The immunomodulatory properties of low-level ionizing radiation as a potential treatment for COVID-19’s life-threatening symptoms

The current outbreak was caused by SARS-CoV 2, also known as COVID-19, entering China in December 2019. Three CoV epidemics have afflicted humanity in the last two decades [1, 2]. The study is still in its early stages, and many published papers may have received insufficient peer review. However, it must be matched by a willingness to share new information to understand better.

The SARS-CoV-2 virus spread quickly worldwide, leaving many countries unprepared for a pandemic threat [3]. Infected patients may develop asymptomatic, moderate to severe upper respiratory illness, pneumonia, ARDS, or die [4]. Most of the ICU patients will require respiratory support [5]. Pneumonia and ARDS treatment are critical during high-mortality periods, but the new pneumonia therapy strategy had to be rethought. Previous research indicates efficacy at doses less than 1 Gy, close to the dose criteria for acute and chronic inflammatory and benign degenerative disorders [4]. In the early twentieth century, X-rays were commonly used to treat pneumonia. Prior research found that LD X-ray reduced pneumonia mortality by 30–10% on average. According to previous research, the development of an LD-RT-induced anti-inflammatory phenotype may account for the observed effects [6].

Irradiation less than 1 Gy into the lungs of a COVID-19 patient reduces inflammation and life-threatening symptoms [7], with a more significant reduction in inflammatory cytokines [8], LD has been shown to have anti-inflammatory properties. Despite the pro-inflammatory effects of high doses [9, 10]. This study investigates the range of data supporting LD-RT use and inherent conflicts in using LD-RT in COVID-19 patients.

The novel CoV has spread rapidly, causing severe disease in many people and putting major healthcare systems under strain. According to some studies, COVID-19 patients should receive LD (less than 1 Gy) thoracic RT to improve their chances of survival [7]. Other studies, however, say the evidence for LD-efficacy RTs is insufficient to justify the higher risk of human pneumonia being treated [5]. There are no effective treatments for COVID-19. A new study is needed to determine whether LD-RT can be used to treat life-threatening symptoms.

Calabrese et al. report that LD-RT induces a highly integrated, sophisticated, and systemic response to the M-2 anti-inflammatory phenotype, including macrophage polarization. In other studies, the anti-inflammatory phenotype M-2 has been found to inhibit leukocyte and polymorphonuclear cell adhesion, reactive oxygen species, nitric oxide, TNF-α, and endothelial cell adhesion. Following the M-2 phenotype, LD-RT is accompanied by increased heme oxygenase, anti-inflammatory cytokines IL-10, and transcription factor activation [8, 23, 24], increased TGF-β1 synthesis, and developed T-regulatory cells [24‐26]; as a result, the LD-RT pathway is validated both in vivo and in vitro by the onset of anti-inflammatory properties [27].

RT is a standard treatment for non-malignant illnesses in many countries. Every year, 5000 people in Germany receive non-cancerous irradiation at more than 300 RT centers. Non-malignant conditions account for 10–30% of all RT patients, which is unusually high compared to most other countries. There is a scarcity of information on RT for pneumonia, and more research is required into this condition’s treatment [28]. The findings suggest that inflammation plays a significant role in the severity of COVID-19 and that IL-6, TNF-α, and IL-8 may be promising treatment targets. In hospitalized COVID patients, IL-6 is a strong predictor of respiratory failure and CS, resulting in a patient's death [29]. IL-6 plays an essential role in treating diseases, such as collagen-induced arthritis, experimental encephalomyelitis, and systemic lupus erythematosus. According to one study, protein plays a vital role in the body's immune system [30]. According to a new study, IL-6 levels in rat models of human disease were elevated in most cases and significantly reduced by LD-RT [24, 26].

With over 37,000 patients treated each year, Germany has been the most enthusiastic promoter of RT for benign disorders [31, 32]. In 2002, the German working group on benign disease RT issued a consensus statement on prospective indications and pharmacological therapy recommendations. It was agreed that LDs should be treated with acute and chronic inflammatory illnesses and painful acute and joint degenerative diseases [33]. In these inflammatory diseases, the LD-RT process is finely regulated by leukocyte–endothelial cell interactions and the activity of inflammatory mediators and adhesion molecules released by various peripheral blood cells, such as leukocytes, neutrophils, and macrophages [9].

Ab El-Fatah et al. looked into the effects of LD-RT on the inflammatory environment of joint, kidney, liver, and hematological diseases. They discovered that LD- RT could cause hormesis-like reactions. After treatment, total leukocyte counts, serum creatinine, and serum liver enzymes decreased significantly (p < 0.01). Treatment was suggested for patients with multi-system pro-inflammatory illnesses, such as chronic renal disease [34].

Calabrese et al. investigated the use of infrared radiation in the treatment of inflammatory diseases. They compiled information from over 37,000 patients suffering from 13 different diseases. RT resolved all 13 instances with a 90 percent response rate. Over a dose range of 0.3–1.5 Gy, this exceptional and consistent RT efficiency was achieved [35]. LD-RT has been shown to have anti-inflammatory properties for nearly a decade [9, 36, 37]. LD-RT is widely used in Germany, although it is still infrequently used in other countries. Because of the possibility of delayed toxicity at much larger RT doses attributable to LD-RT, LD-Treat may only be used as a last resort in benign circumstances [31, 32]. The limited use of RT in benign conditions is due to the risk of carcinogenic IR and a lack of controlled trials investigating this application. Obsolete RT methodologies and data from Hiroshima and Nagasaki, where radiation exposure has spread widely throughout the body, provide evidence of cancer risk. According to the study, the risk of RT cancer for a mild condition is low when using the current recommended procedures [38]. The COVID-19 study's suggested dose is lower than what is typically used for minor diseases.

Genard et al. 2017 investigated macrophage polarization's molecular mechanisms using multiple mouse models and human cell lines. The findings revealed a three-phase response curve in which low- and high-dose RT polarized M2 (anti-inflammatory), but moderate-dose RT (1–10 Gy) polarized M1 (pro-inflammatory phenotype) [39]. The M1 and M2 phenotypes are not absolute in single cells or cell populations but instead show a combination. This theory holds that pro- and anti-inflammatory phenotypes can coexist and that the radiation dose determines the final phenotype [35]. Klug and colleagues discovered that the tissue microenvironment influences cell LD-RT polarization [40]. Roedel and colleagues state that linear energy transfer radiation has shown promise as a treatment option for COVID-19 patients with VP. Because of attenuation through the chest wall, the mean dose ranges from tens to one Gy.

Scientists have been studying the fundamental principles underlying the efficacy of these doses for the past three decades. Indeed, in vitro and in vivo studies have revealed a complicated relationship between LD-RT and inflammatory pathways. Numerous studies have been carried out to investigate methods for modulating the inflammatory properties of leukocytes, macrophages, fibroblasts, and endothelial cells and their cytokine/chemokine production and growth factors [10, 41]. So far, the investigated pathways have similar dose–response relationships, with substantial effects ranging from 0.3 to 0.7 Gy, previously recognized as the most potent in clinical situations, such as pneumonia treatment. Despite the scarcity of experimental or preclinical data on LD-RT testing in COVID-19 respiratory distress patients, a single 0.5 Gy treatment, similar to the previous proof, may be recommended.

For the best therapeutic efficacy, Calabrese et al. recommended a dose range of 0.2 to 2 Gy. According to the researchers, this tailored LD-RT appears most effective during acute illness when cytokines are at their peak. COVID-19 patients with CS should receive a single total dose of 0.3–0.5 Gy, according to the authors. Furthermore, it significantly reduces the possibility of any negative long-term consequences [35].

It was recently demonstrated that LD-RT could treat COVID-19 pneumonia with a single acute dose of 0.3–1 Gy of low radiation to the lungs while causing no natural tissue damage. Ghadimi-Moghadam et al. [42] propose that COVID-19 pneumonia be treated with a few mGy priming doses followed by a single 0.25 Gy dose. In Ramsar, Iran, the maximum natural background radiation exposure is 0.26 Gy/year. Clinical LD-RT investigations are recommended for COVID-19 pneumonia by both Ghadimi-Moghadam et al. and Kirkby and Mackenzie [7, 42].

Researchers believe that more research into the efficacy of complete LD-RT would benefit from treating inflammatory/infectious illnesses, such as COVID-19 pneumonia patients based on its proposed mode of action to reduce the extensive inflammatory repercussions of CS and potentially reduce death. LD-RT has anti-inflammatory effects on systemic inflammation regardless of where the inflammation is located. Clinical and analytical evidence on VP, dose levels, and irradiation timing is lacking. More research is needed to determine whether RT benefits COVID-19 patients suffering from hypoxia.