Strahlenther Onkol https://doi.org/10.1007/s00066-021-01803-3 ORIGINAL ARTICLE Could pulmonary low-dose radiation therapy be an alternative treatment for patients with COVID-19 pneumonia? Preliminary results of a multicenter SEOR-GICOR nonrandomized prospective trial (IPACOVID trial) M. Arenas1,2,3 · M. Algara4,5,6 · G. De Febrer1,7 · C. Rubio8 · X. Sanz4,6,9 · M. A. de la Casa8 et al. [full author details at the end of the article] Received: 1 March 2021 / Accepted: 1 June 2021 © The Author(s) 2021 Abstract Purpose To evaluate the efficacy and safety of lung low-dose radiation therapy (LD-RT) for pneumonia in patients with coronavirus disease 2019 (COVID-19). Materials and methods Inclusion criteria comprised patients with COVID-19-related moderate–severe pneumonia war- ranting hospitalization with supplemental O2 and not candidates for admission to the intensive care unit because of comorbidities or general status. All patients received single lung dose of 0.5 Gy. Respiratory and systemic inflammatory parameters were evaluated before irradiation, at 24 h and 1 week after LD-RT. Primary endpoint was increased in the ratio of arterial oxygen partial pressure (PaO2) or the pulse oximetry saturation (SpO2) to fractional inspired oxygen (FiO2) ratio of at least 20% at 24 h with respect to the preirradiation value. Results Between June and November 2020, 36 patients with COVID-19 pneumonia and a mean age of 84 years were enrolled. Seventeen were women and 19 were men and all of them had comorbidities. All patients had bilateral pulmonary infiltrates on chest X-ray. All patients received dexamethasone treatment. Mean SpO2 pretreatment value was 94.28% and the SpO2/FiO2 ratio varied from 255 mm Hg to 283 mm Hg at 24 h and to 381 mm Hg at 1 week, respectively. In those who survived (23/36, 64%), a significant improvement was observed in the percentage of lung involvement in the CT scan at 1 week after LD-RT. No adverse effects related to radiation treatment have been reported. Conclusions LD-RT appears to be a feasible and safe option in a population with COVID-19 bilateral interstitial pneumonia in the presence of significant comorbidities. Keywords COVID-19 pneumonia · Low-dose radiation therapy · Treatment outcome · Anti-inflammatory effects · Lung irradiation Introduction CoV-2 virus infection derive mainly from the hyperinflam- matory lung response that some infected patients expe- Since the beginning of 2020 when coronavirus disease 2019 rience, which leads to SARS, the cause of death from (COVID-19) appeared, the world has been battling against COVID-19 in many cases [1]. a new and practically unknown highly contagious viral in- Numerous pharmacological alternatives have been pro- fection which yet has no cure. Although the majority of in- posed although none have proven to be definitively effec- fected people develop only mild, if not practically asymp- tive. In this context, a number of groups in different parts tomatic, clinical effects, most serious clinical manifesta- of the world have been exploring the idea of a one-off ef- tions of the severe acute respiratory syndrome (SARS)- fective radiotherapy treatments in lung pneumonia. Several publications have proposed theoretical bases for the useful- ness of radiotherapy in COVID-19 and although the idea  M. Algara, MD, PhD of using radiation therapy to treat different respiratory dis- malgara@parcdesalutmar.cat orders is not new [2–4], it has generally been met with Extended author information available on the last page of the prejudice and fear that often accompany the therapeutic article use of ionizing radiation. Advances in radiobiology help K Strahlenther Onkol us to understand the efficacy of low-dose radiation therapy for admission to the intensive care unit (ICU) because of (LD-RT) as a plausible anti-inflammatory treatment. Radio- comorbidities or low performance status. The LD-RT plan therapy doses conventionally used in the treatment of neo- comprised a single dose of 0.5 Gy, although the protocol plastic diseases induce the production and release of pro- included the possibility of administering a second dose of inflammatory cytokines. However, low doses of between 0.5 Gy after 48 h, depending on the response to the first and 0.3–0.7 Gy induce a totally opposite phenotype thanks to individualizing every case. A planning computed tomogra- their effect on leukocytes, macrophages, polymorphonu- phy (CT) scan with axial images obtained at 3 mm intervals clear cells, and vascular endothelial cells. LD-RT provokes throughout the lung was acquired from all patients who a decrease in pro-inflammatory mediators, such as reac- were candidates for LD-RT. Clinical target volume (CTV) tive oxygen species (ROS), nitric oxide synthetase (iNOS), included both lungs. The radiotherapy plan consisted of an- tumor necrosis factor (TNF)-α, selectin L- and E-, or in- terior posterior–posterior anterior 2-field conformal treat- terleukin (IL)-beta 1. Additionally, LD-RT favors a change ment for both lungs without any type of protection (Sup- in macrophage polarization from a pro-inflammatory M-1 plementary information Figure A1). Due to the ultra-low phenotype to an anti-inflammatory M-2 phenotype at the prescribed, defining dose, specific constraints were not con- same time as increasing the secretion of anti-inflammatory sidered necessary for healthy organs beyond the ALARA mediator transforming anti-inflammatory cytokine growth (as low as reasonably achievable) principle. factor β1 (TGF-β1) and apoptosis mediators nuclear factor To evaluate the efficacy of the treatment, variations in kappa-beta (NF-κB) [5–9]. Based on this knowledge, sev- the daily oxygen supply needs according to the FiO2, which eral studies of pulmonary LD-RT in COVID-19 pneumonia represents the percentage of oxygen participating in gas have been initiated in different countries [10]. exchange, and periodic determinations of PaO2/FiO2 or We hypothesized that pulmonary LD-RT can prevent or SpO2/FiO2 ratio, radiologic evaluation of lung infiltrates reduce the lung inflammatory cascade produced by COVID- and determination of inflammation markers were carried 19 and it can be an alternative treatment for these patients. out and measured before irradiation (basal) and at 24 h and We report here the results of a whole lung LD-RT multicen- at 1 week after treatment. In some cases (13/36), it was ter trial on 36 patients with COVID-19-related pneumonia. also possible to analyze all parameters at 1 month after LD-RT. To assess the functional status and potential risk of the Materials and methods study population, we decided to use two existing tools de- signed for this purpose. The Barthel Index was used to The protocol details of this multicenter, nonrandomized evaluate patients’ functional independence by means of an prospective trial have been published previously [11]. The ordinal scale used to measure performance in activities of main study objective was to evaluate the efficacy of sin- daily living (ADL), and the CURB-65 Severity Score is gle pulmonary LD-RT (0.5 Gy), evaluated according to an a clinical prediction rule that has been validated for estimat- increase in arterial oxygen partial pressure (PaO2) to frac- ing mortality of community-acquired pneumonia measuring tional inspired oxygen (FiO2) (PaO2/FiO2) ratio or the pulse Confusion, blood Urea nitrogen (BUN), Respiratory rate, oximetry saturation (SpO2) to FiO2 (SpO2/FiO2) ratio of at Blood pressure and age over 65. Due to the cognitive im- least 20% at 24 h with respect to the pre-irradiation value pairment and several comorbidities that all elderly patients in at least 30% of the treated and evaluable patients. Sec- presented in this trial, we classified the groups into three dif- ondary objectives included positive changes in radiological ferent subgroups: survivors (group A), deaths from COVID- image, mortality at 15 and 30 days after LD-RT, and the 19 (group B) and deaths from other causes (group C), in effects on inflammatory blood parameters including the de- order to support the initial supposition of severe cognitive termination of C-reactive protein (CRP), interleukin-6 (IL- impairment and associated increased risk of death. 6), ferritin, D-dimer (DD) and lactic acid dehydrogenase All statistical analysis and graph representations were (LDH). We consider necessary to note that although this performed by SPSS software (SPSS 22.0, Chicago, IL, trial was designed in 2 phases: a first exploratory phase USA), ‘R’ software version 4.0.2 (https://www.r-project. that intended to recruit 10 patients to evaluate the viabil- org/) and GraphPad Prism 6.01 (GraphPad Software, San ity and efficacy of single-fraction pulmonary RT-LD, and Diego, CA, USA). To assess the distribution of the vari- a second, nonrandomized comparative phase with a control ables was used the Kolmogorov–Smirnov test. Through the group, its interest during the COVID-19 pandemic triggered Mann–Whitney U-test (nonparametric) we evaluated differ- recruitment from the initial phase to the 36 patients we now ences between any two groups of variables and for compar- report. isons of dependent variables we used the Wilcoxon signed- Inclusion criteria comprised patients with COVID-19-re- rank test. To assess differences between qualitative vari- lated moderate–severe pneumonia who were not candidates ables we employed the χ2 test. Medians and interquartile K Low-dose radiation therapy for COVID-19 pneumonia Table 1 Clinical characteristics of patients with COVID-19 treated Table 1 (Continued) with low-dose radiation therapy Variables (n = 36) Variables (n = 36) Final status Age 83.64 (8.11)b Alive 23 (63.9)a Sex Death due to COVID-19 8 (22.2) Female 17 (47.2)a Death due to other causes 5 (13.9) Male 19 (52.8) CT Computed Tomography; CURB-65 validated clinical prediction Neurologic diseases 10 (27.8)b score for predicting mortality in community-acquired pneumonia and Cardiovascular diseases 30 (83.3)b infection of any site including measurement of: Confusion of new Respiratory diseases 12 (33.3)b onset, Blood Urea Nitrogen, Respiratory rate, Blood pressure and Age; PaFi ratio of arterial oxygen partial pressure (PaO2) to Fractional Other comorbidities 31 (86.1)b Inspired Oxygen (FiO2); SpO2 oxygen saturation; SaFi ratio of SpO2 Days with symptoms 5.72 (1.54)b to FiO2 a Functional status (Barthel Index) Results shown as frequencies and percentages in parenthesis b Independent 6 (16.7)a Results shown as means and standard deviations in parenthesis Minimally dependent 12 (33.3) Partially dependent 7 (19.4) ranges were expressed for quantitative variables and fre- Very dependent 8 (22.2) quencies and percentages for qualitative variables. We con- Total dependent 3 (8.3) sidered significant differences when the p-value was < 0.05. Geriatric Depression Scale (GDS) This protocol conforms to international regulations and No cognitive decline 18 (50)a is in accordance with the recommendations established in Very mild cognitive decline 8 (22.2) the Declaration of Helsinki. The study was approved by the Mild cognitive decline 5 (13.9) Institution Research Board of each center and is registered Moderate cognitive decline – in ClinicalTrials.gov (NCT NCT04380818). Moderately severe cognitive decline 2 (5.6) Severe cognitive decline 3 (8.3) Very severe cognitive decline – Results Pharmacological treatment Corticosteroids (dexamethasone) 36 (100)a Between June and November 2020, 36 patients with Remdesivir 2 (5.6) COVID-19 pneumonia participated in this trial. All of them Tocelizumab 2 (5.6) signed the consent form before treatment. Table 1 gives Basal SpO2 94.28 (2.85)b the patients’ baseline characteristics. In all, 19 men and Basal SaFi 255.42 (117.75)b 17 women were included, with a mean age of 84 years, all Mild 18 (50)a of them presenting multiple comorbidities, the most com- Moderate 5 (13.9) mon being cardiovascular disease. Patients were classified Severe 13 (36.1) according to the Barthel Index as ‘independent’ in 6 cases Basal PaFi 251.39 (128.19)b (16.7%), ‘mild dependence’ in 12 (33.3%), ‘moderate de- Mild 25 (69.4)a pendence’ in 7 (19.4%), ‘severe dependence’ in 8 (22.2%) Moderate 4 (11.1) and ‘completely dependent’ in 3 (8.3%). All patients had Severe 7 (19.4) bilateral pulmonary infiltrates on chest X-ray at diagnosis. CURB-65 Score The radiological pneumonia, measured according to per- 1 points – centage of lung parenchyma affected on pretreatment CT, 2 points 10 (27.8)a showed that 27.8% presented affection of > 75%, 50% of 3 points 17 (47.2) 51–75%, 19.4% of 26–50% and 2.8% only 5–25%. A mean 4 points 9 (25) pre-irradiation SpO2 of 94.28%. Mean value of CRP was CT lung involvement (%) 9 mg/dL (1.14–24.7 mg/dL). All patients received dexam- < 5% – ethasone treatment, one patient also received tocilizumab, 5–25% 1 (2.8)a one received remdesivir, and a third patient received both 26–50% 7 (19.4) of them. All patients received a dose of 0.5 Gy and although 51–75% 18 (50) considered in trial protocol, a second 0.5 Gy dose was not > 75% 10 (27.8) administered in any patient. During the follow-up month, no patients presented radiation-related adverse effects. The evaluation of respiratory parameters at 24 h was pos- sible for 34/36 patients (94.4%). SpO2/FiO2 and PaO2/FiO2 K Strahlenther Onkol Fig. 1 Evolution of respiratory a parameters (SpO2/FiO2 [a] and PaO2/FiO2 [b]) in all patients with COVID-19 treated with low-dose radiation therapy clas- sified by survivors, COVID-19 deaths and deaths from other causes b values were significantly higher (p < 0.01) in survivors than pneumonia with > 50% lung affection on CT. Additionally, COVID-19 deaths only at baseline and 24 h after LD-RT. 5 patients (13.8%) died from other causes during the follow- Seventeen patients (50%) presented an improvement of up. Supplementary Information Table A1 shows the eval- SpO2/FiO2, with a mean percentage of 38.82% compared uation of CURB-65 in survivors, COVID-19 deaths and to baseline value. At 1 week, 25/36 were evaluable and deaths from other causes evaluated before LD-RT, at 24 h, of them, 21 patients (84%) presented a mean SpO2/FiO2 at 1 week and at 1 month after LD-RT. Those patients who improvement of 76%, while the other 4 patients did not died of COVID-19 pneumonia had a significantly worse present any improvement. We were able to examine the CURB-65 score before and at 24 h after LD-RT, confirming first 13 patients after 1 month of LD-RT at the time of the that high-risk pneumonia is a predictor of death (p < 0.01). statistical evaluation, observing that none of them needed Supplementary Information Figure A3 shows an improve- any supplemental oxygen therapy, and SpO2/FiO2 ratio was ment in the evolution of the radiological manifestations of higher in all of them, increasing its value with a mean of COVID-19 pneumonia in one patient. No statistically sig- 77.98% (463 mm Hg) (Fig. 1). Fig. 2 shows all respira- nificant differences were found in the 3 subgroups accord- tory parameters (2A) and inflammatory biochemical results ing to the Barthel Index, probably because of the small (2B) before and at 24 h after LD-RT in all three groups. In sample size in some subgroups, although there seems to be groups A and C, there was an improvement in the respi- a trend towards a greater degree of dependence in group B ratory parameters (SpO2/FiO2, PaO2/FiO2 and FiO2). In all (Supplementary Information Table A2). groups a decrease in CRP was observed. Supplementary Information Figure A2 shows a significant improvement in the respiratory parameters and biochemical results before Discussion and after LD-RT. Table 2 shows biochemical variables of patients with COVID-19, classified by survivors, COVID- When SARS-CoV-2 infects the lungs of a previously 19 deaths and deaths from other causes, before, at 24 h, healthy patient by binding to the membrane receptor for 1 week, and 1 month after LD-RT. angiotensin converting enzyme-2 (ACE2), it stimulates Causes of patients’ death are shown in Table 3. Seven a series of intracellular pathways favoring the release of patients (19.4%) died from COVID-19 in the first week and pro-inflammatory cytokines and the recruitment of immune 1 patient died on day 11 following LD-RT. All of them pre- cells resulting in the induction of a hyperinflammatory sented a high CURB-65 value, 3 and 4 points, and bilateral state. That appears to be the key triggering mechanism K Low-dose radiation therapy for COVID-19 pneumonia Fig. 2 Selected respiratory (a) a and biochemical (b) parameters comparisons between survivors, COVID-19 deaths and deaths from other causes before treat- ment and at 24 h after received treatment with low-dose radia- tion therapy (RT) b for the most severe forms of infection [12]. To date, the who were receiving either invasive mechanical ventilation only measures that have shown any degree of efficacy are or oxygen alone and reinforced the usefulness of cortico- those aimed at combating the process of inflammation and steroids for COVID-19 patients [16]. In the double-blind, pulmonary SARS [13]. The treatments specifically directed randomized Adaptive COVID-19 Treatment Trial (ACTT- against the overexpression of known mediators of inflam- 1), the antiviral agent remdesivir has been shown to be mation such as IL-1 or IL-6 are among the few measures more effective than a placebo in hastening the recovery that have shown certain efficacy [14, 15]. The RECOVERY of hospitalized patients with COVID-19 pneumonia [17]. Collaborative Group randomized phase III study showed Dexamethasone and remdesivir are the only treatments that that the use of dexamethasone reduced death among those have shown true efficacy against COVID-19 [18]. Other K K Table 2 Biochemical variables of patients with COVID-19, classified by survivors, COVID-19 deaths and deaths from other causes, before, at 24 h, 1 week and 1 month after low-dose radiation therapy (LD-RT) Survivors (n = 23) COVID-19 deaths (n = 8) Deaths from other causes (n = 5) Before 24 h after 1 week after 1 month after Before 24 h after Before 24 h after CD4 286.5 383 (211.5–566.5) 478 (230–824)B,D 515 (406.5–749)A,D 273.5 257 (234–493) 355.5 282.5 (244–500.2) (144.5–377.5) (187.7–318.7) (205.2–493.7) CD8 112 (78.7–223.2) 129 (50.5–256)A 181 406.5 169.5 (54.5–350.5) 193.5 133 (106–213.2) 180.5 (88–204.7) (110.5–310.5)A (204.5–640.7)B,E,G (89.7–272.5) CRP 6 (3.4–10.3) 4.6 (2.4–8.1)A 1.4 (0.3–5.8)C,E 0.7 (0.3–1.4)C,F,G 11.8 (8.4–15.6)b 8.3 (7.1–10.1)d 12.2 (2.2–19.3) 10.8 (1.6–19.6) D-Dimer 1000 (640–1813) 920 (680–2070) 995 (637.5–1990) 1490 (700–3100) 1570 1595 770 (559.5–4590) 1304 (644.7–3037.5) (1057.5–3357.5) (907.5–4889.5) Ferritin 535.9 (247–937) 606 (256–1639.5) 493 (225.2–868.2) 265 (57–650.5)A,D 861 614 628 (471–2849) 591 (411–2816) (522.1–1708.5)a (296.8–4327.7)d IL-6 12 (7.7–26.7) 18 (6.7–57) 12.2 (5.0–26.2)D 11.5 (8–22)D 44 (35.5–87)c 158 64.5 (19.2–146.5) 87 (26–258.2) (74.1–683.5)d,e LDH 277.5 273 (201–317.5) 218.5 201 522 (300–600)c 448 (245.5–624.5) 339.5 (212.7–497) 378 (263.5–440.5) (214.5–344.2) (170.7–284.5)C,F (183.2–226.5)A,E Leukocytes 8140 7070 7995 5210 8280 8880 3790 6565 (4520–14600) (3990–11460)B (5535–11530) (4350–7075)A,G (6392.5–17832.5) (6762.5–17267.5) (2535–7840)a,e (3675–8637.5) Lymphocytes 790 (570–1370) 920 (590–1410) 1023 1401 750 840 530 (345–995) 825 (442.5–960) (525–1812.5) (1025–1612)B,D (442.5–1113.5) (558.2–5872.5) Platelets 228000 241000 242500 215000 177500 177000 183000 250000 (175000–291000) (190000–327000) (135000–337500) (116500–304250) (138750–194500)a (132500–260250) (130000–276500) (141500–387750) Values are shown as medians (interquartile ranges). A = p < 0.05; B = p < 0.01, C = p < 0.001 with respect to before RT survivor group; D = p < 0.05, E = p < 0.01, F = p < 0.001 with respect to 24 h after RT survivor group; G = p < 0.05, with respect to 1 week after RT survivor group; a = p < 0.05, b = p < 0.01, c = p < 0.001, with respect to before RT survivor group; d = p < 0.05, with respect to 24h after RT survivor group; e = p < 0.05, with respect to before RT Covid-19 death group. CD4 cluster of quadruple differentiation; CD8 cluster of differentiation 8; CRP C-reactive protein; IL-6 interleukin 6; LDH lactate dehydrogenase. CD4, CD8, leukocytes, lymphocytes and platelets are expressed as cells/mm3; CRP as mg/dL, D-Dimer as mcg/L, Ferritin as ng/mL, IL-6 as pg/mL and LDH as U/L Strahlenther Onkol Low-dose radiation therapy for COVID-19 pneumonia Table 3 Causes of death, from COVID-19 or other causes following low-dose radiation therapy (LD-RT) Patient Death day after COVID-19 Age Reason LD-RT 1 1st Yes 91 Severe cognitive impairment and constantly removed the ventilation mask her- self 2 2nd Yes 86 Acute respiratory distress secondary to COVID-19 (SaFi had worsened by 3%) 3 3rd Yes 72 Severe cognitive impairment and constantly removed the ventilation mask her- self 4 3rd Yes 86 Acute respiratory distress secondary to COVID-19 (SaFi had improved a 3%) 5 4th Yes 89 Severe cognitive impairment and constantly removed the ventilation mask her- self 6 6th Yes 88 Acute respiratory distress secondary to COVID-19 7 7th Yes 88 Acute respiratory distress secondary to COVID-19 (SaFi had improved by 7%) 8 7th No 74 Septic infection of unknown origin without response to empiric antibiotic ad- ministration 9 8th No 73 Bronchoaspiration, having a subdural hemorrhage recent intervention. SaFi was stable without changes since basal determination (350 mm Hg) 10 11th Yes 87 Acute respiratory distress secondary to COVID-19 (SaFi had worsened by 45% in 7 days) 11 12th No 60 Severe worsening of his chronic renal failure under hemodialysis treatment 12 14th No 55 Esophageal varices hemorrhage, having a known antecedent of enolic hepatic disease (he had improved SaFi from basal 95 mm Hg to 277 mm Hg in one week) 13 25th No 85 Severe pulmonary thromboembolism strategies, such as the use of plasma from recovered con- anti-inflammatory environment, would explain the clinical valescent patients might reduce the risk of death and could effects of LD-RT. Studies of pulmonary LD-RT currently be an attractive strategy if subsequent studies confirm its underway are focusing on patients with presence of con- efficacy [19]. firmed COVID-19 disease and radiologically evident pneu- Due to the lack of a definitive treatment and in accor- monia. Most trials have administered a single fraction of dance with the previously mentioned theoretical and experi- 0.5–1.5 Gy to both lungs, although three studies have con- mental bases, the efficacy of LD-RT has been hypothesized sidered administering a second identical fraction if there is for the treatment of respiratory complications associated no adequate response after the first during a time interval with COVID-19 and numerous studies have been initiated that varies between 24 and 240 h after the first fraction. The by various groups [10]. The idea of using LD-RT to the main objective of many of them is an improvement in oxy- lungs to treat pneumonia is not new. The review by Cal- gen saturation rates, although some studies also evaluated abrese et al. collected evidence of 863 cases of pneumonia other aspects, such as the length of hospital stay, the need treated with LD-RT between 1905 and 1946 [4]. Observed for admission to ICU, an improvement in radiology or the results suggested the efficacy of LD-RT, although it must be associated crude mortality rates [22]. In our trial, the pri- kept in mind that these are old studies of retrospective na- mary endpoint of improving the PaO2/FiO2 or SpO2/FiO2 ture, methodologically debatable according to present stan- in 36 consecutive treated patients has been reached without dards, using various treatment techniques considered obso- any observed harmful effects attributable to the treatment. lete today and many of them lacking a control group. Al- To date, five investigation groups have published results though when it was published it showed consistent data with from the use of LD-RT for patients with SARS-CoV-2 the normal evolution of pneumonia at that time, it would be pneumonia. One trial has presented preliminary results for advisable to handle those results with caution. The mech- 2 patients and one case report has also been published. anism of LD-RT, such as those proposed for the treatment Ameri et al. have presented the results of an Iranian study of COVID-19 pneumonia, has different actions, including (NCT04390412) on 5 patients who received a single dose the reduction of pro-inflammatory cytokines while inhibit- of 0.5 Gy to both lungs. In 4/5 patients, an improvement ing the interaction between polymorphonuclear leukocytes in clinical parameters (blood oxygenation and body tem- and the vascular endothelium, and favors the polarization perature) and inflammatory markers (IL-6 and CRP levels) of lung macrophages from a pro-inflammatory M-1 phe- was observed on the first day after treatment. No patient notype to an anti-inflammatory M-2 phenotype [20, 21]. received any other specific treatment for COVID-19 infec- These changes, which favor the establishment of a local tion. One patient died after 3 days, 1 patient chose to drop K Strahlenther Onkol out of the study after 3 days, and another 3 patients were of the reasons that could justify the lack of benefit lies in the discharged. No complications related to LD-RT were re- selection of patients, with an extremely critical condition re- ported [23]. Preliminary results of the Emory University quiring constant mechanical ventilation [29]. Probably, like Hospital RESCUE 1–19 trial have been published by Hess it has been previously commented, LD-RT should be con- et al. Five patients diagnosed with COVID-19 pneumonia sidered in the initial phases of the exacerbated inflammatory received a single 1.5 Gy fraction over both lungs. Four of the response that accompanies the SARS-CoV-2 infection, the 5 patients experienced clinical recovery, 3 of them within so-called ‘cytokine storm’, in order to maximize the anti- the first 24 h after irradiation and could be discharged after inflammatory effect of dexamethasone. a median admission of 12 days. No patient received treat- One of the main barriers when considering the use of ment with drugs directed against COVID-19 in the days LD-RT for the symptomatic treatment of pneumonia in the before or after lung LD-RT. The authors report no acute context of COVID-19 is the safety of the treatment and toxicity attributable to treatment [24]. These same authors the prevention of possible toxicity secondary to radiation recently updated their results during the American Soci- therapy. However, none of the previously cited studies have ety for Radiation Oncology (ASTRO) 2020 Annual Meet- reported complications secondary to radiotherapy. Radia- ing. The results have been presented for 20 patients, 10 tion doses for COVID-19 pneumonia are very low (< 1% of whom received low-dose bilateral pulmonary irradiation of the doses used for cancer radiotherapy), not exceeding while another 10 served as controls. They reported a signif- tolerance doses for critical organs (heart, thyroid, stomach icant decrease in the median time to clinical recovery in the or kidneys) nor increasing the risk of development of sec- pulmonary irradiation group (3 days vs 12 days, hazard ra- ondary cancers, which also remains extremely low [30–32]. tio [HR] 2.0, p = 0.05). Additionally, they reported that LD- Preclinical studies showed that doses higher than 200 cGy RT improved delirium, radiographs, and biomarkers, with induce a pro-inflammatory effect directly related to late no significant acute toxicity [25]. Moreno-Olmedo et al. complications with radiotherapy. However, doses below 100 have reported preliminary results of the ULTRA-COVID cGy were associated with an anti-inflammatory effect [9]. trial (NCT04394182) in 2 patients who received a single Thereby, studies with FDG-PET have shown an increased 0.8 Gy dose whole lung irradiation through a Tomother- risk of pulmonary toxicity in patients who receive a mean apy. Both patients experienced clinical improvement after dose to the lung above 2–5 Gy, far from the doses adminis- LD-RT according to the increase in PaO2/FiO2 ratio above tered for the treatment of COVID-19 pneumonia, as is the 300 mm Hg as well as reduced dyspnea, asthenia and bilat- case with the hypothetical risk of cardiac toxicity [10]. In eral pulmonary infiltrative pattern, visible in the chest CT. a recent study based on a virtual case simulation, a radiation In addition, the authors also report a decrease in inflam- dose ≤ 0.5 Gy provided an acceptable lifetime attributable matory parameters, especially IL-6 levels [26]. Del Castillo risks (LAR) estimate (≤ 1%) for radiation-induced cancer et al. have reported satisfactory results after a single 1 Gy (RIC) and cardiovascular risk of exposure-induced death whole lung irradiation for a 64-year-old patient presenting (REID), regardless of sex and age [33]. Nevertheless, the with COVID-19 pneumonia and a rapidly deteriorating res- risk must always be taken into consideration. The conse- piratory function [27]. Sanmamed et al. (NCT04420390) quences of not receiving a treatment that is proving its ef- recently reported on 9 patients with COVID-19 pneumo- fectiveness should also be evaluated, even more when the nia who underwent whole lung single 1 Gy fraction with target of patients includes those with advanced age and primary endpoint of radiological response. The authors re- worse clinical situation not candidates for extreme mea- ported a significant improvement in the extension of CT sures, for which the benefit–risk balance certainly appears pneumonia as well as in SpO2/FIO2 at 72 h and 1 week after favorable. The safety of treatments for COVID-19 pneu- LD-RT [28]. Finally, Papachristofilou et al. have published monia has also been presented in various studies as well as the results of the first randomized trial of whole lung LD-RT adverse effects has also been associated to other treatments for the treatment of COVID19 pneumonia (NCT04598581). used for the symptomatic relief of patients with COVID- The authors analyze the results observed in 22 patients ran- 19 pneumonia. Thus, the use of remdesivir has been linked domized to receive a single whole lung dose (1 Gy) or not. to an appearance of rash, diarrhea, constipation, impaired Only elderly patients admitted to the ICU who would re- liver and kidney function and, particularly, cardiotoxicity, quire intubation and mechanical ventilation were selected. which can occasionally be severe [34, 35]. Similarly, the Beyond the technique used for LD-RT, also debatable be- humanized recombinant monoclonal antibody tocilizumab, cause it is far from the quality standards required by modern directed against the IL-6 receptor, has also been linked to radiotherapy, the results of the study did not demonstrate the appearance of complications, sometimes severe, includ- the benefit of LD-RT in improving the situation of criti- ing infections, neutropenia, or alterations in liver enzymes cally ill patients in the ICU, therefore advising against its [36]. use. However, as the authors themselves acknowledge, one K Low-dose radiation therapy for COVID-19 pneumonia Our results are in agreement with those reported by other together with the control group according to the original groups. To our knowledge, the present series is the longest design of the IPACOVID trial is ongoing and its results of all the experiences published to date and, although it is are pending publication. Nevertheless, further studies with a nonrandomized trial and the follow-up is still short, ob- longer follow-up are necessary to confirm these promising served results suggest a benefit of pulmonary LD-RT for results. the relief of COVID-19 pneumonia in selected patients. Of Supplementary Information The online version of this article (https:// the 36 patients initially included in this trial, 8 of them doi.org/10.1007/s00066-021-01803-3) contains supplementary mate- died of COVID-19 disease and 5 of other causes. For 21 of rial, which is available to authorized users. the 25 evaluable patients (84%), the rate of improvement Acknowledgements To the Spanish Group for Clinical Research in SpO2/FIO2 reached 76% after 1 week and respiratory in Radiation Oncology—Spanish Society of Radiation Oncology parameters noticeably improved together with a marked re- (GICOR-SEOR 2020) for an extraordinary grant for radiation research duction in serum inflammation parameters. In those who during COVID-19 to cover the cost of legal insurance for the clinical survived, the CT scan at 1 week after LD-RT showed a sig- trial. To Dr. V. Valentí by his draft review and his insight comments. To all professionals who make the treatment of patients possible: ra- nificant improvement in the percentage of lung involve- diotherapy technicians, nurses, physicists, paramedics, cleaning staff, ment. and all the doctors. Pulmonary LD-RT is an alternative that is worth explor- Conflict of interest M. Arenas, M. Algara, G. De Febrer, C. Rubio, ing in the current context of the COVID-19 pandemic and X. Sanz, M.A. de la Casa, C. Vasco, J. Marín, P. Fernández-Letón, LD-RT should be considered before the inflammatory cas- J. Villar, L. Torres-Royo, P. Villares, I. Membrive, J. Acosta, M. López- cade, which is largely responsible for the symptoms of Cano, P. Araguas, J. Quera, F. Rodríguez-Tomás and A. Montero de- COVID-19, is completely established. Otherwise, at the clare that they have no competing interests. moment that the respiratory and clinical condition of pa- Open Access This article is licensed under a Creative Commons At- tients is at serious risk of fatal deterioration, LD-RT would tribution 4.0 International License, which permits use, sharing, adapta- tion, distribution and reproduction in any medium or format, as long as be unable to reverse it. In addition to the possible efficacy you give appropriate credit to the original author(s) and the source, pro- suggested by different studies, other potential advantages vide a link to the Creative Commons licence, and indicate if changes of the use of LD-RT in COVID-19 would be that it is were made. The images or other third party material in this article are not a competitive treatment that would prevent or interfere included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included with the administration of other therapeutic measures, that in the article’s Creative Commons licence and your intended use is not it is already available in most general hospitals, and that permitted by statutory regulation or exceeds the permitted use, you will its availability is not subject to stock shortages or market need to obtain permission directly from the copyright holder. 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Quera, MD marenas@grupsagessa.cat jquera@psmar.cat G. De Febrer, MD, PhD F. Rodríguez-Tomás, MD gdefebrer@grupsagessa.com elisabet.rodriguez@urv.cat C. Rubio, MD, PhD A. Montero, MD, PhD crubio@hmhospitales.com angel.monteroluis@gmail.com X. Sanz, MD, PhD 1 Universitat Rovira i Virgili, Tarragona, Spain jsanz@psmar.cat 2 Institut d’Investigacions Pere Virgili, Tarragona, Spain M. A. de la Casa, MD mdelacasa@hmhospitales.com 3 Department of Radiation Oncology, Hospital Universitari Sant Joan de Reus, Tarragona, Spain C. Vasco, MD carlosarturo.vasco@grupsagessa.com 4 Department of Radiation Oncology, Hospital del Mar, Barcelona, Spain J. Marín, MD, PHD jmarincorral@psmar.cat 5 Autonomous University of Barcelona, Barcelona, Spain P. Fernández-Letón, MD 6 Institut Hospital del Mar d’Investigacions Mèdiques, Barcelona, pfernandezleton@hmhospitales.com Spain 7 J. Villar, MD, PhD Department of Geriatric and Palliative care, Hospital Universitari JVillar@parcdesalutmar.cat Sant Joan de Reus, Tarragona, Spain 8 L. Torres-Royo, MD Department of Radiation Oncology, HM Hospitales., Madrid, laura.torres@grupsagessa.com Spain 9 P. Villares, MD, PhD Pompeu Fabra University Barcelona, Barcelona, Spain pvillares@hmhospitales.com 10 Department of Critical Care, Hospital del Mar, Barcelona, Spain I. Membrive 11 Department of Medical Physics, HM Hospitales, Madrid, Spain imembrive@psmar.cat 12 Department of Infection Diseases, Hospital del Mar, Barcelona, J. Acosta Spain Johana.acosta@grupsagessa.com 13 Department of Internal Medicine, HM Hospitales, Madrid, Spain P. Araguas, MD pablo.araguas@grupsagessa.com K