Low dose lung radiotherapy for COVID-19 pneumonia. The rationale for a cost-effective anti-inflammatory treatment Pedro C. Laraa,b,c,⇑, Javier Burgosa, David Maciasa aDept Radiation Oncology, Hospital Universitario San Roque, Las Palmas Gran Canaria, SpainbUniversidad Fernando Pessoa Canarias, Las Palmas Gran Canaria, SpaincInstituto Canario de Investigación del Cáncer, Canary Islands, Spain article info Article history: Received 7 April 2020 Revised 11 April 2020 Accepted 13 April 2020 Available online 25 April 2020 Keywords: COVID-19 pneumonia Low dose radiotherapy Lung abstract The COVID-19 pandemia is affecting people worldwide. Most of the patients suffered of a respiratory dis- ease that will progress to an acute respiratory distress syndrome (ARDS). SARS-CoV-2 pneumonia severely ill patients, develop a systemic inflammatory response with a Cytokine Release Syndrome (CRS), that is characterized by a sudden increase in several pro-inflammatory cytokines, mainly IL-1, IL-6 and TNF-alfa by activated macrophages (M1 phenotype). Blocking IL-6 with tocilizumab and using respirator equipment seems to be a very important issue in this (SARS-CoV-2) pneumonia, but not all patients are referred to such treatments. Low dose radiotherapy (0,5 Gy), is an evidence-based anti-inflammatory treatment, that could modify the immune landscape in the lung affected of SARS-CoV-2 pneumonia, through macrophages polarization to alternatively activated Macrophages (M2 phenotype). Radiation-induced cancer risk could be assumed due to the very low dose used, the advanced age of the patients and the life-threatening condition of SARS-Cov2 pneumonia. LDRT is a cost-effective non-toxic treatment already available in most general hospitals. This fact allows that it would be used for the large number of patients that will suffer this disease, and that would not receive specific anti-IL-6 treatments in ICUs in low and middle income countries. 2020 Published by Elsevier B.V. on behalf of European Society for Radiotherapy and Oncology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). 1. Introduction The COVID-19 pandemia is affecting people worldwide. By April 11th 102.774 patients have died of this disease. Most of the patients suffered of a respiratory disease that will progress to an acute respiratory distress syndrome (ARDS). The affected lung pre- sents alveolar edema, proteinaceous exudates, and reactive pneu- mocyte hyperplasia, accompanied by monocytes and lymphocytes alveolar inflammatory infiltration. The so-called SARS-CoV-2 pneumonia, is associated with high mortality specially for those included in high risk categories: advanced age, underly- ing comorbidities (hypertension, diabetes, cardiovascular disease) and high levels of inflammatory Dimer D/Ferritin[1]. 1.1. Macrophages in the immune basis for SARS-CoV2 pneumonia SARS-CoV-2 pneumonia severely ill patients, develop a systemic inflammatory response with a Cytokine Release Syndrome (CRS),that is characterized by a sudden increase in several pro- inflammatory cytokines, mainly IL-1, IL-6 and TNF-alfa[2]. This CRS was also observed in other viral infections SARS-Cov and MERS-Cov pneumonia)[3]and is one of the major adverse- effects after immune system-related diseases therapy (Chimeric Antigen Receptor T-Cell Immunotherapy, CAR-T cell therapy)[4]. The COVID-19 activates both innate and adaptive immune sys- tem. Macrophages seems to be an important component of this CRS syndrome, related to its phagocytic activity through the danger-associated molecular patters (DAMPS) activated by Toll- Like Receptors (TLR). COVID-19 activated TLRs makes possible the liberation of cytokines by macrophages (IL-1/IL-6/TNF- a) and subsequent activation of inflammasome[5]. This classically activated, ‘‘proinflammatory” M1 subset is acti- vated by infectious microorganisms (lipopolysaccharides) and cytokines (interferon- c). As already discussed, M1 macrophages participate in the initiation and development of inflammatory events, through the liberation of inflammatory cytokines such as IL-1b, IL-6, and TNF- a. Continued, non-controlled activation of M1 macrophages can cause tissue damage[6]. The alternatively activated, ‘‘anti-inflammatory” M2 macro- phages, are primed in response to Th2-related cytokines such as https://doi.org/10.1016/j.ctro.2020.04.006 2405-6308/2020 Published by Elsevier B.V. on behalf of European Society for Radiotherapy and Oncology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). ⇑Corresponding author at: Dept Radiation Oncology, Hospital Universitario San Roque, Las Palmas Gran Canaria, Spain. E-mail address:plara@dcc.ulpgc.es(P.C. Lara). Clinical and Translational Radiation Oncology 23 (2020) 27–29 Contents lists available atScienceDirect Clinical and Translational Radiation Oncology journal homepage: www.elsevier.com/locate/ctro
IL-4 and IL-10, and they express high levels of anti-inflammatory cytokines. At present time, available evidence suggests that M1/ M2 imbalances, favoring M1 phenotype, is in the pathogenesis of rheumathoid arthritis[7]and possibly in the SARS-CoV-2 IL-6 related pneumonia[2,3]. Although Inflammation changes try to restore the homeostasis after COVID-19 infection, can cause deleterious effects in uncon- trolled. Cytokines release in response to virus, by immune, endothelial cells and fibroblasts are crucial in the progression of pulmonary fibrosis[8]. Interleukin-6 (IL-6) is produced by TLR stimulated macrophages in the early stages of inflammation and plays a central role in pro- moting acute inflammation. IL-6 promotes the expansion and acti- vation of T cell /B cell populations. IL-6, is activated by IL-1band tumor necrosis factor (TNF- a)[9]. Cytokine storms play an important role in severe cases of (SARS-CoV-2) pneumonia, so neutralizing key inflammatory fac- tors in Cytokine Release Syndrome (CRS) will be of great value in reducing mortality of this disease[2]. 1.2. The treatment of SARS-CoV-2 pneumonia Blocking IL-6 seems to be a very important issue in this (SARS- CoV-2) pneumonia[2]. Tocilizumab is a monoclonal antibody against human IL-6 receptor. Although is worldwide approved for the treatment of rheumatoid arthritis[10], tocilizumab is also effective in the treatment of severe CRS patients caused by CAR-T (Chimeric Antigen Receptor T-Cell Immunotherapy) therapy[11]. As CRS occurred in severe patients with SARS-CoV-2 and all of them showed high levels of IL-6, tocilizumab is used in Covid19 patients at the present time[2]. Steroids are also a used treatment in SARS-CoV-2 CRS, but there are several concerns about toxicity in patients already affected by comorbidities or advanced age, that precludes it use in a relevant number of cases[2]. Unfortunately, restrictive criteria for the use of tocilizumab and referral to Intensive Care Units (ICUs) during this COVID-19 pan- demia, is the daily practice in most hospitals worldwide, due to the shortage of breath assisted equipment and access to tocilizu- mab treatment. New approaches should be considered for the treatment of this SARS-CoV-2 pneumonia. 1.3. Low-Dose radiotherapy in the treatment of SARS-Cov-2 pneumonia Among those demonstrated effective anti-inflammatory treat- ments, radiotherapy has been widely used since the early 20th cen- tury. Patients who are progressing to or unfit for common anti- inflammatory treatments, low-dose radiotherapy (LD-RT)) emerges as a evidence-based beneficial alternative. In fact, LD-RT reduces the existing inflammation in musculoskeletal diseases when used at very low doses (0.5 Gy/fraction)[12]. Ionizing radiation is able to reduce inflammation through vari- ous mechanisms including the induction of apoptosis in immune cells, the secretion of anti-inflammatory factors, and a reduced function of macrophages[13]. Concerning the use of low-dose radiotherapy in SARS-CoV-2 IL-6-related pneumonia, the role of radiotherapy in the modification of monocyte-macrophage axis would be very relevant. Recent studies indicate that LDRT polarizes macrophages towards a M2-like phenotype in a rheumathoid arthritis model. In this study, LDRT at a single dose of 0.5 Gy influenced M1/M2 bal- ance towards M2 ‘‘anti-inflammatory” phenotype when Fibroblast- like synoviocytes and bone marrow-derived macrophages were co- cultured in a experimental model of RA. Therefore LDRT could have a relevant role in those situations that hyperinflammation resem-bles RA, through reduction of IL-1 and TNF-alfa target cells produc- ing IL-6. Therefore, localized very low dose radiotherapy, would modify the inflammatory environment in the lung of SARS-CoV-2 IL-6 related pneumonia patients[14]. Radiotherapy for pneumonia has been used since the 30´ s of the last century with promising results[15]including and specially in interstitial viral pneumonia. Openheimmer[16]treated 56 patients with life-threatening progressive interstitial pneumonia at doses of 0,5 Gy. Patients treated in the first 14 days responds successfully to the therapy but after 14 days responses were around 50%. Experi- mental LDRT treatment for influenza virus in animals models demonstrated the efficacy of such treatment in almost half of the experimental cases[17]. LDRT is available worldwide, as is administered in standard LINACS. One single-fraction at very low doses, the whole lung vol- ume, would make possible to treat large number of patients in a dedicated LINAC. This initiative would result in cost-efficient and non-toxic treatment for the large number of patients that will suf- fer this disease, and that would not receive specific anti-IL-6 treat- ments in ICUs. 1.4. The fear of radiation induced cancer (RIC) after LDRT The only limitation to the use of low dose radiotherapy as a potent, non-toxic, anti-inflammatory treatment is the fear for long term radiation induced diseases, specially cancer. However, many of the considered ‘‘standard treatments” (NSAIDS, COX-inhibitors, steroids, etc) also have side effects that has to be weighted against the very small risk of RIC. Major evidence of radiation induced cancer, comes from acci- dental exposures to radiation of general population. The linear non-threshold (LNT) model developed from such accidental expo- sures, may overestimate the risks by one order of magnitude. Therefore cannot be useful for estimating the risk of cancer by the use of LDRT for nonmalignant diseases. The cancer-induced risks due to the RT of benign diseases based on data from epidemi- ological studies, showed no increased risk at low-dose[18]. A very important issue concerning cancer-induced risk by radi- ation is age. In fact due to the expected long latency of tumor development, the risk of inducing cancer would be even lower in patients over 40 years of age[12]. Concerning the present situation either the real risk of dying from the SARS-CoV-2 IL-6 pneumonia and the advanced age of the patients at such risk, would make irrelevant such concerns. 2. Conclusion Low doses radiotherapy to the whole lung should be explored under clinical trials[19]to patients in early stages of the SARS- CoV-2 IL-6 pneumonia, especially those with unfavourable risk fac- tors as advanced age, comorbidities and hyperinflammation mark- ers of elevated Ferritin and Dimer D. LDRT is a cost-effective non- toxic treatment already available in most general hospitals. Besides that would be used for the large number of patients that will suffer this disease, and that would not receive specific anti-IL-6 treat- ments in ICUs in low and middle income countries. Authors contribution 1) Pedro C Lara, developed the idea, write the paper and criti- cally discussed the final format. 2) David Macias-Verde, contributed to the idea, write the paper and critically discussed the final format. 3) Javier Burgos-Burgos, contributed to the idea, write the paper and critically discussed the final format. 28P.C. Lara et al. / Clinical and Translational Radiation Oncology 23 (2020) 27–29
Funding source Hospital Universitario San Roque/Universidad Fernando Pessoa Grant 19-001. Declaration of Competing Interest The authors declare that they have no known competing finan- cial interests or personal relationships that could have appeared to influence the work reported in this paper. References [1]Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020;395(10223):497–506. [2]Mehta P, McAuley DF, Brown M, et al. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet 2020;395(10229):1033–4. [3]Channappanavar R, Perlman SN. Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology. Semin Immunopathol 2017;39:529–39 . [4]Norelli M, Camisa B, Barbiera G, et al. Monocyte-derived IL-1 and IL-6 are differentially required for cytokine-release syndrome and neurotoxicity due to CAR T cells. Nat Med 2018;24(6):739–48 . [5]Crayne CB, Albeituni S, Nichols KE. Cron R.Q The immunology of macrophage activation syndrome. Front Immunol 2019;10:119. [6]Murray PJ, Wynn TA. Protective and pathogenic functions of macrophage subsets. Nat Rev Immunol 2011;11:723–37. [7]Fukui S, Iwamoto N, Takatani A, et al. M1 and M2 monocytes in rheumatoid arthritis: a contribution of imbalance ofM1/M2 monocytes to osteoclastogenesis. Front Immunol 1958;2018:8 .[8] McGonagle D, Sharif K, O’Regan A, Bridgewood C. Interleukin-6 use in COVID- 19 pneumonia related macrophage activation syndrome. Autoimmun Rev 2020 Apr;3:102537 . [9]Jones SA, Jenkins BJ. Recent insights into targeting the IL-6 cytokine family in inflammatory diseases and cancer. Nat Rev Immunol 2018;18(12):773–89. [10]Navarro G, Taroumian S, Barroso N, et al. Tocilizumab in rheumatoid arthritis: a meta-analysis of efficacy and selected clinical conundrums. Sem Arthr Rheum 2014;4(4):458–69 . [11]Le RQ, Li L, Yuan W, et al. FDA approval summary: tocilizumab for treatment of chimeric antigen receptor t cell-induced severe or life-threatening cytokine release syndrome. Oncologist 2018;23(8):943–7 . [12]Ott OJ, Niewald M, Weitmann HD, et al. DEGRO guidelines for the radiotherapy of non-malignant disorders. Part II: painful degenerative skeletal disorders. Strahlenther Onkol 2015;191(1):1–6 . [13]Arenas M, Sabater S, Hernández V, et al. Anti-inflammatory effects of low-dose radiotherapy. Indications, dose, and radiobiological mechanisms involved. Strahlenther Onkol 2012;188(1):975–81 . [14]Deloch L, Fuchs J, Rückert M, et al. Low-dose irradiation differentially impacts macrophage phenotype in dependence of fibroblast-like synoviocytes and radiation dose. J Immunol Res 2019 Aug;14:3161750 . [15]Calabrese EJ, Dhawan G. How radiotherapy was historically used to treat pneumonia: could it be useful today?. Yale J Biol Med 2013;86(4):555–70. [16]Oppenheimer A. Roentgen therapy of ‘‘virus” pneumonia. Am J Roentgenol Rad Ther 1943;49:635–8. [17]Dubin IN, Baylin GJ, Gobble Jr WG. The effect of roentgen therapy on experimental virus pneumonia; on pneumonia produced in white mice by swine influenza virus. Am J Roentgenol Radium Ther 1946;55:478–81 . [18]Trott KR, Kamprad F. Estimation of cancer risks from radiotherapy of benign diseases. Strahlenther Onkol 2006;182(8):431–6. [19] Kirby C and MacKenzie M; Radiotherapy Oncology, Letter to the editor, in press. P.C. Lara et al. / Clinical and Translational Radiation Oncology 23 (2020) 27–2929