In Regard to Papachristofilou et al

To the Editor:

This comment is regarding the paper by Papachristofilou et al.¹ To study the morbidity and mortality of patients with COVID-19 who needed mechanical ventilation, the authors investigated the use of whole-lung low-dose (1 Gy) radiation therapy (LDRT). Their randomized trial showed that whole-lung LDRT did not improve clinical outcomes in critically ill COVID-19 patients.¹ These results contradict the findings of earlier clinical trials. To identify the source of the descrepancy, it should be noted that substantial evidence shows that 1 Gy, at least for a proportion of the COVID-19 patients, may be beyond the range of therapeutically effective doses. In March 2020, LDRT was proposed for COVID-19 using doses up to 250 mGy.² However, later different researchers around the world, in competition, increased the radiation doses. Emory University Hospital used 1.5 Gy³ and Ameri et al tried both 0.5 Gy⁴ and 1.0 Gy.⁵ Sanmamed et al also used 1.0 Gy.⁶ Interestingly, a paper⁷ published recently clearly indicates that although doses <1 Gy have anti-inflammatory effects, doses >1 Gy have proinflammatory effects and cause fibrosis. Thus, the doses used in the clinical trials such by Papachristofilou et al were possibly unjustified as the doses were not within the optimal window of dose. We believe that this is 1 reason that Papachristofilou et al failed to find any therapeutic effects of LDRT for COVID-19.¹ Addtionally, there is probably a window of opportunity during which LDRT can effectively address the pulmonary symnptoms of COVID-19 or other viral pneumonias. This concept is akin to the window of opportunity during which external beam radiation therapy is effective for spinal cord compression. In the case of COVID pneumonia, the window of opportunity is likely before the patient becomes so ill that mechanical ventilation is required. In addition, the concept of a “therapeutic window” clearly explains why Ameri et al concluded that in their trial, 0.5 Gy was more effective than 1.0 Gy.⁵

Using doses <1 Gy (in particular, doses <0.5 Gy) not only increases the therapeutic effects of low-dose radiation therapy but also reduces the cancer risk to an acceptable level. Arruda et al have recently reported that regardless of the sex, enrolling patients older than 40 years, particularly elderly patients older than 60 years, can provide acceptable lifetime attributable risks of radiation-induced cancer for a radiation dose of 0.7 Gy.⁸ It is of crucial importance to note that using doses ≤0.5 Gy not only increases the thrapeutic effects of LDRT and maintains the risks at an acceptable level but also prevents potential deterministic effects such as transient bone marrow damage. Studies conducted in patients with acute radiation sickness in Chernobyl show that even a modest dose of 0.5 to 0.7 Gy may compromise marrow function.⁹

In summary, both the timing and delivered dose are important considerations in LDRT studies. These factors are important considerations in developing an effective LDRT approach to treating patients with COVID-19.