Could Pulmonary Inflammation of COVID-19 ARDS Patients Worsen Due to an Excessive Repetition of Follow up Radiological Studies?

1. Introduction

Healthy population on Earth locations with larger natural radioactivity levels show increased amounts of autoimmune biomarkers. China, Iran, Brazil, and India are between the countries with higher natural background radioactivity [4]. It was remarkable, during the hardest part of the COVID-19 pandemic, in 2020 Figure 1, that those locations experienced an excess of mortality rates after inflammatory issues related to acute respiratory distress syndrome (ARDS) linked to SARS-CoV-2 [5]. Radiation driven biomarkers were common to those shown by ARDS, and, therefore, a summative effect could be assumed.

2. Ionizing radiation dose response models

Radiation effects on living matter have a variety of consequences on human immunity [6,7]. Diverse self defence paths are found along the whole dose range, from very low to high absorbed radiation levels [8]. According to that publication, dose intervals can be described in four steps: very low dose radiation, ≤ 10 mSv, as the dose to an individual from multiple conventional radiology imaging, not considering either computed tomography or fluoroscopy; low dose radiation dose (LDR), in the closed interval [10, 100] mSv, is to be the dose to an individual from multiple whole-body CT scans; moderate dose radiation, in the closed interval [100, 1000] mSv, is to be the dose to about 100,000 of the recovery operation workers after Chernobyl accident; and high dose radiation (HDR), > 1000 mSv, is to be the dose to individuals after severe radiation accidents or from radiotherapy treatments.

Although Japanese Hiroshima-Nagasaki mathematical radiation effects model for survivors had never fit well enough with the classical Linear Non-Threshold (LNT) hypothesis, where dose response supposed radiation risks as linear to damage (straight line in Figure 2), as it was accepted by the scientific community since 1958 [9]. This attitude was unethically advocated both, by key scientists within radiation genetics, and by editorial practices in four important papers in Science journal, already a well-known and leading international scientific publication at the time. Editorial decisions to circumvent peer review of this work occurred, at least in two cases. One of them, on which a senior editor of the journal was co-author, was alleged to have intentionally falsified the research record [10]. Hence, prominent US scientists suppressed evidence to promote adoption of LNT behaviour, as it was consistently verified an adaptive innate protection promoted by the immune system, where body learned to self-protect when irradiated again after a first low dose exposure [11]. This is call hormesis and it is present with greater evidence in the interval between 10 and 100 mSv in most of the mammals [12]. Delayed temporary adaptive protection involves ROS induced detoxification, deoxyribonucleic acid (DNA) repair enhanced rate, damaged cells removal due to apoptosis followed by normal cell replacement and by cell differentiation and stimulated immune response [13]. Natural shields are developed with a delay of hours and may last for days to months. Hormesis is a biphasic dose response that is generated by almost all biological systems as a result of their interactions with various physical or chemical stimuli. A dose-response relationship is biphasic when low doses are stimulatory and high doses are inhibitory. The low-dose stimulatory response is the Hormetic phase that is often, but not always, associated with beneficial biological effects [14].

Protective gap decreases steadily around 100 to 200 mSv with the presence of M1 type macrophages, and it is not observed anymore above 500 mSv [13]. The activation of the so-called nuclear factor erythroid 2-related transcription factor (Nrf2) is achieved between 500 and 1000 mSv, where anti-inflammatory behaviour is replaced through forcing polarisation shifts from pro-inflammatory macrophage M1 into anti-inflammatory M2 phenotype, rebalancing the immunological redox status [15,16,17]. Nrf2 restores cellular redox, ending ROS proliferation and promoting inflammation resolution. M2 phagocytic capacity is reduced as dose grows towards 1000 mSv, shifting back to M1 and contributing to the increase of apoptotic cells [7].

Therefore, a kind of initial low dose rounded function, up to approximately 100 mSv (see Figure 2) invalidates the LNT linear straight growing line. Hormesis stimulate body defences against LDR danger developing inter-cellular tools to better recover from subsequent X-ray photon hitting and aborting the outdated concept of a linear risk response without protection thresholds. If dose continue to raise before linear behaviour reappears, the number of death cells in the neighbourhood, but outside the radiation field, is increased by the Bystander effects (BE). Bystander dose response function is defined by the linear positive slope rapidly growing up as danger become more important with doses located after the hormesis band, which is closer to the LNT classical model. Because reliable epidemiologic data at low doses are not available, a series of in vitro and in vivo investigations have put into question the validity of the LNT model based on the observations of BE and adaptive response. The BE counts the induction of damage in the cells located in the vicinity of irradiated cells but have not been directly hit themselves. A possible adaptive protection against DNA damage is considered AR or hormesis [18].

A J-shaped dose-response model explains more pronounced non-linearity radiation risks between low and moderate levels [19]. It is preferred to talk about a Hormesis Linear Non-Threshold (H-LNT) behaviour instead of the Linear Non-Threshold scheme (LNT). The LNT is based on the concept that damage to genetic material from ionizing radiation increases in direct proportion to the absorbed dose and that this DNA damage results in causing cancer in proportion to dose. The LNT hypothesis does not consider the complex nonlinear interactions before cancer formation is expressed. The dose-response relationship cannot be based on a simple mathematical equation of the first order, thus, the model should be rejected [18]. Feinendegen suggested, in his dual effect of low-dose ionizing radiation model, that the LNT model appears invalid and should be replaced by a function that includes both linear and nonlinear terms [12]. He summarised the basic assumptions of his model:

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DNA damage in mammalian cells is proportional to the dose with additional possible Bystander effects.

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DNA damage comes overwhelmingly from non-radiation sources at background radiation exposure levels.

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The probability of radiation induced adaptive protection measurably outweighs that of damage from doses well below 200 mSv low-LET (linear energy transfer) radiation.

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The delayed and temporarily adaptive protection at low doses involves damage prevention, damage repair and immune response.

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Cell and DNA damage appear increasingly to overrule, negate, or annihilate the more subtle signalling effects seen after low doses, at higher doses in tissue.

3. Inflammation biomarkers due to abnormal levels of radiation

Humans are exposed to small doses of ionizing radiation from natural sources all the time, in particular, cosmic radiation, mainly from the sun, and radon, a radioactive gas that comes from the natural breakdown of uranium in soil, rock, water, and building materials. How much of this background radiation you are exposed to depends on many factors, including altitude and home ventilation. It is estimated a normal average is 3 milliSieverts (mSv) per year but this number may vary upon geographical coordinates.

Cytokines are the most important mediators by which cells of the immune system are increased or decreased due to low dose radiation interaction [20]. IR induces ROS by triggering NLRP3 inflammasome that might change the function and number of immune system cells increasing levels of lymphocytes T and macrophages, given rise to the secretion of several inflammatory intermediators: NF-$\kappa$B (Nuclear Factor-Kappa B), IL-1 (Interleukin-1), IL-2 (Interleukin-2), IL-6 (Interleukin-6), IL-8 (Interleukin-8), IL-33 (Interleukin-33), TNF-$\alpha$ (tumor necrosis factor-$\alpha$), TGF-$\beta$ (Tumor Growth Factor-$\beta$), and IFN-$\gamma$ (Interferon-$\gamma$) [21,22].

Primary radioactive elements causing natural ionizing radiation exposure to humans are potassium (K), uranium (U), thorium ($Th$), and their radioactive decay products, like radium ($Ra$) and radon ($Rn$). Been deposited in the lungs, ${}^{222}Rn$, a radioactive noble gaseous element part of the ${}^{238}U$ disintegration chain [23], release $\alpha$ radiation after inhalation and is associated with biomarkers of inflammation and endothelial dysfunction [24]. Radon gas tends to accumulate indoors especially in areas with highly permeable soils with a high ${}^{226}Ra$ content, resulting in high levels of concentration. Chinese workers exposed to natural background radiation from uranium mines, with high concentrations of indoor ${}^{222}Rn$, showed evident inflammation issues [20]. Two different categories were studied, a control group, underground for < 5 years (cumulative dose < 20 mSv, based on 4mSv per year) and an experimental group, underground for ≥ 5 years (≥ 20mSv). Long-term exposed subjects presented up-regulation of pro-inflammatory cytokines, such as IFN-$\gamma$, IL-10, IL-6, and TNF$-\alpha$ [20].

Lead (Pb) abundance and toxicity makes it the second most dangerous environmental poison according to the Agency for Toxic Substances and Disease Registry’s Priority Substance List. Although leaded petrol has been removed away from use in many countries, $Pb$ compounds are yet being used in aviation fuel [25]. Besides the well-known poisoning by its stable nuclei, there are also unstable radioactive forms suspended in air, like Lead-214 (${}^{214}Pb$) which is a radioactive $\beta$ emitter. It promotes inflammatory responses producing IL-2, IL-4, IL-8, IL-1$\beta$, IL-6, TNF-$\alpha$) IFN-$\gamma$, and influencing the immune system cells (T and B lymphocytes, Langerhans cells, macrophages) and the secretion of immunoglobulin A, Immunoglobulin E, Immunoglobulin G, endothelin, and histamine [26,27].

Since the 1960’s tobacco manufacturers have been aware of the $\alpha$-radioactivity contained in cigarette smoke [28] as several studies links plant fertilisers as the principal source, rich in polyphosphates containing ${}^{226}Ra$, as well as its decay products (${}^{210}Pb$ and ${}^{210}Po$). Polonium-210 (${}^{210}Po$) may also be generated along the ${}^{238}U$ and ${}^{226}Ra$ disintegration chains. Radioactivity in tobacco leaves collected from fifteen different regions in Greece, before the cigarette production, was studied looking for any association between crop root uptake of radionuclides from soil and the effective dose induced to smokers from cigarette tobacco due to the naturally occurring primordial radionuclides (${}^{226}Ra$ and ${}^{210}Pb$ in the uranium series, ${}^{228}Ra$ in the thorium series and/or man-made radionuclides, such as ${}^{137}Cs$ of Chernobyl origin) [29]. Radiation doses to lung bronchial epithelium from ${}^{210}Po$ inhaled from two packs of cigarettes a day individual smoking is at least seven times that from background sources [30]. Ref. [31] reported that one and a half packs of cigarettes a day deliver 80 mSv per year in areas of bronchial epithelium bifurcation, which is equivalent to the skin dose from 300 chest X-ray plane images per year.

It is well accepted an upper limit of 20 mSv/year as a normal low level exposure to IR in a normal background. However, this threshold is not the same everywhere, depending on the ground composition. There are regions where this background radiation is 10 to 15 times higher than that considered normal. Taleshmahaleh and Chaparsar, two villages in the northern Iran present a higher value, around 260 mSv per year [32]. Some results on blood tests on normal population showed that the total serum antioxidant level in the exposed people was significantly lower than the individuals not exposed to high dose natural IR. These subjects also had higher lymphocyte-induced IL-4 and IL-10 production, and lower IL-2 and IFN-$\gamma$ production [33].

4. Inflammation biomarkers on COVID-19 cases

SARS-CoV-2 affected patients exhibits a spread spectrum of clinical conditions, ranging from asymptomatic cases to severe pneumonia or even death. Increased levels of proinflammatory cytokines has been observed in the bloodstreamIn of severe COVID-19 cases. NLRP3 inflammasome activation intensely induces cytokine production as an inflammatory response to viral infection, causing what has become known as a cytokine storm [34]. Most infected individuals present with mild flu-like symptoms, while between 5 and 10% are severe cases suffering from a compromised respiratory system and life-threatening pneumonia [35]. In general, severe cases result in acute respiratory distress syndrome (ARDS) and acute lung injury (ALI), which are known to be induced by a storm of inflammatory cytokines, especially IL-1$\beta$, IL-6, and TNF-$\alpha$ [36].

COVID-19 may induce severe lung inflammation leading to acute respiratory distress syndrome (ARDS), respiratory failure, and death despite artificial ventilation. There is an intense inflammatory reaction characterised by mononuclear cells infiltration, fibrin exudates, multinucleated giant cells, and thickened alveoli secondary to proliferating interstitial fibroblasts and type II pneumocyte hyperplasia [37]. Lung hyper-inflammation observed in SARS-CoV-2 patients was also observed in previous pandemics such as SARS-CoV and MERS-CoV [38]. The so-called Macrophage Activation Syndrome (MAS) is the origin of the cytokine storm characterized by elevation of IL-1, TNF-$\alpha$ and IL-6 produced by inflammatory macrophage M1 [39]. When our immune system faces a foreign antigen, i.e. SARS-CoV2, peripheral blood monocytes are recruited into the alveoli where they differentiate into M1 macrophage which produce inflammatory cytokines such as IL-1, IL-6, and IL-18 which in turn attract neutrophils cells into the alveoli to fight the infection, leading to infection clearance through reactive oxygen species (ROS) and phagocytosis [40]. The normal response to an eliminated infection is the reversal polarization to M2 anti inflammation macrophages [41], but in ARDS and some other autoimmune disorders the hyper inflammatory state continues leading not only to lung damage but to multiple normal organs destructions such as kidney failure, cardiac damage and ultimately death. Persistence of inflammatory neutrophils in the alveoli along with increased concentration of ROS and TNF are thought to contribute to lung injury [42].

5. Discussion

Proponents of radiation hormesis typically claim that radio-protective responses in cells and the immune system not only counter the harmful effects of radiation but additionally act to inhibit spontaneous cancer not related to radiation exposure. Radiation hormesis is a dose-response phenomenon and it is one of alternative hypothesis, that low doses of ionizing radiation induces beneficial health effects. According to radiation hormesis, low doses of low LET radiation can stimulate the activation of repair mechanisms, that protect against disease, that are not activated in absence of IR.

Exposure from background sources has not changed since about 1980, but Americans’ total per capita radiation exposure has nearly doubled, and experts believe the main reason is increased use of medical imaging. The proportion of total radiation exposure that comes from medical sources has grown from 15% in the early 1980s to 50% today. CT alone accounts for 24% of all radiation exposure in the United States, according to a report issued in March 2009 by the US National Council on Radiation Protection and Measurements (https://ncrponline.org). In the case of chest CT, the average dose is between the range 4 and 18 mSv, although the actual radiation exposure depends on many things, including the device itself, the duration of the scan, patient size, and the sensitivity of the tissue being targeted [43]. There is direct evidence from epidemiologic studies that the organ doses corresponding to a common CT study (two or three scans, resulting in a dose in the range of 30 to 90 mSv) result in an increased risk of cancer. The evidence is reasonably convincing for adults and very convincing for children [3].

Numbers place X-ray CT monitoring in the dose band ≥ 10 mSv and ≤ 200 mSv, that initiates hard-to-assess inflammatory processes because they are made to old patients with incredibly significant previous inflammation. A retrospective study performed at Tongji Hospital, the largest health center for the treatment of SARS-CoV-2 infected patients in Wuhan, China, showed up that chest CT was used to a wide extent in the follow-up of ordinary COVID-19 cases [44]. Including paediatric cases, 394 patients underwent a total of 1493 exams with a mean time interval between illness onset and discharge of 31.68 ± 8.71 days and a median admitted time of 19 days [44]. The total number of valid CTs and non-value added CTs per patient were related to a high degree to the disease duration [44]. Homayounieh et al. survey [45] remarks that about 30% of the patients (n=225) underwent 2 to 8 chest CT examinations in less than a month [45]. Although it is estimated that no tissue expresses clinically relevant functional deterioration, it has been found that IR produces pro-inflammatory effects even when reduced radiation dose scanning protocols are used [46,47,48].

Low exposures are controversial. It is accepted 100 mSv as a threshold where excess of cancer issues could be potentially observed over the long term [49]. Although pulmonary X-ray CT is a well established technique for diagnosing and managing lung ARDS complications, too much patients were receiving IR doses in the interval between 10 mSv and 200 mSv due to recurrent X-ray exams [50]. There are details not completely understood yet about the effects of ionizing radiation on macrophages [51]. While low doses attenuate inflammation throughout the Abscopal effect, higher levels, like the applied in tumor therapy, increase systemic anti-tumor immune reactions [52]. The Abscopal effect is a phenomenon where the response to radiation is seen in an organ distant to the irradiated area, that is, the responding cells are not juxtaposed with the irradiated cells, like un the Bystander effect.

Despite LDR have been largely related with cancer issues based on the studies over the Japanese survivals affected by the atomic bombs [53], dose response effects are also linked to other secondary effects as inflammation and should be taken in consideration in the LDR Hormetic zone. As the lower dose interval represents a much more relevant exposure scenario for the general population, as it may have broader public health consequences because of the common and frequent indication of X-ray images in general diagnosis [2], this potential danger should limit drastically the number of those type of IR exams if not antioxidant supplements are prescribed along the process [54].

6. Conclusions

Controversy on health effects of IR in the low-range as it has benefits and not risks is served but, currently, there is not valid data supporting the use of LNT in the low-dose range, so dose as a surrogate for risk in X-ray imaging is not appropriate, and therefore, the use of the classical ALARA (As Low As Reasonably Achievable) concept might be considered as obsolete [55]. Concerns have been raised over alleged overuse of CT scanning and inappropriate selection of protocol exams. Although computed tomography is crucial in the follow up of ARDS disease, it cannot be forgotten that it is needed an estimation of the equivalent doses in the organs at risk as it is stated, for instance, in the European Union by the Council Directive 2013/59/Euratom, laying down basic safety standards for protection against the dangers arising from exposure to IR [56].

Extra and additional inflammation throughout X-ray imaging follow-up over elderly population include an excess of lung ionizing radiation shots in a brief time interval of weeks, inappropriate from the radiation protection scope. Obsessive screening will ad up ROS presence to their established inflammatory status while redox products after IR subatomic interactions on tissues will increase free radical basal levels. The interrelationship between the immune system and IR is complex, multi factorial, and dependent on radiation dose and immune cell type. Higher dose radiation levels usually results in immune suppression, while low values modulates a variety of immune responses that have exhibited the properties of immune hormesis [6]. Inflammatory early effects are difficult to isolate and study independently as they are much more subtle and not so obvious functional alterations, and can be easily confused or be hidden by other comorbidities [2].

We hypothesize that the adaptive response given by hormesis due to an excessive number of CT scans in ICU-admitted patients suffering from COVID-19 dramatically adds to the large viral inflammation caused by SARS-CoV-2. It is this enormous lung inflammation that leads to fatal outcomes in ARDS cases. Hormesis protects against cancer but should also be important in autoinflammatory processes. In the absence of data related to LDR and inflammation, we have resorted to the effects that produce the same dose levels but from natural sources to establish analogies between the effects produced but it will required further investigation.