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)
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Abstract
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. Clinical Trial Registration: NCT04366791 .
Funding
None
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SciScore for 10.1101/2021.02.10.21251242: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics Consent: All participants gave written informed consent prior to any study procedures.
IRB: The research protocol was approved by the Emory University Institutional Review Board.Sex as a biological variable not detected. Randomization not detected. Blinding Thereafter, a cohort of age- and comorbidity-matched controls was blindly and retroactively selected for comparative outcome analysis, using methods described previously.9 Twenty new controls were selected among SARS-CoV-2-positive patients who had previously enrolled on a separate, non-therapeutic, prospective institutional trial and matched by age, comorbidity, and disease severity. Power Analysis not detected. Table 2: Resources
… SciScore for 10.1101/2021.02.10.21251242: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics Consent: All participants gave written informed consent prior to any study procedures.
IRB: The research protocol was approved by the Emory University Institutional Review Board.Sex as a biological variable not detected. Randomization not detected. Blinding Thereafter, a cohort of age- and comorbidity-matched controls was blindly and retroactively selected for comparative outcome analysis, using methods described previously.9 Twenty new controls were selected among SARS-CoV-2-positive patients who had previously enrolled on a separate, non-therapeutic, prospective institutional trial and matched by age, comorbidity, and disease severity. Power Analysis not detected. Table 2: Resources
Software and Algorithms Sentences Resources Statistical analysis was performed using SAS 9.4 (SAS Institute Inc., Cary, NC), and statistical significance was two-sided and assessed at the 0.05 level. SAS Institutesuggested: (Statistical Analysis System, RRID:SCR_008567)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:While we have controlled for prior study weaknesses including variations in recovery definitions and transport eligibility, certain limitations remain. These include a non-randomized approach, exploratory intent, small patient numbers, differing control treatments, different laboratory and imaging schedules between the LD-RT and control cohorts, variable times of symptom onset, limited imaging (Figure S2) and serological (Figure S3) studies in the control cohort before intervention and beyond 7 days, and lack of detailed viral load evaluations in the LD-RT and control cohorts. Future work with LD-RT will include confirmatory testing for efficacy using a phase III design, exploration of lower dose ranges, detailed CD-8 T-cell activation studies, CD-4 T cell activation, changes in B-cell profiles, antibody formation, cytokine analysis, and neutralization tests. In summary, this report corroborates prior finding that LD-RT may prevent intubation in COVID-19. Our results show that LD-RT again demonstrated an anti-inflammatory effect in COVID-19 that may lower the risk of mechanical ventilation, the duration of oxygen supplementation, and total hospital recovery time, especially in patients who experience rapid decline in CRP following LD-RT. LD-RT again reduced CRP and CK levels, denoting cardiac protection. Early LD-RT may be protective against downstream elevations in troponin-1, D-dimer, hepatic injury, and cardiac injury. Reduction of CRP following LD-RT may be indicative of ...
Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT04366791 Suspended Radiation Eliminates Storming Cytokines and Unchecked Edema … NCT04280705 Completed Adaptive COVID-19 Treatment Trial (ACTT) NCT04433949 Recruiting Best Supportive Care With or Without Low Dose Whole Lung Rad… Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
Results from scite Reference Check: We found no unreliable references.
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