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.

Estimating cancer risks due to whole lungs low dose radiotherapy with different techniques for treating COVID-19 pneumonia.

BACKGROUND: Low dose radiotherapy (LDRT) of whole lungs with photon beams is a novel method for treating COVID-19 pneumonia. This study aimed to estimate cancer risks induced by lung LDRT for different radiotherapy delivery techniques. METHOD: Four different radiotherapy techniques, including 3D-conformal with anterior and posterior fields (3D-CRT AP-PA), 3D-conformal with 8 coplanar fields (3D-CRT 8 fields), eight fields intensity-modulated radiotherapy (IMRT), and volumetric modulated arc therapy using 2 full arcs (VMAT) were planned on the CT images of 32 COVID-19 patients with the prescribed dose of 1 Gy to the lungs. Organ average and maximum doses, and PTV dose distribution indexes were compared between different techniques. The radiation-induced cancer incidence and cancer-specific mortality, and cardiac heart disease risks were estimated for the assessed techniques. RESULTS: In IMRT and VMAT techniques, heart (mean and max), breast (mean, and max), and stomach (mean) doses and also maximum dose in the body were significantly lower than the 3D-CRT techniques. The calculated conformity indexes were similar in all the techniques. However, the homogeneity indexes were lower (i.e., better) in intensity-modulated techniques (P < 0.03) with no significant differences between IMRT and VMAT plans. Lung cancer incident risks for all the delivery techniques were similar (P > 0.4). Cancer incidence and mortality risks for organs located closer to lungs like breast and stomach were higher in 3D-CRT techniques than IMRT or VMAT techniques (excess solid tumor cancer incidence risks for a 30 years man: 1.94 ± 0.22% Vs. 1.68 ± 0.17%; and women: 6.66 ± 0.81% Vs. 4.60 ± 0.43%: cancer mortality risks for 30 years men: 1.63 ± 0.19% Vs. 1.45 ± 0.15%; and women: 3.63 ± 0.44% Vs. 2.94 ± 0.23%). CONCLUSION: All the radiotherapy techniques had low cancer risks. However, the overall estimated risks induced by IMRT and VMAT radiotherapy techniques were lower than the 3D-CRT techniques and can be used clinically in younger patients or patients having greater concerns about radiation induced cancers.

Low-dose radiation therapy for COVID-19 pneumonia: a pilot study.

OBJECTIVES: The World Health Organization (WHO) has declared coronavirus disease 2019 (COVID-19) as pandemic in March 2020. Currently there is no specific effective treatment for COVID-19. The major cause of death in COVID-19 is severe pneumonia leading to respiratory failure. Radiation in low doses (<100 cGy) has been known for its anti-inflammatory effect and therefore, low dose radiation therapy (LDRT) to lungs can potentially mitigate the severity of pneumonia and reduce mortality. We conducted a pilot trial to study the feasibility and clinical efficacy of LDRT to lungs in the management of patients with COVID-19. METHODS: From June to Aug 2020, we enrolled 10 patients with COVID-19 having moderate to severe risk disease [National Early Warning Score (NEWS) of ≥5]. Patients were treated as per the standard COVID-19 management guidelines along with LDRT to both lungs with a dose of 70cGy in single fraction. Response assessment was done based on the clinical parameters using the NEWS. RESULTS: All patients completed the prescribed treatment. Nine patients had complete clinical recovery mostly within a period ranging from 3 to 7 days. One patient, who was a known hypertensive, showed clinical deterioration and died 24 days after LDRT. No patients showed the signs of acute radiation toxicity. CONCLUSION: The results of our pilot study suggest that LDRT is feasible in COVID-19 patients having moderate to severe disease. Its clinical efficacy may be tested by conducting randomized controlled trials. ADVANCES IN KNOWLEDGE: LDRT has shown promising results in COVID-19 pneumonia and should be researched further through randomized controlled trials.

Low Doses of Radiation Increase the Immunosuppressive Profile of Lung Macrophages During Viral Infection and Pneumonia.

PURPOSE: Severe pneumonia and acute respiratory distress syndrome (ARDS) have been described in patients with severe coronavirus disease 2019 (COVID-19). Recently, early clinical data reported the feasibility of low doses of radiation therapy (RT) in the treatment of ARDS in patients with severe COVID-19. However, the involved mechanisms remained unknown. METHODS AND MATERIALS: Here, we used airways-instilled lipopolysaccharide (LPS) and influenza virus (H1N1) as murine models of pneumonia, and toll-like receptor (TLR)-3 stimulation in human lung macrophages. RESULTS: Low doses of RT (0.5-1 Gray) decreased LPS-induced pneumonia, and increased the percentage of nerve- and airway-associated macrophages producing interleukin (IL) 10. During H1N1 viral infection, we observed decreased lung tissue damage and immune cell infiltration in irradiated animals. Low doses of RT increased IL-10 production by infiltrating immune cells into the lung. Irradiation of TLR-3 ligand-stimulated human lung macrophages ex vivo increased IL-10 secretion and decreased interferon γ production in the culture supernatant. The percentage of human lung macrophages producing IL-6 was also decreased. CONCLUSIONS: Our data highlight a mechanism by which low doses of RT regulate lung inflammation and skew lung macrophages toward an anti-inflammatory profile. These data provide a preclinical mechanistic support to clinical trials evaluating low doses of RT, such as COVID-19-induced ARDS.

Radiotherapy in the COVID-19 Pandemic Era.

BACKGROUND/AIM: In 2020, because of coronavirus pandemic, medical activities changed. The aim of this report is to compare the volumes of Pisa radiotherapy activities from March 9th to May 31st, 2020, with the same period in 2019. PATIENTS AND METHODS: We analyzed the activity of our Unit to evaluate how logistics changes, related to the COVID-19 epidemic, impacted on volumes of radiotherapy (RT) activity and on the number of cases of COVID-19 infections observed in healthcare professionals and patients. RESULTS: The total number of first-time visits between March-May 2020 was reduced by 18%, probably due to delays in diagnosis and histological tests as well as the temporary closure of the operating rooms. None of the healthcare professionals and only two patients contracted the infection. CONCLUSION: We were able to treat all patients referred to our hospital and we were able to reduce risk of infection for both our patients and healthcare staff, guaranteeing continuum of care for our oncological patients.

Low-Dose Radiation Therapy (LDRT) for COVID-19: Benefits or Risks?

The limited impact of treatments for COVID-19 has stimulated several phase 1 clinical trials of whole-lung low-dose radiation therapy (LDRT; 0.3-1.5 Gy) that are now progressing to phase 2 randomized trials worldwide. This novel but unconventional use of radiation to treat COVID-19 prompted the National Cancer Institute, National Council on Radiation Protection and Measurements and National Institute of Allergy and Infectious Diseases to convene a workshop involving a diverse group of experts in radiation oncology, radiobiology, virology, immunology, radiation protection and public health policy. The workshop was held to discuss the mechanistic underpinnings, rationale, and preclinical and emerging clinical studies, and to develop a general framework for use in clinical studies. Without refuting or endorsing LDRT as a treatment for COVID-19, the purpose of the workshop and this review is to provide guidance to clinicians and researchers who plan to conduct preclinical and clinical studies, given the limited available evidence on its safety and efficacy.

A 57-Year-Old African American Man with Severe COVID-19 Pneumonia Who Responded to Supportive Photobiomodulation Therapy (PBMT): First Use of PBMT in COVID-19.

BACKGROUND Coronavirus disease 2019 (COVID-19) is associated with lung inflammation and cytokine storm. Photobiomodulation therapy (PBMT) is a safe, non-invasive therapy with significant anti-inflammatory effects. Adjunct PBMT has been employed in treating patients with lung conditions. Human studies and experimental models of respiratory disease suggest PBMT reduces inflammation and promotes lung healing. This is the first time supportive PBMT was used in a severe case of COVID-19 pneumonia. CASE REPORT A 57-year-old African American man with severe COVID-19 received 4 once-daily PBMT sessions by a laser scanner with pulsed 808 nm and super-pulsed 905 nm modes for 28 min. The patient was evaluated before and after treatment via radiological assessment of lung edema (RALE) by CXR, pulmonary severity indices, blood tests, oxygen requirements, and patient questionnaires. Oxygen saturation (SpO2) increased from 93-94% to 97-100%, while the oxygen requirement decreased from 2-4 L/min to 1 L/min. The RALE score improved from 8 to 5. The Pneumonia Severity Index improved from Class V (142) to Class II (67). Additional pulmonary indices (Brescia-COVID and SMART-COP) both decreased from 4 to 0. CRP normalized from 15.1 to 1.23. The patient reported substantial improvement in the Community-Acquired Pneumonia assessment tool. CONCLUSIONS This report has presented supportive PBMT in a patient with severe COVID-19 pneumonia. Respiratory indices, radiological findings, oxygen requirements, and patient outcomes improved over several days and without need for a ventilator. Future controlled clinical trials are required to evaluate the effects of PBMT on clinical outcomes in patients with COVID-19 pneumonia.

Effect of an E-Learning Module on Personal Protective Equipment Proficiency Among Prehospital Personnel: Web-Based Randomized Controlled Trial.

BACKGROUND: To avoid misuse of personal protective equipment (PPE), ensure health care workers' safety, and avoid shortages, effective communication of up-to-date infection control guidelines is essential. As prehospital teams are particularly at risk of contamination given their challenging work environment, a specific gamified electronic learning (e-learning) module targeting this audience might provide significant advantages as it requires neither the presence of learners nor the repetitive use of equipment for demonstration. OBJECTIVE: The aim of this study was to evaluate whether a gamified e-learning module could improve the rate of adequate PPE choice by prehospital personnel in the context of the coronavirus disease (COVID-19) pandemic. METHODS: This was an individual-level randomized, controlled, quadruple-blind (investigators, participants, outcome assessors, and data analysts) closed web-based trial. All emergency prehospital personnel working in Geneva, Switzerland, were eligible for inclusion, and were invited to participate by email in April 2020. Participants were informed that the study aim was to assess their knowledge regarding PPE, and that they would be presented with both the guidelines and the e-learning module, though they were unaware that there were two different study paths. All participants first answered a preintervention quiz designed to establish their profile and baseline knowledge. The control group then accessed the guidelines before answering a second set of questions, and were then granted access to the e-learning module. The e-learning group was shown the e-learning module right after the guidelines and before answering the second set of questions. RESULTS: Of the 291 randomized participants, 176 (60.5%) completed the trial. There was no significant difference in baseline knowledge between groups. Though the baseline proportion of adequate PPE choice was high (75%, IQR 50%-75%), participants' description of the donning sequence was in most cases incorrect. After either intervention, adequate choice of PPE increased significantly in both groups (P<.001). Though the median of the difference in the proportion of correct answers was slightly higher in the e-learning group (17%, IQR 8%-33% versus 8%, IQR 8%-33%), the difference was not statistically significant (P=.27). Confidence in the ability to use PPE was maintained in the e-learning group (P=.27) but significantly decreased in the control group (P=.04). CONCLUSIONS: Among prehospital personnel with an already relatively high knowledge of and experience with PPE use, both web-based study paths increased the rate of adequate choice of PPE. There was no major added value of the gamified e-learning module apart from preserving participants' confidence in their ability to correctly use PPE.

Far-UVC light (222 nm) efficiently and safely inactivates airborne human coronaviruses.

A direct approach to limit airborne viral transmissions is to inactivate them within a short time of their production. Germicidal ultraviolet light, typically at 254 nm, is effective in this context but, used directly, can be a health hazard to skin and eyes. By contrast, far-UVC light (207-222 nm) efficiently kills pathogens potentially without harm to exposed human tissues. We previously demonstrated that 222-nm far-UVC light efficiently kills airborne influenza virus and we extend those studies to explore far-UVC efficacy against airborne human coronaviruses alpha HCoV-229E and beta HCoV-OC43. Low doses of 1.7 and 1.2 mJ/cm2 inactivated 99.9% of aerosolized coronavirus 229E and OC43, respectively. As all human coronaviruses have similar genomic sizes, far-UVC light would be expected to show similar inactivation efficiency against other human coronaviruses including SARS-CoV-2. Based on the beta-HCoV-OC43 results, continuous far-UVC exposure in occupied public locations at the current regulatory exposure limit (~3 mJ/cm2/hour) would result in ~90% viral inactivation in ~8 minutes, 95% in ~11 minutes, 99% in ~16 minutes and 99.9% inactivation in ~25 minutes. Thus while staying within current regulatory dose limits, low-dose-rate far-UVC exposure can potentially safely provide a major reduction in the ambient level of airborne coronaviruses in occupied public locations.

Optimizing lung cancer radiation treatment worldwide in COVID-19 outbreak.

COVID-19 has spread around the planet, sending billions of people into lockdown as health services struggle to cope. Meanwhile in Asia, where the disease began, the spread continues, in China it seems for now to have passed its peak. Italy, Spain, France, UK, and the US have been the countries more affected in terms of deaths. The coronavirus is more dangerous to the elderly and those with certain pre-existing medical conditions which is precisely the profile of lung cancer patients. Essential cancer services should be delivered but all steps should be taken to protect patients and the health workforce from infection with COVID-19. This presents a major challenge to radiotherapy (RT) departments worldwide. An international panel with expertise in the management of lung cancer in high-volume comprehensive centres has come together to share its experience on COVID-19 preparedness to deliver optimal care in such exceptional circumstances. A comprehensive systematic review of the literature through a PubMed search was undertaken. Twelve recommendations including, among others, the consideration of shorter courses, delays, and the omission of RT for lung cancer are proposed by the panel. In summary, we recommend the screening of every single person accessing the treatment room, the consideration of hypofractionation and to delay postoperative RT for non-small cell lung cancer, to avoid twice-daily treatments and delay or deliver prophylactic cranial irradiation during radio(chemo)therapy for limited-stage small cell lung cancer, review image guided RT images for suspicious image findings, and the use of single-fraction RT for the palliative treatment of stage IV lung cancer patients. Given that lung cancer is one of the most common and severe pathologies in radiation oncology departments, the following recommendations require particularly urgent consideration. The decision-making paths strongly depend on locally available resources, and a tailored approach should be used to attend lung cancer patients during this pandemic.

Is there any supportive evidence for low dose radiotherapy for COVID-19 pneumonia?

Since early April 2020, there has been intense debate over proposed clinical use of ionizing radiation to treat life-threatening pneumonia in Coronavirus Disease 2019 (COVID-19) patients. At least twelve relevant papers appeared by 20 May 2020. The radiation dose proposed for clinical trials are a single dose (0.1-1 Gy) or two doses (a few mGy followed by 0.1-0.25 Gy involving a putative adaptive response, or 1-1.5 Gy in two fractions 2-3 days apart). The scientific rationale for such proposed so-called low dose radiotherapy (LDRT) is twofold (note that only doses below 0.1 Gy are considered as low doses in the field of radiation protection, but here we follow the term as conventionally used in the field of radiation oncology). Firstly, the potentially positive observations in human case series and biological studies in rodent models on viral or bacterial pneumonia that were conducted in the pre-antibiotic era. Secondly, the potential anti-inflammatory properties of LDRT, which have been seen when LDRT is applied locally to subacute degenerative joint diseases, mainly in Germany. However, the human and animal studies cited as supportive evidence have significant limitations, and whether LDRT produces anti-inflammatory effects in the inflamed lung or exacerbates ongoing COVID-19 damage remains unclear. Therefore, we conclude that the available scientific evidence does not justify clinical trials of LDRT for COVID-19 pneumonia, with unknown benefit and known mortality risks from radiogenic cancer and circulatory disease. Despite the significant uncertainties in these proposals, some clinical trials are ongoing and planned. This paper gives an overview of current situations surrounding LDRT for COVID-19 pneumonia.

Photobiomodulation: Shining Light on COVID-19.

Objective: To evaluate the hypothesis that light could reduce the lethality of COVID-19. Methods: Most models for projections of the spread and lethality of COVID-19 take into account the ambient temperature, neglecting light. Recent advances in understanding the mechanism of action of COVID-19 have shown that it causes a systemic infection that significantly affects the hematopoietic system and hemostasis, factors extremely dependent of light, mainly in the region of visible and infrared radiation. Results: In the COVID-19 patients hemoglobin is decreasing and protoporphyrin is increasing, generating an extremely harmful accumulation of iron ions in the bloodstream, which are able to induce an intense inflammatory process in the body with a consequent increase in C-reactive protein and albumin. Observing the unsaturation characteristics of the cyclic porphyrin ring allows it to absorb and emit radiation mainly in the visible region. This characteristic can represent an important differential to change this process in the event of an imbalance in this system, through the photobiomodulation to increase the production of adenosine triphosphate (ATP) using red and near-infrared radiation (R-NIR) and vitamin D using ultraviolet B (UVB) radiation. These two compounds have the primary role of activating the defense mechanisms of the immune system, enabling greater resistance of the individual against the attack by the virus. According to the theory of electron excitation in photosensitive molecules, similar to hemoglobin heme, after the photon absorption there would be an increase in the stability of the iron ion bond with the center of the pyrrole ring, preventing the losses of heme function oxygen transport (HbO2). The light is also absorbed by cytochrome c oxidase in the R-NIR region, with a consequent increase in electron transport, regulating enzyme activity and resulting in a significant increase of oxygen rate consumption by mitochondria, increasing ATP production. Conclusions: The most favorable range of optical radiation to operate in this system is between R-NIR region, in which cytochrome c oxidase and porphyrin present absorption peaks centered at 640 nm and HbO2 with absorption peak centered at 900 nm. Based on the mechanisms described earlier, our hypothesis is that light could reduce the lethality of COVID-19.

Low dose radiation therapy as a potential life saving treatment for COVID-19-induced acute respiratory distress syndrome (ARDS).

The new coronavirus COVID-19 disease caused by SARS-CoV-2 was declared a global public health emergency by WHO on Jan 30, 2020. Despite massive efforts from various governmental, health and medical organizations, the disease continues to spread globally with increasing fatality rates. Several experimental drugs have been approved by FDA with unknown efficacy and potential adverse effects. The exponentially spreading pandemic of COVID-19 deserves prime public health attention to evaluate yet unexplored arenas of management. We opine that one of these treatment options is low dose radiation therapy for severe and most critical cases. There is evidence in literature that low dose radiation induces an anti-inflammatory phenotype that can potentially afford therapeutic benefit against COVID-19-related complications that are associated with significant morbidity and mortality. Herein, we review the effects and putative mechanisms of low dose radiation that may be viable, useful and of value in counter-acting the acute inflammatory state induced by critical stage COVID-19.