key: cord-0818487-3rm6zvvq authors: Govindaraj, G.; Sasipriya, P.; Sundaram, Vivek; Praveen Kumar, M.; Venkatraman, P.; Manigandan, C.; Janakiraman, T.; Gunasekaran, K.; Prabhu, R.; Brindha, T.; Shree Vaishnavi, R. title: Whole lung Irradiation as a Novel treatment for COVID-19: Interim Results of an Ongoing Phase 2 trial in India date: 2021-08-12 journal: Radiother Oncol DOI: 10.1016/j.radonc.2021.08.001 sha: ee20796b5ef8408f40cb3428cdc388169ffb378f doc_id: 818487 cord_uid: 3rm6zvvq Background and Purpose The main cause of death in COVID-19 pneumonia is acute respiratory distress syndrome which is preceded by massive cytokine release. Low-dose radiation therapy (LDRT) has anti-inflammatory and immunomodulatory effects that can interfere with the inflammatory cascade, reducing the severity of associated cytokine release. Material & Methods 25 patients with RT-PCR proven COVID-19 disease were enrolled between November 2020 and May 2021. All patients had SpO2 < 94% on room air, respiratory frequency > 24/min and SpO2/FiO2 ratio (SF ratio) of >89 but < 357. Patients were treated according to standard COVID-19 management guidelines along with single fraction LDRT of 0.5Gy to bilateral whole lungs within 10 days of symptom onset and 5 days of hospital admission. Results LDRT was well tolerated by all patients. There was a statistically significant improvement in oxygenation as given by the SF ratio between pre-RT and day 2 (p<0.05), day 3 (p<0.001) and day 7 (p<0.001) post RT. Demand for supplemental oxygen showed statistically significant reduction between pre-RT and day 2 (p<0.05), day 3 (p<0.001), day 7 (p<0.001) post RT. 88% patients attained clinical recovery within 10 days post LDRT and median time to hospital discharge from day of LDRT was 6 days. Three patients deteriorated and died. Conclusion As per our initial experience, LDRT appears to be a promising modality of treatment with rapid relief of respiratory distress in selected patients with moderate to severe COVID-19 pneumonia. This translates to early clinical recovery and hospital discharge in the selected patient group. 25 patients with RT-PCR proven COVID-19 disease were enrolled between November 2020 and May 2021. All patients had SpO2 < 94% on room air, respiratory frequency > 24/min and SpO2/FiO2 ratio (SF ratio) of >89 but < 357. Patients were treated according to standard COVID-19 management guidelines along with single fraction LDRT of 0.5Gy to bilateral whole lungs within 10 days of symptom onset and 5 days of hospital admission. LDRT was well tolerated by all patients. There was a statistically significant improvement in oxygenation as given by the SF ratio between pre-RT and day 2 (p<0.05), day 3 (p<0.001) and day 7 (p<0.001) post RT. Demand for supplemental oxygen showed statistically significant reduction between pre-RT and day 2 (p<0.05), day 3 (p<0.001), day 7 (p<0.001) post RT. 88% patients attained clinical recovery within 10 days post LDRT and median time to hospital discharge from day of LDRT was 6 days. Three patients deteriorated and died. As per our initial experience, LDRT appears to be a promising modality of treatment with rapid relief of respiratory distress in selected patients with moderate to severe COVID-19 pneumonia. This translates to early clinical recovery and hospital discharge in the selected patient group. Trial Title: Whole lung Irradiation as a Novel treatment for COVID-19 Trial Registration Number: CTRI/2020/10/028597 As of May 31, 2021, COVID-19 has been confirmed in more than 170 million individuals worldwide and has resulted in over 3.5 million deaths. India is the second worst country in the world in terms of case numbers with over 28 million cases cumulatively and third worst in terms of mortality reporting over 329,000 deaths at the time of writing. 1 Amongst the several pharmacological therapies, apart from corticosteroids, 2 most of the other widely used pharmacologic therapies like remdesivir, hydroxychloroquine, lopinavir/ritonavir, interferon had little or no effect on overall mortality, initiation of ventilation or duration of hospital stay in hospitalized patients. 3 Recently, Indian Council of Medical Research had recommended against the use of plasma therapy for COVID patients in the country. As the pandemic continues to cause large number of casualties worldwide, there is a desperate need for a life-saving modality of treatment for those severely affected by the disease. Low dose radiation therapy (LDRT) is being explored around the world in many institutions for terminally ill COVID-19 patients. The potential benefits of such an approach is well documented in literature. 4, 5 LDRT acts via polarization of macrophages to a M2 phenotype, which is the basis for its anti-inflammatory effects in COVID associated pneumonia. 6 Based on pre-clinical observations, a dose range of 0.5-1Gy was suggested for clinical use. This low dose range was observed to induce human lung macrophage reprogramming through production of the immunosuppressive IL-10 cytokine and the suppression of the inflammatory signals from IFNγ. 7 The need for this research is to evaluate this novel treatment option as an anti-inflammatory/immunomodulatory approach in moderate to severely diseased COVID-19 patients. 1. Actual or planned Pregnancy  No fever for prior 48 consecutive hours without the use of anti-pyretic medication  Oxygen saturation ≥95% on room air and ability to maintain the same without the use of supplemental oxygen for more than 48 hours  Mild symptoms requiring minimal supportive care like oral medication  Ability to adhere to home isolation recommendations The data was analyzed using SPSS Software version 23. Descriptive statistics were performed for demographic data and clinical characteristics at baseline and post-intervention. 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 such as oxygen requirement (L/min), SpO 2 /FiO 2 (SF) ratio and absolute lymphocyte counts at various time points before and after the intervention, and also assess the presence of outliers. Normality was assessed for these distributions at each time point by use of the Shapiro-Wilk test. Upon violation of the assumption of normality, a Friedman test was run to determine the difference in clinical parameters pre-and post-intervention. Post hoc analysis was performed with a Bonferroni correction applied for multiple comparisons. A two-sided p value less than 0.05 was considered to be statistically significant. and compared using a box plot in figure 3 . There was an improvement in hypoxia as given by statistically significant increase in SF ratio before and after radiotherapy, χ2 (3) There was evident radiological resolution correlating with clinical improvement as seen on Chest radiographs taken on day 3 and day 7 post RT compared to the pre-RT radiograph that was taken 2 hours before RT. One of the patients' comparative radiograph series is represented in Fig (4A-D) . The utilization of low dose radiotherapy for the treatment of viral pneumonia is documented in literature since the first half of 20 th century. It had shown great promise with cure rates up to 80% as observed by several authors. 9 The treatment was replaced by wide availability of antibiotics and was never again used for this indication for several decades until the emergence of COVID-19. As of date, there are several published preliminary reports examining various aspects on the use of LDRT. [10] [11] [12] [13] [14] The key parameters are outlined and compared with our study in Table 7 . We concur with the authors describing the transition from viral pulmonary phase to hyper-inflammatory phase as the "hypothetical therapeutic window of opportunity" for LDRT 15 Probably the most prominent finding in our study was the dramatic reduction in demand for oxygen supplementation, with reduction up to 66.6% at 48 hours compared to pre-LDRT levels. Given the current situation in India, this finding is of great importance as it addresses the core issue of oxygen shortage. Our median time to clinical recovery of 3 days is comparable with that of Hess et al. 11 Median duration of hospital admission post RT in our study was 6 days (5-9 days). Hess et al 11 worsening of clinical grade of lymphopenia in two patients on day 3 and in one patient on day 7 following a LDRT dose of 1Gy. In our study group, the median lymphocyte counts reached nadir by day 7 post RT but we did not observe a worsening of clinical grade of lymphopenia post RT compared to pre-RT. The lethal dose required for 50% reduction in surviving fraction of lymphocytes was reported to be 2Gy by Nakamura et al. 17 . Our LDRT dose of 0.5Gy could have played a part in reduction in lymphocyte counts but had not resulted in clinically significant toxicity. Its noteworthy that previously published studies that utilized the dose range of 0.5-0.7Gy did not report any acute toxicity. 10, 12 Chance of cancer induction at later life is the chief concern, both for physicians and patients while deciding for LDRT. The lifetime excess absolute risk of cancer induction, by the Preston formula was 0.4% for a whole-body dose of 0.5Gy. 18 A whole lung dose of 0.5Gy will reduce this percentage further. But, a recent review suggested that the lifetime attributable risk of cancer for a dose of 0.5Gy for ages 20-80 can range from 0.29-1.7% for males and 0.5-4.9% for females. 19 The physician should discuss the benefits and risks in detail with the patient and take an informed decision about LDRT on a case-to-case basis. Till date, there is no evidence to suggest LDRT will induce selective pressure and cause new viral mutations. 7 There are some limitations in this study. Absence of early inflammatory response evaluation of patients makes the study lacking in terms of correlation between oxygenation, radiological and inflammatory response. A short follow-up of 2 weeks chosen for these preliminary results precludes comparison with the control group to achieve solid conclusions. Mortality data will especially be more valid if patients are followed up longer. Time to clinical recovery is defined in a subjective manner. LDRT has the potential to prevent selected patients with moderate COVID pneumonia from deteriorating to severe and critical stage in majority of the cases. 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