Low-dose radiation therapy suppresses viral pneumonia by enhancing broad-spectrum anti-inflammatory responses via transforming growth factor-ß production.

Low-dose radiation therapy (LDRT) can suppress intractable inflammation, such as that in rheumatoid arthritis, and is used for treating more than 10,000 rheumatoid arthritis patients annually in Europe. Several recent clinical trials have reported that LDRT can effectively reduce the severity of coronavirus disease (COVID-19) and other cases of viral pneumonia. However, the therapeutic mechanism of LDRT remains unelucidated. Therefore, in the current study, we aimed to investigate the molecular mechanism underlying immunological alterations in influenza pneumonia after LDRT. Mice were irradiated to the whole lung 1 day post-infection. The changes in levels of inflammatory mediators (cytokines and chemokines) and immune cell populations in the bronchoalveolar lavage (BALF), lungs, and serum were examined. LDRT-treated mice displayed markedly increased survival rates and reduced lung edema and airway and vascular inflammation in the lung; however, the viral titers in the lungs were unaffected. Levels of primary inflammatory cytokines were reduced after LDRT, and transforming growth factor-ß (TGF-ß) levels increased significantly on day 1 following LDRT. Levels of chemokines increased from day 3 following LDRT. Additionally, M2 macrophage polarization or recruitment was increased following LDRT. We found that LDRT-induced TGF-ß reduced the levels of cytokines and polarized M2 cells and blocked immune cell infiltration, including neutrophils, in BALF. LDRT-induced early TGF-ß production was shown to be a key regulator involved in broad-spectrum anti-inflammatory activity in virus-infected lungs. Therefore, LDRT or TGF-ß may be an alternative therapy for viral pneumonia.

Low-Dose Radiation Therapy (LDRT) against Cancer and Inflammatory or Degenerative Diseases: Three Parallel Stories with a Common Molecular Mechanism Involving the Nucleoshuttling of the ATM Protein?

Very early after their discovery, X-rays were used in multiple medical applications, such as treatments against cancer, inflammation and pain. Because of technological constraints, such applications involved X-ray doses lower than 1 Gy per session. Progressively, notably in oncology, the dose per session increased. However, the approach of delivering less than 1 Gy per session, now called low-dose radiation therapy (LDRT), was preserved and is still applied in very specific cases. More recently, LDRT has also been applied in some trials to protect against lung inflammation after COVID-19 infection or to treat degenerative syndromes such as Alzheimer's disease. LDRT illustrates well the discontinuity of the dose-response curve and the counterintuitive observation that a low dose may produce a biological effect higher than a certain higher dose. Even if further investigations are needed to document and optimize LDRT, the apparent paradox of some radiobiological effects specific to low dose may be explained by the same mechanistic model based on the radiation-induced nucleoshuttling of the ATM kinase, a protein involved in various stress response pathways.

The clinical efficacy of low-dose whole-lung irradiation in moderate-to-severe COVID-19 pneumonia: RTMX-20 trial.

This is a paired prospective comparative cohort study with 58 patients, in order to analyze the clinical LD-WLI in patients with moderate or severe COVID19 pneumonia. The results of this study show that the Radiotherapy could be an option to improve the clinical response for patients with COVID-19.

Low-dose Radiation Therapy in the Management of COVID-19 Pneumonia (LOWRAD-Cov19). Final results of a prospective phase I-II trial.

BACKGROUND AND PURPOSE: To evaluate the results of low-dose radiation therapy (LD-RT) to lungs in the management of patients with COVID-19 pneumonia. MATERIAL AND METHODS: We conducted a prospective phase I-II trial enrolling COVID-19 patients ≥50 years-old, with bilateral lung involvement at imaging study and oxygen requirement (oxygen saturation ≤93% on room air). Patients received 1 Gy to whole lungs in a single fraction. Primary outcome was a radiological response assessed as severity and extension scores at days +3 and +7. Secondary outcomes were toxicity (CTCAE v5.0), days of hospitalization, changes in inflammatory blood parameters (ferritin, lymphocytes, C-reactive protein, d-dimer and LDH) and SatO2/FiO2 index (SAFI), at day +3 and +7. Descriptive analyses were summarized as means with standard deviation (SD) and/or medians with interquartile ranges (IQR). A Wilcoxon sign rank test for paired data was used to assess the CT scores and Chi Square was used to assess for comparison of categorical variables. RESULTS: Forty-one patients were included. Median age was 71 (IQR 60-84). Eighteen patients (44%) previously received an anti-COVID treatment (tocilizumab, lopinavir/ritonavir, remdesivir) and thirty-two patients (84%) received steroids during LD-RT. The extension score improved significantly (p = 0.02) on day +7. Mean baseline extension score was 13.7 (SD ± 4.9) with a score of 12.2 (±5.2) at day 3, and 12.4 ± 4.7 at day 7. No differences were found in the severity score. SAFI improved significantly on day +3 and +7 (p < 0.01). Median SAFI on day 0 was 147 (IQR 118-264), 230 (IQR 120-343) on day +3 and 293 (IQR 121-353) on day +7. Significant decrease was found in C-reactive protein on day +7 (p = 0.02) and in lymphocytes counts on day +3 and +7 (p = 0.02). The median number of days in hospital after RT was 11 (range 4-78). With a median follow-up of 60 days after LD-RT, 26 (63%) patients were discharged, 11 (27%) died because of COVID respiratory failure and 4 (10%) died of other causes. CONCLUSIONS: LD-RT is a feasible and well-tolerated treatment that could lead to rapid clinical improvement. Large randomized trials would be required to establish the efficacy of LD-RT to treat COVID-19 pneumonia.

The Role of Ionizing Radiation for Diagnosis and Treatment against COVID-19: Evidence and Considerations.

The Coronavirus disease 2019 (COVID-19) pandemic continues to spread worldwide with over 260 million people infected and more than 5 million deaths, numbers that are escalating on a daily basis. Frontline health workers and scientists diligently fight to alleviate life-threatening symptoms and control the spread of the disease. There is an urgent need for better triage of patients, especially in third world countries, in order to decrease the pressure induced on healthcare facilities. In the struggle to treat life-threatening COVID-19 pneumonia, scientists have debated the clinical use of ionizing radiation (IR). The historical literature dating back to the 1940s contains many reports of successful treatment of pneumonia with IR. In this work, we critically review the literature for the use of IR for both diagnostic and treatment purposes. We identify details including the computed tomography (CT) scanning considerations, the radiobiological basis of IR anti-inflammatory effects, the supportive evidence for low dose radiation therapy (LDRT), and the risks of radiation-induced cancer and cardiac disease associated with LDRT. In this paper, we address concerns regarding the effective management of COVID-19 patients and potential avenues that could provide empirical evidence for the fight against the disease.

Whole lung irradiation as a novel treatment for COVID-19: Final results of the prospective randomized trial (WINCOVID trial).

BACKGROUND AND PURPOSE: The ability of low dose radiotherapy (LDRT) to control the unprecedented cytokine release associated with COVID-19 pathogenesis has been an area of widespread research since the COVID pandemic. It has not been studied adequately whether the anti-inflammatory effect of LDRT provides additional benefit when used concurrently with steroids amongst other standard pharmacologic therapy. MATERIAL AND METHODS: 51 RT-PCR positive COVID-19 patients were recruited between November 2020 and July 2021. 34 patients were allotted to receive 0.5 Gy single session LDRT along with standard pharmacologic therapy while 17 patients received standard pharmacologic therapy alone. All had SpO2 <94% on room air, respiratory frequency >24/min and SpO2/FiO2 (SF) ratio between >89 but <357. All patients underwent a baseline CT scan. They were followed up for 28 days during when serial SF ratio, blood biomarkers (CRP, Serum ferritin, IL-6), Absolute lymphocyte count (ALC), repeat CT scan were performed at pre-defined time points. RESULTS: LDRT showed a statistically significant early improvement in oxygenation, an early time to clinical recovery, early hospital discharge and better radiological resolution compared to control group. There was no statistically significant difference between the two groups with respect to ALC or blood biomarkers at any of the measured time points. The 28-day mortality rate did not show statistically significant difference between the two groups. CONCLUSION: LDRT can be considered for selected oxygen-dependent moderate to severe COVID-19 patients for rapid relief of respiratory distress. It can be safely combined with standard pharmacologic treatment in such patients for added clinical benefit.

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

Novel mechanistic insights are discussed herein that link a single, nontoxic, low-dose radiotherapy (LDRT) treatment (0.5-1.0 Gy) to (1) beneficial subcellular effects mediated by the activation of nuclear factor erythroid 2-related transcription factor (Nrf2) and to (2) favorable clinical outcomes for COVID-19 pneumonia patients displaying symptoms of acute respiratory distress syndrome (ARDS). We posit that the favorable clinical outcomes following LDRT result from potent Nrf2-mediated antioxidant responses that rebalance the oxidatively skewed redox states of immunological cells, driving them toward anti-inflammatory phenotypes. Activation of Nrf2 by ionizing radiation is highly dose dependent and conforms to the features of a biphasic (hormetic) dose-response. At the cellular and subcellular levels, hormetic doses of <1.0 Gy induce polarization shifts in the predominant population of lung macrophages, from an M1 pro-inflammatory to an M2 anti-inflammatory phenotype. Together, the Nrf2-mediated antioxidant responses and the subsequent shifts to anti-inflammatory phenotypes have the capacity to suppress cytokine storms, resolve inflammation, promote tissue repair, and prevent COVID-19-related mortality. Given these mechanistic considerations-and the historical clinical success of LDRT early in the 20th century-we opine that LDRT should be regarded as safe and effective for use at almost any stage of COVID-19 infection. In theory, however, optimal life-saving potential is thought to occur when LDRT is applied prior to the cytokine storms and before the patients are placed on mechanical oxygen ventilators. The administration of LDRT either as an intervention of last resort or too early in the disease progression may be far less effective in saving the lives of ARDS patients.

Low-dose radiotherapy (LD-RT) for COVID-19-induced pneumopathy: a worth considering approach.

PURPOSE: It seems that 2020 would be always remembered by the name of novel coronavirus (designated as SARS-CoV-2), which exerted its deteriorating effects on the health care, economy, education, and political relationships. In August 2020 more than eight hundred thousand patients lost their lives due to acute respiratory syndrome. In the limited list of therapeutic approaches, the effectiveness of low-dose radiation therapy (LD-RT) for curing inflammatory-related diseases have sparkled a light that probably this approach would bring promising advantages for COVID-19 patients. LD-RT owns its reputation from its ability to modulate the host inflammatory responses by blocking the production of pro-inflammatory cytokines and hampering the activity of leukocytes. Moreover, the cost-effective and availability of this method allow it to be applied to a large number of patients, especially those who could not receive anti-IL-6 treatments in low-income countries. But enthusiasm for applying LD-RT for the treatment of COVID-19 patients has been muted yet. CONCLUSION: In this review, we take a look at LD-RT mechanisms of action in the treatment of nonmalignant diseases, and then through studying both the dark and bright sides of this approach, we provide a thorough discussion if LD-RT might be a promising therapeutic approach in COVID-19 patients.

A combinatorial approach of a polypharmacological adjuvant 2-deoxy-D-glucose with low dose radiation therapy to quell the cytokine storm in COVID-19 management.

COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a pandemic disease and is the major cause of deaths worldwide. The clinical complexities (inflammation, cytokine storm, and multi-organ dysfunction) associated with COVID-19 poses constraints to effective management of critically ill COVID-19 patients. Low dose radiation therapy (LDRT) has been evaluated as a potential therapeutic modality for COVID-19 pneumonia. However, due to heterogeneity in disease manifestation and inter-individual variations, effective planning for LDRT is limited for this large-scale event. 2-deoxy-D-glucose (2-DG) has emerged as a polypharmacological agent for COVID-19 treatment due to its effects on the glycolytic pathway, anti-inflammatory action, and interaction with viral proteins. We suggest that 2-DG will be a potential adjuvant to enhance the efficacy of LDRT in the treatment of COVID-19 pneumonia. Withal, azido analog of 2-DG, 2-azido-2-DG can produce rapid catastrophic oxidative stress and quell the cytokine storm in critically ill COVID-19 patients.

Whole-lung Low Dose Irradiation for SARS-Cov2 Induced Pneumonia in the Geriatric Population: An Old Effective Treatment for a New Disease? Recommendation of the International Geriatric Radiotherapy Group.

A cytokine storm induced by SARS-Cov2 may produce pneumonitis which may be fatal for older patients with underlying lung disease. Hyper-elevation of Interleukin1 (IL-1), Tumor necrosis factor-1alfa (TNF-1 alfa), and Interleukin 6 (IL-6) produced by inflammatory macrophage M1 may damage the lung alveoli leading to severe pneumonitis, decreased oxygenation, and potential death despite artificial ventilation. Older patients may not be suitable candidates for pharmaceutical intervention targeting IL-1/6 blockade or artificial ventilation. Low dose total lung (LDTL) irradiation at a single dose of 50 cGy may stop this cytokine cascade, thus preventing, and/or reversing normal organs damage. This therapy has been proven in the past to be effective against pneumonitis of diverse etiology and could be used to prevent death of older infected patients. Thus, LDRT radiotherapy may be a cost-effective treatment for this frail patient population whom radiation -induced malignancy is not a concern because of their advanced age. This hypothesis should be tested in future prospective trials.