Response to Whole-Lung Low-Dose Radiation Therapy (LD-RT) Predicts Freedom from Intubation in Patients Receiving Dexamethasone and/or Remdesevir for COVID-19-Related Acute Respiratory Distress Syndrome (ARDS)

Background: Phase I/II clinical trials have explored whole-lung low-dose radiotherapy (LD-RT) as a potential treatment for patients with COVID-19-related acute respiratory distress syndrome (ARDS). Initial findings require reproduction. Concomitant LD-RT administration with existing therapies requires safety evaluation. Methods: Patients with COVID-19-related pneumonia receiving dexamethasone and/or remdesevir were treated with 1.5 Gy whole-lung LD-RT, followed for 28 days or until hospital discharge, and compared to controls blindly matched by age, comorbidity, and disease severity. Eligible patients were hospitalized, SARS-CoV-2 positive, had radiographic consolidations, and required supplemental oxygen. Endpoints included safety, clinical recovery, intubation, radiographic changes, and biomarker response. Findings: 20 patients received whole-lung LD-RT between Jun 11 and Dec 7, 2020 and were compared to controls. Freedom from intubation improved from 68% in controls to 86% following LD-RT (p=0.09) as did C-reactive protein (CRP) (p=0.02) and creatine kinase (CK) (p<0.01) levels, consistent with prior report. Eighty percent of LD-RT patients experienced rapid decline in CRP within 3 days and were classified as LD-RT responders. Intubation-free survival (100% vs 66%, p=0.01) and oxygenation loads were lower in LD-RT responders compared to matched controls: 32% lower per individual (p=0.03) and 56% lower for the cohort (p=0.06). No patient whose CRP declined following LD-RT died or required intubation, whereas all LD-RT non-responders died. Observed reduction of prolonged recoveries and hospitalization times did not reach significance. Radiographic changes were equivalent. Interpretation: A cohort of patients with COVID-19-related ARDS treated with LD-RT demonstrated superior freedom from intubation compared to matched controls, especially LD-RT responders (p=0.01). LD-RT appears safe to deliver with concurrent drugs. LD-RT lowered CRP and CK biomarkers. CRP response predicted favorable outcome. Optimal timing for LD-RT after oxygen dependence but before intubation may extinguish immunopathology prior to systemic spread. Confirmatory clinical trials are warranted.