Submit Your Article CMED MEACR meeting
Home Print this page Email this page Users Online: 373
Home About us Editorial board Search Ahead of print Current issue Archives Submit article Instructions Subscribe Contacts Login 


 
 Table of Contents  
REVIEW ARTICLE
Year : 2021  |  Volume : 10  |  Issue : 1  |  Page : 1-4

Low-dose radiation therapy for COVID-19 pneumonia


Department of Radiation Oncology, All India Institute of Medical Sciences, Bathinda, Punjab, India

Date of Submission27-Aug-2020
Date of Decision06-Oct-2020
Date of Acceptance20-Oct-2020
Date of Web Publication19-Feb-2021

Correspondence Address:
Sapna Marcus
Department of Radiation Oncology, All India Institute of Medical Sciences, Bathinda, Punjab
India
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ccij.ccij_126_20

Rights and Permissions
  Abstract 


The new coronavirus COVID-19 disease was declared a global public health emergency by the World Health Organization on January 2020. In the current dismal situation of the COVID-19 pandemic, effective management of patients with pneumonia and acute respiratory distress syndrome is of utmost importance. Due to the current lack of effective pharmacological concepts, this situation has caused interest in re-considering historical reports on the treatment of patients with low-dose radiation therapy for pneumonia. Although these historical reports are of low-level evidence per se, hampering recommendations for decision-making in the clinical setting, they indicate effectiveness in the dose range between 0.3 and 1 Gy, similar to more recent dose concepts in the treatment of acute and chronic inflammatory/degenerative benign diseases with, for example, a single dose per fraction of 0.5 Gy. Thus, we review the effects and mechanism and highlight the evidence for low-dose radiation that may be viable and useful in counteracting the acute inflammatory state induced by critical stage COVID-19 in the treatment of COVID-19 pneumopathy.

Keywords: COVID-19, low-dose radiotherapy, pneumonia


How to cite this article:
Mahajan R, Marcus S. Low-dose radiation therapy for COVID-19 pneumonia. Clin Cancer Investig J 2021;10:1-4

How to cite this URL:
Mahajan R, Marcus S. Low-dose radiation therapy for COVID-19 pneumonia. Clin Cancer Investig J [serial online] 2021 [cited 2021 Apr 21];10:1-4. Available from: https://www.ccij-online.org/text.asp?2021/10/1/1/309798




  Introduction Top


The outbreak of the new coronavirus (severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]/COVID-19) has spread at a very alarming rate throughout the world, with most of the countries being medically, economically, socially, and politically unprepared to meet and respond to the pandemic threat. The clinical spectrum of COVID-19 ranges from an asymptomatic form to mild respiratory symptoms such as dry cough, fever, and moderate dyspnea, to more severe presentations, such as neurologic manifestations (e.g., cerebrovascular accident consequential to cytokine-induced changes in blood clotting; direct encephalitic effects), viral pneumonia, acute respiratory distress syndrome (ARDS), and sequential organ failure as a result of cytokine storm.[1],[2] ARDS requires the use of mechanical ventilatory support and supplemental oxygen, and despite such measures, often incurs high mortality (30%–40%).[3] The patients who have required ventilator support for long duration have produced an unanticipated shortage of these devices and have imposed a significant burden on hospital systems. This situation has caused interest in re-considering the historical treatment of patients with low-dose radiation therapy for pneumonia.


  Pathogenesis of COVID-19 Effects Top


SARS-CoV-2/COVID-19 virus belongs to the Coronaviridae family and is a single-stranded RNA virus that can infect both humans and animals. The entry of pathogenic COVID-19 virus in humans leads to activation of inflammatory cells, specifically CD4 lymphocytes that subsequently transform to T-helper 1 (Th1) cells. Th1 cells participate in increasing production of several pro-inflammatory cytokines and chemokines, including interleukin (IL) 1-b, IL-2, IL1RA, IL7, IL8, IL9, IL10, granulocyte colony-stimulating factor (GCSF), GMCSF, basic fibroblast growth factor 2, interferon c, IP10, MCP1, MIP1a, MIP1b, platelet-derived growth factor, tumor necrosis factor-alpha (TNFa), and vascular endothelial growth factor A. These mediators initiate the cascade of events that lead to an accelerated inflammatory state. The cytokines that appear to be most directly related to the severity of respiratory illness in COVID-19 are GCSF, IL2, IL7, IL10, GCSF, IP10, MCP1, MIP1a, and TNFa. Activated inflammatory cells (Th1 cells and macrophages) enter the pulmonary circulation and induce a ubiquity of cytokines (i.e., “cytokine storm”) that lead to rapid, wide-spread damage of the pulmonary epithelium and alveolar cells, as well as other vital organs.[1],[4],[5],[6],[7]

Pathological features of COVID-19 infection have been described recently to involve three stages: Stage one, is incubation wherein the patient is most often asymptomatic and during which time the systemic viral load may be low and thus may not be detectable; Stage two, during which the patient is symptomatic, but symptoms are not severe, although the systemic viral load has increased and the virus is detectable; and Stage three, in which symptoms become severe and the viral load is very high and detectable.[8] The immune response to COVID-19 infection can show one of two patterns. The first is a protective immune response that eliminates the virus and prevents progression to more severe stages of disease, and the second involves an impaired immune response upon entry of virus, thus leading to progressively more severe disease. This latter pattern displays extensive involvement of organs expressing the high concentration of angiotensin-converting enzyme 2, such as heart, kidneys, intestines, and lungs, with lung alveolar type II pneumocytes being the principal target site of COVID-19 virus. The damage to these tissues initiates the renin–angiotensin–aldosterone system cascade and induces pulmonary parenchymal inflammation via the activity of (pro-inflammatory) macrophages and granulocytes, which leads to ARDS.[9],[10],[11]

Comorbidities, such as diabetes, chronic renal disease, and/or chronic pulmonary disease predispose a greater risk of severe complications and mortality from respiratory viral infections such as COVID-19. The diabetic hyperglycemic environment hinders immune response, and chronic renal disease establishes a pro-inflammatory state that manifests functional defects in both innate and adaptive immunity. The lability of lung tissues in chronic pulmonary disease renders the pulmonary parenchyma precompromised and therefore at greater risk of ARDS. These comorbidities dispose patients to both increased severity of COVID-19-related multi-organ involvement and higher risk of mortality.[12],[13],[14] Given current scenario and inadequacies in treating this disease, utility and value of exploring and recognizing novel therapeutic modalities, such as low-dose radiotherapy (RT), may prove to be of benefit to critically ill patients.


  Evidence on Low-Dose Irradiation for Treatment of Pneumonia Top


Calabrese and Dhawan published in 2013 a report on “How radiotherapy was historically used to treat pneumonia: Could it be useful today?,” which may serve as a basis for current considerations.[15] This review on 15 reports covers 863 patients with severe pneumonia of different pathogeneses, including two studies of viral origin treated with low doses of kilovoltage X-rays. Good clinical responses, including a reduction of mortality, were reported, usually with a short clinical onset of 1–3 days after radiation. In addition, response rates were similar between bacterial and viral pneumonia. From a current point of view, however, these historical studies (ranging from 1905 to 1946) have to be treated with care. As compared to present standards, they are of low-level evidence, some cover low numbers of patients, and in many cases, appropriate control groups are lacking. In addition, for more than seven decades, not a single report has been published on low-dose RT for pneumonia, further hampering recommendations for decision-making based upon clinical and scientific knowledge. However, joint features of these investigations are that RT should be given early in the development of inflammation and that dose effectiveness does not vary much between 0.1 and 1 Gy. Similar protocols of radiation therapy are currently prescribed in Germany for benign painful chronic inflammatory degenerative disorders such as periarthritis of the shoulder.[16] In addition, low-dose RT has been reported to be effective in acute inflammation. In a cohort of 130 patients treated for postpartum mastitis with single doses of 0.2–0.5 Gy up to a total dose of 1–1.5 Gy, Herrmann reported on a cure rate of over 90% if given within the first 24 h of the first signs of inflammation but a decline to 50% if given at full-blown inflammation.[17]

Calabrese et al. published in 2019 that low-dose RT induces a highly integrated, complex, and systemic response that involves polarization of macrophages to an M-2 anti-inflammatory phenotype.[18] This anti-inflammatory phenotype mediates decreased adhesion of leukocytes and polymorphonuclear cells (PMNs) to endothelial cells, decrease in reactive oxygen species, reduction of nitric oxide (NO), decreased inducible nitric oxide synthetase (iNOS), decrease in TNF-a, and decreased tumor growth factor-alpha (TGFa). Further, and perhaps synergistically, the low-dose RT induction of the M2 phenotype invokes increased hemeoxygenase, increased anti-inflammatory cytokines – IL-10, increased tumor necrosis factor-beta (TNF-b), activation of several transcription factors, such as nuclear factor kappa beta and activating protein-1,[19],[20],[21] induction of apoptosis,[22],[23],[24],[25],[26],[27],[28] increased tumor growth factor-beta 1,[20],[21] and enhancement of T-regulatory cells.[21],[29],[30] Low-dose RT can induce the M2 anti-inflammatory macrophage phenotype irrespective of being administered to a localized inflamed area or to the whole body.[31],[32],[33]

Calabrese et al. 2019 have indicated that diseases with a significant inflammatory component demonstrate reduced pathognomic features following exposure to radiation doses <1.0 Gy (i.e., that induce an anti-inflammatory phenotype (M2 polarization)). However, diseases with an infectious component such as pneumonia, gas gangrene, and sinusitis respond to radiation doses more than 1.0 Gy (i.e., that induce a pro-inflammatory phenotype [M1 Polarization]). The authors further suggested that the existence of M1 and M2 phenotypes at both the single-cell and cell population levels is not absolute but rather represents a combinatory presentation of these phenotypes. This hypothesis assumes that both pro- and anti-inflammatory phenotypes are simultaneously induced, but the final phenotypic potential (i.e., which determines the relative constitution of pro-inflammatory or anti-inflammatory phenotype) depends on the radiation dose being greater or <1.0 Gy.[18] In addition, Klug et al. 2013 demonstrated that M1/M2 polarization via a low dose of RT also depends on the tissue microenvironment.[34]

Based on the historical use of radiation for treating various inflammatory and infectious diseases, Calabrese et al. 2019 proposed a dose range from 0.2 to 2.0 Gy for optimal human therapeutic effectiveness. The authors assert that this dose range has the potential to induce polarization of both M1 and M2 macrophage phenotypes.[18] Considering the available evidence and the proposed mechanism of action of low-dose RT, a single total dose of 0.3–0.5 Gy would be beneficial for COVID-19 patients that present with and have corroborative clinical findings of cytokine storm. This dose can be administered to the chest region using both anterior and posterior fields (50% of total dose administered in each field). This targeted low dose of RT appears to be of most benefit in the acute phase of illness when cytokines surge occurs and reduces the possibility of any immediate or long-term adverse effects considerably.[18]

Dose per fraction >200 cGy exerts pro inflammatory effects, triggering common toxicities observed in radiation therapy. However, more recent work shows low doses (<100 cGy) incites anti inflammatory properties such as decreasing levels of pro inflammatory cytokines like IL 1b, or inhibiting leukocyte recruitment.[32] Therefore, it stands to reason that a low-dose RT treatment of 30–100 cGy to the lungs of a patient with COVID-19 pneumonia could reduce the inflammation and relieve the life-threatening symptoms.

The only limitation to the use of low-dose RT as a potent, nontoxic, anti-inflammatory treatment is the fear for long-term radiation-induced diseases, especially cancer. However, many of the considered “standard treatments” (nonsteroidal anti-inflammatory drugs, COX-inhibitors, steroids, etc.) also have side effects that have to be weighed against the very small risk of radiation-induced cancer. Major evidence of radiation-induced cancer comes from accidental exposures to radiation of the general population. The linear nonthreshold model developed from such accidental exposures may overestimate the risks by one order of magnitude, therefore cannot be useful for estimating the risk of cancer by the use of low dose-RT for nonmalignant diseases. The cancer-induced risks due to the RT of benign diseases based on data from epidemiological studies showed no increased risk at low dose.[17] A very important issue concerning cancer-induced risk by radiation is age. In fact, due to the expected long latency of tumor development, the risk of inducing cancer would be even lower in patients over 40 years of age. Concerning the present situation either the real risk of dying from the COVID pneumonia or the advanced age of the patients at such risk would make irrelevant such concerns.

Unlike vaccines and pharmacological treatments that are dependent on stock production and distribution from manufacturers, X-ray devices are readily available in most of the clinical settings such as urgent care, outpatient, and hospital settings. Countries with poor socioeconomic demographic profile and lack of infrastructure to avail costly trial drugs and X-ray facilities are available to serve the purpose of using low-dose RT for treatment of COVID-19 patients with ARDS.

The portable X-ray machines in hospitals can be used to deliver low-dose RT in a most hassle-free manner, such as in an isolation room and/or intensive care unit (ICU) for patients on ventilators. However, the use of diagnostic X-ray machines or CT which typically deliver between 0.1 and 10 mGy for diagnostic scans and are not designed to deliver therapeutic doses may not be a practical option. Transporting the patient and treating them in a RT department is the best current option. The highly skilled staff and specialized equipment seem the safest approach. There could be a risk of infection to other immunocompromised cancer patients receiving RT. Due to the current COVID-19 pandemic, most RT departments have well-developed protocols for dealing with the treatment of COVID-19 patients by separation from other RT patients and infection control.


  Conclusion Top


Thus, low-dose RT can be considered for those patients who are most critical and for whom other treatments options are unsuccessful or unavailable. Low-dose RT to the whole lung should be explored under clinical trials to patients in early stages of the SARS-CoV-2 pneumonia. Low-dose RT is a cost-effective nontoxic treatment already available in most general hospitals, besides that would be used for the large number of patients that will suffer this disease and that would not receive specific anti-IL-6 treatments in ICUs in low- and middle-income countries.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Cascella M, Rajnik M, Cuomo A, Dulebohn SC, Di Napoli R. Features, Evaluation and Treatment Coronavirus (COVID-19). In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2020. Available from: https://www.ncbi.nlm.nih.gov/books/NBK554776/. [Last accessed on 2020 Mar 20].  Back to cited text no. 1
    
2.
Zhou L, Zhang M, Wang J, Gao J. SARS-Cov-2: Underestimated damage to the nervous system. Trop Med Infect Dis 2020;36:101642.  Back to cited text no. 2
    
3.
American Thoracic Society, Chapter 2 Acute Respiratory Distress Syndrome. Available from: https://www.thoracic. org/patients/patient resources/breathing in america/resource es/chapter 2 acute respiratory distress syndrome.pdf.Am J Respir Crit Care Med. 2017; 196:17-18. [Last. [Last accessed on 2020 April 20].  Back to cited text no. 3
    
4.
Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan China. Lancet 2020;395:497-506.  Back to cited text no. 4
    
5.
Yang P, Wang X. COVID-19: A new challenge for human beings. Cell Mol Immunol 2020;17:555-7.  Back to cited text no. 5
    
6.
Rothan HA, Byrareddy SN. The epidemiology and pathogenesis of coronavirus disease (COVID-19) outbreak. J Autoimmun 2020;109:102433.  Back to cited text no. 6
    
7.
Zhou Y, Fu B, Zheng X, Wang D, Zhao C, Qi Y, et al. Pathogenic T cells and inflammatory monocytes incite inflammatory storm in severe COVID 19 patients. Natl Sci Rev 2020 Mar 13:nwaa041. [doi: 10.1093/nsr/nwaa041].  Back to cited text no. 7
    
8.
Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA 2020;323:1061-9.  Back to cited text no. 8
    
9.
Shi Y, Wang Y, Shao C, Huang J, Gan J, Huang X, et al. COVID-19 infection: the perspectives on immune responses. Cell Death Differ 2020;27:1451-4.  Back to cited text no. 9
    
10.
Vaduganathan M, Vardeny O, Michel T, McMurray JJ, Pfeffer MA, Solomon SD. Renin – Angiotensin Aldosterone system inhibitors in patients with Covid-19. N Engl J Med 2020;382:1653-9.  Back to cited text no. 10
    
11.
Hamming I, Timens W, Bulthuis ML, Lely AT, Navis G, van Goor H. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol 2004;203:631-7.  Back to cited text no. 11
    
12.
Cheng Y, Luo R, Wang K, Zhang M, Wang Z, Dong L, et al. Kidney disease is associated with in-hospital death of patients with COVID-19. Kidney Int 2020;97:829-38.  Back to cited text no. 12
    
13.
Madsbad S. COVID-19 infection in people with diabetes. Touch Endocrinology. 2020. https://www. touchendocrinology.com/insight/covid-19-infectionin-people-with-diabetes/. [Last accessed on 10 Jun 2020].  Back to cited text no. 13
    
14.
Siddiqi HK, Mehra MR. COVID-19 illness in native and immunosuppressed states: A clinical Therapeutic staging proposal. J Heart Lung Transplant 2020;39:405-7.  Back to cited text no. 14
    
15.
Calabrese EJ, Dhawan G. How radiotherapy was historically used to treat pneumonia: Could it be useful today? Yale J Biol Med 2013;86:555-70.  Back to cited text no. 15
    
16.
Seegenschmiedt MH, Micke O, Muecke R, German Cooperative Group on Radiotherapy for Non-malignant Diseases (GCG-BD). Radiotherapy for non-malignant disorders: State of the art and update of the evidence-based practice guidelines. Br J Radiol 2015;88:20150080.  Back to cited text no. 16
    
17.
Trott KR. Therapeutic effects of low radiation doses. Strahlenther Onkol 1994;170:1-12.  Back to cited text no. 17
    
18.
Calabrese EJ, Dhawan G, Kapoor R, Kozumbo WJ. Radiotherapy treatment of human inflammatory diseases and conditions: Optimal dose. Hum Exp Toxicol 2019;38:888-98.  Back to cited text no. 18
    
19.
Hildebrandt G, Seed MP, Freemantle CN, Alam CA, Colville-Nash PR, Trott KR. Mechanisms of the anti-inflammatory activity of low-dose radiation therapy. Int J Radiat Biol 1998;74:367-78.  Back to cited text no. 19
    
20.
Schaue D, Jahns J, Hildebrandt G, Trott KR. Radiation treatment of acute inflammation in mice. Int J Radiat Biol 2005;81:657-67.  Back to cited text no. 20
    
21.
Nakatsukasa H, Tsukimoto M, Ohshima Y, Tago F, Masada A, Kojima S. Suppressing effect of low-dose gamma-ray irradiation on collagen-induced arthritis. J Radiat Res 2008;49:381-9.  Back to cited text no. 21
    
22.
Kern P, Keilholz L, Forster C, Seegenschmiedt MH, Sauer R, Herrmann M. In vitro apoptosis in peripheral blood mononuclear cells induced by low-dose radiotherapy displays a discontinuous dose-dependence. Int J Radiat Biol 1999;75:995-1003.  Back to cited text no. 22
    
23.
Huynh ML, Fadok VA, Henson PM. Phosphatidylserine-dependent ingestion of apoptotic cells promotes TGF-b1 secretion and the resolution of inflammation. J Clin Invest 2002;109:41-50.  Back to cited text no. 23
    
24.
Ren Y, Xie Y, Jiang G, Fan J, Yeung J, Li W, et al. Apoptotic cells protect mice against lipopolysaccharide-induced shock. J Immunol 2008;180:4978-85.  Back to cited text no. 24
    
25.
DosReis GA, Lopes MF. The importance of apoptosis for immune regulation in Chagas disease. Mem Inst Oswaldo Cruz 2009;104 Suppl 1:259-62.  Back to cited text no. 25
    
26.
Ferri LA, Maugeri N, Rovere-Querini P, Calabrese A, Ammirati E, Cianflone D, et al. Anti-inflammatory action of apoptotic cells in patients with acute coronary syndromes. Atherosclerosis 2009;205:391-5.  Back to cited text no. 26
    
27.
Perruche S, Saas P, Chen W. Apoptotic cellmediated suppression of streptococcal cell wall-induced arthritis is associated with alteration of macrophage function and local regulatory T-cell increase: A potential cellbased therapy? Arthritis Res Ther 2009;11:R104.  Back to cited text no. 27
    
28.
Esmann L, Idel C, Sarkar A, Hellberg L, Behnen M, Möller S, et al. Phagocytosis of apoptotic cells by neutrophil granulocytes: Diminished proinflammatory neutrophil functions in the presence of apoptotic cells. J Immunol 2010;184:391-400.  Back to cited text no. 28
    
29.
Nakatsukasa H, Tsukimoto M, Tokunaga A, Kojima S. Repeated gamma irradiation attenuates collagen-induced arthritis via up-regulation of regulatory T cells but not by damaging lymphocytes directly. Radiat Res 2010;174:313-24.  Back to cited text no. 29
    
30.
Weng L, Williams RO, Vieira PL, Screaton G, Feldmann M, Dazzi F. The therapeutic activity of low-dose irradiation on experimental arthritis depends on the induction of endogenous regulatory T cell activity. Ann Rheum Dis 2010;69:1519-26.  Back to cited text no. 30
    
31.
Arenas M, Gil F, Gironella M, Hernández V, Jorcano S, Biete A, et al. Anti-inflammatory effects of low-dose radiotherapy in an experimental model of systemic inflammation in mice. Int J Radiat Oncol Biol Phys 2006;66:560-7.  Back to cited text no. 31
    
32.
Arenas M, Gil F, Gironella M, Hernández V, Biete A, Piqué JM, et al. Time course of anti-inflammatory effect of low-dose radiotherapy: Correlation with TGF-beta(1)expression. Radiother Oncol 2008;86:399-406.  Back to cited text no. 32
    
33.
Frey B, Gaipl US, Sarter K, Zaiss MM, Stillkrieg W, Rödel F, et al. Whole body low dose irradiation improves the course of beginning polyarthritis in human TNF-transgenic mice. Autoimmunity 2009;42:346-8.  Back to cited text no. 33
    
34.
Klug F, Prakash H, Huber PE, Seibel T, Bender N, Halama N, et al. Low-dose irradiation programs macrophage differentiation to an iNOS-/M1 phenotype that orchestrates effective T cell immunotherapy. Cancer Cell 2013;24:589-602.  Back to cited text no. 34
    




 

Top
 
 
  Search
 
Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

 
  In this article
Abstract
Introduction
Pathogenesis of ...
Evidence on Low-...
Conclusion
References

 Article Access Statistics
    Viewed436    
    Printed8    
    Emailed0    
    PDF Downloaded0    
    Comments [Add]    

Recommend this journal