This is a preprint. Preprints are preliminary reports that have not undergone peer review. They should not be considered conclusive, used to inform clinical practice, or referenced by the media as validated information.
Short Report
Low-dose Whole-lung Irradiation for COVID-19 Pneumonia: Short Course Results
Nazanin Rahnama
Department of Clinical Oncology, Imam Hossein Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Corresponding Author
License:
This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License
Declarations:
Declarations
- This study involved human subjects.
- The author confirmed that all appropriate ethical guidelines for the use of human subjects have been followed, any necessary IRB and/or ethics committee review has been obtained, and information about the IRB/ethics committee is included in the manuscript.
- The author has confirmed that all necessary patient/participant consent or assent has been obtained and the appropriate institutional forms have been archived. If the IRB/ethics committee waived the requirement for patient/participant consent or assent, an explanation for the waiver is included in the text.
- This study reports on a clinical trial.
- The author has confirmed that this trial has been registered with an ICMJE-approved registry, and the trial registration ID has been provided in the text. If the article reports on a study that was registered retrospectively, a statement explaining why the study was not registered in advance has been provided in the text.
- The author has confirmed that a statement listing potential conflicts of interest or lack thereof is included in the text.
Objectives: The COVID-19 outbreak is affecting people worldwide. Most of the infected patients suffering from respiratory involvement that may progress to acute respiratory distress syndrome. This pilot study aimed to evaluate the clinical efficacy of low-dose whole-lung radiotherapy in patients with COVID-19 pneumonia.
Methods: In this clinical trial, done in Iran, we enrolled patients with COVID-19 who were older than 60 years and hospitalized to receive supplementary oxygen for their documented pneumonia. Participants were treated with whole-lung irradiation in a single fraction of 0.5 Gy plus national protocol for the management of COVID-19. Vital signs (including blood oxygenation and body temperature) and laboratory findings (IL-6 and CRP) were recorded before and after irradiation.
Results: Between 21 May 2020 and 24 June 2020, five patients received whole-lung irradiation. They followed for 5-7 days to evaluate response to treatment and toxicities. The clinical and paraclinical findings of four patients (except for patient #4 that get worst and died on day 3) improved on the first day of irradiation. Patient #3 opted-out the trial on the third day of irradiation. The mean time to discharge was 6 days for the other three patients. No acute radiation-induced toxicity was recorded.
Conclusion: With a response rate of 80%, whole-lung irradiation in a single fraction of 0.5 Gy had encouraging results in oxygen-dependent patients with COVID-19 pneumonia.
Keywords
COVID-19, Pneumonia, Low dose radiotherapy, Lung
Figure 1
Since the end of 2019, the novel coronavirus disease (COVID-19) has been a major health issue all over the world. It is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that has led to more than five hundred thousand deaths until July 2020 with an estimated crude mortality rate of 3-4% [1-3]. Four phases are proposed for the pathogenesis of SARS-CoV-2, including suppression of interferon type 1 (IFN-1) production, blockage of IFN-1 signaling, massive inflammatory response (so-called cytokine storm), and immune exhaustion [4]. The lethality of COVID-19 mainly pertains to the cytokine storm-induced thrombotic dysregulation and multi-organ failure [5]. During the cytokine storm, monocytes and macrophages mainly recruit, which may explain elevated levels of pro-inflammatory cytokines such as interleukin-6 (IL-6) [5]. Suppression of cytokine storm can potentially reduce the morbidity and mortality of COVID-19 [6]. Experimental studies have demonstrated the anti-inflammatory effect of low dose radiotherapy (LD-RT) by modulating the function of a variety of inflammatory cells, including endothelial cells, polymorphonuclear leukocytes, and macrophages [7-12]. Being such, LD-RT is considered as an opportunity to block the deadly cytokine storm and save the patients’ lives. Herein we report the outcomes of the first 5 patients with COVID-19 pneumonia who were treated with low-dose whole-lung irradiation at Imam Hossein Educational Hospital, Tehran, Iran.
Ethical consideration
Before commencing the study, ethical clearance was obtained from the Ethical Committee of Shahid Beheshti University of Medical Sciences, Tehran, Iran (Ethical code: IR.SBMU.RETECH.REC.1399.073). Prior to assigning the patients to radiotherapy, written informed consent was obtained.
Trial design and participants
This pilot clinical trial was conducted at Imam Hossein Educational Hospital to examine the safety and efficacy of single-fraction low-dose whole-lung irradiation in patients with COVID-19 pneumonia (Clinical Trial Registration Number NCT04390412). Individuals more than 60 years old who had clinical manifestations of COVID-19 with a positive polymerase chain reaction (PCR) of the nasopharyngeal swab, antibody test, or radiographic pneumonic consolidations that required oxygen supplementation (with SpO2 ≤ 93% and/or PaO2/FiO2 ≤ 300 mmHg) were enrolled. For patients who had stable vital signs, we used SpO2 to estimate PaO2 [13]. The exclusion criteria were patients with hemodynamic instability or requiring mechanical ventilation, with a history of malignancy or heart failure, with contraindication for radiotherapy, with septic shock or end-organ failure, and with severe acute respiratory distress syndrome (with PaO2/FiO2 ≤ 100 mmHg). The primary objectives were alteration in blood oxygenation (in terms of O2 saturation) and the number of hospital/ICU stay days. The secondary objectives were changes in laboratory results [including C-reactive peptide (CRP) and IL-6]. Clinical recovery was defined as the first day a subject was discharged or weaned from supplemental oxygen. A total of five of 40 eligible patients who approached were signed the consent and entered the study between May 2020 and June 2020. This clinical trial was approved by the Institutional Review Board.
Radiotherapy and follow-up
The treatment protocol was low-dose whole-lung irradiation in conjunction with the standard national guideline for the management of COVID-19 [14]. All participants allocated to receive single-fraction 0.5 Gy to the whole lungs. Radiation therapy planning was done on patients’ diagnostic CT scans with patients in a supine position using a multislice spiral CT scanner without intravenous contrast. Planning target volume (PTV) covered both lungs in all patients with sufficient margins to account for the intrafraction movements (5–10 mm in our unit). All patients were planned with AP/PA photon fields with a three-dimensional conformal technique using the ISOgray treatment planning system. Vital signs, consciousness, performance status, blood oxygenation, CRP, and IL-6 were assessed at baseline and then daily following the irradiation. To assess core body temperature, we used tympanic membrane thermometry.
From 21 May 2020 to 24 June 2020, forty patients with COVID-19 pneumonia were asked to participate in the trial and five of them (four males and one female) signed the consent form and received low-dose whole-lung irradiation at the Clinical Oncology department of Imam Hossein Hospital. All participants but one (patient #3) were positive for PCR of the nasopharyngeal swab. Patient #3 was admitted for her loss of consciousness, typical findings of COVID-19 pneumonia in chest CT scan, and elevated CRP level. The baseline characteristics of participants are summarized in Table 1. The patients were between 60 and 84 years old (mean: 71.8 years). All patients had comorbidities, including hypertension in three patients, past ischemic heart disease in two patients, and heart failure in one patient. At the time of admission, the median Karnofsky Performance Score (KPS) and Glasgow Coma Scale (GCS) were 60 (range 50-80) and 15 (range 10-15), respectively. LD-RT was delivered one to three days after admission day (median 2 days).
Table 1ǀ Patients’ demographics and clinical characteristics
|
Characteristics |
Patient #1 |
Patient #2 |
Patient #3 |
Patient #4 |
Patient #5 |
|
|
|
|
|
|
|
|
Gender |
Male |
Male |
Female |
Male |
Male |
|
Age |
60 |
69 |
82 |
84 |
64 |
|
Comorbidity |
Heart failure |
HTN, IHD |
IHD |
HTN |
HTN |
|
KPS at admission |
80 |
80 |
60 |
50 |
60 |
|
GCS at admission |
15 |
15 |
10 |
15 |
15 |
|
Presenting symptom(s) |
Shortness of breath |
Fever & cough |
depressed level of consciousness |
Fever & cough |
Shortness of breath & Cough |
|
Vital signs at admission Pulse rate (per minute) Respiratory rate (per minute) Systolic blood pressure (mmHg) Temperature (°C) O2 saturation (%) P/F ratio |
75 12 110 37.5 87 192 |
88 16 130 38.1 86 126.7 |
90 20 110 37.6 75 160 |
82 12 140 37 89 101.4 |
90 15 120 39 74 110 |
|
Between onset of symptoms and RT |
1 day |
3 days |
3 days |
2 days |
2 days |
|
Diagnosis of COVID-19 |
Clinical findings & PCR |
Clinical findings & PCR |
Clinical & imaging findings |
Clinical findings & PCR |
Clinical & imaging finding & PCR |
|
O2 supplementation |
Facial mask |
Nasal cannula |
Facial mask with reservoir bag |
Facial mask |
Facial mask with reservoir bag |
|
Length of stay at hospital after RT |
7 days |
5 days |
3 days |
3 days |
6 days |
|
Outcome |
Discharged |
Discharged |
opted out of trial |
Expired |
Discharged |
|
|
|
|
|
|
GCS, Glasgow coma scale; HTN, hypertension; IHD, ischemic heart disease; KPS, Karnofsky performance scale; PCR, Polymerase chain reaction; P/F ratio, PaO2/FiO2; RT; radiation therapy.
Four patients (80%) clinically recovered for their O2 saturation and body temperature within one day. Of these, one patient (patient #3) chose to opt-out of the trial on the third day of irradiation. The mean time to discharge was 6 days for three patients (patient #1, #2, and #5). Patient #4 started to deteriorate with his O2 saturation and body temperature from the first day of irradiation and died on the third day of irradiation. The laboratory findings (IL-6 and CRP) were in line with the clinical findings. Regarding IL-6, although the fluctuation pattern was documented in patient #1, the overall trendline was as per clinical findings. Figure 1 demonstrates the change in clinical and laboratory findings following irradiation. During the observation, no acute skin, cardiac, pulmonary, or gastric toxicities were detected.
This pilot trial had several important findings. First, for oxygen-dependent patients with COVID-19 pneumonia, whole-lung irradiation had a response rate of 80% in terms of clinical and paraclinical findings. Second, considering the patient opted-out the trial, the clinical recovery of patients receiving LD-RT was 75%. Third, our results showed that LD-RT starts to demonstrate its efficacy from the first day of irradiation. Fourth, CRP changes were consistent with the clinical findings, however, IL-6 showed a fluctuation pattern in one patient but followed the patient’s clinical condition. This may be due to the short-term release of IL-6 upon irradiation [15]. Fifth, despite the clinical efficacy no acute toxicity was reported with LD-RT.
To the best of our knowledge, there are three other ongoing clinical trials applying LD-RT in patients with COVID-19 pneumonia. The summary of these trials is presented in Table 2.
Table 2ǀ Overview of clinical trials evaluating the efficacy of low-dose whole-lung irradiation in patients with COVID-19 pneumonia
|
Clinical trial |
RESCUE 1-19 |
COLOR-19 |
Present trial |
VENTED |
|
|
|
|
|
|
|
NCT number |
NCT04366791 |
NCT04377477 |
NCT04390412 |
NCT04427566 |
|
|
|
|
|
|
|
Start date |
April 29, 2020 |
May 6, 2020 |
May 15, 2020 |
June 11, 2020 |
|
|
|
|
|
|
|
Country of origin |
United States |
Italy |
Iran |
United States |
|
|
|
|
|
|
|
Current status |
Preliminary results are published in a non-peer reviewed journal |
Recruiting patients |
Pilot study (published) |
Recruiting patients |
|
|
|
|
|
|
|
Participants Gender Age (years) Clinical presentation |
Male/Female ≥ 18 Receiving O2 with NIV |
Male/Female ≥ 50 Receiving O2 with NIV |
Male/Female > 60 Receiving O2 with NIV |
Male/Female ≥ 18 Receiving O2 with MV |
|
|
|
|
|
|
|
Number of participants |
5 |
30 |
5 (for pilot study) |
24 |
|
|
|
|
|
|
|
Treatment plan |
Single-fraction whole-lung irradiation |
Single-fraction whole-lung irradiation |
Single-fraction whole-lung irradiation + national guideline |
Single-fraction whole-lung irradiation |
|
|
|
|
|
|
|
Radiation dose (Gy) |
1.5 |
0.7 (on average) |
0.5 (+ an additional 0.5 if needed) |
0.8 |
|
|
|
|
|
|
|
Primary Objectives |
- Safety - Clinical recovery |
- Length of hospital stay - No. of ICU admission |
- Change in blood oxygenation - Length of hospital/ICU stay |
Mortality rate after 30 days of ICU-based MV initiation |
|
|
|
|
|
|
ICU, intensive care unit; MV, Mechanical ventilation; NIV, non-invasive ventilation.
To the best of our knowledge, the only available results are from RESCUE 1-19 trial that was recently published in a non-peer-reviewed journal [8]. The study detail is summarized in Table 2. In this pilot study, five patients with COVID-19 pneumonia received whole-lung irradiation with a single-fraction of 1.5 Gy. Four of the patients recovered rapidly and weaned from supplemental oxygen at a mean time of 1.5 days. In all patients, no acute toxicity was reported.
Similar findings were reached by our trial in terms of response rate and safety. However, we obtained these results with lower radiation doses. This finding supports the hypothesis that radiation doses as low as 0.5 Gy can modify the immune reaction of COVID-19 pneumonia by activation of macrophages with M2 phenotype [9]. We also included the national protocol for the management of COVID-19 in the treatment plan that may affect the results. We went beyond the RESCUE 1-19 trial by examining the body temperature, IL-6, and CRP of patients following irradiation.
Notwithstanding the small sample size, the interim results of the RESCUE 1-19 trial and ours demonstrate that LD-RT may be a successful treatment to save patients with severe COVID-19 pneumonia. Longer follow-up with more patients is needed to confirm this notion. Given the encouraging results of this pilot trial, the Ethical Committee of Shahid Beheshti University of Medical Sciences allowed continuing the trial using 1.0 Gy whole-lune irradiation.
Conflicts of interest: The authors have no relevant relationships to disclose.
Funding: Not applicable
Clinical trial registration number: NCT04390412
Acknowledgments: The authors would like to express their gratitude to staffs of Imam Hossein Hospital, Tehran, Iran. Likewise, authors would like to express their gratitude to all physicians and nurses all around the world who are doing their best efforts to treat patients suffering from COVID-19.
[1] Our World in Data. (2020, June 28, 2020). Mortality risk of COVID-19, . Available: https://ourworldindata.org/coronavirus
[2] A. Shankar et al., "Cancer care delivery challenges amidst coronavirus disease–19 (COVID-19) outbreak: specific precautions for cancer patients and cancer care providers to prevent spread," Asian Pacific Journal of Cancer Prevention, vol. 21, no. 3, pp. 569-573, 2020.
[3] World Health Organization. (2020, June 28, 2020). Coronavirus disease 2019 (COVID-19) situation report – 46, . Available: https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200306-sitrep-46-covid-19.pdf?sfvrsn=96b04adf_4
[4] F. Taghizadeh-Hesary and H. Akbari, "The powerful immune system against powerful COVID-19: A hypothesis," Medical Hypotheses, p. 109762, 2020.
[5] M. Soy, G. Keser, P. Atagündüz, F. Tabak, I. Atagündüz, and S. Kayhan, "Cytokine storm in COVID-19: pathogenesis and overview of anti-inflammatory agents used in treatment," Clinical Rheumatology, p. 1, 2020.
[6] P. Horby et al., "Effect of Dexamethasone in Hospitalized Patients with COVID-19: Preliminary Report," medRxiv, 2020.
[7] M. Arenas et al., "Anti-inflammatory effects of low-dose radiotherapy," Strahlentherapie und Onkologie, vol. 188, no. 11, pp. 975-981, 2012.
[8] C. B. Hess et al., "Low-Dose Whole-Lung Radiation for COVID-19 Pneumonia: Planned Day-7 Interim Analysis of a Registered Clinical Trial," medRxiv, 2020.
[9] P. C. Lara, J. Burgos, and D. Macias, "Low dose lung radiotherapy for COVID-19 pneumonia. The rationale for a cost-effective anti-inflammatory treatment," Clinical and Translational Radiation Oncology, 2020.
[10] A. Kefayat and F. Ghahremani, "Low dose radiation therapy for COVID-19 pneumonia: a double-edged sword," Radiotherapy and Oncology, 2020.
[11] C. Kirkby and M. Mackenzie, "Is low dose radiation therapy a potential treatment for COVID-19 pneumonia?," Radiotherapy and Oncology, 2020.
[12] E. V. POWELL, "Roentgen therapy of lobar pneumonia," Journal of the American Medical Association, vol. 110, no. 1, pp. 19-22, 1938.
[13] S. M. Gadrey et al., "Imputation of partial pressures of arterial oxygen using oximetry and its impact on sepsis diagnosis," Physiological Measurement, vol. 40, no. 11, p. 115008, 2019.
[14] Ministry of Health. (July 1, 2020). دستورالعمل درمان رادیوتراپی در بیماران مبتلا به سرطان در پاندومی کووید 19. Available: http://treatment.sbmu.ac.ir/uploads/2-2-zip_saratan.zip
[15] V. De Sanctis et al., "Cytokines, fatigue, and cutaneous erythema in early stage breast cancer patients receiving adjuvant radiation therapy," BioMed research international, vol. 2014, 2014.
SMJ Mortazavi
ORCiDcommented on 09 July, 2020
There are many questions about the methods used in this study. Moreover, it is not justified at all that the authors state "Given the encouraging results of this pilot trial, the Ethical Committee of Shahid Beheshti University of Medical Sciences allowed continuing the trial using 1.0 Gy whole-lune irradiation". How did they come to this conclusion that higher doses might be more effective? The concept of using low dose radiation for treatment of COVID_19 associated pneumonia was first introduced by our team in March 2020. The doses suggested by our team were less than 250 mGy ( DOI: 10.31661/JBPE.V0I0.2003-1085). Given this consideration, we believe that if the authors had used lower doses, they would have more promising results.
View 1 reply
SMJ Mortazavi
ORCiDcommented on 09 July, 2020
There are many questions about the methods used in this study. Moreover, it is not justified at all that the authors state "Given the encouraging results of this pilot trial, the Ethical Committee of Shahid Beheshti University of Medical Sciences allowed continuing the trial using 1.0 Gy whole-lune irradiation". How did they come to this conclusion that higher doses might be more effective? The concept of using low dose radiation for treatment of COVID_19 associated pneumonia was first introduced by our team in March 2020. The doses suggested by our team were less than 250 mGy ( DOI: 10.31661/JBPE.V0I0.2003-1085). Given this consideration, we believe that if the authors had used lower doses, they would have more promising results.
Mohan Doss
commented on 09 July, 2020
The results are encouraging. The authors reported that 4 out of 5 patients recovered with the low-dose radiation treatments. Can the authors indicate what fraction of equivalent patients in their institution recovered following other treatments, from recent hospital data? Thanks.
SMJ Mortazavi
ORCiDcommented on 09 July, 2020
@Mohan Doss Thank you for your thoughtful comment! As you know, the preliminary findings of Emory University Hospital's trial have previously been published. In their trial, a single treatment of low-dose (1.5 Gy) irradiation of both lungs was administered after a 72-hour wait while hospitalized. Again, 4 of the 5 patients greatly benefited from the LDRT. I am among the scientists who believe if the dose had been lower and the waiting time for the radiation therapy had been shorter (e.g., 24 hours) all of the 5 patients may have benefited from the therapy. Clinical trials started by other groups involved radiation doses less than 1 Gy.
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Short Report
Low-dose Whole-lung Irradiation for COVID-19 Pneumonia: Short Course Results
Nazanin Rahnama
Department of Clinical Oncology, Imam Hossein Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Corresponding Author
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
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CURRENT STATUS: Posted
Version 1
Posted 07 Jul, 2020
Community comments: 5
Metrics
Comments: 5
PDF Downloads: ...
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License:
This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License
Declarations:
Declarations
- This study involved human subjects.
- The author confirmed that all appropriate ethical guidelines for the use of human subjects have been followed, any necessary IRB and/or ethics committee review has been obtained, and information about the IRB/ethics committee is included in the manuscript.
- The author has confirmed that all necessary patient/participant consent or assent has been obtained and the appropriate institutional forms have been archived. If the IRB/ethics committee waived the requirement for patient/participant consent or assent, an explanation for the waiver is included in the text.
- This study reports on a clinical trial.
- The author has confirmed that this trial has been registered with an ICMJE-approved registry, and the trial registration ID has been provided in the text. If the article reports on a study that was registered retrospectively, a statement explaining why the study was not registered in advance has been provided in the text.
- The author has confirmed that a statement listing potential conflicts of interest or lack thereof is included in the text.
Objectives: The COVID-19 outbreak is affecting people worldwide. Most of the infected patients suffering from respiratory involvement that may progress to acute respiratory distress syndrome. This pilot study aimed to evaluate the clinical efficacy of low-dose whole-lung radiotherapy in patients with COVID-19 pneumonia.
Methods: In this clinical trial, done in Iran, we enrolled patients with COVID-19 who were older than 60 years and hospitalized to receive supplementary oxygen for their documented pneumonia. Participants were treated with whole-lung irradiation in a single fraction of 0.5 Gy plus national protocol for the management of COVID-19. Vital signs (including blood oxygenation and body temperature) and laboratory findings (IL-6 and CRP) were recorded before and after irradiation.
Results: Between 21 May 2020 and 24 June 2020, five patients received whole-lung irradiation. They followed for 5-7 days to evaluate response to treatment and toxicities. The clinical and paraclinical findings of four patients (except for patient #4 that get worst and died on day 3) improved on the first day of irradiation. Patient #3 opted-out the trial on the third day of irradiation. The mean time to discharge was 6 days for the other three patients. No acute radiation-induced toxicity was recorded.
Conclusion: With a response rate of 80%, whole-lung irradiation in a single fraction of 0.5 Gy had encouraging results in oxygen-dependent patients with COVID-19 pneumonia.
Figure 1
Since the end of 2019, the novel coronavirus disease (COVID-19) has been a major health issue all over the world. It is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that has led to more than five hundred thousand deaths until July 2020 with an estimated crude mortality rate of 3-4% [1-3]. Four phases are proposed for the pathogenesis of SARS-CoV-2, including suppression of interferon type 1 (IFN-1) production, blockage of IFN-1 signaling, massive inflammatory response (so-called cytokine storm), and immune exhaustion [4]. The lethality of COVID-19 mainly pertains to the cytokine storm-induced thrombotic dysregulation and multi-organ failure [5]. During the cytokine storm, monocytes and macrophages mainly recruit, which may explain elevated levels of pro-inflammatory cytokines such as interleukin-6 (IL-6) [5]. Suppression of cytokine storm can potentially reduce the morbidity and mortality of COVID-19 [6]. Experimental studies have demonstrated the anti-inflammatory effect of low dose radiotherapy (LD-RT) by modulating the function of a variety of inflammatory cells, including endothelial cells, polymorphonuclear leukocytes, and macrophages [7-12]. Being such, LD-RT is considered as an opportunity to block the deadly cytokine storm and save the patients’ lives. Herein we report the outcomes of the first 5 patients with COVID-19 pneumonia who were treated with low-dose whole-lung irradiation at Imam Hossein Educational Hospital, Tehran, Iran.
Ethical consideration
Before commencing the study, ethical clearance was obtained from the Ethical Committee of Shahid Beheshti University of Medical Sciences, Tehran, Iran (Ethical code: IR.SBMU.RETECH.REC.1399.073). Prior to assigning the patients to radiotherapy, written informed consent was obtained.
Trial design and participants
This pilot clinical trial was conducted at Imam Hossein Educational Hospital to examine the safety and efficacy of single-fraction low-dose whole-lung irradiation in patients with COVID-19 pneumonia (Clinical Trial Registration Number NCT04390412). Individuals more than 60 years old who had clinical manifestations of COVID-19 with a positive polymerase chain reaction (PCR) of the nasopharyngeal swab, antibody test, or radiographic pneumonic consolidations that required oxygen supplementation (with SpO2 ≤ 93% and/or PaO2/FiO2 ≤ 300 mmHg) were enrolled. For patients who had stable vital signs, we used SpO2 to estimate PaO2 [13]. The exclusion criteria were patients with hemodynamic instability or requiring mechanical ventilation, with a history of malignancy or heart failure, with contraindication for radiotherapy, with septic shock or end-organ failure, and with severe acute respiratory distress syndrome (with PaO2/FiO2 ≤ 100 mmHg). The primary objectives were alteration in blood oxygenation (in terms of O2 saturation) and the number of hospital/ICU stay days. The secondary objectives were changes in laboratory results [including C-reactive peptide (CRP) and IL-6]. Clinical recovery was defined as the first day a subject was discharged or weaned from supplemental oxygen. A total of five of 40 eligible patients who approached were signed the consent and entered the study between May 2020 and June 2020. This clinical trial was approved by the Institutional Review Board.
Radiotherapy and follow-up
The treatment protocol was low-dose whole-lung irradiation in conjunction with the standard national guideline for the management of COVID-19 [14]. All participants allocated to receive single-fraction 0.5 Gy to the whole lungs. Radiation therapy planning was done on patients’ diagnostic CT scans with patients in a supine position using a multislice spiral CT scanner without intravenous contrast. Planning target volume (PTV) covered both lungs in all patients with sufficient margins to account for the intrafraction movements (5–10 mm in our unit). All patients were planned with AP/PA photon fields with a three-dimensional conformal technique using the ISOgray treatment planning system. Vital signs, consciousness, performance status, blood oxygenation, CRP, and IL-6 were assessed at baseline and then daily following the irradiation. To assess core body temperature, we used tympanic membrane thermometry.
From 21 May 2020 to 24 June 2020, forty patients with COVID-19 pneumonia were asked to participate in the trial and five of them (four males and one female) signed the consent form and received low-dose whole-lung irradiation at the Clinical Oncology department of Imam Hossein Hospital. All participants but one (patient #3) were positive for PCR of the nasopharyngeal swab. Patient #3 was admitted for her loss of consciousness, typical findings of COVID-19 pneumonia in chest CT scan, and elevated CRP level. The baseline characteristics of participants are summarized in Table 1. The patients were between 60 and 84 years old (mean: 71.8 years). All patients had comorbidities, including hypertension in three patients, past ischemic heart disease in two patients, and heart failure in one patient. At the time of admission, the median Karnofsky Performance Score (KPS) and Glasgow Coma Scale (GCS) were 60 (range 50-80) and 15 (range 10-15), respectively. LD-RT was delivered one to three days after admission day (median 2 days).
Table 1ǀ Patients’ demographics and clinical characteristics
|
Characteristics |
Patient #1 |
Patient #2 |
Patient #3 |
Patient #4 |
Patient #5 |
|
|
|
|
|
|
|
|
Gender |
Male |
Male |
Female |
Male |
Male |
|
Age |
60 |
69 |
82 |
84 |
64 |
|
Comorbidity |
Heart failure |
HTN, IHD |
IHD |
HTN |
HTN |
|
KPS at admission |
80 |
80 |
60 |
50 |
60 |
|
GCS at admission |
15 |
15 |
10 |
15 |
15 |
|
Presenting symptom(s) |
Shortness of breath |
Fever & cough |
depressed level of consciousness |
Fever & cough |
Shortness of breath & Cough |
|
Vital signs at admission Pulse rate (per minute) Respiratory rate (per minute) Systolic blood pressure (mmHg) Temperature (°C) O2 saturation (%) P/F ratio |
75 12 110 37.5 87 192 |
88 16 130 38.1 86 126.7 |
90 20 110 37.6 75 160 |
82 12 140 37 89 101.4 |
90 15 120 39 74 110 |
|
Between onset of symptoms and RT |
1 day |
3 days |
3 days |
2 days |
2 days |
|
Diagnosis of COVID-19 |
Clinical findings & PCR |
Clinical findings & PCR |
Clinical & imaging findings |
Clinical findings & PCR |
Clinical & imaging finding & PCR |
|
O2 supplementation |
Facial mask |
Nasal cannula |
Facial mask with reservoir bag |
Facial mask |
Facial mask with reservoir bag |
|
Length of stay at hospital after RT |
7 days |
5 days |
3 days |
3 days |
6 days |
|
Outcome |
Discharged |
Discharged |
opted out of trial |
Expired |
Discharged |
|
|
|
|
|
|
GCS, Glasgow coma scale; HTN, hypertension; IHD, ischemic heart disease; KPS, Karnofsky performance scale; PCR, Polymerase chain reaction; P/F ratio, PaO2/FiO2; RT; radiation therapy.
Four patients (80%) clinically recovered for their O2 saturation and body temperature within one day. Of these, one patient (patient #3) chose to opt-out of the trial on the third day of irradiation. The mean time to discharge was 6 days for three patients (patient #1, #2, and #5). Patient #4 started to deteriorate with his O2 saturation and body temperature from the first day of irradiation and died on the third day of irradiation. The laboratory findings (IL-6 and CRP) were in line with the clinical findings. Regarding IL-6, although the fluctuation pattern was documented in patient #1, the overall trendline was as per clinical findings. Figure 1 demonstrates the change in clinical and laboratory findings following irradiation. During the observation, no acute skin, cardiac, pulmonary, or gastric toxicities were detected.
This pilot trial had several important findings. First, for oxygen-dependent patients with COVID-19 pneumonia, whole-lung irradiation had a response rate of 80% in terms of clinical and paraclinical findings. Second, considering the patient opted-out the trial, the clinical recovery of patients receiving LD-RT was 75%. Third, our results showed that LD-RT starts to demonstrate its efficacy from the first day of irradiation. Fourth, CRP changes were consistent with the clinical findings, however, IL-6 showed a fluctuation pattern in one patient but followed the patient’s clinical condition. This may be due to the short-term release of IL-6 upon irradiation [15]. Fifth, despite the clinical efficacy no acute toxicity was reported with LD-RT.
To the best of our knowledge, there are three other ongoing clinical trials applying LD-RT in patients with COVID-19 pneumonia. The summary of these trials is presented in Table 2.
Table 2ǀ Overview of clinical trials evaluating the efficacy of low-dose whole-lung irradiation in patients with COVID-19 pneumonia
|
Clinical trial |
RESCUE 1-19 |
COLOR-19 |
Present trial |
VENTED |
|
|
|
|
|
|
|
NCT number |
NCT04366791 |
NCT04377477 |
NCT04390412 |
NCT04427566 |
|
|
|
|
|
|
|
Start date |
April 29, 2020 |
May 6, 2020 |
May 15, 2020 |
June 11, 2020 |
|
|
|
|
|
|
|
Country of origin |
United States |
Italy |
Iran |
United States |
|
|
|
|
|
|
|
Current status |
Preliminary results are published in a non-peer reviewed journal |
Recruiting patients |
Pilot study (published) |
Recruiting patients |
|
|
|
|
|
|
|
Participants Gender Age (years) Clinical presentation |
Male/Female ≥ 18 Receiving O2 with NIV |
Male/Female ≥ 50 Receiving O2 with NIV |
Male/Female > 60 Receiving O2 with NIV |
Male/Female ≥ 18 Receiving O2 with MV |
|
|
|
|
|
|
|
Number of participants |
5 |
30 |
5 (for pilot study) |
24 |
|
|
|
|
|
|
|
Treatment plan |
Single-fraction whole-lung irradiation |
Single-fraction whole-lung irradiation |
Single-fraction whole-lung irradiation + national guideline |
Single-fraction whole-lung irradiation |
|
|
|
|
|
|
|
Radiation dose (Gy) |
1.5 |
0.7 (on average) |
0.5 (+ an additional 0.5 if needed) |
0.8 |
|
|
|
|
|
|
|
Primary Objectives |
- Safety - Clinical recovery |
- Length of hospital stay - No. of ICU admission |
- Change in blood oxygenation - Length of hospital/ICU stay |
Mortality rate after 30 days of ICU-based MV initiation |
|
|
|
|
|
|
ICU, intensive care unit; MV, Mechanical ventilation; NIV, non-invasive ventilation.
To the best of our knowledge, the only available results are from RESCUE 1-19 trial that was recently published in a non-peer-reviewed journal [8]. The study detail is summarized in Table 2. In this pilot study, five patients with COVID-19 pneumonia received whole-lung irradiation with a single-fraction of 1.5 Gy. Four of the patients recovered rapidly and weaned from supplemental oxygen at a mean time of 1.5 days. In all patients, no acute toxicity was reported.
Similar findings were reached by our trial in terms of response rate and safety. However, we obtained these results with lower radiation doses. This finding supports the hypothesis that radiation doses as low as 0.5 Gy can modify the immune reaction of COVID-19 pneumonia by activation of macrophages with M2 phenotype [9]. We also included the national protocol for the management of COVID-19 in the treatment plan that may affect the results. We went beyond the RESCUE 1-19 trial by examining the body temperature, IL-6, and CRP of patients following irradiation.
Notwithstanding the small sample size, the interim results of the RESCUE 1-19 trial and ours demonstrate that LD-RT may be a successful treatment to save patients with severe COVID-19 pneumonia. Longer follow-up with more patients is needed to confirm this notion. Given the encouraging results of this pilot trial, the Ethical Committee of Shahid Beheshti University of Medical Sciences allowed continuing the trial using 1.0 Gy whole-lune irradiation.
Conflicts of interest: The authors have no relevant relationships to disclose.
Funding: Not applicable
Clinical trial registration number: NCT04390412
Acknowledgments: The authors would like to express their gratitude to staffs of Imam Hossein Hospital, Tehran, Iran. Likewise, authors would like to express their gratitude to all physicians and nurses all around the world who are doing their best efforts to treat patients suffering from COVID-19.
[1] Our World in Data. (2020, June 28, 2020). Mortality risk of COVID-19, . Available: https://ourworldindata.org/coronavirus
[2] A. Shankar et al., "Cancer care delivery challenges amidst coronavirus disease–19 (COVID-19) outbreak: specific precautions for cancer patients and cancer care providers to prevent spread," Asian Pacific Journal of Cancer Prevention, vol. 21, no. 3, pp. 569-573, 2020.
[3] World Health Organization. (2020, June 28, 2020). Coronavirus disease 2019 (COVID-19) situation report – 46, . Available: https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200306-sitrep-46-covid-19.pdf?sfvrsn=96b04adf_4
[4] F. Taghizadeh-Hesary and H. Akbari, "The powerful immune system against powerful COVID-19: A hypothesis," Medical Hypotheses, p. 109762, 2020.
[5] M. Soy, G. Keser, P. Atagündüz, F. Tabak, I. Atagündüz, and S. Kayhan, "Cytokine storm in COVID-19: pathogenesis and overview of anti-inflammatory agents used in treatment," Clinical Rheumatology, p. 1, 2020.
[6] P. Horby et al., "Effect of Dexamethasone in Hospitalized Patients with COVID-19: Preliminary Report," medRxiv, 2020.
[7] M. Arenas et al., "Anti-inflammatory effects of low-dose radiotherapy," Strahlentherapie und Onkologie, vol. 188, no. 11, pp. 975-981, 2012.
[8] C. B. Hess et al., "Low-Dose Whole-Lung Radiation for COVID-19 Pneumonia: Planned Day-7 Interim Analysis of a Registered Clinical Trial," medRxiv, 2020.
[9] P. C. Lara, J. Burgos, and D. Macias, "Low dose lung radiotherapy for COVID-19 pneumonia. The rationale for a cost-effective anti-inflammatory treatment," Clinical and Translational Radiation Oncology, 2020.
[10] A. Kefayat and F. Ghahremani, "Low dose radiation therapy for COVID-19 pneumonia: a double-edged sword," Radiotherapy and Oncology, 2020.
[11] C. Kirkby and M. Mackenzie, "Is low dose radiation therapy a potential treatment for COVID-19 pneumonia?," Radiotherapy and Oncology, 2020.
[12] E. V. POWELL, "Roentgen therapy of lobar pneumonia," Journal of the American Medical Association, vol. 110, no. 1, pp. 19-22, 1938.
[13] S. M. Gadrey et al., "Imputation of partial pressures of arterial oxygen using oximetry and its impact on sepsis diagnosis," Physiological Measurement, vol. 40, no. 11, p. 115008, 2019.
[14] Ministry of Health. (July 1, 2020). دستورالعمل درمان رادیوتراپی در بیماران مبتلا به سرطان در پاندومی کووید 19. Available: http://treatment.sbmu.ac.ir/uploads/2-2-zip_saratan.zip
[15] V. De Sanctis et al., "Cytokines, fatigue, and cutaneous erythema in early stage breast cancer patients receiving adjuvant radiation therapy," BioMed research international, vol. 2014, 2014.
SMJ Mortazavi
ORCiDcommented on 09 July, 2020
There are many questions about the methods used in this study. Moreover, it is not justified at all that the authors state "Given the encouraging results of this pilot trial, the Ethical Committee of Shahid Beheshti University of Medical Sciences allowed continuing the trial using 1.0 Gy whole-lune irradiation". How did they come to this conclusion that higher doses might be more effective? The concept of using low dose radiation for treatment of COVID_19 associated pneumonia was first introduced by our team in March 2020. The doses suggested by our team were less than 250 mGy ( DOI: 10.31661/JBPE.V0I0.2003-1085). Given this consideration, we believe that if the authors had used lower doses, they would have more promising results.
View 1 reply
Vincent Paglioni
ORCiDreplied on 09 July, 2020
Thank you for linking your research. I agree, there are several shortcomings of this pilot study that need to be addressed in the full experiment. For instance (I have no experience in medicine) - is it common to admit patients into a COVID-19 related trial that were not tested via PCR? It seems like the authors are looking to the previous studies with larger doses (0.7 - 1.0 Gy) and attempting to validate those results with this study, which would normally be a fine effort. However, this seems to be in contradiction with their stated purpose of investigating lower doses - should not the next step be to lower the administered dose below 0.5 Gy?
SMJ Mortazavi
ORCiDcommented on 09 July, 2020
There are many questions about the methods used in this study. Moreover, it is not justified at all that the authors state "Given the encouraging results of this pilot trial, the Ethical Committee of Shahid Beheshti University of Medical Sciences allowed continuing the trial using 1.0 Gy whole-lune irradiation". How did they come to this conclusion that higher doses might be more effective? The concept of using low dose radiation for treatment of COVID_19 associated pneumonia was first introduced by our team in March 2020. The doses suggested by our team were less than 250 mGy ( DOI: 10.31661/JBPE.V0I0.2003-1085). Given this consideration, we believe that if the authors had used lower doses, they would have more promising results.
Mohan Doss
commented on 09 July, 2020
The results are encouraging. The authors reported that 4 out of 5 patients recovered with the low-dose radiation treatments. Can the authors indicate what fraction of equivalent patients in their institution recovered following other treatments, from recent hospital data? Thanks.
SMJ Mortazavi
ORCiDcommented on 09 July, 2020
@Mohan Doss Thank you for your thoughtful comment! As you know, the preliminary findings of Emory University Hospital's trial have previously been published. In their trial, a single treatment of low-dose (1.5 Gy) irradiation of both lungs was administered after a 72-hour wait while hospitalized. Again, 4 of the 5 patients greatly benefited from the LDRT. I am among the scientists who believe if the dose had been lower and the waiting time for the radiation therapy had been shorter (e.g., 24 hours) all of the 5 patients may have benefited from the therapy. Clinical trials started by other groups involved radiation doses less than 1 Gy.
Vincent Paglioni
ORCiDreplied on 09 July, 2020
Thank you for linking your research. I agree, there are several shortcomings of this pilot study that need to be addressed in the full experiment. For instance (I have no experience in medicine) - is it common to admit patients into a COVID-19 related trial that were not tested via PCR? It seems like the authors are looking to the previous studies with larger doses (0.7 - 1.0 Gy) and attempting to validate those results with this study, which would normally be a fine effort. However, this seems to be in contradiction with their stated purpose of investigating lower doses - should not the next step be to lower the administered dose below 0.5 Gy?