Personal View: Low-Dose Lung Radiotherapy Should be Evaluated as a Treatment for Severe COVID-19 Lung Disease

Abstract

As of July 2020, infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused more than 600 000 deaths globally [[1]WHO Coronavirus Disease (COVID-19) Dashboard. World Health Organisation.https://covid19.who.int/?gclid=EAIaIQobChMI2p-w_MjA6gIVRLTtCh16DAnTEAAYASAAEgKq1fD_BwEGoogle Scholar]. Infection by SARS-CoV-2 causes the clinical syndrome COVID-19, which varies widely in severity from asymptomatic to severe pneumonia and life-threatening acute respiratory distress syndrome (ARDS). The population-wide case–fatality ratio is estimated at 2.3% [[2]Wu Z. McGoogan J.M. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72,314 cases from the Chinese Center for Disease Control and Prevention.JAMA. 2020; 323: 1239-1242https://doi.org/10.1001/jama.2020.2648Crossref PubMed Scopus (10609) Google Scholar]; 20 times higher than seasonal influenza. The case–fatality ratio rises sharply with age (14.8% > 80 years) and pre-existing comorbidities. The highest mortality rates are seen in patients with severe pneumonia and ARDS, which account for 14% of cases [[2]Wu Z. McGoogan J.M. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72,314 cases from the Chinese Center for Disease Control and Prevention.JAMA. 2020; 323: 1239-1242https://doi.org/10.1001/jama.2020.2648Crossref PubMed Scopus (10609) Google Scholar]. Hospitalisation rates are estimated at 4.6 per 100 000 and correlate with age and comorbidities [[3]Garg S. Kim L. Whitaker M. O’Halloran A. Cummings C. Holstein R. et al.Hospitalization rates and characteristics of patients hospitalized with laboratory-confirmed coronavirus disease 2019 – COVID-NET, 14 states, March 1-30, 2020.MMWR Morb Mortal Wkly Rep. 2020; 69: 458-464https://doi.org/10.15585/mmwr.mm6915e3Crossref PubMed Scopus (0) Google Scholar]. The COVID-19 pandemic is putting severe strain on health and social care and causing unprecedented social and economic disruption. Severe disease is characterised by hypoxia and a requirement for oxygen or ventilatory support [[4]Kim A.Y. Gandhi R.T. Coronavirus disease 2019 (COVID-19): management in hospitalized adults.https://www.uptodate.com/contents/coronavirus-disease-2019-covid-19-management-in-hospitalized-adults?search=covid%2019%20inpatient&source=search_result&selectedTitle=1∼150&usage_type=default&display_rank=1Date accessed: June 27, 2020Google Scholar]. Ward-based management includes oxygen, antibiotics for superimposed bacterial infections, proning, non-invasive ventilation and management of thromboembolic risks and complications [[4]Kim A.Y. Gandhi R.T. Coronavirus disease 2019 (COVID-19): management in hospitalized adults.https://www.uptodate.com/contents/coronavirus-disease-2019-covid-19-management-in-hospitalized-adults?search=covid%2019%20inpatient&source=search_result&selectedTitle=1∼150&usage_type=default&display_rank=1Date accessed: June 27, 2020Google Scholar]. In cases of ARDS, intensive care unit admission may be required, where specialised management involves intubation, low tidal volume and prone ventilation [[4]Kim A.Y. Gandhi R.T. Coronavirus disease 2019 (COVID-19): management in hospitalized adults.https://www.uptodate.com/contents/coronavirus-disease-2019-covid-19-management-in-hospitalized-adults?search=covid%2019%20inpatient&source=search_result&selectedTitle=1∼150&usage_type=default&display_rank=1Date accessed: June 27, 2020Google Scholar]. Treatment options for COVID-19 remain limited. The RECOVERY trial (UK) reported that dexamethasone reduced 28-day mortality in patients requiring ventilatory support (relative risk 0.65) or oxygenation (relative risk 0.80), but not in patients not requiring respiratory support (relative risk 1.22) [[5]Horby P. Lim W.S. Emberson J. Mafham M. Bell J. Linsell L. et al.The Recovery Collaborative GroupDexamethasone in hospitalized patients with COVID-19 - preliminary report.NEJM. 2020; (In press)https://doi.org/10.1056/NEJMoa2021436Crossref Scopus (5223) Google Scholar]. Of note, this study awaits peer-reviewed publication and baseline mortality was higher than in other trials. Antiviral therapies are under intense investigation. Preliminary results from one study indicated that remdesivir reduced the time to recovery from severe COVID-19, but no impact on mortality has yet been shown [[6]Beigel J.H. Tomashek L.E. Dodd A.K. Mehta B.S. Zingman A.C. Kalil A.C. et al.Remdesivir for the treatment of Covid-19 – preliminary report.NEJM. 2020; (In press)https://doi.org/10.1056/NEJMoa2007764Crossref Scopus (3895) Google Scholar]. Recent unpublished data from the RECOVERY trial indicated no benefit from lopinavir/ritonavir in hospitalised patients [[7]Statement from the chief investigators of the randomised evaluation of COVid-19 thERapY (RECOVERY) trial on lopinavir-ritonavir. University of Oxford, 29 June 2020https://www.recoverytrial.net/files/lopinavir-ritonavir-recovery-statement-29062020_final.pdfGoogle Scholar]. Ongoing trials are evaluating convalescent plasma [[8]Casadevall A. Joyner M.J. Pirofski L. A randomized trial of convalescent plasma for COVID-19–potentially hopeful signals.JAMA. 2020; 324: 455-457https://doi.org/10.1001/jama.2020.10218Crossref PubMed Scopus (64) Google Scholar] and there is interest in hyperimmune globulin and the development of monoclonal antibodies to neutralise SARS-CoV-2. Despite this progress, many patients do not respond to treatment and morbidity and mortality remain high, providing a strong argument to consider innovative therapies and test them appropriately. This concept is recognised within the Helsinki declaration, which states:where proven … therapeutic methods do not exist or have been ineffective, the physician, with informed consent from the patient, must be free to use unproven or new … therapeutic measures, if in the physician's judgment it offers hope of saving life, re-establishing health or alleviating suffering [[9]World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects.JAMA. 2000; 284: 3043-3045Crossref PubMed Scopus (1132) Google Scholar]. COVID-19 lung disease exhibits an acute, hyper-inflammatory state, the severity of which correlates with morbidity and mortality [[10]Mehta P. McAuley D.F. Brown M. Sanchez E. Tattersall R.S. Manson J.J. COVID-19: consider cytokine storm syndromes and immunosuppression.Lancet. 2020; 395: 1033-1034https://doi.org/10.1016/S0140-6736(20)30628-0Abstract Full Text Full Text PDF PubMed Scopus (5723) Google Scholar]. The characteristic lung pathology and associated systemic deterioration are consistent with ARDS and cytokine release syndrome, respectively. The immunopathology of COVID-19 lung disease is reviewed elsewhere [[11]Cao X. COVID-19: immunopathology and its implications for therapy.Nat Rev Immunol. 2020; 20: 269-270https://doi.org/10.1038/s41577-020-0308-3Crossref PubMed Scopus (965) Google Scholar], but the key features include florid alveolar infiltration by neutrophils, macrophages and lymphocytes plus markedly increased proinflammatory cytokines, including interleukin-6 (IL-6), IL-1β, tumour necrosis factor and interferon gamma (IFNγ). Nerve and airway associated macrophages (NAMs) may play a role in regulating infection-induced inflammation via pro- (IFNγ/IL-6) and anti-inflammatory (IL-10) cytokines [[12]Ural B.B. Yeung S.T. Damani-Yokota P. Devlin J.C. de Vries M. Vera-Licona P. et al.Identification of a nerve-associated, lung-resident interstitial macrophage subset with distinct localization and immunoregulatory properties.Sci Immunol. 2020; 5Crossref PubMed Scopus (92) Google Scholar]. The early efficacy data for dexamethasone support the concept of hyper-inflammation as a critical pathological process, and the pulmonary focus of this immune response indicates that a lung-specific immunosuppressive intervention may have therapeutic value. Numerous case series from the early 20th century document the successful use of low-dose radiotherapy (LDRT) to the lungs to treat pneumonia of various aetiologies [[13]Calabrese E.J. Dhawan G. How radiotherapy was historically used to treat pneumonia: could it be useful today?.Yale J Biol Med. 2013; 86: 555-570PubMed Google Scholar]. That LDRT acts primarily by curbing inflammation is supported by multiple pre-clinical and clinical studies that illustrate efficacy in a broad range of inflammatory (non-malignant) pathologies [[14]Seegenschmiedt M.H. Olschewski T.O. Guntrum F. Radiotherapy optimization in early-stage Dupytren’s contracture: first results of a randomized clinical study.Int J Radiat Oncol Biol Phys. 2001; 49: 785-798https://doi.org/10.1016/S0360-3016(00)00745-8Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar,[15]Royo L.T. Redondo G.A. Pianeyya M.A. Prat M.A. Low-dose radiation therapy for benign pathologies.Rep Pract Oncol Radiother. 2020; 25: 250-254https://doi.org/10.1016/j.rpor.2020.02.004Crossref PubMed Scopus (38) Google Scholar]. The severity and global impact of the current pandemic and the paucity of effective drug treatments have prompted renewed interest in the use of LDRT to treat COVID-19-related pneumonitis [[16]Lara P.C. Burgos J. Macias D. Low dose lung radiotherapy for COVID-19 pneumonia. The rationale for a cost-effective anti-inflammatory treatment.Clin Transl Radiat Oncol. 2020; 23: 27-29Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar,[17]Kirkby C. Mackenzie M. Is low dose radiation therapy a potential treatment for COVID-19 pneumonia?.Radiother Oncol. 2020; 147: 221https://doi.org/10.1016/j.radonc.2020.04.004Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar]. Calabrese and Dhawan [[13]Calabrese E.J. Dhawan G. How radiotherapy was historically used to treat pneumonia: could it be useful today?.Yale J Biol Med. 2013; 86: 555-570PubMed Google Scholar] reviewed 15 studies comprising about 860 individuals with severe pneumonia who were treated with LDRT. Viral and bacterial pneumonias were included, and comparisons with historical controls were made in most studies. Radiation doses below 100 cGy per session were generally delivered, with absorbed lung doses as low as 20 cGy if superficial absorption of low beam energies is considered. These studies independently reported LDRT to be associated with reduced mortality and shorter recovery times [[13]Calabrese E.J. Dhawan G. How radiotherapy was historically used to treat pneumonia: could it be useful today?.Yale J Biol Med. 2013; 86: 555-570PubMed Google Scholar]. These reports lack dosimetric rigor, fail to meet current clinical trials standards and were probably subject to publication bias. Nonetheless, there is clear consensus that thoracic irradiation did not adversely affect outcomes, and reductions in mortality were consistently reported [[13]Calabrese E.J. Dhawan G. How radiotherapy was historically used to treat pneumonia: could it be useful today?.Yale J Biol Med. 2013; 86: 555-570PubMed Google Scholar]. Reduced usage of LDRT coincided with the introduction of effective antimicrobial therapy and heightened awareness of radiation-induced malignancies. The development of effective alternative therapies has also seen the use of radiotherapy for other non-malignant conditions fall sharply. Reports by the UK Royal College of Radiologists on the use of radiation for non-malignant disease reveal highly varied practice and recognise the difficulties in estimating carcinogenic risk [[18]Taylor R.E. Hatfield P. McKeown S.R. Prestwich R.J. Shaffer R. Radiotherapy for benign disease: current evidence, benefits and risks.Clin Oncol. 2015; 27: 433-435https://doi.org/10.1016/j.clon.2015.01.009Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar]. This paradigm therefore sits outside the ‘comfort zone’ of UK-trained radiation oncologists. By contrast, LDRT remains widely used in Germany for the management of non-malignant diseases [[19]Glauner R. Die Behandlung entzündlicher Er krankungen mit Röntgenstrahlen.in: Die strahlentherapie. Georg Thieme, Stuttgart1949Google Scholar,[20]Glauner R. Die entzündungsbestrahlung. Georg Thieme, Stuttgart1951Google Scholar], with about 50 000 patients treated per annum [[21]Seegenschmiedt M.H. Micke O. Muecke R. Radiotherapy for non-malignant disorders: state of the art and update of the evidence-based practice guidelines.Br J Radiol. 2015; 88: 20150080Crossref PubMed Scopus (74) Google Scholar]. Data relating to the use of LDRT for degenerative joint disease, for example, are insufficient to determine dose, scheduling and patient selection in the context of COVID-19 pneumonitis [[22]Trott KR. Zschaeck S. Beck M. Radiation therapy for COVID-19 pneumopathy.Radiother Oncol. 2020; 147: 210-211https://doi.org/10.1016/j.radonc.2020.05.003Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar]; thus, clinicians are rightly calling for more relevant pre-clinical data. In response, Meziani and colleagues [[23]Meziani L. Robert C. Mordant P. Deutsch E. Low doses of radiation therapy increase the immunosuppressive profile of lung macrophages via IL-10 production and IFNγ/IL-6 suppression: a therapeutic strategy to counteract lung inflammation?.BioRxiv. 2020; (05.11)077651https://doi.org/10.1101/2020.05.11.077651Crossref Scopus (0) Google Scholar] initiated laboratory experiments, using intratracheal lipopolysaccharide to induce pneumonitis in a mouse model. Their early data (not yet peer-reviewed) show that LDRT (0.5–1 Gy) increased the immunosuppressive profiles of human lung macrophages in vitro and murine NAMs ex vivo, and reduced lung inflammation in mice with lipopolysaccharide-induced pneumonitis [[23]Meziani L. Robert C. Mordant P. Deutsch E. Low doses of radiation therapy increase the immunosuppressive profile of lung macrophages via IL-10 production and IFNγ/IL-6 suppression: a therapeutic strategy to counteract lung inflammation?.BioRxiv. 2020; (05.11)077651https://doi.org/10.1101/2020.05.11.077651Crossref Scopus (0) Google Scholar]. The proposed mechanism is induction of anti-inflammatory IL-10 and suppression of proinflammatory IL-6 and IFNγ (Figure 1) [[24]Calabrese E. Dhawan G. Kapoor R. Kozumbo W. Radiotherapy treatment of human inflammatory diseases and conditions: optimal dose.Hum Exp Toxicol. 2019; 38: 888-898https://doi.org/10.1177/0960327119846925Crossref PubMed Scopus (64) Google Scholar,[25]Clinicaltrials.govLow-dose radiotherapy for patients with SARS-COV-2 (COVID-19) pneumonia (PreVent). Arnab Chakravarti: Ohio State University Comprehensive Cancer Center, 2020https://clinicaltrials.gov/ct2/show/NCT04466683Google Scholar]. These early findings, and the established roles of these factors in cytokine release syndrome and ARDS, support further investigation of LDRT in COVID-19 patients with acute pneumonitis. Very early interim data from a US pilot trial in which older, comorbid patients with severe COVID-19 lung disease received LDRT (1.5 Gy) at standard dose rate are reassuring, with no acute deteriorations or measurable early toxicity [[26]Hess C.B. Buchwald Z.S. Stokes W. Switchenko J.M. Nasti T.H. Weinberg B.D. et al.Low-dose whole-lung radiation for COVID-19 pneumonia: planned day-7 interim analysis of an ongoing clinical trial.MedRxiv. 2020; (Submitted for publication)https://doi.org/10.1101/2020.06.03.20116988Crossref PubMed Scopus (0) Google Scholar]. Although the study is too small to provide an efficacy signal, the observation that four of the five patients exhibited clinical improvement within 1–3 days provides further evidence of safety [[26]Hess C.B. Buchwald Z.S. Stokes W. Switchenko J.M. Nasti T.H. Weinberg B.D. et al.Low-dose whole-lung radiation for COVID-19 pneumonia: planned day-7 interim analysis of an ongoing clinical trial.MedRxiv. 2020; (Submitted for publication)https://doi.org/10.1101/2020.06.03.20116988Crossref PubMed Scopus (0) Google Scholar]. Alongside the biological rationale for testing LDRT in COVID-19 patients exist valid and well-articulated concerns [[27]Tharmalingam H. Díez P. Tsang Y. Hawksley A. Conibear J. Thiruthaneeswaran N. Personal view: Low-dose lung radiotherapy for COVID-19 pneumonia - the atypical science and the unknown collateral consequence.Clin Oncol. 2020; 32: 497-500https://doi.org/10.1016/j.clon.2020.06.002Abstract Full Text Full Text PDF Scopus (8) Google Scholar]. The pre-clinical data are inconsistent and largely extrapolated from other models of inflammation. Potential risks to the patient include acute toxicity, lymphopenia and immunosuppression, viral activation or mutation, and secondary malignancy. Exposure of radiotherapy staff and facilities to infection is another significant hazard [[28]Kirsch D.G. Diehn M. Cucinotta F.A. Weichselbaum R. Lack of supporting data make the risks of a clinical trial of radiation therapy as a treatment for COVID19 pneumonia unacceptable.Radiother Oncol. 2020; 147: 217-220https://doi.org/10.1016/j.radonc.2020.04.060Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar]. Full discussion of these important issues is not possible within this article, but some key points are summarised here:(i)Although extensive clinical experience provides reassurance that radiation doses below 1 Gy are extremely unlikely to induce clinically significant acute toxicity, the integral dose delivered to the irradiated volume could cause lymphocytopenia. In patients with COVID-19, lymphopenia has been correlated with disease severity and mortality [[29]Joseph N. Choudhury A. Lymphocytopenia and radiotherapy treatment volumes in the time of COVID-19.Clin Oncol. 2020; 32: 420-422Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar]. Owing to pulmonary infiltration by proinflammatory lymphocytes, the local anti-inflammatory effects of LDRT within the lungs will probably be more significant than effects on circulating immune cells [[11]Cao X. COVID-19: immunopathology and its implications for therapy.Nat Rev Immunol. 2020; 20: 269-270https://doi.org/10.1038/s41577-020-0308-3Crossref PubMed Scopus (965) Google Scholar]. Similarly, alveolar macrophages (antiviral response contributors), are generally mobilised from the circulation and should be minimally affected by thoracic LDRT, particularly if delivered at standard high dose rates [[12]Ural B.B. Yeung S.T. Damani-Yokota P. Devlin J.C. de Vries M. Vera-Licona P. et al.Identification of a nerve-associated, lung-resident interstitial macrophage subset with distinct localization and immunoregulatory properties.Sci Immunol. 2020; 5Crossref PubMed Scopus (92) Google Scholar]. Lymphocyte subset analyses in clinical trials may help to mitigate concerns and inform patient selection by enabling a better understanding of the impact of LDRT on the systemic immune response.(ii)Radiotherapy techniques such as volumetric modulated arc therapy often deliver significant doses to organs located outside the target volume, and integral diffused lung doses of 0.15–0.5 Gy are frequently recorded [[30]Teoh M. Clark C.H. Wood K. Whitaker S. Nisbet A. Volumetric modulated arc therapy: a review of current literature and clinical use in practice.Br J Radiol. 2011; 84: 967-996https://doi.org/10.1259/bjr/22373346Crossref PubMed Scopus (411) Google Scholar]. Despite this, the shift from three-dimensional techniques to volumetric modulated arc therapy has not been associated with detectable increases in acute or late lung toxicity [[31]Journy N. Mansouri I. Allodji R.S. Demoor-Goldschmidt C. Ghazi D. Haddy N. et al.Volume effects of radiotherapy on the risk of second primary cancers: a systematic review of clinical and epidemiological studies.Radiother Oncol. 2019; 131: 150-159https://doi.org/10.1016/j.radonc.2018.09.017Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar].(iii)LDRT to infected lungs is expected to induce RNA damage and, theoretically, may induce viral mutations. However, as discussed by Rödel et al. [[32]Rödel F. Arenas M. Ott O.J. Fournier C. Georgakilas A.G. Low-dose radiation therapy for COVID-19 pneumopathy: what is the evidence?.Strahlenther Onkol. 2020; 196: 679-682https://doi.org/10.1007/s00066-020-01635-7Crossref PubMed Scopus (31) Google Scholar], anti-viral drug treatments would generate more intensive selective pressure on the SARS-CoV-2 virus than radiation doses of 1 Gy or less. Anxiety that viral infectivity might be exacerbated by LDRT is countered by evidence that radiation doses of 1 Gy have not been shown to induce viral re-activation [[33]Lai Y.L. Su Y.C. Kao C.H. Liang J.A. Increased risk of varicella-zoster virus infection in patients with breast cancer after adjuvant radiotherapy: a population-based cohort study.PLoS One. 2019; 14e0209365https://doi.org/10.1371/journal.pone.0209365Crossref PubMed Scopus (7) Google Scholar].(iv)Kirsch and colleagues [[28]Kirsch D.G. Diehn M. Cucinotta F.A. Weichselbaum R. Lack of supporting data make the risks of a clinical trial of radiation therapy as a treatment for COVID19 pneumonia unacceptable.Radiother Oncol. 2020; 147: 217-220https://doi.org/10.1016/j.radonc.2020.04.060Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar] have cited concerns about late-occurring toxicities, specifically secondary lung cancers and cardiovascular disease. Their mortality estimations and approximation of overall lifetime risk of LDRT-induced cancer are based on models developed to define dose limits for occupational radiation exposure. These reflect the recommendations of the International Commission for Radiological Protection and are not necessarily accurate in the context of individual medical exposures. Nonetheless, long-term outcomes must be measured in phase II and III trials.(v)Radiotherapy teams advocating for the study of LDRT in COVID-19 propose a safe procedural approach consistent with modern trial methodologies and ethics. Key components such as ethical approvals, patient age ≥50 years, informed consent, continuous monitoring of patient outcomes and clearly defined stopping rules for unexpected toxicities are included in the clinical protocols currently accruing [[34]U.S. National Library of Science, NIHhttps://clinicaltrials.gov/ct2/results?cond=Covid-19&term=radiation+low-dose+therapy&cntry=&state=&city=&dist=Google Scholar]. Staff safety is a high priority and is achieved by strict adherence to the use of personal protective equipment and protocols to maintain ‘clean’ treatment facilities, including ‘end-of-day’ treatment on designated linear accelerators. We have outlined historical and contemporary evidence for a potential role of LDRT in managing the acute inflammatory response associated with severe COVID-19 infection. In the absence of definitive, effective treatments for these patients, we believe that the potential benefits of LDRT outweigh the theoretical risks, and thus support its evaluation in carefully designed clinical trials.