid 19 disease. (B): To generate an anti-inflammatory environment: stimulate the polarization of the M2 macrophages with low dose radiotherapy (RT). Macrophages also switch to an anti-inflammatory (M2) phenotype, leading to a wound healing phase: Maintains M1/M2 balance or slowing the progression of lung damage induced by covid 19 disease. 1/2/3 represent the 3 steps generated in case A, an M1 macrophage phenotype within the lungs of covid 19 patients, in case B, step 1 (effects of low doses of RT in lung, with ↘ NO, ROS, ↘leukocytes/endothelial cells adhesion and ↗IL-10, TNF-β, NFkB, TGF 1, AP-1 et T-regulatory cells), step 2 (stimulation of the polarization of M2 macrophages in this environment post-low dose RT) and step 3: the secretion products of M2 promoting an anti-inflammatory environment.