RADIOTHERAPY AGAINST SARS-COV-2: RISK OR BENEFIT

RADIOTHERAPY AGAINST SARS-COV-2: RISK OR BENEFIT

P. Neupane, A. Adhikari, S. Alok, A. K. Singh and A. Verma ^*

Bioorganic and Medicinal Chemistry Research Laboratory, Department of Pharmaceutical Sciences, Sam Higginbottom University of Agriculture, Technology and Sciences, Prayagraj, U. P, India.

ABSTRACT: The noble coronavirus SARS-CoV-2 results in a devastating, multisystem disease among which COVID-19 pneumonia creates serious complications and most of COVID-19 related deaths. COVID-19 patients develop a systemic inflammatory response through interleukin (IL) and tumor necrosis factors. In COVID-19 patients, cytokine storm controlling is the key step for treatment because cytokine attacks own body cells instead of fighting with the virus. We reviewed several literatures to summarize the safety and efficacy of LD-RT in COVID-19 patients. Low dose chest radiation may reduce the inflammation in the lungs in severely ill patients. The radiation offset an immune system called AS a cytokine storm. Several randomized/non-randomized, single/multi-centered, open/close clinical trials are underway in U.S, India, Iran and around the globe. Early studies showed LD-RT reduces the inflammatory cytokines, time of hospitalization, duration of ventilation, and a number of deaths. However, some researchers warned for radiation-induced cancer (lung, breast, and esophageal) and cardiovascular diseases. So, further extensive preclinical studies should be conducted to identify the risk-benefit ratio in COVID-19 patients.

Keywords: Low-dose Radiotherapy, Inflammatory cytokines, COVID-19 pneumonia, Cytokine release syndrome, Macrophage.

INTRODUCTION: A novel coronavirus was outbroken in Wuhan, China ^{1, 2}. Later the World Health Organization (WHO) named as Coronavirus Disease 2019 (COVID-19) ³ and declared a pandemic on 11^th March. As of now, COVID-19 affected all the countries around the globe ⁴. The high rate of transmission and rapid escalation in several COVID-19 cases resulted in an unpredictable strain in the healthcare system worldwide ^{5, 6}. Currently, there are no proven effective treatments, so; there is an urgent need against clinical trials to test new therapeutic interventions ^{7, 8}.

Acute respiratory distress syndrome (ARDS), sepsis, pneumonia and respiratory failure are distinguished as severe COVID-19 9 and the lungs are the vital organ commonly affected by COVID-19 ¹⁰. The majority of patients with a respiratory illness can, in some, progress to a life-threatening acute respiratory distress syndrome (ARDS) ¹¹ associated with a systemic inflammatory response govern by the rapid escalation in the release of pro-inflammatory cytokines ¹², such as interleukin-1, interleukin-6 and tumor necrosis factor-α. Radiotherapy is a commonly used modality for the treatment of cancers either for curative or palliative purposes ¹³. Radiation damage tumor as well as normal cells by generating free radicals ^{14, 15}. To obtain better results from the high dose of radiotherapy, the surrounding normal tissues should be protected against radiation ¹⁶. Thus, the radio-protective agents are very important in clinical radiotherapy ¹⁴. These free radicals are resulting from the aqueous hydrolysis of water present in cells. Thus, formed free radicals react with cellular macromolecules such as DNA, RNA, Protein, etc., leading to cell damage and cellular death ¹⁴. In the 20^th century lobular pneumonia caused a serious risk of mortality. In the 1930s, radiotherapy was discovered as an alternative to serum therapy for pneumonia patients because of its wide range of success in different inflammatory and infectious diseases such as sinusitis, arthritis, gas gangrene, carbuncles. Radiotherapy was also broadly accepted by the radiological community due to its wide success in different areas ¹⁷.

FIG. 1: PATHOPHYSIOLOGY OF CORONAVIRUS IN LUNG CELLS AND PROBABLE MECHANISM OF ACTION OF LOW DOSE RADIOTHERAPY (LD-RT) ON COVID-19 PATIENTS.

COVID-19 pneumonia critically ill patients, develop a systemic inflammatory response with a cytokine release syndrome (CRS) ^{18, 19}. Low dose radiotherapy (LD-RT) can cause apoptosis and decrease the adhesion of leukocytes to endothelial cells, relieve pro-inflammatory effects associated with macrophages through depletion of nitric oxide secretion and reactivation of oxygen species ²⁰. LD-RT also reduces the COVID-19 inflammatory cytokines, namely, IL-1β, IL-2, IL-6, IL-8 and TNF-ϒ ²¹.  COVID-19 activates both innate and adaptive immunity systems ²³ so, reducing the inflammatory response in COVID-19. The patient’s is the important step in reducing mortality of disease ^{22, 24}. The probable mechanism of action and pathophysiology is elucidated in Fig. 1. To reduce the inflammatory response, different medications such as steroids, monoclonal antibodies and IL-6 inhibitors were found to some effective. In contrast, toxicity-related steroids and lesser effectiveness of other medication driven us to approach a new treatment strategy, i.e., radiotherapy. LD-RT may reduce the lung's hyper-activation and relief of the COVID-19 symptoms in hospitalized patients ²⁵.

COVID-19 Induced Immune Responses: COVID-19 patients develop a Cytokine Release Syndrome (CRS), marked by a sudden increase in pro-inflammatory cytokines, namely IL-1, IL-6, and TNF-α ^26. Those cytokines were also observed in SARS-CoV, MERS CoV, and COVID-19 pneumonia ²⁷. COVID-19 activates both innate and adaptive immunity. Macrophages seem to be a key component of CRS syndrome, phagocytic activity of macrophages was through the donger-associated molecular patterns (DAMPS) activated by Troll-like receptors (TLR). COVID-19 is activated by TLRs, which subsequently trigger the release of cytokines from macrophages. The activated macrophages manage and repair the inactive tissue-destructive M 1 responses ²⁸.  They also activate immune regulatory proteins such as IL-10, resistin-like molecules-α (RELMα), chitinase-like proteins, and arginase 1 (ARG1). The initiation and resolution of immune responses critically depend on inflammatory (M1) and suppressive (M2) macrophages ¹⁸. Thus, the neutralization of inflammatory cytokines in COVID-19 pneumonia will be of great value in treating severe patients ³⁹. However, the regulation and activation of macrophages in COVID-19 were not completely clear.

Management of Immune Responses in COVID-19 Patients: Several pro-inflammatory cytokines, such as leukotrienes and tumor necrosis factor-α, develop cytokines release syndrome (CRS) ³⁰. Different off-label medications have shown effectiveness for controlling inflammatory cytokines namely, Tocilizumab, Convalescent plasma, Dexamethasone, and vitamin D. Tocilizumab is a humanized monoclonal antibody that works against interleukin-6 (IL-6) receptors ^{31, 32}. IL-6 is one of the key inflammatory cytokines present in COVID-19. Convalescent plasma is a passive polyclonal antibody that provides immediate immunity to patients with COVID-19 pneumonia ³³ while Dexamethasone is the first-line corticosteroid against chemotherapy-induced nausea and vomiting ³⁴. Dexamethasone is likely to depletion of B and T cells, which cause immune suppression ³⁵. A higher dose of corticosteroids may increase the risk of secondary infections ³⁶. Meanwhile, there is no FDA-approved medication present for COVID-19 ³⁷ so, researchers and scientists are working deliberately to find the medication and vaccine. In the earlier 20^th century, radiotherapy was used as a control measure of pneumonia and shown some effectiveness. LD-RT reduces the time of clinical improvement by 3 fold compared to patients receiving COVID-19 directed therapy for COVID-19 pneumonia and also decreases pro-inflammatory effects associated with macrophages. Researches are going on to evaluate the effectiveness of radiotherapy on COVID-19 pneumonia ³⁸.

Low Dose of Radiotherapy for COVID-19 Patients: Radiotherapy has been widely used since the early 20^th century in the treatment of pneumonia ³⁹. Low-dose radiotherapy (LD-RT) has emerged as an evidence-based beneficial alternative to patients who are progressing to or unfit for common anti-inflammatory treatments. Ionizing radiation is able to lower inflammation via various mechanisms, including apoptosis in the immune cells ⁴⁰ reducing the function of macrophages and secretion of anti-inflammatory factors ⁴¹. Focusing on the use of low-dose radiotherapy in SARS-CoV-2 IL-6-related pneumonia, radiotherapy's role in modifying the monocyte-macrophage axis would be very relevant ⁴². According to recent studies, LDRT has the ability to polarize macrophages towards an M2-like phenotype in a rheumatoid arthritis model ⁴³. In the study, LDRT gave at a single dose of of O.5 Gy influenced M1/M2 balance towards M2 anti-inflammatory phenotype when bone marrow-derived macrophages and fibroblasts like synoviocytes were co-cultured in an experimental model of RA, which suggest that LDRT could play a relevant role in those situations that hyper inflammation resembles RA, through reduction of IL-1 and TNF-alfa target cells producing IL-6. Therefore, a very dose of localized radiotherapy would modify the inflammatory environment in the lung of SARS-CoV-2 IL-6 related pneumonia patients ^{18, 44}. Radiotherapy doses > 200 cGy tend to show pro-inflammatory effects, which may trigger common toxicities. However, the lower doses (<100 cGy) incite anti-inflammatory properties such as a decrease in the levels of pro-inflammatory cytokines ⁴⁵ like IL-1 β, or inhibition of leukocyte recruitment.

A single fraction of 30-100 cGy treatment can be given easily on a conventional megavoltage radiation therapy unit ⁴⁶. According to the proof of principle simulations, POP treatment with a megavoltage beam could easily ensure 99% of the whole lung volume received between 90% and 120% of the prescribed dose of 70 cGy ⁴⁴. However, on a routine basis, much higher single fraction doses can be delivered in a palliative context with fast-tracked patients going through the full workflow process of scanning, planning, and treatment in a matter of hours. Due to the low dose, the common radiotherapy toxicities would be avoided ¹⁸.

Researchers at Emory University's Win ship Cancer institute, Georgia was conducted the experiment between 23 to 28 April where five patients of 64-94 years old were treated with low dose radiation therapy. All these patients had pneumonia visible on their chest X-rays, required supplemental oxygen and had declining health. A single dose of radiation (1.5 Gray) was delivered to patient's lungs for 10-15 min. The preliminary studies showed that within 24 h of the therapy, four patients showed rapid improvement in breathing and started to recover at an average of 1.5 days and Were Were discharged on day 14. Blood tests and repeat imaging further confirmed that the therapy showed no toxicities, radiation-related dermatitis or cytopenia. No signs of Increased cytokine storm were observed ⁴⁷.

TABLE 1: SUMMARY OF DIFFERENT REGISTERED CLINICAL TRIALS OF LOW DOSE RADIOTHERAPY AGAINST COVID-19 AROUND THE GLOBE

A recent study was conducted in Imam Hossein Educational Hospital, Iran from 21 May -24 June 2020. Individuals with positive polymerase chain reaction Tests, antibody tests and patients which require oxygen supplementation who enrolled. 5 out of 40 eligible patients (4 males and 1 female) Ageing 60-84 years (mean: 71.8 years) were approached for the clinical trials. All patients were allowed to receive a single fraction of O.5 Gy to the whole lungs. All these participants were planned with AP/PA photon fields with a 3-dimensional conformal technique with the help of The ISO gray treatment planning system. Tympanic membrane thermometry was used to assess core body temperature. Performance status, Blood oxygenation, CRP, Vital signs, and IL-6 were assessed at baseline. 4 out of 5 patients (80%) recovered from oxygen saturation on day one. Therefore, with a single fraction of of O.5 Gy had encouraging results in oxygen-dependent patients ⁴⁸. 10 patients with COVID-19 pneumonia were treated with lung radiation by the doctors at Emory University in Atlanta, the USA in a randomized controlled trial and compared them with 10 patients of the similar age group who received usual normal treatment apart from radiation. The patients with radiotherapy treatment showed significant improvement in 3 days, whereas the controlled group patients took 10 days to show any significant improvement. The other benefits of LDRT shown by this study are the shorter average time to hospital discharge (i.e. 12 days with radiation whereas 20 days with usual treatment) and also the lower risk of mechanical ventilation (only 10% with radiation) than usual treatment (40%) ⁴⁷. Throughout the world, trials of low-dose radiation therapy are being carried out, including the countries like Spain, U.S., Italy, India, Iran and so on. These studies are participating around 5 to 106 volunteers with covid-19 pneumonia in which half of the patients are at least 40 years of age.

Ohio State Radiation and Oncology department is dividing LDRT trials into two groups, the first trial being PREVENT, which 100 oxygen-dependent patients will be selected at 20 different hospitals around U.S. and the second trial named VENTED, unlike the previous is limited only in to Ohio State, where only 24 critically ill patients requiring ventilated support will be enrolled. Apart from this, VENTED is not restricted to older patients like PREVENT and is open to participants of and above 18 years old. Ohio State University Comprehensive Cancer Centre is conducting a randomized Phase II Clinical trial for low dose whole thorax megavoltage radiotherapy with 100 participants from July 1, 2020. The participants will be randomized 2:1 to receive radiation therapy of 2 different doses, (35 cGy and 100 cGy doses) or control (with no radiation). Doctors are planning to find out the best dose for radiation therapy. The sixty patients will be selected to 3 arms (low dose, high dose, and control arm) and best dose will be chosen. After this, randomization of an additional ⁴⁰ participants will be performed in 2:1 to find out the best suited dose versus control with no radiation ⁴⁹.

The clinical trial conducted in AIIMS, India to study the effects of one-time low dose radiation therapy to treat COVID-19 symptoms. The Pilot study was conducted from June to August 2020, nine out of 10 patients recovered within 3-7 days. One patient having hypertension showed clinical deterioration and died after 24 days. Less than 1 Gray was used for the study and trial carried out in those patients who needing oxygen support or mechanical support ⁵⁰.

Risk of Radiation-Induced Cancer in COVID-19 Patients: There is no FDA-approved COVID-19 medications; some researchers have experimented 0.5-1 Gy of whole thorax radiation therapy would decrease risk to COVID-19 patients in a clinical trials. It can be believed that LD-RT could revamp inflammation and benefit COVID-19 patients. However, radiotherapy will kill B and T cells necessary to fight SARS-CoV-2, which ultimately increases the risk of mortality from COVID-19. Although the risk generated by 0.5-1 Gy radiation can be evaluated, the risk of radiation exposure to cancer, and cancer mortality was different in males lung and esophagus and in the female lung, breast, and esophagus at different doses. The risk of radiation induces lung and breast cancer for 25 years, old women with 1 Gy radiation dose was higher than 5.9% and 5.5%. For same-age males risk of radiation-induced esophageal cancer was higher than 0.32%. The risk of radiation-induced cancer decline sharply with age at exposure for breast cancer and a small degree for lung and esophageal cancer. Different researches showed exposure to radiotherapy also generates lifetime risks of circulatory diseases. The major proof of radiation-induced cancer comes from the accidental exposure of the general population to radiation ^{51, 52}. Cancer, a long-term radiation-induced disease, is the major limitation of radiotherapy ^{53, 54}. However, cancer-induced risks with radiotherapy treatment of benign diseases based on various epidemiology data showed no increased risk of cancer at a very low dose of radiation ⁵⁵. The major issue about the cancer-induced risk is age ⁵⁶. The risk of inducing cancer is even lesser in patients over 40 years of age due to the expected long latency of tumor development ⁵⁷.

The available weak clinical anecdotes and preclinical animal models data showed the potential risk of trial exceeds the potential benefits ⁵⁸. Furthermore, the preclinical trial should be conducted to investigate the safety profile of radiotherapy before conducting the clinical trial in COVID-19 patients. Unlike the other sites treated by LDRT for inflammatory conditions, the human lung is very radiosensitive. Radiation-induced edema, fibrosis is the complications seen in patients in radiotherapy treatment for pulmonary neoplasms, Hodgkin's disease, or esophageal carcinoma ⁵⁹. Early reactions may develop within days or weeks; however, the late reactions may be seen after months or years after the treatment ^{60, 61}. Radiation-induced lung damage is principally based on the lung volume irradiated, pre-existing lung disease and the dose administered ⁶².

The pre-treatment inflammation in the lung could make pulmonary tissue much more susceptible to radiation-induced lung injury. The risk associated with radiation therapy in COVID-19 patients is elucidated in Fig. 2.

FIG. 2: SUMMARY OF RISK FACTORS ASSOCIATED WITH LOW-DOSE RADIOTHERAPY.

Low radiation (0.5-2 Gy) causes a significant change in the microfilament organization as well as the morphology of pulmonary vascular endothelial cells (PEMC) ^{63, 64}. It is characterized by loss of close contact and retraction within the individual cells in the monolayer ⁶⁵. In-vitro studies using radiation dose levels and time course for PMEC retraction demonstrated that low dose thoracic radiation induces pulmonary edema characterized by increased lung wet weight ⁶⁶.

The incidence of increased weight is radiation dose-dependent up to 2 Gy and found to be coincident with the time course for radiation-induced endothelial retraction ⁶⁷. PEMC model system may be beneficial for screening different compounds and physical agents, which could be useful clinically in the prevention of acute and late lung and other tissue injuries due to radiation ⁶⁸. The selection of the right time to administer LD-RT in COVID-19 patients is very challenging ⁶⁹. It is at the beginning of the pro-inflammatory phase where LDRT to both lungs would be effective in acting against the cascade of pro-inflammatory cytokines ⁷⁰.

LDRT treatment from 30 to 100 cGy to the lungs of COVID-19 pneumonia patients could reduce inflammation but may alleviate the symptoms that are life-threatening ^{71, 72}. However, viral reactivation may be a problem at a very low dose as reported in other viruses such as hepatitis B/C virus (HBC/HCV) ⁷³ and human immunodeficiency virus (HIV), although the impact on CoV is unknown ⁷⁴.

CONCLUSION: The COVID-19 pandemic has created unprecedented challenges to our world. Researchers are working tirelessly to discovered medication and vaccines. Based on available evidence of LD-RT to treat several non-malignant inflammatory conditions, the researcher summarizes that LD-RT can control the inflammatory response to COVID-19 in the lungs. LD-RT is believed to counteract against cytokine storm that was created by SARS-CoV-2. But the dose-related radiation-induced cancer was the major concern after radiotherapy so, further preclinical studies should be conducted in animal models to evaluate safety, efficacy, and risk-benefit ratio.

CONFLICTS OF INTEREST: Authors declared no conflict of interest, financial or otherwise.

ACKNOWLEDGMENT: Authors are thankful to the Sam Higginbottom University of Agriculture Technology and Sciences.

REFERENCES:

1. Yang X, Yu Y, Xu J, Shu H, Liu H, Wu Y, Zhang L, Yu Z, Fang M, Yu T and Wang Y: Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. The Lancet Respiratory Medicine 2020; 8(5): 475-81.
2. Qu YM, Kang EM and Cong HY: Positive result of Sars-Cov-2 in sputum from a cured patient with COVID-19. Travel Medicine and Infectious Disease 2020; 34: 101619.
3. World Health Organization: Rational use of personal protective equipment for coronavirus disease (‎‎‎‎‎‎ COVID-19)‎‎‎‎‎‎ and considerations during severe shortages: interim guidance, 6 April 2020. World Health Organization 2020.
4. Agarwal V and Sunitha BK: COVID–19: current pandemic and its societal impact. International Journal of Advanced Science and Technology 2020; 29(5).
5. Shim E, Tariq A, Choi W, Lee Y and Chowell G: Transmission potential and severity of COVID-19 in South Korea. Int Journal of Infectious Diseases 2020; 93: 339-44
6. Deng SQ and Peng HJ: Characteristics of and public health responses to the corona virus disease 2019 outbreak in China. Journal of Clinical Medicine 2020; 9(2): 575.
7. Multi-site Adaptive Trials Using Hydroxycholoroquine for COVID-19.
8. Neupane NP, Das AK, Singh AK and Verma A: Off label medication to combat COVID-19: Review Results to Date. Bentham Sci Coronaviruses 2020; 1: 1-2.
9. Ware LB and Matthay MA: The acute respiratory distress syndrome. New England Journal of Medicine 2000; 342(18): 1334-49.
10. COVID-19 Patient Positioning Pragmatic Trial. 2020.
11. Fan E, Brodie D and Slutsky AS: Acute respiratory distress syndrome: advances in diagnosis and treatment. Jama 2018; 319(7): 698-10.
12. Sydora BC, MacFarlane SM, Lupicki M, Dmytrash AL, Dieleman LA and Fedorak RN: An imbalance in mucosal cytokine profile causes transient intestinal inflammation following an animal's first exposure to faecal bacteria and antigens. Clinical & Experimental Immunology 2010; 161(1): 187-96.
13. Drouet F, Cahu X, Pointreau Y, Denis F and Mahé MA: Lymphomes malins non hodgkiniens. Cancer Radiotherapie 14: 2010.
14. Maurya DK, Salvi VP and Nair CK: Radiation protection of DNA by ferulic acid under in-vitro and in-vivo Molecular and Cellular Biochemistry 2005; 280(1): 209-17.
15. Kim JH, Jenrow KA and Brown SL: Mechanisms of radiation-induced normal tissue toxicity and implications for future clinical trials. Radiation Oncology Journal 2014; 32(3): 103.
16. Wang L: Screening and biosensor-based approaches for lung cancer detection. Sensors 2017; 17(10): 2420..
17. Calabrese EJ and Dhawan G: How radiotherapy was historically used to treat pneumonia: could it be useful today. The Yale Journal of Biology and Medicine 2013; 86(4): 555.
18. Lara PC, Burgos J and Macias D: Low dose lung radiotherapy for COVID-19 pneumonia. The rationale for a cost-effective anti-inflammatory treatment. Clinical and Translational Radiation Oncology 2020; 23: 27-9.
19. Polidoro RB, Hagan RS, de Santis Santiago R and Schmidt NW: Overview: systemic inflammatory response derived from lung injury caused by SARS-CoV-2 infection explains severe outcomes in COVID-19. Frontiers in Immunology 2020; 11: 1626.
20. Kern PM, Keilholz L, Forster C, Hallmann R, Herrmann M and Seegenschmiedt MH: Low-dose radiotherapy selectively reduces adhesion of peripheral blood mononuclear cells to endothelium in-vitro. Radiotherapy and Oncology 2000; 54(3): 273-82.
21. Conti P, Ronconi G and Caraffa A: Induction of pro-inflammatory cytokines (Interleukin-1 and Interleukin-6) and lung inflammation by Coronavirus-19 (COVI-19 or SARS-CoV-2): anti-inflammatory strategies. J Biol Regul Homeost Agents 2020; 34(2): 10-23812.
22. Butler MJ and Barrientos RM: The impact of nutrition on COVID-19 susceptibility and long-term consequences. Brain Behavior and Immunity 2020; 87: 53-4.
23. Kruglikov IL and Schere PE: The role of adipocytes and adipocytelike cells in the severity of COVID-19 infections Published Online Ahead of Print 27: 2020.
24. Yousefi B, Valizadeh S, Ghaffari H, Vahedi A, Karbalaei M and Eslami M: A global treatments for coronaviruses including COVID‐19. Journal of Cellular Physiology. 2020; 235(12): 9133-42.
25. Zheng Q, Lu Y, Lure F, Jaeger S and Lu P: Clinical and radiological features of novel corona virus pneumonia. Journal of X-ray Science and Technology 2020; 28(3): 391-04.
26. Kotta S, Aldawsari HM, Badr-Eldin SM, Alhakamy NA, Md S, Nair AB and Deb PK: Combating the pandemic COVID-19: clinical trials, therapies and perspectives. Frontiers in Molecular Biosciences 2020; 7.
27. Sun X, Wang T, Cai D, Hu Z, Liao H, Zhi L, Wei H, Zhang Z, Qiu Y, Wang J and Wang A: Cytokine storm intervention in the early stages of COVID-19 pneumonia. Cytokine & Growth Factor Reviews 2020; 53: 38-42.
28. Magrone T, Magrone M and Jirillo E: Focus on receptors for corona viruses with special reference to angiotensin-converting enzyme 2 as a potential drug target-a perspective. Endocrine Metabolic & Immune Disorders Drug Targets Formerly Current Drug Targets-Immune Endocrine & Metabolic Disorders 2020; 20(6): 807-11.
29. Algara M, Arenas M, Marin J, Vallverdu I, Fernandez-Letón P, Villar J, Fabrer G, Rubio C and Montero A: Low dose anti-inflammatory radiotherapy for the treatment of pneumonia by covid-19: A proposal for a multi-centric prospective trial. Clinical and Translational Radiation Oncology 2020; 24: 29-33.
30. Addeo A, Obeid M and Friedlaender A: COVID-19 and lung cancer: risks, mechanisms and treatment interactions. Journal for Immunotherapy of Cancer 2020; 8(1).
31. Kang S, Tanaka T and Kishimoto T: Therapeutic uses of anti-interleukin-6 receptor antibody. International Immunology 2015; 27(1): 21-9.
32. Mihara M, Kasutani K, Okazaki M, Nakamura A, Kawai S, Sugimoto M, Matsumoto Y and Ohsugi Y: Tocilizumab inhibits signal transduction mediated by both mIL-6R and sIL-6R, but not by the receptors of other members of IL-6 cytokine family. International Immune Pharmacology 2005; 5(12): 1731-40.
33. Convalescent plasma for hospitalized adults with covid-19 respiratory illness (concor-1).
34. Chu CC, Hsing CH, Shieh JP, Chien CC, Ho CM and Wang JJ: The cellular mechanisms of the antiemetic action of dexamethasone and related glucocorticoids against vomiting. European Journal of Pharmacology 2014 Jan; 722: 48-54.
35. Tebartz C, Horst SA, Sparwasser T, Huehn J, Beineke A, Peters G and Medina E: A major role for myeloid-derived suppressor cells and a minor role for regulatory T cells in immune suppression during Staphylococcus aureus The Journal of Immunology 2015; 194(3): 1100-11.
36. Crowther CA, McKinlay CJ, Middleton P and Harding JE: Repeat doses of prenatal corticosteroids for women at risk of preterm birth for improving neonatal health outcomes. Cochrane Database of Systematic Reviews 2015; 7.
37. Stahlmann R and Lode H: Medication for COVID-19—an overview of approaches currently under study. Deutsches Ärzteblatt International 2020; 117(13): 213.
38. Ivermectin and Nitazoxanide Combination Therapy for COVID-19 2020.
39. Connell PP, Kron SJ and Weichselbaum RR: Relevance and irrelevance of DNA damage response to radiotherapy. DNA Repair 2004; 3(8-9): 1245-51.
40. Yahyapour R, Amini P, Rezapoor S, Rezaeyan A, Farhood B, Cheki M, Fallah H and Najafi M: Targeting of inflammation for radiation protection and mitigation. Current Molecular Pharmacology 2018; 11(3): 203-10.
41. Joyce DA, Steer JH and Abraham LJ: Glucocorticoid modulation of human monocyte/macrophage function: control of TNF-α secretion. Inflammation Research 1997; 46(11): 447-51.
42. Brizel D: 368 the role of adaptive and functional imaging modalities. Radiotherapy and Oncology 2012; (102): S189.
43. Stalder R, Zhang B, Jean Wrobel L, Boehncke WH, Brembilla NC. The Janus Kinase inhibitor tofacitinib impacts human dendritic cell differentiation and favours M1 macrophage development. Experimental Dermatology 2020; 29(1): 71-8.
44. Kirkby C and Mackenzie M: Is low dose radiation therapy a potential treatment for COVID-19 pneumonia. Radiotherapy and Oncology 2020; 147: 221.
45. Boscoboinik D, Szewczyk A, Hensey C and Azzi A: Inhibition of cell proliferation by alpha-tocopherol. Role of protein kinase C. J of Biol Che; 266(10): 6188-94.
46. Mohiuddin M, Fujita M, Regine WF, Megooni AS, Ibbott GS and Ahmed MM: High-dose spatially-fractionated radiation (GRID): a new paradigm in the management of advanced cancers. International Journal of Radiation Oncology* Biology* Physics 1999; 45(3): 721-7.
47. Hess CB, Nasti TH, Dhere VR, Kleber TJ, Switchenko JM, Buchwald ZS, Stokes WA, Weinberg BD, Rouphael N, Steinberg JP and Godette KD: Immuno modulatory low-dose whole-lung radiation for patients with corona virus disease 2019-related pneumonia. International Journal of Radiation Oncology* Biology* Physics 2021; 109(4): 867-79.
48. Hess CB, Buchwald ZS, Stokes W, Nasti TH, Switchenko JM, Weinberg BD, Rouphael N, Steinberg JP, Godette KD, Murphy DJ and Ahmed R: Low-dose whole-lung radiation for COVID-19 pneumonia. Med Rxiv 2020; 1.
49. NCT04427566: Low dose whole lung radiation therapy for patients with covid-19 and respiratory compromise. Clin Search Results 08/24/2020. 2020:2020.
50. Deokar K, Shadrach BJ, Asfahan S, Chawla G, Agarwal M, Dutt N and Niwas R: Low dose radiotherapy for COVID pneumonia: Irradiate to Eradicate–Will it be possible. Acta Bio Medica Atenei Parmensis 2021; 92(1).
51. Pannkuk EL, Fornace Jr AJ and Laiakis EC: Metabolomic applications in radiation biodosimetry: exploring radiation effects through small molecules. International Journal of Radiation Biology 2017; 93(10): 1151-76.
52. Narendran N, Luzhna L and Kovalchuk O: Sex difference of radiation response in occupational and accidental exposure. Frontiers in Genetics 2019; 10: 260.
53. Mok G, Glicksman R, Sykes J, Bayley A, Chung P and Bristow R: Short term hormone therapy and dose escalated radiation for localized prostate cancer: a randomized phase III study. Radiol Oncol 2012; 105: 273-82.
54. Soussain C, Ricard D, Fike JR, Mazeron JJ, Psimaras D and Delattre JY: CNS complications of radiotherapy and chemotherapy. The lancet 2009; 374(9701): 1639-51.
55. Seegenschmiedt MH, Micke O, Niewald M, Mücke R, Eich HT, Kriz J and Heyd R: DEGRO guidelines for the radiotherapy of non-malignant disorders. Strahlentherapie und Onkologie 2015; 191(7): 541-8.
56. Cushman M: Epidemiology and risk factors for venous thrombosis. In Seminars in Hematology 2007; 44(1): 62-69.
57. Ribnikar D, Ribeiro JM, Pinto D, Sousa B, Pinto AC, Gomes E, Moser EC, Cardoso MJ and Cardoso F: Breast cancer under age 40: a different approach. Current Treatment Options in Oncology 2015; 16(4): 16.
58. Simpson D and Noble S: Tacrolimus Ointment. Drugs 2005; 65(6): 827-59.
59. Minami A, Mowafy M, Al-Adwan S and Minami T: Hemoptysis 38 years after radiation therapy for hodgkin's lymphoma: a rare but serious complication. Ind50. Clot On The Rocks: Case Reports Of Pe And Cteph 2018 May (Pp. A7048-A7048.
60. Siddiqui MA and Scott LJ: Infliximab. Drugs 2005; 65(15): 2179-08.
61. Hofstad H: IS6. 05: Scandinavian challenges in geriatric rehabilitation: early discharge for stroke patients. European Geriatric Medicine 2014; (5): S8-9.
62. Perol M: ES01. 04 Immunotherapy, radiotherapy and chemotherapy combination: a potential new standard. Journal of Thoracic Oncology 2019; 14(10): S14-5.
63. World Health Organization. Guideline: sugars intake for adults and children. World Health Organization 2015; 31.
64. El-Shanshoury H, El-Shanshoury G and Abaza A: Evaluation of low dose ionizing radiation effect on some blood components in animal model. Journal of Radiation Research and Applied Sciences 2016; 9(3): 282-93.
65. Fletcher TF, Hammer RF and Bradley WE: Nerve endings in the urinary bladder of the cat. Journal of Comparative Neurology 1969; 136(1): 1-9.
66. Onoda JM, Kantak SS and Diglio CA: Radiation induced endothelial cell retraction in-vitro: correlation with acute pulmonary edema. Pathology and Oncology Research 1999; 5(1): 49-55.
67. Lawrence YR, Li XA, El Naqa I, Hahn CA, Marks LB, Merchant TE and Dicker AP: Radiation dose–volume effects in the brain. International Journal of Radiation Oncology* Biology*Physics. 2010; 76(3): S20-7.
68. Abratt RP and Morgan GW: Lung toxicity following chest irradiation in patients with lung cancer. Lung Cancer 2002; 35(2): 103-9.
69. Hope WW, McEntee L, Livermore J, Whalley S, Johnson A, Farrington N, Kolamunnage-Dona R, Schwartz J, Kennedy A, Law D and Birch M: Pharmacodynamics of the orotomides against Aspergillus fumigatus: new opportunities for treatment of multidrug-resistant fungal disease. M Bio 2017; 8(4): e01157-17.
70. Zeitlin P: THE role of estrogen in cystic fibrosis: s6. 2. Pediatric Pulmonology 2013; 48: 130-1.
71. Desilles JP, Gregoire C, Le Cossec C, Lambert J, Mophawe O, Losser MR, Lambiotte F, Le Tacon S, Cantier M, Engrad N and Trouiller P: Efficacy and safety of aerosolized intra-tracheal dornase alfa administration in patients with SARS-CoV-2-induced acute respiratory distress syndrome (ARDS): a structured summary of a study protocol for a randomised controlled trial. Trials 2020; 21(1): 1-3.
72. NCT04333368: Cell Therapy Using Umbilical Cord-derived Mesenchymal Stromal Cells in SARS-CoV-2-related ARDS.
73. Wagstaff AJ and Bryson HM: Foscarnet. Drugs 1994; 48(2): 199-226.
74. Maisch B, Hufnagel G, Kölsch S, Funck R, Richter A, Rupp H, Herzum M and Pankuweit S: Treatment of inflammatory dilated cardiomyopathy and (peri) myocarditis with immunosuppression and iv immunoglobulins. Herz 2004; 29(6): 624-36.
    

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    How to cite this article:

    Neupane NP, Adhikari A, Alok S, Singh AK and Verma A: Radiotherapy against sars-cov-2: risk or benefit. Int J Pharm Sci & Res 2021; 12(9): 4580-87. doi: 10.13040/IJPSR.0975-8232.12(9).4580-87.

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