Whole lung irradiation as a novel treatment for COVID-19: Final results of the prospective randomized trial (WINCOVID trial)

Published:December 24, 2021DOI:https://doi.org/10.1016/j.radonc.2021.12.024

      Highlights

      • First prospective, randomized trial comparing LDRT + pharmacological therapy vs pharmacological therapy alone for moderate to severe COVID-19.
      • Significant improvement in SF ratio leading to earlier, rapid relief from severe respiratory distress in LDRT group.
      • Quicker time to clinical recovery, fewer days to hospital discharge and better radiological resolution in LDRT group.
      • No significant difference in 28-day mortality rate, blood biomarkers response or incidence of significant lymphopenia between the groups.
      • LDRT could be useful as an adjunctive treatment in selected moderate to severe COVID-19 patients.

      Abstract

      Background and purpose

      The ability of low dose radiotherapy (LDRT) to control the unprecedented cytokine release associated with COVID-19 pathogenesis has been an area of widespread research since the COVID pandemic. It has not been studied adequately whether the anti-inflammatory effect of LDRT provides additional benefit when used concurrently with steroids amongst other standard pharmacologic therapy.

      Material and methods

      51 RT-PCR positive COVID-19 patients were recruited between November 2020 and July 2021. 34 patients were allotted to receive 0.5 Gy single session LDRT along with standard pharmacologic therapy while 17 patients received standard pharmacologic therapy alone. All had SpO2 <94% on room air, respiratory frequency >24/min and SpO2/FiO2 (SF) ratio between >89 but <357. All patients underwent a baseline CT scan. They were followed up for 28 days during when serial SF ratio, blood biomarkers (CRP, Serum ferritin, IL-6), Absolute lymphocyte count (ALC), repeat CT scan were performed at pre-defined time points.

      Results

      LDRT showed a statistically significant early improvement in oxygenation, an early time to clinical recovery, early hospital discharge and better radiological resolution compared to control group. There was no statistically significant difference between the two groups with respect to ALC or blood biomarkers at any of the measured time points. The 28-day mortality rate did not show statistically significant difference between the two groups.

      Conclusion

      LDRT can be considered for selected oxygen-dependent moderate to severe COVID-19 patients for rapid relief of respiratory distress. It can be safely combined with standard pharmacologic treatment in such patients for added clinical benefit.

      Keywords

      The emergence of new variants leading to outbreaks, slow vaccination rates, growing costs of pharmacological therapies, shortage of beds and supplemental oxygen in hospitals are some of the challenges faced by several countries across the world in the fight against COVID-19 pandemic. The probability of future outbreaks cannot be entirely ruled out, especially in densely populated countries. There remains a need for a widely available, non-toxic, cost-effective treatment approach for patients with moderate to severe COVID-19.
      Low dose radiotherapy (LDRT) is being evaluated across many institutions around the world as an anti-inflammatory/immunomodulatory approach against moderate to severe COVID-19. There has been recent advancement in understanding the underlying mechanism of action of LDRT. Calabrese et al proposed that the clinical benefit from LDRT was derived from various subcellular effects mediated by activation of nuclear factor erythroid 2-related transcription factor (Nrf-2) resulting in anti-oxidant responses and subsequent polarization shift of macrophages from pro-inflammatory (M1) to anti-inflammatory (M2) phenotype. This could not only help in resolving inflammation, but also in suppressing the cytokine storm, promoting tissue repair thereby preventing COVID-19 related mortality [
      • Calabrese E.J.
      • Kozumbo W.J.
      • Kapoor R.
      • Dhawan G.
      • Lara P.C.
      • Giordano J.
      NRF2 activation putatively mediates clinical benefits of low-dose radiotherapy in COVID-19 pneumonia and acute respiratory distress syndrome (ARDS): novel mechanistic considerations.
      ].
      As per our preliminary observations, LDRT appeared to be a promising modality for selected patients with moderate to severe COVID-19 [
      • Govindaraj G.
      • Sasipriya P.
      • Sundaram V.
      • Kumar M.P.
      • Venkatraman P.
      • Manigandan C.
      • et al.
      Whole lung Irradiation as a Novel treatment for COVID-19: Interim Results of an Ongoing Phase 2 trial in India.
      ]. In this manuscript, we discuss the final results from our single-institutional experience in treating COVID-19 patients with low dose whole-lung radiotherapy.

      Material and methods

       Study design

      This prospective, randomized, parallel group active-controlled clinical trial was approved by the Institutional Ethics committee registered with the Central Drugs Standard Control Organization, India (Registration number ECR/926/Inst/TN/2017/RR-20). The study protocol was registered in Clinical Trial Registry of India (CTRI/2020/10/028597), available at www.ctri.nic.in.
      The study was done toevaluate bilateral whole lung LDRT using a Linear Accelerator (6 MV), as a treatment for interstitial pneumonia in patients with moderate to severe COVID-19. It was conducted in 2 phases:
      • 1.
        An initial exploratory phase enrolling 10 patients, which assessed the feasibility and efficacy of low-dose whole lung irradiation, evaluated according to an increase in the SpO2/FiO2 ratio of at least 20% at 48 hours with respect to the pre-irradiation value. Only upon achieving this minimum pre-defined improvement in at least 30% of patients treated, did the study proceed to the next phase
      • 2.
        Randomized comparative phase in two groups:
      • a.
        a control group, which received pharmacological treatment only, and
      • b.
        an experimental LDRT arm with pharmacological treatment and LDRT. It included 51 patients, the allocation was2:1, that is, 34 in the LDRT arm and 17 in the control arm. Computer based random sequences were generated and no blinding was done.
      The flowchart of study design is shown in Fig. 1.Fig 2.
      Figure thumbnail gr2
      Fig. 2Flow diagram of “Randomized comparative phase” study participants.

       Patient selection

      All patients with moderate to severe COVID-19 pneumonia were evaluated by a multidisciplinary board (including specialties such as Radiation Oncology, Internal Medicine, Pulmonology, Critical Care and Anesthesia) to determine the benefits and risks of their inclusion in the study.

       Inclusion criteria

      1. Adult patients above the age of 40 with RT-PCR proven COVID-19 with fewer than 14 days of symptom onset, that warranted hospitalization and currently receiving pharmacological therapy for COVID-19 at appropriate doses as per national standard COVID-19 management recommendations
      And
      2. Patients with moderate to severe dyspnea requiring oxygen support (Nasal Cannula/Simple face mask/Venturi mask/non-rebreathermask/High flow nasal cannula/CPAP) with respiratory frequency ≥ 24/min, oxygen saturation on room air SpO2 <94% and SpO2/FiO2 ratio >89 and <357.
      And/or
      3. Laboratory abnormalities such as C-reactive protein >100 mg/L or D-dimer >1000 ng/ml or IL-6 >50 IU or suspected cytokine release syndrome
      (Criteria 1 and 2 were mandatory and 3 was optional)

       Exclusion criteria

      • 1.
        Actual or planned Pregnancy
      • 2.
        Prior lobectomy or pneumonectomy
      • 3.
        Prior thoracic radiotherapy resulting in a maximum lung dose of 100 cGy or higher within 14 days of enrollment
      • 4.
        Prior chemotherapy or other systemic therapy with potential for pulmonary toxicity or radio sensitization within 14 days or 5 half-lives, whichever is greater, of enrollment, e.g., bleomycin, gemcitabine
      • 5.
        Prior cancer immunotherapy with an immune checkpoint inhibitor within 60 days of enrollment
      • 6.
        Severe pre-existing heart disease, e.g., New York Heart Association (NYHA) functional class ≥3 congestive heart failure
      • 7.
        History of bone marrow or solid organ transplantation
      • 8.
        Known history of autoimmune collagen vascular disease, e.g., scleroderma
      • 9.
        Known hereditary syndrome with increased sensitivity to ionizing radiation, e.g., Ataxia-telangiectasia or Fanconi anemia

       End points:

      Primary endpoint:
      • Comparison of efficacy of LDRT based on an improvement in SpO2/FiO2 (SF) ratio, defined as the ratio of Oxygen saturation by pulse oximetry to that of fraction of inspired oxygen, measured at 48 h, 72 h, 7 days and 14 days from the time of intervention (LDRT in LDRT group and first steroid dose in control group) compared to the baseline measurement in LDRT group and controls.
      Secondary endpoints:
      • Assessment and comparison of radiological response with the help of CT scan done at baseline and 14 days post intervention in LDRT group and controls
      • Assessment and comparison of mortality rate at day 28 post intervention in LDRT group and controls
      • Assessment and comparison of Absolute Lymphocyte counts (ALC) at baseline, day 1, day 3, day 7 and day 14 post intervention in LDRT group and controls
      • Assessment and comparison of inflammatory response with the help of CRP, Serum Ferritin and immunological response with the help of IL-6 done at baseline and on Day 3, Day 7 and day 14post intervention in LDRT group and controls
      Tertiary endpoints
      • Time to clinical recovery, defined as time to wean from supplemental oxygen and remain off supplemental oxygen for at least 12 consecutive hours
      • Time to hospital discharge

       Statistical analysis

      The data was analyzed using SPSS Software version 23. Descriptive statistics were performed for demographic and clinical characteristics independently for intervention and control groups. Frequency was reported for categorical variables and mean (±SD) or median (Interquartile range) for continuous variables as appropriate. Boxplots were used to visualize the distribution of clinical parameters and assess the presence of outliers. Normality was assessed by use of the Shapiro -Wilk test. Upon violation of the assumption of normality, Friedman tests and Wilcoxon-signed rank tests were run where applicable to determine significant difference in clinical parameters over time separately for the intervention and control groups. Post hoc analysis was performed with a Bonferroni correction applied for multiple comparisons. Change in clinical and laboratory parameters at each time point compared to the baseline, were assessed for statistically significant difference between the two arms using a Mann Whitney U test. Kaplan Meier curves for time to clinical recovery, hospital discharge and death in the two arms were assessed using the Log Rank test. A two-sided p value less than 0.05 was considered to be statistically significant.

       Pharmacological treatment

      General measures for all patients included Awake prone positioning and Protein rich diet (1 g/kg/day). All patients received corticosteroids (Methylprednisolone/Dexamethasone), anti-coagulants (Enoxaparin sodium), Antibiotics, Pirfenidone, Vitamin Cand Zinc supplementation. Dose of corticosteroids were 1 mg/kg/day of methylprednisolone in two divided doses (or an equivalent dose of dexamethasone) for moderate cases (SF ratio >213 but <357) and 1.5 mg/kg/day of methylprednisolone in two divided doses (or an equivalent dose of dexamethasone) for severe cases (SF ratio >89 but <214). For both the groups, corticosteroids were given for a median of 7 days (Range 5–10days). 16/34 (47%) patients in the LDRT group and 10/17 (58.8%) patients in the control group received Remdesivir. Six (17.6%) patients in the LDRT group and five (29.4%) patients in the control group received Tocilizumab.

      Results

      Upon conclusion of the initial exploratory phase in 10 patients at 1 month follow-up, we found that LDRT was well tolerated. Clinical profile and baseline parameters of these 10 patients are tabulated in Table 1, Table 2 respectively. The pre-defined efficacy criteria of “minimum 20% improvement in SF ratio in at least 30% of the patients at 48 h” was achieved, as50% of treated patients fulfilled this (Table 3). SF ratio distribution of these 10 patients is depicted using a boxplot in Fig. 3.
      Table 1Profile of patients in exploratory phase (n = 10).
      CharacteristicNumber of study participants, n (%)
      Age in years
      40–594 (40)
      60–695 (50)
      ≥701 (4.0)
      Sex
      Male5 (50)
      Female5 (50)
      Presence of comorbidity
      Co-morbid6 (60)
      Diabetes6(60)
      Hypertension5(50)
      Non-comorbid4 (40)
      Baseline SpO2 in room air, %
      70–792 (20)
      80–898 (80)
      ≥900
      CT severity score
      12–195 (50)
      ≥205 (50)
      Table 2Baseline parameters of study participants (n = 10).
      Test nameLaboratory values
      MinimumMaximumMedian (IQR)
      CRP18316138 (98–215)
      Ferritin155567360 (234–468)
      IL-62.458884 (24–170)
      D-dimer1006000150 (100–2325)
      NLR1.210.36 (4.4–6.7)
      CT Severity Score162320 (17–23)
      Table 3Relative difference in SF ratio between baseline and Day 2 (n = 10).
      SF ratio percentage difference (%)Number of study participants, n (%)
      <205 (50)
      ≥205 (50)
      Figure thumbnail gr3
      Fig. 3Boxplot showing distribution of SpO2/FiO2 (SF) ratio in “Initial Exploratory phase” patients (n = 10).
      The randomized phase of the study comprised of 34 cases and 17 controls. The characteristics of the participants and baseline lab parameters are outlined in Table 4, Table 5. Median time to intervention was 24 h (12–72 h) in the LDRT group and 2 h (2–3 h) in the control group (first steroid dose). Median time to first steroid dose in the LDRT group was 2 h (2–3 h).
      Table 4Baseline characteristics of ‘Randomized phase’ study participants.
      CharacteristicIntervention armControl arm
      Frequency, n (%)
      Age in years
      41–5516 (47)5 (29)
      56–7012 (35)11 (65)
      71–856 (18)1 (6)
      Sex
      Male22 (65)12 (71)
      Female12 (35)5 (29)
      Comorbidity
      Comorbid29 (85)10 (59)
      Diabetes25 (74)10 (59)
      Hypertension13 (38)5 (29)
      Asthma1(2.9)
      Liver Disease4 (12)
      Non-comorbid5 (15)7 (41)
      SpO2 in room air, %
      60–692(5.8)
      70–793 (9.0)3 (18)
      80–8922(65)8 (47)
      ≥907 (20)6 (35)
      CT Severity score
      12–1929 (85)15 (88)
      ≥205 (15)2 (12)
      Table 5Baseline Laboratory Parameters of the study participants.
      Laboratory parameterIntervention armControl arm
      Median (IQR)
      CRP66 (46–81)90(24–109)
      D-dimer650 (357–1335)970 (393–3421)
      Ferritin520 (286–855)463 (381–1188)
      IL-664 (36–94)48 (36–87)
      NLR7.9 (6–16)7.2 (5.5–17)
      Lymphocyte count782 (621–1195)1092 (711–1375)
      TLC9450(6942–11637)8000 (4950–11770)
      For the primary endpoint of SF ratio assessment, comparison was done both within and between the two groups. Key time points defined for comparison were baseline, day 2, day 3, day 7 and day 14.
      Within the LDRT group, there was a statistically significant increase in SF ratio with time, χ2(4) = 94.20, p < 0.001. Post hoc analysis revealed that LDRT elicited a statistically significant reduction in SF ratio beyond Day 3 of the intervention.
      Within the Control group, a statistically significant reduction in oxygen requirement was observed with time, χ2(4) = 41.88, p < 0.001. Post hoc analysis revealed a significant increase in SF ratio only beyond Day 7 of the intervention.
      Between the two groups, there was a significant difference in increase of SF-ratio in LDRT group compared to the control group on Days 2, 3 and 7 of radiotherapy (p < 0.001).
      Within and between group comparisons are tabulated in Table 6, Table 7 respectively and depicted using a boxplot in Fig. 4.
      Table 6Within-group temporal difference in SF ratio in Intervention and Control Arms.
      TimeIntervention groupControl group
      SF ratio, Median (IQR)p valueSF ratio, Median (IQR)p value
      Baseline208 (147–276)Reference174 (141–260)Reference
      Day 2285 (188–378)0.70155 (152–312)1.000
      Day 3319 (204–470)0.000204 (157–324)0.545
      Day 7485 (475–490)0.000303 (229–376)0.001
      Day 14485 (482–490)0.000475 (475–480)0.000
      Table 7Between-group comparison of Temporal change in SF ratio.
      TimeDifference in SF ratio, Median (IQR)p value
      Intervention armControl arm
      Baseline to Day 271 (4–153)18 (–19–48)0.008
      Baseline to Day 3123 (4.3–214)26 (–11–76)0.007
      Baseline to Day 7231 (205–318)108 (13–160)0.000*
      Baseline to Day 14258 (212–340)225 (151–322)0.176
      *Statistically significant at p < 0.05.
      Figure thumbnail gr4
      Fig. 4Boxplot showing SF ratio: Within and Between group comparison.
      Incidence of lymphopenia was compared between the groups by monitoring serial absolute lymphocyte counts at baseline, day 1, day 3, day 7 and day 14 and no statistically significant reduction was found at the measured time points (Table 8). Inflammatory and immunological response biomarkers such as CRP, Serum ferritin and IL-6 were compared based on their baseline, day 3, day 7 and day 14 values between the groups. There was no statistically significant difference with respect to any of the biomarkers (Table 9, Table 10, Table 11).
      Table 8Between-group comparison of Temporal change in Lymphocyte count.
      Time Point differenceMedian (IQR)p value
      Intervention armControl arm
      Baseline to Day 1−19 (–154, −147.25)−80 (–31, −158)0.510
      Baseline to Day 3−105 (–397, − 26.25)−59 (–465, −157)0.984
      Baseline to Day 7−231 (–600, −118)−280 (–546, −83)0.770
      Baseline to Day 14101 (–72.95, −354)−71 (–203, −116)0.087
      * Statistically significant at p < 0.05.
      Table 9Between-group comparison of Temporal change in CRP.
      Time Point differenceMedian (IQR)p value
      Intervention armControl arm
      Baseline to Day 3−24 (–31, −12.8)–23(–38, −2.8)0.952
      Baseline to Day 7−49 (–62.9, −30.3)−80 (–110, −8.8)0.246
      Baseline to Day 14−56 (–69, 27)−86 (–104, −12)0.316
      *Statistically significant at p < 0.05, χ2(3) = 31.03.
      Table 10Between-group comparison of Temporal change in Serum Ferritin.
      Time Point differenceMedian (IQR)p value
      Intervention armControl arm
      Baseline to Day 3−38(–76, −0.37)−53(–133, −14)0.569
      Baseline to Day 7−90 (–162, −35)−85(–99, −40)0.453
      Baseline to Day 14−163 (–257, −71)−170(–279, −73)0.939
      *Statistically significant at p < 0.05.
      Table 11Between-group comparison of Temporal change in IL-6 value.
      Time Point differenceMedian (IQR)p value
      Intervention armControl arm
      Baseline to Day 3−42 (–64, –23)−34 (–62, −26)0.780
      Baseline to Day 7−53 (–84, −28)−43 (–67, −31)0.542
      Baseline to Day 14−56(–89, −29)−42 (–56, –33)0.366
      *Statistically significant at p < 0.05.
      All patients in the LDRT and control group had undergone a baseline CT scan. The radiological response in terms of reduction of CT severity score (CTSS) was observed in the LDRT group as compared to the control group showing statistically significant difference (p = 0.011). This is given in Table 12. The median (IQR) baseline CTSS for LDRT group was 16 (15–17) which reduced to 12(10–14) on day 14 post intervention (p < 0.001). For the control group, the median (IQR) baseline CTSS was 15 (14–17) which reduced to 13 (12–17) on day 14 post intervention (p = 0.094).
      Table 12Between-group comparison of temporal change in CT severity score.
      Time PointMedian (IQR)p value
      Intervention armControl arm
      Baseline to Day 14−4(–5, −2.75)−2(–3, −1)0.011
      * Statistically significant at p < 0.05.
      Five patients in LDRT group and four patients in control group progressed to critical stage and required mechanical ventilation. Allof these patients succumbed to the disease eventually. Mortality rate at 28 days post-admission was 0.59 per 100 person-days and 1.02 per 100 person-days in the intervention and control group respectively. A log rank test was run to determine if there were differences in the survival distributions among the two arms and it showed no statistically significant difference, χ2(1) = 0.545, p = 0.460. Kaplan Meier curves were drawn to represent the survival data, depicted in Fig. 5.
      Figure thumbnail gr5
      Fig. 5Kaplan Meier Curves for survival at 28 days post-admission in LDRT (n = 34) and control groups (n = 17).
      The median time to clinical recovery was 4 (2.1–5.8) days and 11 (10–12) days in the intervention and control groups respectively. A log rank test noted a statistically significant difference in the distributions, χ2(1) = 19.510, p < 0.001. This is represented using a Kaplan Meier curve in Fig. 6.
      Figure thumbnail gr6
      Fig. 6Kaplan Meier Curves for Time to Clinical Recovery in LDRT (n = 34) and control groups (n = 17).
      The median time to discharge was 7 (5.6–8.3) days and 13 (12–14) days in the intervention and control arms respectively. A log rank test noted a statistically significant difference in the distributions, χ2(1) = 20.013, p < 0.001. The corresponding Kaplan Meier curve is represented in Fig. 7.
      Figure thumbnail gr7
      Fig. 7Kaplan Meier Curves for Time to hospital discharge in LDRT (n = 34) and control groups (n = 17).

      Discussion

      Several hematological, coagulation, immunological and inflammatory biomarkers have been associated with severity and progression of COVID-19 [
      • Ponti G.
      • Maccaferri M.
      • Ruini C.
      • Tomasi A.
      • Ozben T.
      Biomarkers associated with COVID-19 disease progression.
      ]. A meta-analyses commented that most of these biomarkers could not be ranked in terms of correlation with severity of COVID-19 [
      • Ji P.
      • Zhu J.
      • Zhong Z.
      • Li H.
      • Pang J.
      • Li B.
      • et al.
      Association of elevated inflammatory markers and severe COVID-19: A meta-analysis.
      ]. In this study, we assessed response of selected biomarkers to LDRT in terms of inflammatory (CRP, Serum ferritin) and immunological (IL-6) aspects and compared it with controls. A significant reduction from the baseline values was noted for both the groups individually, for CRP, Serum ferritin and IL-6 at day 7 and day 14. However, we did not observe a significant difference in terms of response of these biomarkers between the two groups at any of the measured timepoints. Amongst the patients who died, except for one LDRT group patient’s baseline serum ferritin, all other patients in both the groups had a higher baseline CRP, serum ferritin and IL-6 when compared to their respective median baseline values. While these are very useful prognostic markers, they may not be the ideal response assessment markers as these are prone to fluctuations in presence of factors like co-existing bacterial infections.
      LDRT group had a significant improvement in SF ratio on day 2, day 3 and 7 compared to the control group. Also, LDRT group patients had much earlier improvement in median SF ratio compared to control group (Day 3 for LDRT vs Day 7 for controls) while compared within the group. A wide range of SF ratio has been considered for inclusion (90–356) causing a notable difference in the median baseline SF ratio values between the two groups (208 for LDRT group vs 174 for controls). However, the median values fall within the definition of severe respiratory distress (SF ratio >89 and <214) defined earlier [
      • Govindaraj G.
      • Sasipriya P.
      • Sundaram V.
      • Kumar M.P.
      • Venkatraman P.
      • Manigandan C.
      • et al.
      Whole lung Irradiation as a Novel treatment for COVID-19: Interim Results of an Ongoing Phase 2 trial in India.
      ]. In one of the largest series of LDRT for moderate to severe COVID-19, Arenas et al noted a considerable improvement in SF ratio by a median of 76% at day 7 in majority of the patients treated after a single fraction of 0.5 Gy [
      • Arenas M.
      • Algara M.
      • De Febrer G.
      • Rubio C.
      • Sanz X.
      • de la Casa M.A.
      • et al.
      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).
      ]. Our LDRT and control groups had a median SF ratio improvement of 128.77% and 74.1% at day 7post intervention respectively.
      We observed speedy clinical recovery and an earlier hospital discharge for patients who underwent LDRT compared to the control group. This meant better availability of beds for other needy patients and conservation of oxygen supplies for the hospital. Notably, a major part of patient recruitment happened during the times of acute oxygen crisis in our country.
      Radiological assessment was done using the scoring criteria proposed by Li et al. [
      • Li K.
      • Wu J.
      • Wu F.
      • Guo D.
      • Chen L.
      • Fang Z.
      • et al.
      The clinical and chest CT features associated with severe and critical COVID-19 pneumonia.
      ]. Three out of five patients in the LDRT group who died, had a baseline CT severity score of ≥20. LDRT may be of limited use in these patients and upcoming clinical trials could consider the same while devising selection criteria.
      At 28 days of follow-up, the all-cause mortality rate was 14.7% in the LDRT group and 23.5% in the control group. The clinical characteristics of the patients who died is represented in Table 13. It is noteworthy that the percentage of co-morbid patients in LDRT group (85%) was markedly higher compared to the control group (59%). Also, the overall median baseline CT severity score was worse for the LDRT group compared to the control group (16 vs 15). Amongst the non-survivors, the median baseline CT severity score was 20 for LDRT group vs 18 for control group. These factors might have adversely impacted the mortality outcome of LDRT group. Given the remarkable improvement in SF ratio and early clinical recovery observed in the LDRT group, a possible reduction in mortality rate cannot be disregarded, although the difference could not be perceived in statistically significant terms in this study.
      Table 13Clinical Characteristics of patients who died.
      GroupAgeCo morbiditiesBaseline SF ratioBaseline CRPBaseline IL6Baseline FerritinBaseline CTSSRemdesivirTocilizumab
      LDRT75/MDiabetic150.078.388167621NONO
      LDRT70/FNil182.086.881238722NONO
      LDRT43/MDiabetic & Hypertensive200.080.276159020NONO
      LDRT59/FDiabetic112.367.511078819YESNO
      LDRT42/MDiabetic182.096161475.617YESNO
      CONTROL48/FNil153104124140618YESNO
      CONTROL59/FNil174125110135017YESYES
      CONTROL54Diabetic15011091114518YESYES
      CONTROL60Diabetic1617482216019YESYES
      Arruda et al assessed the risk of radiation-induced cancer (RIC) and cardiovascular risk of radiation exposure induced death (REID) following LDRT for COVID-19 on a virtual case. They concluded that an acceptable lifetime attributable risk of ≤ 1% for RIC and REID was observed with a dose ≤ 0.5 Gy irrespective of sex and age [
      • Arruda G.V.
      • Weber R.R.D.S.
      • Bruno A.C.
      • Pavoni J.F.
      The risk of induced cancer and ischemic heart disease following low dose lung irradiation for COVID-19: estimation based on a virtual case.
      ]. This is further supported by Shuryak et al. who estimated the excess absolute risk (EAR) of lung cancer and heart disease in patients receiving 0.5 Gy dose of LDRT for COVID-19 to be in the ≤1% range across age groups 50–85 for both men and women belonging to the non-smoking group with no or few cardiac risk factors [
      • Shuryak I.
      • Kachnic L.A.
      • Brenner D.J.
      Lung cancer and heart disease risks associated with low-dose pulmonary radiotherapy to COVID-19 patients with different background risks.
      ].
      Risk-benefit balance needs to be assessed and discussed with the patient before irradiating relatively younger female patients with smoking history and in those with several cardiac risk factors as the EAR % may be higher for this sub-group. In our study, neither female smokers nor pre-existing cardiac co-morbidity cases were part of the patient population.
      Several published preliminary results have shown favorable outcomes with the use of LDRT for COVID-19 with negligible side effects [
      • Govindaraj G.
      • Sasipriya P.
      • Sundaram V.
      • Kumar M.P.
      • Venkatraman P.
      • Manigandan C.
      • et al.
      Whole lung Irradiation as a Novel treatment for COVID-19: Interim Results of an Ongoing Phase 2 trial in India.
      ,
      • Arenas M.
      • Algara M.
      • De Febrer G.
      • Rubio C.
      • Sanz X.
      • de la Casa M.A.
      • et al.
      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).
      ,
      • Hess C.B.
      • Nasti T.H.
      • Dhere V.R.
      • Kleber T.J.
      • Switchenko J.M.
      • Buchwald Z.S.
      • et al.
      Immunomodulatory low-dose whole-lung radiation for patients with coronavirus disease 2019-related pneumonia.
      ,
      • Ameri A.
      • Rahnama N.
      • Bozorgmehr R.
      • Mokhtari M.
      • Farahbakhsh M.
      • Nabavi M.
      • et al.
      Low-dose whole-lung irradiation for COVID-19 pneumonia: short course results.
      ,
      • Sanmamed N.
      • Alcantara P.
      • Cerezo E.
      • Gaztañaga M.
      • Cabello N.
      • Gómez S.
      • et al.
      Low-dose radiation therapy in the management of coronavirus disease 2019 (COVID-19) pneumonia (LOWRAD-Cov19): Preliminary report.
      ]. But some clinicians in the radiation oncology community continue to be hesitant on usage of this approach, quoting lack of robust data, feasibility and logistic issues [
      • Hanna C.R.
      • Robb K.A.
      • Blyth K.G.
      • Jones R.J.
      • Chalmers A.J.
      Clinician attitudes to using low-dose radiation therapy to treat COVID-19 lung disease.
      ]. These barriers need to be overcome for LDRT to be studied under a large scale multi-institutional research setting worldwide.
      This prospective, randomized study is not without its limitations. It utilized a 2:1 allocation ratio for statistical comparison between the intervention and control group. Although this is scientifically not validated, this allocation has been selected for better patient recruitment and gathering additional safety profile of LDRT. Remdesivir, tocilizumab, Pirfenidone, Vitamin C and zinc were used for patients in both groups in addition to ‘standard pharmacologic treatment’ according to physician’s discretion. Notably, there were several revisions to guidelines about the best use of these pharmacological drugs throughout the duration in which this trial was conducted. This had resulted in varying number of patients receiving these drugs between the two groups and some patients not receiving the drugs, which may have influenced the outcome.

      Conclusion

      This prospective, randomized trial shows that addition of LDRT to pharmacological treatment hastens clinical recovery and time to hospital discharge compared to pharmacological treatment alone in selected moderate to severe COVID-19 patients. This was achieved by improvement in oxygenation and is backed by radiological resolution of pneumonia in majority of patients treated, in the absence of limiting side effects. The all-cause mortality rate was lower in the LDRT group compared to the control group, although this was not statistically significant. These findings need to be further validated by larger samples and long-term follow-up.

      Conflicts of interest

      None.

      Financial support

      The authors declare that there has been no significant financial support from any fund source(s) that could have influenced the outcome of the study.

      Acknowledgements

      The Authors would like to acknowledge the following people for their inputs and assistance in this research: Dr Manoharan, Dr Nishanth M, Dr Deepan Chakravarthi, Dr Shruthee Deepan, Dr Pugazhenthan T, Dr Divya, Mr Manimaran R, Mr Selva Kumar K, Mr Bharath Babu, Ms Muthulakshmi K.

      References

        • Calabrese E.J.
        • Kozumbo W.J.
        • Kapoor R.
        • Dhawan G.
        • Lara P.C.
        • Giordano J.
        NRF2 activation putatively mediates clinical benefits of low-dose radiotherapy in COVID-19 pneumonia and acute respiratory distress syndrome (ARDS): novel mechanistic considerations.
        Radiother Oncol. 2021; 160: 125-131
        • Govindaraj G.
        • Sasipriya P.
        • Sundaram V.
        • Kumar M.P.
        • Venkatraman P.
        • Manigandan C.
        • et al.
        Whole lung Irradiation as a Novel treatment for COVID-19: Interim Results of an Ongoing Phase 2 trial in India.
        Radiother Oncol. 2021 Aug 12;
        • Ponti G.
        • Maccaferri M.
        • Ruini C.
        • Tomasi A.
        • Ozben T.
        Biomarkers associated with COVID-19 disease progression.
        Crit Rev Clin Lab Sci. 2020; 57: 389-399
        • Ji P.
        • Zhu J.
        • Zhong Z.
        • Li H.
        • Pang J.
        • Li B.
        • et al.
        Association of elevated inflammatory markers and severe COVID-19: A meta-analysis.
        Medicine. 2020; 99: e23315https://doi.org/10.1097/MD.0000000000023315
        • Arenas M.
        • Algara M.
        • De Febrer G.
        • Rubio C.
        • Sanz X.
        • de la Casa M.A.
        • et al.
        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).
        Strahlenther Onkol. 2021; 197: 1010-1020
        • Li K.
        • Wu J.
        • Wu F.
        • Guo D.
        • Chen L.
        • Fang Z.
        • et al.
        The clinical and chest CT features associated with severe and critical COVID-19 pneumonia.
        Invest Radiol. 2020; 55: 327-331
        • Arruda G.V.
        • Weber R.R.D.S.
        • Bruno A.C.
        • Pavoni J.F.
        The risk of induced cancer and ischemic heart disease following low dose lung irradiation for COVID-19: estimation based on a virtual case.
        Int J Radiat Biol. 2021; 97: 120-125
        • Shuryak I.
        • Kachnic L.A.
        • Brenner D.J.
        Lung cancer and heart disease risks associated with low-dose pulmonary radiotherapy to COVID-19 patients with different background risks.
        Int J Radiat Oncol Biol Phys. 2021; 111: 233-239
        • Hess C.B.
        • Nasti T.H.
        • Dhere V.R.
        • Kleber T.J.
        • Switchenko J.M.
        • Buchwald Z.S.
        • et al.
        Immunomodulatory low-dose whole-lung radiation for patients with coronavirus disease 2019-related pneumonia.
        Int J Radiat Oncol Biol Phys. 2021; 109: 867-879
        • Ameri A.
        • Rahnama N.
        • Bozorgmehr R.
        • Mokhtari M.
        • Farahbakhsh M.
        • Nabavi M.
        • et al.
        Low-dose whole-lung irradiation for COVID-19 pneumonia: short course results.
        Int J Radiat Oncol Biol Phys. 2020; 108: 1134-1139
        • Sanmamed N.
        • Alcantara P.
        • Cerezo E.
        • Gaztañaga M.
        • Cabello N.
        • Gómez S.
        • et al.
        Low-dose radiation therapy in the management of coronavirus disease 2019 (COVID-19) pneumonia (LOWRAD-Cov19): Preliminary report.
        Int J Radiat Oncol Biol Phys. 2021; 109: 880-885
        • Hanna C.R.
        • Robb K.A.
        • Blyth K.G.
        • Jones R.J.
        • Chalmers A.J.
        Clinician attitudes to using low-dose radiation therapy to treat COVID-19 lung disease.
        Int J Radiat Oncol Biol Phys. 2021; 109: 886-890