cells Review COVID-19: The Disease, the Immunological Challenges, the Treatment with Pharmaceuticals and Low-Dose Ionizing Radiation Jihang Yu 1 , Edouard I. Azzam 1, Ashok B. Jadhav 1 and Yi Wang 1,2,* 1 Radiobiology and Health, Isotopes, Radiobiology & Environment Directorate (IRED), Canadian Nuclear Laboratories (CNL), Chalk River, ON K0J 1J0, Canada; [email protected] (J.Y.); [email protected] (E.I.A.); [email protected] (A.B.J.) 2 Department of Biochemistry Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada * Correspondence: [email protected]; Tel.: +1-613-584-3311 (ext. 42653) Abstract: The year 2020 will be carved in the history books—with the proliferation of COVID-19 over the globe and with frontline health workers and basic scientists worldwide diligently fighting to alleviate life-threatening symptoms and curb the spread of the disease. Behind the shocking prevalence of death are countless families who lost loved ones. To these families and to humanity as a whole, the tallies are not irrelevant digits, but a motivation to develop effective strategies to save lives. However, at the onset of the pandemic, not many therapeutic choices were available besides supportive oxygen, anti-inflammatory dexamethasone, and antiviral remdesivir. Low-dose radiation (LDR), at a much lower dosage than applied in cancer treatment, re-emerged after a Citation: Yu, J.; Azzam, E.I.; Jadhav, 75-year silence in its use in unresolved pneumonia, as a scientific interest with surprising effects in A.B.; Wang, Y. COVID-19: The soothing the cytokine storm and other symptoms in severe COVID-19 patients. Here, we review Disease, the Immunological the epidemiology, symptoms, immunological alterations, mutations, pharmaceuticals, and vaccine Challenges, the Treatment with development of COVID-19, summarizing the history of X-ray irradiation in non-COVID diseases Pharmaceuticals and Low-Dose (especially pneumonia) and the currently registered clinical trials that apply LDR in treating COVID- Ionizing Radiation. Cells 2021, 10, 19 patients. We discuss concerns, advantages, and disadvantages of LDR treatment and potential 2212. https://doi.org/10.3390/ avenues that may provide empirical evidence supporting its potential use in defending against cells10092212 the pandemic. Academic Editors: Serge Candéias and Katalin Lumniczky Keywords: COVID-19; SARS-CoV-2; low-dose radiotherapy; X-ray Received: 27 July 2021 Accepted: 23 August 2021 Published: 27 August 2021 1. Introduction Humans have been living in a world affected by the novel coronavirus disease (COVID- Publisher’s Note: MDPI stays neutral 19) for more than a year. Starting from a small group of infections, the highly infectious with regard to jurisdictional claims in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral strain has caused over published maps and institutional affil- 213 million reported infections, leading to ~4.46 million deaths so far [1]. Among the closed iations. cases that had an outcome of either recovery and discharge or death, the case fatality rate is ~2% [1]. Although it has been argued that social measures have been largely ineffective [2], without the assistance of non-pharmaceutical interventions such as stay-at-home, use of sanitizers (hand washing), early case detection, and face masking, it is unlikely that the size Copyright: © 2021 by the authors. of the outbreak can be mitigated or reduced [3]. Whereas active cases temporally declined Licensee MDPI, Basel, Switzerland. in February and June 2021, they have rapidly risen again reaching an even higher record This article is an open access article set in late April, and reaching over 744,000 daily new cases as of 19 August 2021 (among distributed under the terms and infected patients, 0.6% being in serious conditions) [1]. conditions of the Creative Commons As an infectious disease, COVID-19 can be transmitted from human to human through Attribution (CC BY) license (https:// respiratory droplets and aerosols created within a short distance, as well as prolonged creativecommons.org/licenses/by/ interaction [4]. The World Health Organization (WHO) presented the “three Cs” as places 4.0/). Cells 2021, 10, 2212. https://doi.org/10.3390/cells10092212 https://www.mdpi.com/journal/cells Cells 2021, 10, x FOR PEER REVIEW 2 of 28 As an infectious disease, COVID-19 can be transmitted from human to human through respiratory droplets and aerosols created within a short distance, as well as pro- longed interaction [4]. The World Health Organization (WHO) presented the “three Cs” Cells 2021, 10, 2212 as places with higher COVID-19 spreading risk: Crowded places with many2 people of 28 nearby, close-contact settings, where close-range conversations take place, and con- fined/enclosed spaces with poor ventilation [5]. These places include restaurants, bars, fitnesswith higherfacilities, COVID-19 theaters, spreading and museums risk: Crowded where people places tend with to many be crowded people nearby, and less close- fresh aircontact is available settings,. Thus, where social close-range distancing conversations (at least take 2 m place, apart and and confined/enclosed less than 30-min spaces of close contact)with poor has ventilation been advocated [5]. These as a places measure include to reduce restaurants, cluster bars, transmission fitness facilities, [6]. theaters, andSimilar museums to wherethe seasonal people flu, tend COVID to be crowded-19 is a andviral, less respiratory fresh air is illness. available. Whereas Thus, social the flu resultsdistancing from (at an least influenza 2 m apart virus and infection less than, 30-minCOVID of-19 close is caused contact) by has a new been type advocated of corona- as virusa measure—SARS to-CoV reduce-2 [7,8] cluster. SARS transmission-CoV-2 is [ 6one]. of the seven pathogenic coronaviruses that cause Similarhuman toresp theiratory seasonal diseases, flu, COVID-19 which also is a viral,include respiratory SARS-CoV, illness. MERS Whereas-CoV the(Middle flu - Eastresults respiratory from an influenzasyndrome virus coronavirus infection,) COVID-19, HCoV-OC43 is caused (human by a coronavirus new type of coronavirus— OC43), HCoV- HKU1SARS-CoV-2 (human [ 7coronavirus,8]. SARS-CoV-2 HKU1) is one, HCoV of the-NL63 seven (human pathogenic coronavirus coronaviruses NL63) that, and cause HCoV- 229Ehuman (human respiratory coronavirus diseases, 229E) which [9]. also include SARS-CoV, MERS-CoV (Middle-East respiratory syndrome coronavirus), HCoV-OC43 (human coronavirus OC43), HCoV-HKU1 2.(human Epidemiology coronavirus of COVID HKU1),-19 HCoV-NL63 (human coronavirus NL63), and HCoV-229E (human coronavirus 229E) [9]. Although the mortality data of COVID-19 are always compared with those of the flu as2. both Epidemiology induce severe of COVID-19 respiratory symptoms that can lead to death, caution must be exer- cised whenAlthough interpreting the mortality incidence data of. The COVID-19 Center for are Disease always comparedControl (CDC) withthose in the of United the Statesflu as of both America induce (USA) severe estimates respiratory the symptomsseasonal influenza that can leadmortality to death, to be caution at ~0.1% must over be the pastexercised years when[10]. In interpreting contrast to incidence. indirect Thecounting Center as for in Disease the case Control of the (CDC) flu, the in CDC the United collects eachStates COVID of America-19-related (USA) death estimates report the directly. seasonal Hence, influenza researchers mortality suggested to be at ~0.1% that overa com- parisonthe past between years [10 the]. Inweekly contrast deaths to indirect due to countingCOVID-19 as inor thethe caseflu could of the be flu, a themore CDC valid methodcollects [11] each. For COVID-19-related example, in the death USA report, the directly.weekly Hence,flu deaths researchers were around suggested 500 thatin early a 2020comparison and decrease betweend at the a weeklylater time deaths in duethe toyear COVID-19, whereas or the the fluweekly could COVID be a more-19 valid deaths soaredmethod to [over11]. For 16,000 example, and fluctuated in the USA, with the weeklytime (Figure flu deaths 1) [12] were. This around fluctuation 500 in early may 2020 result fromand a decreased shortageat of a ventilators later time in and the limit year,ations whereas associated the weekly with COVID-19 the work deaths of health soared provid- to over 16,000 and fluctuated with time (Figure1)[ 12]. This fluctuation may result from a ers. shortage of ventilators and limitations associated with the work of health providers. Figure 1. Weekly death analysis of COVID-19 and influenza in the USA. Data may lag by an Figure 1. Weekly death analysis of COVID-19 and influenza in the USA. Data may lag by an aver- average of 1–2 weeks, so the trend of decline in recent weeks may not accurately reflect the current age of 1–2 weeks, so the trend of decline in recent weeks may not accurately reflect the current situation. Available online: https://data.cdc.gov/NCHS/Provisional-COVID-19-Death-Counts-by- situation. Available online: https://data.cdc.gov/NCHS/Provisional-COVID-19-Death-Counts-by- Week-Ending-D/r8kw-7aab (accessed on 24 August 2021). Week-Ending-D/r8kw-7aab (accessed on 24 August 2021). Several situations complicate the statistics and treatment of COVID-19, including co-infectionSeveral situations with SARS-CoV-2 complicate and the commonstatistics fluand virus treatment simultaneously, of COVID or-19 infection, including with co- infectionSARS-CoV-2 with itself SARS rendering-CoV-2 and existing the diseasescommon to flu deteriorate virus simultaneously, further and causing or infection death [13 with]. Although asthma was associated with severe diseases during past influenza epidemics, and respiratory viruses were recognized as cause of acute exacerbations of asthma, sci- entific analyses did not correlate asthma with a higher severity or mortality in cases of Cells 2021, 10, 2212 3 of 28 COVID-19 [14]. As of early 2021, scientists still could not draw definitive conclusions on the correlation between asthma and COVID-19 outcomes due to various potential bias factors [15,16].