Low doses of radiation in the form of chest x-rays has been in the past to treat people with pneumonia. This treatment was thought to reduce inflammation and was found to be effective without side effects. However, it was an expensive treatment and was eventually replaced with less expensive treatment options like penicillin.

The COVID-19 virus has emerged recently, causing high rates of pneumonia in people. The authors believe that giving a small dose of radiation to the lungs may reduce inflammation and neutralize the pneumonia caused by COVID-19. For this study, the x-ray given is called radiation therapy. Radiation therapy uses high-energy X-ray beams from a large machine to target the lungs and reduce inflammation. Usually, it is given at much higher doses to treat cancers.

The purpose of this study is to find out if adding a single treatment of low-dose x-rays to the lungs might reduce the amount of inflammation in the lungs from COVID-19 infection, which could reduce the need for a ventilator or breathing tube.

The authors propose a two-step randomized Phase II study to determine if single fraction low dose whole thorax megavoltage radiotherapy (LD-WTRT) can produce meaningful clinical benefit in COVID-19 patients. In Step 1, patients would be randomized 1:2 to standard of care without or with LD-WTRT. Patients randomized to LD-WTRT would be further randomized to either 35 cGy or 100 cGy. After 20 patients have been enrolled on each low-dose radiotherapy arm, they will be evaluated to determine the selection of the "best radiotherapy dose-arm" for the remainder of the patients. This will be done by analyzing clinical benefit, risk profile, and the dynamics of biomarker change, specifically focusing on IL-6

1. If the rate of Grade 4 toxicity is lower by an absolute rate of 15% when comparing the 35 cGy and 100 cGy arms, the arm with the lower toxicity rate will be used for Step 2 of the trial.

2. If the crude clinically meaningful event rate (CMER) which is a composite endpoint, is lower by an absolute rate of 20% when comparing the 35 cGy and 100 cGy arms, the lower CMER rate arm will be used for Step 2. CMER is defined as a composite of :

   1. Rate of mechanical ventilation (MV)
   2. Rate of prolonged hospital stay >10 days (PHS)
   3. Crude all-cause mortality rate at the time of analysis

3. If the crude CMER is < 20% difference between the 35 cGy and 100 cGy arms, the investigators will determine whether there is a trend suggesting less Facility Resource Utilization Rate (FRUR). If the FRUR is 20% lower in either the 35 cGy or 100 cGy arms, that dose will be used for Step 2. The FRUR is based upon:

   1. Days of mechanical ventilation
   2. Days of hospitalization.

4. If both crude CMER and FRU rates do not differ by at least 20%, the investigators will evaluate the area under the curve (AUC) for IL-6 levels drawn within 24 hours before LD-WTRT and at 48 hours (2d) and 168 hours (7d) after radiation. If one of the two arms has a 20% lower serum IL-6 AUC one week after radiotherapy, the investigators will select that arm for Step 2.

5. If none of the parameters in numbers 1-4 above differ in the criteria listed, the investigators will use the lower dose of 35 cGy for Step 2.

Inclusion Criteria:

• Laboratory-confirmed diagnosis of SARS-CoV-2 pneumonia

• Currently hospitalized with COVID-19

• Symptomatic fever, cough and/or dyspnea for < 9 days

• Patient or legal/authorized representative can understand and sign the study informed consent document

• Able to be positioned on a linear-accelerator couch for Radiation Therapy delivery

• And at least one of the following risk factors for significant pulmonary compromise:

  1. Fever > 102 degrees Fahrenheit during index admission
  2. Respiratory rate of ≥ 26 / minute within 24 hours of screening
  3. SpO2 ≤ 95% on room air within 24 hours of screening
  4. Any patient requiring 4 L/min oxygen therapy to maintain SpO2 >93% within 24 hours of screening
  5. Ratio of partial pressure of arterial oxygen to fraction of inspired air < 320.

• Patients may be enrolled on this trial while concurrently enrolled on other COVID-19 clinical trials.

Exclusion Criteria:

• Currently requiring mechanical ventilation

• Prior thoracic radiotherapy, with the exception of the following:

  1. Breast or post-mastectomy chest wall radiation (without regional nodal irradiation) may be included at the discretion of the site primary investigator, and
  2. Thoracic skin radiation therapy (without regional nodal irradiation) is allowed.

• Known hereditary syndrome with increased sensitivity to radiotherapy, including ataxia-telangiectasia, xeroderma pigmentosum, and Nijmegen Breakage Syndrome

• Known prior systemic use of the following drugs: Bleomycin, Carmustine, Methotrexate, Busulfan, Cyclophosphamide, or Amiodarone

• History of or current diagnosis of pulmonary fibrosis, or an alternative pulmonary condition responsible for significant lung compromise at the discretion of the site primary investigator

• History of lung lobectomy or pneumonectomy

• Known history of pulmonary sarcoidosis, Wegener's granulomatosis, systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis, polymyositis/dermatomyositis, Sjögren's syndrome, mixed connective tissue disease, Churg-Strauss syndrome, Goodpasture's syndrome, or ankylosing spondylitis.

• Symptomatic congestive heart failure within the past 6 months including during current hospitalization

• History of recent or current malignancy receiving any cytotoxic chemotherapy or immunotherapy within the past 6 months.

• History of bone marrow transplantation.

• History of any solid organ transplant (renal, cardiac, liver, lung) requiring immunosuppressive therapy.

• Females who are pregnant or breast feeding.

• Inability to undergo radiotherapy for any other medical or cognitive issues.