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Year : 2021  |  Volume : 17  |  Issue : 6  |  Page : 1294-1296

Can low-dose radiation therapy reduce the risk of mucormycosis in COVID-19 patients?

1 Department of Radiation Oncology, All India Institute of Medical Sciences, New Delhi, India
2 Department of Radiation Oncology, Stritch School of Medicine, Loyola University, Chicago; Department of Radiation Oncology, Edward Hines Jr VA Hospital, Hines, Illinois, USA

Date of Submission07-Nov-2021
Date of Acceptance09-Nov-2021
Date of Web Publication14-Dec-2021

Correspondence Address:
Daya Nand Sharma
Department of Radiation Oncology, All India Institute of Medical Sciences, New Delhi - 110 029
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.JCRT_2011_21

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How to cite this article:
Sharma DN, Welsh J, Kumar R. Can low-dose radiation therapy reduce the risk of mucormycosis in COVID-19 patients?. J Can Res Ther 2021;17:1294-6

How to cite this URL:
Sharma DN, Welsh J, Kumar R. Can low-dose radiation therapy reduce the risk of mucormycosis in COVID-19 patients?. J Can Res Ther [serial online] 2021 [cited 2022 Jan 20];17:1294-6. Available from: https://www.cancerjournal.net/text.asp?2021/17/6/1294/332373

Worldwide, several cases of mucormycosis have been reported recently in patients with COVID-19, an entity being termed as COVID-19-associated mucormycosis (CAM). The disease has been declared notifiable in India due to the unprecedented rise in the number of CAM patients. More than 40,845 cases have already been reported till June 28, 2021.[1] Due to the high mortality associated with CAM, there is a panic in the public and the health caregivers. Since low-dose radiation therapy (LDRT) has been used in COVID-19 patients and certain trials[2],[3],[4],[5] have reported successful results to some extent, there is some inquisitiveness about the possible role of LDRT in CAM. One of the authors of this editorial, who conducted a study[5] in India on LDRT in COVID-19, has been receiving queries about whether LDRT can be a remedy for CAM. This led us to write this editorial to appraise the radiation oncology community about CAM and if radiation therapy (RT) can treat or prevent or mitigate it.

Mucormycosis is a rare but deadly fungal infection caused mainly by the Rhizopus oryzae. It generally affects patients with altered immunity. It can involve the nose, sinuses, orbit, brain, gastrointestinal tract, lung, skin, jawbones, heart, kidney, and joints, but rhino-orbital-cerebral mucormycosis is the most common variety encountered in clinical practice. The treatment consists of an antifungal agent such as amphotericin B and surgical debridement. The overall case fatality rate is approximately 50%.[6] Although a causal association between COVID-19 and mucormycosis is yet to be divulged, several factors have been implicated. Uncontrolled diabetes mellitus (DM) and the use of steroids are the two main etiological factors for CAM.[7] It also raises the question of whether COVID-19 itself might predispose patients to unusual opportunistic infections due to immune dysfunction. While chronic use of steroids has been related to several opportunistic fungal infections, even a shorter course has been linked with mucormycosis, especially in patients with DM. According to a recent report,[8] CAM was predominantly seen in males (79%), who were either active (59%) or recovered (41%) from COVID-19. Preexisting DM and concomitant diabetic ketoacidosis were present in 80% and 15% of the cases, respectively. Corticosteroid use for the treatment of COVID-19 was observed in 76.3% of the cases. Mucormycosis involved nose and sinuses in 89% of the cases, followed by rhino-orbital in 57% of the cases. Mortality was recorded in 31% of the cases. The authors alerted the medical community of an “unholy trinity” of COVID-19, DM, and corticosteroid intake as a new potential cause of mucormycosis. They cautioned that corticosteroids should be used judiciously in patients with COVID-19.

When the diabetic population is combined with COVID-19, which affects the immunity not only by reducing T lymphocytes, CD4+, and CD8+ cells but also indirectly through its treatment course, involving corticosteroids and other immunosuppressive drugs such as remdesivir, it provides perfect conditions for mucormycosis to break out in epidemic numbers.[9] Although uncontrolled diabetes, inadvertent use of corticosteroids, and high fungal load in the environment elucidate the surge to a certain extent, several other factors may be responsible and need to be further studied: (a) Does COVID-19-induced immune dysregulation cause any mucor-specific immunity disturbance? (b) Do the new variants such as alpha and delta disturb mucor-specific immunity? (c) Does the Indian population have any genetic susceptibility for mucormycosis? (d) If the presently rampant Rhizopus arrhizus strains are more virulent than earlier strains? and (e) Is there some existing environmental factor responsible?

Although treatment does exist for fungal infections, it is associated with high morbidity and mortality. In low-income countries, the health-care system is already burdened with COVID-19; infections such as mucormycosis can further cripple the health-care facilities. In addition, the emergence of multiple viral mutants compromises the efficacy of vaccinations; novel treatment modalities that prevent complications such as cytokine storm and acute respiratory distress syndrome (ARDS) are the need of the hour. LDRT provides one such hope.

In the preantibiotic era, LDRT has been tried for almost all kinds of infections.[10] Although no specific studies are available in the literature, there are some anecdotal reports about the use of RT for fungal infections. Ringworm (tinea capitis) was endemic toward the end of the 19th century in several European countries and the USA.[11] It was considered a major health and economic hazard. RT was the mainstay of treatment for tinea capitis till 1959 when griseofulvin was introduced. During the second world war, nonhealing wounds contaminated with fungal infections were treated with LDRT.[12] Although the exact mechanism of action is unclear in these reports, apparently epilation caused by RT was the main rationale used for tinea capitis.

There are some recent in vivo and in vitro studies[13],[14],[15] regarding the positive inhibitory effect of RT on the fungal infection. In a study by Ben-Yosef et al.,[13] the growth of Candida albicans (measured by the colony diameter) was astonishingly low in the 5 Gy irradiated samples as compared to the nonirradiated samples. In the same study, the authors reported that 20 patients with established fungal infection in either the paranasal sinuses or lungs were referred for stem cell transplant for underlying leukemia/lymphoma between 1992 and 1998. Thirteen patients received total body irradiation (TBI) as a part of the induction regimen before stem cell transplant. Nine out of 13 patients treated with TBI did not develop fungal infection, whereas two out of seven patients without TBI were free of fungal infection (P = 00.8). The authors concluded that RT has an inhibitory effect on the growth of C. albicans without any excessive adverse effects, and it may play a role in the treatment of fungal infections although they did not explain the exact mechanism of this inhibitory effect. Based on the historical evidence and the recent anecdotal reports, the role of RT, as of now, cannot be justified for the treatment of fungal infections including CAM. However, LDRT has the potential of preventing or reducing the risk and severity of CAM if it is used in the treatment of COVID-19.

LDRT has shown encouraging results in moderate-to-severe COVID-19 illness in several clinical trials.[2],[3],[4],[5] The immunomodulatory nature of LDRT causes anti-inflammation by reducing IL-6, inducible nitric oxide synthase, ROS, IL-4, tumor necrosis factor alpha, IL-1 beta, IL-10, increasing NF-KB, transforming growth factor beta, AP-1, and polarization into M2 macrophages. LDRT can also increase CD3, CD4, and CD8 cells depending on the microenvironment and enhance the transformation to CD8 T-cells that destroy severe acute respiratory syndrome-infected cells.[16],[17] Recently, Nrf2 activation has been shown to mediate the benefits of LDRT in COVID-associated ARDS.[18] This immunomodulatory nature of LDRT in COVID-19 appears beneficial compared to steroids that result in pan immunosuppression. However, optimal lifesaving potential occurs when LDRT is given to the patients before the stage of cytokine storm, as proven in a recent randomized control trial.[19] Thus, LDRT can mitigate or prevent a severe cytokine storm and drastically reduce oxygen and steroid dependence. Due to these potential benefits, it is hypothetically possible that the severe diabetogenic state can be prevented, thereby preventing or reducing the risk of CAM. It is noteworthy that none of the patients treated with LDRT in various trials[2],[3],[4],[5],[19] have developed mucormycosis. It will be unethical not to investigate the immunomodulatory nature of LDRT in preventing severe COVID-19 pneumonia, ARDS, and CAM.[20]

 > References Top

Sharma NC. India Reports 40,854 Cases of Black Fungus so Far. Available from: https://www.livemint.com/news/india-records-over-40k-cases-of-mucormycosis-11624875874985.html. [Last accessed on 2021 Jul 12].  Back to cited text no. 1
Hess CB, Nasti TH, Dhere VR, Kleber TJ, Switchenko JM, Buchwald ZS, et al. Immunomodulatory low-dose whole-lung radiation for patients with coronavirus disease 2019-related pneumonia. Int J Radiat Oncol Biol Phys 2021;109:867-79.  Back to cited text no. 2
Ameri A, Ameri P, Rahnama N, Mokhtari M, Sedaghat M, Hadavand F, et al. Low-dose whole-lung irradiation for COVID-19 pneumonia: Final results of a pilot study. Int J Radiat Oncol Biol Phys 2021;109:859-66.  Back to cited text no. 3
Sanmamed N, Alcantara P, Cerezo E, Gaztañaga M, Cabello N, Gómez S, et al. Low-dose radiation therapy in the management of coronavirus disease 2019 (COVID-19) pneumonia (LOWRAD-Cov19): Preliminary report. Int J Radiat Oncol Biol Phys 2021;109:880-5.  Back to cited text no. 4
Sharma DN, Guleria R, Wig N, Mohan A, Rath G, Subramani V, et al. Low-dose radiation therapy for COVID-19 pneumonia: A pilot study. Br J Radiol 2021;94:20210187.  Back to cited text no. 5
Available from: https://www.who.int/india/emergencies/coronavirus-disease-(covid-19)/mucormycosis. [Last accessed on 2021 Jul 12].  Back to cited text no. 6
John TM, Jacob CN, Kontoyiannis DP. When uncontrolled diabetes mellitus and severe COVID-19 converge: The perfect storm for mucormycosis. J Fungi (Basel) 2021;7:298.  Back to cited text no. 7
Singh AK, Singh R, Joshi SR, Misra A. Mucormycosis in COVID-19: A systematic review of cases reported worldwide and in India. Diabetes Metab Syndr 2021;15:102146.  Back to cited text no. 8
Suvvari TK, Arigapudi N, Kandi VR, Kutikuppala LS. Mucormycosis: A killer in the shadow of COVID-19. J Mycol Med 2021;31:101161.  Back to cited text no. 9
van Dijk B, Lemans JV, Hoogendoorn RM, Dadachova E, de Klerk JM, Vogely HC, et al. Treating infections with ionizing radiation: A historical perspective and emerging techniques. Antimicrob Resist Infect Control 2020;9:121.  Back to cited text no. 10
Mottram ME, Hill HA. Radiation therapy of ringworm of the scalp. Calif Med 1949;70:189-93.  Back to cited text no. 11
Friedman M. Radiation therapy. In: Ahnfeldt AL, editor. Radiology in World War II. Washington, DC: Department of the Army; 1966. p. 207.  Back to cited text no. 12
Ben-Yosef R, Zeira M, Polacheck I. The effect of radiation therapy on fungal growth: results of in vitro and in vivo studies. J Infect 2005; 50:450-2.  Back to cited text no. 13
Dadachova E, Nakouzi A, Bryan RA, Casadevall A. Ionizing radiation delivered by specific antibody is therapeutic against a fungal infection. Proc Natl Acad Sci U S A 2003;100:10942-7.  Back to cited text no. 14
Bryan RA, Jiang Z, Howell RC, Morgenstern A, Bruchertseifer F, Casadevall A, et al. Radioimmunotherapy is more effective than antifungal treatment in experimental cryptococcal infection. J Infect Dis 2010;202:633-7.  Back to cited text no. 15
Dhawan G, Kapoor R, Dhawan R, Singh R, Monga B, Giordano J, et al. Low dose radiation therapy as a potential life saving treatment for COVID-19-induced acute respiratory distress syndrome (ARDS). Radiother Oncol 2020;147:212-6.  Back to cited text no. 16
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. 17
Calabrese EJ, Kozumbo WJ, Kapoor R, Dhawan G, Lara PC, Giordano J. Nrf2 activation putatively mediates clinical benefits of low-dose radiotherapy in COVID-19 pneumonia and acute respiratory distress syndrome (ARDS): Novel mechanistic considerations. Radiother Oncol 2021;160:125-31.  Back to cited text no. 18
Papachristofilou A, Finazzi T, Blum A, Zehnder T, Zellweger N, Lustenberger J, et al. Low-dose radiation therapy for severe COVID-19 pneumonia: A randomized double-blind study. Int J Radiat Oncol Biol Phys 2021;110:1274-82.  Back to cited text no. 19
Cuttler JM, Bevelacqua JJ, Mortazavi SMJ. Unethical not to Investigate Radiotherapy for COVID-19. Dose Response. 2020; 18; 18(3): 1559325820950104. doi: 10.1177/1559325820950104.  Back to cited text no. 20


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