A Bioelectromagnetic Proposal Approaching the Complex Challenges of COVID-19

DOI: 10.4236/ojbiphy.2021.111001   PDF   HTML   XML   36 Downloads   192 Views  

Abstract

The COVID-19 pandemic has experienced unprecedented limitations and extraordinary scientific efforts to address this exceptional situation. Despite blanket closures that have resulted in significant financial constraints and losses around the world, research has an “unlimited” budget, with an exceptional concentration of medical and scientific care on a single topic: understanding the mechanisms for overcoming the disease. A large number of clinical trials have been launched with different drugs that have been behind different concepts and solutions. I would like to focus on the complexity aspect of COVID-19. Living systems are organized in a complex way, which implies dynamic stochastic phenomena, and deterministic reductionism can mislead research. When research focuses on individual molecules or pathways as products, it is distracted from the processes in which these products operate, thus neglecting the complex interactions between regulations and feedback controls. Common problems in product-oriented research are articulated as “double-edged swords”, “Janus behavior”, “two-sided action”, with a simple question: “friend or foe?” I focus on the missing complexity. I propose a bioelectromagnetic process that can maintain a complex approach, affecting processes rather than products. This hypothetical proposal is not a comprehensive solution. Complexity itself limits the overall effects of causing “miracles”. Well-designed electromagnetic effects can support current efforts and, in combination with intensively developed pharmaceuticals, bring us closer to a pharmaceutical solution against COVID-19.

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Szasz, A. (2021) A Bioelectromagnetic Proposal Approaching the Complex Challenges of COVID-19. Open Journal of Biophysics, 11, 1-67. doi: 10.4236/ojbiphy.2021.111001.

Graphical Abstract: Targeting the well-known and measured hallmarks of the infection does not deliver a cure. The process which produces “hallmarks” has to be considered in its dynamism. Instead of “products”, we have to concentrate on the “processes”.

1. Introduction

Human coronavirus-induced severe acute respiratory syndrome (SARS-CoV) first appeared in March 2003 [1] [2]. The current global pandemic is a disease called COVID-19. It is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It is the third known coronavirus disease, probably zoonotic, after SARS-CoV-1 and the Middle East respiratory syndrome (MERS). The new coronavirus strain was recognized for the first time in Wuhan, China [3]. It is classified as SARS-CoV-2, and the COVID-19 pandemic was declared on March 11 by the WHO [4]. The number of people affected by COVID-19 is exceptional. The epidemiological investigation shows the validity of the networking complexity (long-tail distribution). SARS-CoV-2 follows approximately the 80/20 law [5], which means that 80% of transmissions occur by 20% of infected individuals, “super-spreaders” contagious” [6]. The analyses of the network show how “super-spreader” individuals spread the disease, locating “super-susceptible sites” [7]. Viruses appear active for quite some time on various surfaces [8], promoting the potency of pandemic danger [9]. The SARS-CoV-2 has much in common with previous coronaviruses, but their essential characteristics clearly differ [10]. The similarities allow us to use some experiences from previous viruses, such as slowing down the host’s inflammatory response or using some antibodies or compounds that neutralize cytokines, but the essential challenge of complete therapy remains unresolved today.

The tipping point of the COVID-19 pandemic was seriously underestimated at the onset of the disease [11]. The SARS-CoV-V2 coronavirus behind the pandemic is a “great imitator” [12] showing symptoms of other simple diseases. You may be asymptomatic, or you may have simple symptoms like a runny nose. However, it differs completely from an upper respiratory tract infection (URI). Later, when the disease develops, you may have more severe symptoms such as loss of smell, fatigue, vomiting, diarrhea, abdominal pain, muscle aches, and even whole-body symptoms such as rashes or redness. Severe organic damage (heart failure, kidney damage, liver damage, etc.) is also possible, which usually occurs as a complication after the period of curative treatment. The long incubation period and mild symptoms of URI do not alert the patient, and many times when the disease worsens, it is too late to avoid harm. It should be noted that the relative “weakness” of SARS-Cov-2 compared to other viral infections that manifest its possible asymptomatic or misdiagnosed cold symptoms is also the strength of this virus. Asymptomatic and unrecognized presymptomatic individuals promote viral shedding by improving community transmission. URIs’ symptoms do not alert the patient, and, many times, when the disease becomes severe, it is too late to prevent transmission. Since the long, possibly asymptomatic incubation period allows the virus to multiply in large numbers in the subject, the virus will inadvertently spread to other people and accelerate the pandemic.

Massive research has begun with the advent of the COVID-19 disease to understand the causal effects of SARS-CoV-2 and other related viruses [13]. The goal of elucidating its infection mechanism is vivid, and, unfortunately, the solution is still waiting. 8764 publications (Aug. 10, 2020) had been published on the subject [14], including the record start of several clinical trials [15], and 68 ongoing clinical trials (Sep. 27, 2020) are also attempting to develop appropriate prevention and treatment [16]. Our knowledge is expanding day by day, and probably when this article appears, we will have more vital information on the subject than we have now. This is why I focus more on the general challenges, mainly on the on-demand hypothesis of the paradigm shift of SARS research.

The central request for successful clinical therapy is an accurate understanding of the infection mechanism, given its complexity, which is determined by the interrelated physiological feedback mechanisms of human homeostatic regulation. The human body has developed defense mechanisms to prevent the growth and multiplication of invading pathogens. One of the oldest immune response types is the termination of cells infected with bacterial pathogens by apoptosis [17]. In plants, pathogens elicit a hypersensitivity response (HR), which induces systemic acquired resistance (SAR) [18] as a form of apoptosis. In animals and humans, dynamic homeostatic processes regulate the activation of apoptosis in a highly controlled manner. In both animals and plants, apoptosis is promoted by the production of anti-inflammatory molecules that are associated with tissue development and homeostasis [19]. Despite the differences, both types of apoptosis are associated with the induction of similar morphological characteristics, including membrane blowing, cytosolic fragmentation, nuclear condensation, and fragmentation, as well as biochemical events such as degradation of genomic DNA, proteolysis, and lipid redistribution of membrane [20] [21]. These changes are mainly due to the activation of a family of cysteine proteases, caspases [22] [23]. Furthermore, infected host cells produce defensins, innate immune host protection peptides [24], and induce anti-inflammatory cytokines that play an important role in eliminating the invading pathogen.

Proper vaccination could be decisive in preventing infection and stopping the pandemic, but it could also be an effective curative therapy tool for patients at different stages of the disease. So far, many solutions have been proposed to overcome the pandemic [25]. Many drugs are proposed for therapies [26], but none have currently been shown to be successful. The use of various virus-specific antibodies for active treatment is currently being tested more intensively [27]. Many companies compete in the race to develop antiviral drugs and vaccines to defeat the pandemic [28]. Research on basic vaccines, such as nucleic acid-based vaccines (RNA or DNA vaccine), recombinant protein vaccines, and viral vector-based vaccines, has not produced the results expected so far [14].

Inhibition of coronavirus cell penetration (e.g., Hydroxycoquine [29], Umifenovir (arbidol) [30], etc.), inhibition of virus replication (e.g., Remdesivir [31] [32], Ritonavir [33], Ribavirin [34], Oseltamivir (Tamiflu) [35], Favipiravir [30], etc.), the synthesis of bacterial proteins, the use of antiparasitic agents (Ivermectin), the rethinking of other drugs previously used against the virus (Lopinavir [36], Ritonavir [37] ), or plasma extracts from people who have recovered (immunoglobulins [38] ), or monoclonal antibodies that enhance general immunity (interferon) (for example, tocilizumab [39] ), have achieved clinical phase. However, many of them fail to the point of expectations [14]. The method that had superheated hopes, convalescent plasma from patients, who developed effective antibodies and transferred it as passive antibody treatment to patients in the intensive care unit (ICU), has not yet been tested [40], and the decision on the validity of the “hopes” could not be made [41]. The drug hydroxycoquine, despite enormous political and financial support, was unable to produce satisfactory efficacy as the Cochrane meta-analysis had shown [42]. A new trend to develop vaccines is related to interferons [43] [44]. The intranasal application of recombinant interferon (rINF-α-2b) effectively shortened the duration and reduced the severity of coronavirus cold symptoms. A comprehensive summary of the activities in vaccine development reviews the actualities [45].

Numerous drugs were tested in preclinical experiments with additional expectations, but most did not pass safety tests. One of the recent is that the University of Pittsburgh has published some fascinating information about its success with one component (Ab8) of the antibody. It had been successfully tested in animal experiments as a possible viral vaccine [46]. However, it has yet to reach any human research, so in our opinion, the “news flash” is too early. Vector-based heterologous prime-boost immunization (Gam-COVID-Vac, [Sputnik-V]) is presently the first approved drug in the world [47]. The international professional community has serious doubts about this approval for security reasons [48]. Experts explain the irresponsible side of the decision to certify this treatment [49]. Currently, we do not have enough knowledge about its effects, but doubts are increasing. A promising drug (AZD1222) and its clinical trial developed in collaboration with Astra-Zeneca and the University of Oxford [50]. However, the studies were stopped due to serious side effects [51] and then partially reauthorized, but doubts remain [52].

The meta-analysis of the clinical trials of new, hopeful medications (Remdesivir, Hydroxychloroquine, Lopinavir, and Interferon) had little or no effect on hospitalized patients with COVID-19 [53]. The evaluation was based on overall mortality, initiation of ventilation, and duration of hospital stay. No drug reduced the mortality (in unventilated patients or any other subgroup of entry characteristics), initiation of ventilation, or hospitalization duration. 405 hospitals in 30 countries 11.266 adults were randomized, with 2750 allocated Remdesivir, 954 Hydroxychloroquine, 1411 Lopinavir, 651 Interferon plus Lopinavir, 1412 only Interferon, and 4088 no study drugs were involved in the analysis. Presently (middle of October 2020) two extensive clinical studies are on halt because of safety concerns [54] [55].

The currently known curative support (not vaccination) proven in clinical trials are glucocorticosteroids and corticosteroids [28]. Dexamethasone (a corticosteroid) with respiratory support is the first drug that has been shown to improve survival in COVID-19 disease [56]. These steroids are anti-inflammatory immunosuppressants. Immunosuppression is required to suppress overstimulated immune responses. This is very helpful against a cytokine storm that occurs late in the disease. Despite the apparent contradiction to steroids’ success, immune system support provides the best means when we consider the complex integration of immune effects into the body’s regulatory system. The immune effects could cause prevention to escalate the disease while blocking autoimmune reactions with steroids is needed in the severe stages when cytokine storm appears to be the most challenging danger.

The task is to regulate the complex processes rather than control individual molecular products. The disease’s complexity can only be managed through the therapy’s appropriate complexity. With a unique molecular healing effect, a “miracle drug”, we can expect total success, that hope is unrealistic. The possibility of a paradigm shift lies in the tracking of physiological complexity, which essentially seeks to restore control at the system level rather than control individual threads. For this, the use of the immune system is more pronounced, which can best be achieved by a combination of chemical and physical methods.

2. Challenges of the Complexity

Medical history strikes a balance between two comprehensive but competing sets of methodologies: the inductive and deductive approaches. The inductive studies the details of the system, like the organs, tissues, cells, organelles, etc. and builds the whole body based on data from the parts and their function. The deductive view focuses on the whole body as a unit, taking it into its environmental interactions and deduces from them the to the parts, to organs and their functions. The two approaches build the diagnosis oppositely. The inductive is up from parts to the whole, while the deductive is down, from whole to details. The inductive system builds the complete system as workers do; the walls are built with bricks, while the engineer makes a general plan and breaks down deductively in detail how to connect the bricks to a functional structure. Both processes require professionals, and only together can they get the job done correctly. In medicine, a very similar situation occurs when an organ specialist studies the organ to determine a patient’s health. We are well aware that having perfect organs does not mean that the system is organized healthily. Conversely, as the deductive practitioner claims, having a perfectly organized system does not mean that all the system’s organs are functioning properly. Both approaches and their cross-talks and regulations are necessary to ensure healthy functioning, Figure 1.

Unfortunately, the current clinical paradigm is very unbalanced in terms of inductive/deductive attitudes. Well-developed and educated medical knowledge characterizes the organ and its functions in the description of professionally well-trained organ specialists; but the whole system, the patient, does not receive as much attention. The same can be observed in the field of therapies: the focus is on the actual local disease drugs, paying less attention to the patient as a whole.

Biological complexity is a well-proven fact based on physical and physiological principles [57]. The stochastic approach is fundamental in biological dynamism, including RNA polymerization and the most basic gene exchanges [58]. Darwin developed the uncertain (non-deterministic) idea through the theory of evolution that introduces probability in biological species development. This idea drives biological development everywhere. Contrary to the complexity of human organisms, the paradigm of modern medical research loses it. The concept of homeostasis is ignored, and reductionist attempts to become the central dogma. This approach reduces the focus of medical actions to a set of the whole in almost isolated parts, components smaller and simpler than network interconnections, and hoping that the sum of these parts can explain the complete

Figure 1. The complex thinking is the key to solve the problem of the present COVID-19 viral infection.

system. This reductionism contradicts the concept of physiology and also science in general.

The reductionist management and control of the disease are based on influencing, inhibiting, or assisting molecular interactions, mainly leading to adequate medication through the creation of the effects of known drugs or through physical intervention (such as ionizing radiation) to modify the chosen molecular task. The forcing influence of certain molecules and signaling pathways strongly determines the research’s objective; complex interactive network processes are out of the majority of studies. However, living matter has a dynamic equilibrium (homeostasis) that implies a balance of sensitively adjusted feedback controls, showing the complexity of this highly organized material [59]. Complexity does not mean complication, but the intertwining of processes, which at each step seeks to have a dynamic and interconnected balance of suppressor-promoter pairs of the regulatory process [60]. Predominantly negative feedback characterizes these mechanisms. Homeostasis is often ignored and used as a static framework for effects [61]. The challenge is the complexity of living organs, the highly interconnected interactions between the parts. The demand to understand and use dynamic equilibrium develops a new paradigm for investigating the living matter, which requires a stochastic approach (probability of events dependent on time) instead of conventional thinking that requires deterministic changes [62]. The dynamic homeostatic equilibrium keeps the system in a stable but constantly changing state. The first efforts to show this complexity were made at the beginning of the last century by von Bertalanffy with general systems theory [63] emphasizing the openness of the living organisms, the deep embedment in the environmental interactions, Figure 2 . All living organisms

Figure 2. The viral infection is embedded in a complex network of interactions and species.

are open systems, taking energy from the environment, and emitting waste there. A living subject’s environment is a network of the non-living and living objects that relate to the subject and connected with each other. The lives modify the environment, and vice versa. The environment modifies the lives. The infections are excellent examples of this complex interconnection. The infected cells are deeply embedded in the complex interactions, so the attempt to stop the infection with a simple one-to-one deterministic approach is a mistake.

The research objective of drug development’s actions is to modify the imbalanced inhibitor-promoter system with agonist-antagonist molecules [64]. Turing’s pioneering work on complexity established the first exact discipline of the life sciences, “decoded of the life, the mathematical biology [65]. The formulation of morphogenesis was the first complex description, which could explain the chemical basis of dynamical interactions, and successfully predicted the oscillating chemical reactions. Most of the pharma products miss Turing’s dynamism, ignoring the fundamental complexity. Agonist ligands bind to a receptor, while antagonist ligands prevent an agonist from binding to a receptor, trying to balance a dynamic equilibrium. Most of the researches miss the dynamical feedback mechanisms which make the agonis/antagonist relations complex. One part of the complex network appears in the adverse effects of the difference in agonist-antagonist pair drugs.

In most cases, the enzyme inhibition could occur due to the modification of homeostatic regulation [66]. The important principle is the feedback mechanism, which controls the balance within a predetermined range around the reference value. It is usually well modeled with fuzzy logic, an approach to counting “degrees of truth” rather than the usual “true or false” decisions [67]. This logic governs homeostatic equilibria in all ranges of space and time in living systems. This uncertain value is undoubtedly in a controlled reference interval, where strongly interconnected negative feedback loops regulate the balance in the micro and macro ranges, forming the system’s dynamic stability. Due to this dynamism, the proposed paradigm shift towards the living system’s complexity is not an easy turn.

The disease damages the network’s complexity in the human body, forming local or systemic sub-units, which declines from the equilibrium of the entire body. The homeostatic dynamic equilibrium is at least partially out of control. Restoring healthy complex mechanisms requires a careful balance of actions. The chosen treatment has to fit the complex challenges of the patient’s individual conditions, the environmental loads, and the physiologic (homeostatic) control Figure 3 . It is easy to make an agonist or antagonist change the faulty mechanisms, but it is not easy to keep the system’s balance. The unstable spatio-temporal regulation and the variation of doses of infection destroy the homeostatic balance of the healthy dynamics of the infected region. In this way, the repairing process in a focused part of the system can induce adverse effects in whole, challenging safety. Many experiments went through rigorous testing in the preclinical phase, and some drugs made it possible for clinical trials. These

Figure 3. The complex control of the living state has to be counted at the chosen treatment.

trials require long periods of time because safety and side effects need to be monitored in a large patient cohort population and over a long follow-up period. Furthermore, the dosing and practice protocol takes time to fix, considering that “there is only one difference between the drug and the poison: the dose”.

Serious side effects can occur when drug rebalancing does not pay enough attention to the relationships built into the balances, which are often dose-related. The often serious side effects of chemotherapies depend in part on the imbalance situation, and the risk/benefit ratio decides their applicability [68]. Pharmacodynamics offers a mixed-effect agonist/antagonist (selective receptor modulation) approach, acting as an agonist for some types of receptors or some tissues and an antagonist for others. Correcting one side of the scale by a drastic regulation, side effects appear as a whole because the unbalance appears in the unfocused subsystem [69]. The need to move the paradigm towards the pharmaceutical industry has also been explicitly articulated in Science Magazine [70].

A fundamental reason is why the transfer of research results cannot find a faster path from laboratory to clinical applications. The problem is that the present investigation paradigm is losing complexity due to our reductionism, leading the investigation in the wrong direction. The question is addressed: “where did the medicine go wrong” and in the response of B. West, the chief scientist of the United States Army laboratory, formulates the necessary task: “rediscover the path to complexity” [71].

Our task is to assist the patient’s natural dynamic homeostasis, which again underscores the importance of patient-oriented therapies. Patient orientation involves using the patient’s homeostatic capacity, regulating the patient to drive processes and establish general control. For this, it is not enough to administer an agonist or antagonist; regulation of the processes is needed that balances the dynamic agonist-antagonist balance in healthy control. The promoter-suppressor circles characterize all the dynamical changes in the organism from the molecular to the systemic level. These controlling circles are deeply interconnected, and a modification in one could affect multiple, directly not connected, but networked regulations (Figure 4 ).

When the research identifies a defect of one of the particular regulating circles, a severe challenge occurs. Various solutions could be applied to correct the damaged regulation in an isolated circle (Figure 5 ). Albeit the study and modification of one regulating ring in isolated conditions offer a relatively easy solution, the consequences in the complex network are unconditionally out of control. The lack of complexity in the research concepts in practice regularly shows its negative side: it is easy to develop a drug that eradicates the virus. Unfortunately, it is also often harmful to human lives. The reason is simple: when the

Figure 4. The regulation circle of promoter-suppressor balance guides all the processes in the body. These are interconnected in a large complex network, and any individual change could cause an unexpected and unpredictable “avalanche” of the changes.

Figure 5. The balancing corrections of one certain promoter/suppressor pair. (a) A healthy balance of a certain process (a part of normal homeostasis); (b) A pair of promoter/suppressor is out-balanced; (c) Rebalancing of a certain process, but the extra “weight” unbalances other regulatory pairs, where the promoters are also involved; (d) Resetting the reference value for rebalancing, but it disturbs all the regulatory links, connected to both, promoter and suppressor; (e) Rebalancing by catching the complex process in a network, where the certain pair is involved.

drug produces an imbalance in complex dynamic regulation, it could help in the desired part (killing the viral infection), but the preference suppresses other processes, and the system goes haywire.

Our research task starts being complex, and new ideas are necessary for going over the obstacles. The focus changes. Re-establishing the regulation does not work correctly when we make rebalancing by the kind of extra promoter (like in Figure 5(c)), or by shifting the reference value of regulation (like in Figure 5(d)), due to the complex network reacts making the complete homeostatic control effective. The physiological changes can cause unexpected consequences and appear new symptoms, called adverse effects. The task is to correct the regulation by taking care of the complexity and re-establishing the regulation circle smoothly with the natural homeostatic mechanisms (like in Figure 5(e)). Note our aggressive actions based on the high scientific ego leads us to a dead-end. We have to recognize the natural complexity and help these natural interconnections to correct the regulatory fault. Ignoring this humble serving of natural process forces the complex control to fight against the actual fault to repair and against our aggressive “invasion”-like action.

We rarely recognize that the current dominant medical paradigm often ignores patient homeostasis [61], even though it is the central theory of physiology that unifies knowledge about the system’s self-regulatory processes. Hierarchical process control enables a wide range of dynamic adaptation to changing internal and external conditions. The center of the new paradigm is the homeostasis of the organism. It is bad news that life’s dynamic processes are probabilistic, but good news that this “chaos” is by no means the category that has no order [72]. The well-organized harmonic hierarchy of dynamic complexity manifests itself well in the entire organism’s interconnectedness and follows a bioscaling [73], which is universal for life [74].

The dominant universality shows multiple-scale behavior at all levels, from the molecular to the organism [75], emphasizing the importance of interconnected and interacting networks. The spatio-temporal self-similarity [76] creates a self-organized network [77]. Learning this, a new science is emerging: the “fractal physiology” [78] [79]. The fractal-based biological scale could serve as a model of developmental dynamism by describing the main characteristics of the clinical stages of viral disease [80]. Fractal analysis gives a structural idea of viral rearrangement in infected tissue [81]. In a matter of time, dynamic interactions have a long-range correlation time lag, composing harmony in the system [82]. External stimuli must conform to homeostatic harmony [83].

Instead of deterministic expectations of each molecular change, complex considerations must focus on the dynamic process and not on the resulting or artificially introduced substances. Understanding the living dynamism of deeply interconnected events implies a necessary paradigm shift in modern medicine, moving from conventional deterministic methodology to complex approaches, considering stochastic processes [84].

The missing homeostatic harmony disrupts the healthy state and leads to disease. The homeostatic balance of promotion and inhibition is activated in parallel “like twins” [85]. Deterministic “one-sided” actions alter homeostasis’s balance and reduce the chances of success by causing adverse reactions. Effective therapy attempts to restore the lost dynamic balance in harmony with and without imposing restrictions against natural personal abilities. This approach allows individualized therapy, taking into account the specific characteristics of the patient [85]. Proper diagnosis finds interrupted control of regulatory mechanisms and points to the damage of self-organizing mechanisms [62]. The therapeutic intention launches modifications that help the natural repair mechanisms find the self-controlled and self-organized homeostatic state.

The medical task must be focused on controllable regulations, so thinking on one side of the action could have serious consequences. Curing the patient as a complete organism has to be in the center of medical efforts, and the local infection is only a part of it. The focus on the patient’s defective part should be shifted to a patient-oriented approach (Figure 6 ). The patient is a complex system, so medical therapy must concentrate on this dynamic equilibrium.

The missing complexity is well illustrated by the fluctuating evaluation of AZD1222, [50] [51] [52]. We have to evaluate all sides of complex phenomena before medical actions [86]. Similar challenges have appeared in other large, well

Figure 6. The main clinical focus has to be on the entire patient with their actual personal conditions. The viral-oriented clinical approach must be shifted to the patient oriented one, concentration of the developing processes more than on the developed products of these.

supported clinical trials [54] [55], too. The strictly deterministic clinical decisions must be differentiated. Even though the symptoms are similar, the complete unification of patients’ collected cohort does not result in success. The individual homeostatic regulation affects the actual principal treatment protocol, and it could develop complications.

Here is a key issue. How can we ensure homeostatic equilibrium if we artificially interfere with a complex stochastic system’s functioning? How can we direct natural processes towards the solution? The solution is probably to support the existing complexity of the living matter, removing the complex balance disorder as harmoniously as possible. The treatment strategy has to be formed as the army leads a war: Attacking the enemy’s weakest points and avoiding being embroiled in a conflict with their most potent forces. In this medical “war”, we could follow the winning strategy. The most powerful forces of the virus are in its process of replication. Of course, it could be the goal of stopping replication initiated within cells, as many of the drug developments (e.g. Lopinavir, GRL0617, Ribavirin, Remdesivir, Favipiravir, Alisporivir, etc.). Thus drive the blocking of various signal pathways intracellularly [87]; however, it is arduous work, and we must expect many adverse effects due to unwanted changes in general cellular mechanisms. We have to focus on processes rather than products [70]. It nicely shows the problem of complexity when the successful use of immunosuppressive steroids has caused some surprises when the mainstream of viral research favors immune enhancement.

The expansion of COVID-19 clearly divides clinical actions into three interconnected parts. The first period of clinical care begins when the first symptoms appear. In the first period of the infection the focus has to block the further aggravation of the disease. The innate immune actions are in the front of the fight against the virus. Intent to stabilize the patient’s condition was unsuccessful, and the patient experiences a more severe illness, the task changes. The patient needs medical help in severe symptoms like shortness of breath, fatigue, and other quality of life suppressants. In the third period, when the previous two could not block development, emergency medicine, mostly in the intensive care unit (ICU) continues the treatment to prevent death. All three periods have some specialties, which we will discuss below in this article.

2.1. Challenges of the Physiologic Regulation and Control

The first coronavirus pandemic (SARS-CoV-1) had shown a fundamental role of the angiotensin-converting enzyme-2 (ACE2) in the cellular invasion of the virus [88]. The same had also been observed in the SARS-CoV-2 virus [89] [90]. The enzyme ACE2 converts angiotensin I to angiotensin 1-9, just as ACE converts angiotensin I to angiotensin II, which again ACE2 converts to angiotensin 1-7. ACE inhibitors generally block the conversion of angiotensin I to II, while angiotensin receptor blockers (ARBs) block the angiotensin II receptor.

The invasion process towards internalization in cells fundamentally depends on the peak glycoprotein (S) (fundamentally on the S1 subunit) of the SARS-CoV-2 virus [91]. The cellular entry of SARS-CoV-2 is promoted by type II transmembrane serine proteases (TTSP) [92]. The participation of TTSPs is confirmed in the viral entry of SARS-CoV-2 into cells. The participating TTSPs are the transmembrane serine protease isoform 2 (TMPRSS2) [93], the lysosomal endopeptidase cathepsin-L (CTSL) [94], the proprotein peptidase furin [95]. The heparan sulfate proteoglycans [96] [97], which are potentially membrane-bound in the glycocalyx layer of epithelial cells [98] could be involved as well, as it was proposed earlier, before COVID-19 [99] [100]. Heparan sulfate could block SARS-CoV-2 infection [101], and, consequently, the multiple clinical application of heparin was proposed [102] [103] [104].

TTSPs, firstly TMPRSS2 [94], facilitate binding to ACE2. The virus mainly uses the ACE2 receptor to enter the host cell, with the help of TMPRSS2. When the receptor binds to the SARS spike protein (S), the process is preactivated by furin, cleaving the spike to prepare it for membrane fusion with the host cell. Furin’s assistance in binding is a special feature of SARS-CoV-2, which helps the virus to penetrate the cell. These types of shared structures also appeared in highly pathogenic viruses, such as avian influenza. The frequent mutation capability is another risk of SARS-CoV-2 infection, which is usual in cases of RNA-based viruses.

Even though both SARS-CoV-1 and SARS-CoV-2 share the characteristic that the main receptor for viral entry is ACE2, there are essential differences in intensity. The binding affinity of human ACE2 to the receptor-binding domain (RBD, which selectively recognizes ACE2) is significantly higher in CoV-2 than in CoV-1 [105]. Interestingly, RBD’s position also differs in the two viruses. The active state (standing) is more frequent in CoV-1 than in CoV-2, which apparently could mean a lower virus binding efficiency in COVID19. Unfortunately, higher binding compensates for hidden RBD, and more importantly, hidden RBD allows immune evasion, greatly improving its binding efficiency [102]. A significant part of the high SARS-CoV-2 infectivity connected with the new mutations in the RBD and the acquisition of a TTSP cleavage site in the S-spike protein. There are some formal, deterministic approaches to stop the viral replication by blocking the entry to the cells (Figure 7 ). These, however, could drastically modify some key steps of the replication mechanisms by homeostatic regulation. These all have attempted to develop drugs without concerns about its complex feedback effects. The feedbacks are considered as side effects only, and so their applications are rather limited. The symptoms of infection or the side effects of drugs correlate with the dysfunction of the complex homeostasis.

The ACE2 receptor has a central role in developing the disease, being the door to the virus’s cellular invasion. What would be the medical intervention? The first logical deterministic answer is relatively straightforward: block the most probable “gate” of the ACE2 receiver [106]. Consequently, the application of the anti-ACE2 antagonist seems an optimal medication. In fact, viral infection in the cell could be drastically suppressed by blocking “entry.” However, we learned

Figure 7. The basic steps to inhibit: neutralize the spike-protein of the virus, block the cellular entry of the virus, block the intracellular moving, bonding, block the RNA replication or block the egress of the newly produced virus from the cell.

that additional ACE2 inhibition could increase the imbalance, leading to the patient becoming critically ill. In many cases, it requires ICU care, and some of these became fatal. Not only is ACE2 a helper for virus invasion, but its double-edged actions address the question “Is it friend or foe?” [107]. The apparent contradiction illustrates the limits of the reductive deterministic thinking when the fundamental physiological knowledge of homeostatic regulation is not involved in the concepts and consequent clinical actions [70].

The series of built-in negative feedback mechanisms ensure the complete equilibrium of all participating molecules. ACE2 viral involvement dysfunction induces an imbalance in the RAS and, through this, involves the immune system (Figure 8 ). The immune connection was recognized at the beginning of the pandemic in China [108]. The massive interconnection of regulatory networks also points to the complexity of COVID and its interaction of the homeostatic system unbalanced by a viral infection. The unbalanced participation of ACE2 in SARS-CoV-2 explains why multiple symptoms can appear during infection, involving different organs that express a considerable amount of ACE and processes regulated by this enzyme.

As usual, in complex systems, ACE2 also has “two faces” [109], which are, in fact, multiple functions, deeply connected to the homeostatic complexity, which must be considered. The complex thinking takes attention to the participation of ACE2 in a wide range of physiological processes [110]. The actions of ACE2 include protecting against inflammation [111], compromising immunity [112], and protecting the active organ against hypertension, diabetes, and cardiovascular disease, as well as protecting against some types of acute lung injury [113].

Figure 8. The complex RAS circle shows the interconnections and feedback of the various involved products during the regulation process. The most frequent attack of SARS-CoV is shown in influencing the ACE2 processes.

ACE2 plays an essential role in immune reactions that affect the innate and adaptive immune systems through the action of macrophages and neutrophils [114]. Inhibiting ACE2 could increase dangerous inflammation, grow reactive oxygen species (ROS), create vasoconstriction, and lead to thrombosis. The weakening of immune control could increase the risk of developing a critical condition and need ICU.

The challenge of inhibitors of the ACE enzyme (ACEIs) or angiotensin receptor blockers (ARBs) is reducing the severity of the consequences of virus invasion, reducing their mortality rate [115] [116] or out of balance causing other severe consequences (Figure 9 ). When the ACEI is administered in the wrong time or wrong dose, the regulatory function of ACE2 decreases and the disease may worsen. The patient could develop a severe or critical condition. However, the angiotensin-converting-enzyme gene has polymorphisms [117] capable of forming more than 160 versions [118]. This could cause inequalities in humans in the level of ACE expression [119], requesting more detailed information and consideration of the patient’s personal status. On the other hand, a large study showed that ACEIs and ARBs were not associated with the infectivity of SARS-CoV-2. When the dosing of these administered according to the standard protocol for the patients suffering hypertension as comorbidity and had taken the medication regularly as they did before, the viral infection does not exacerbate [120]. These findings support the continuation of ACEI or ARB II among

Figure 9. Typical balancing is shown in the most frequently studied ACE2 receptors. Their imbalance drives the RAS processes, which activate the connected KKS and CS circles too.

patients with coexisting hypertension, cardiovascular disease, and COVID-19 [121]. The ACE2 activation has a protective effect on lung injury, including acute respiratory distress syndrome (ARDS), so it could be a potential curative action in COVID-19 [122].

Current statistics show a correlation of COVID-19 with gender [123] [124], and age [125] of infected patients. Comorbidities, such as hypertension [126], diabetes [127], cardiovascular disease [128], asthma, chronic obstructive pulmonary disease (COPD) [129] can lead to serious difficulties. Triggering of comorbidities was also detected in SARS-CoV-1 infection in patients who did not have such damage before [130]. The virus can activate comorbidities like diabetes [131] [132], kidney disease [133] or induce cardiovascular damage [134]. Furthermore, the risk of multi-organ infection by the virus remained a challenge [135] too. An unhealthy lifestyle (such as smoking) and obesity are also risk factors [136] due to weakening the body’s healthy physiological regulations. These risks of coronavirus infections have the same root. The virus attacks ACE2 receptors, which have high expression in these organs, causing an increased risk of ACE2 damage.

One of the further challenges in the pathogenesis of SARS-CoV-2 is the imbalance in RAS, which favors severe effects. Viral interstitial pneumonia and diffuse alveolar lung damage appear in early pathologic changes in COVID-19, and pulmonary edema is also commonly seen [137]. The possible extensive cytokine storm could develop the patient’s critical condition, an acute lung injury causing an irreversible impairment of restrictive lung function and death. The RAS balance has complex actions on the immune system, and ACE2 may affect antiviral immunity in this context [138]. ACE2 downregulation overstimulates RAS [139], so ACE2 inhibition may decrease viral penetration potential, and altered RAS needs to be balanced. RAS maintains electrolyte and fluid balance and also regulates vascular resistance [140]. RAS imbalance could even cause oxidative stress alone [140], inducing many diverse diseases in clinical practice [141].

The impoverished ACE2 availability with the expansion of the infection or the too intense ACEI/ARB activates the kallikrein-quinine system (KKS), counteracting the RAS [142], i.e. that is, any decrease or predominance causes the opposite corrective change in the paired system [143]. The counterbalance action covers multilevel interactions [144]. The RAS-KKS system’s effect plays an important role in the entry of SARS-CoV-2 into cells [145]. The virus’s extensive invasion causes a shortage of the ACE2 receptors, the widespread viral infection developing the ACE2 dysfunction, and it plays a major role in the induction of the fibrosis [146]. The altered RAS through KKS impacts on bradykinin [147], inducing its overexpression, eliciting an overwhelming action [148]. The central role of bradykinin in the worsening of symptoms as advanced infection binds to ACE2 enzymes to such an extent that its lack can increase bradykinin level. In this phase of the viral infection, the bradykinin leads to the disease’s progress, the exhausted immune reaction, and the cytokine storm inevitable. The vast bradykinin expression could cause pulmonary edema [149] and induce pulmonary fibrosis, too [150]. Interestingly, bradykinin’s crucial role has recently been “discovered” by programs running on supercomputers [151]. Clinical practice shows that bradykinin-associated angioedema can recover rapidly when the bradykinin pathway is blocked [152].

Another control in complex regulation is the contact system (CS), which is part of the innate immune system and the inflammatory response mechanism against artificial materials [153]. The decision proteins in CS are the members of the coagulation cascades, factor XII (FXII, Hageman factor), prekallikrein (PK, Fletcher factor) and high molecular weight kininogen (HK) that participates in the initiation of the blood coagulation and in the generation of the vasodilator bradykinin with regulation KKS. FXII acts as a growth factor. It promotes angiogenesis and wound repair [154] in healthy conditions; however, pathologically, it can promote pulmonary fibroblasts’ proliferation leading to pulmonary fibrosis [155]: COVID-19 can also progress to pulmonary fibrosis. Surfaces that are recognized as “unusual” appear from damaged host cells and will activate CS. Furthermore, damaged cells release characteristic molecules into the extracellular matrix (ECM), forming a damage-associated molecular pattern (DAMP) and a pathogen-associated molecular pattern (PAMS), which could trigger a defense reaction that includes CS activation. The three large regulating feedback mechanisms (RAS, KKS, and CS) are complex themselves and also complexly interconnected, too, Figure 10 .

It was also recognized that ACE2 alone is insufficient to explain the virus’s invasion into the cell [156]. The metalloproteinase inducing receptor (basigin, CD147) was discovered as a new alternative route [157], which is additional to the invasion of ACE2 [157] [158]. Basigin (BSG) is a highly glycosylated single transmembrane protein of the immunoglobulin superfamily. It is relatively small; it has 50 - 60 kDa.

Figure 10. The regulatory feedbacks are profoundly interconnected and undoubtedly modifies the homeostatic balance.

The alternate route of entry of cells through BSG also participates in numerous negative feedback controls, and thus its imbalance re-induces challenges. BSG is widely distributed in the human body with various functions. It is involved in a broad spectrum of interactions [159]: regulates angiogenesis through VEGF, affects inflammation through Matrix metallopeptidases (MMPs), and IL-6, it induces pro-inflammatory cytokines through TRAF6, it is involved in the regulation of the cell cycle with P13K/AKT, etc. While ACE2 and TMPRSS2 are co-expressed in epithelial cell membranes, BSG expression appears in both epithelium and immune cells [136], so BSG inhibition may produce more consequences than in ACE2. In the bronchial biopsy, in the cells of the bronchoalveolar fluid (BAL) and the blood, a greater expression of genes related to ACE2 and BSG was found; and in addition, genes related to BSG were positively correlated with body mass index (BMI) [136].

On the other hand, BSG is involved in multiple physiological regulations. BSG regulates cell proliferation, apoptosis, migration, metastasis, and differentiation of tumor cells, especially under hypoxic conditions [160]. Inhibition of the BSG protein prevents interleukin IL-17 and CD4+ and CD8+ memory T-cells in the peripheral circulation [161]. The activity of BSG (CD147) increases under hypoxic conditions [160], which is usually generated by the massive use of ATP for cellular viral infection. It is well-known that BSG appears in most of the malignant processes [162] that are involved in the production of vascular endothelial growth factor and can promote tumor cell invasion and metastasis. The BSG protein appears to be a hallmark of cancer through metabolic reprogramming. BSG improves glucose metabolism [163] and contributes to immunosuppression by inhibiting the p53-dependent signaling pathway [164]. The BSG is a part of the complex physiological regulation (Figure 11 ). The SARS-CoV-2 virus can

Figure 11. The complex regulatory effects of BSG. BSG is an alternative of the SARS-CoV-2 entering into the host cell, but its presence and change broadly act in the entire body’s physiology.

reprogram cell bioenergetics supporting its replication [165]. In such a way, the SARS-CoV-2 virus shifts the cellular metabolic activity activating the simple glycolysis, similarly to the malignant cells. The glycolytic shift induces hypoxia triggering inflammatory changes in the lungs. This regulates the respiratory activity creating hypoxemia, which could support the viral infection by a positive feedback loop.

Importantly other feedback regulations help the extension of the viral infection [166]. The RAS-KKS-CS complex regulation has extensions with evading the immune response (vicious viral loop, “sneaky virus”) gaining hyper-inflammation, including T-cell lymphopenia and infiltration of macrophages and polymorphonuclear neutrophils (hyper-inflammatory loop, “gathering storm”), the non-canonical RAS, the ACE2/angiotensin-1-7 loop involving platelet dysfunction and at the end vascular leakage, (loop of the “helpless lung”), and the hypercoagulation loop developing fibrosis (“an epidemic within a pandemic”), [166]. This interconnected networking shows the complexity of the COVID-19 processes, which must be considered in the therapy approaches.

Inhibition of the BSG protein (like the same for ACE) may be a useful strategy in preventing or first-line treatment of infection by the SARS-CoV-2 virus, suppressing the possibility of developing the disease to a severe phase. However, the regulatory action needs a careful choice of the right time with the right dose; otherwise, the treatment could seriously affect other connected functions, causing severe adverse effects or even directly opposite processes than the expected. The involvement of various receptors in SARS-CoV-2 infection shows a wide range in epithelial barriers and immune cells [63], so inhibition of a key player could come at a price broadening the spectrum of the fights during the disease.

The spike proteins of the SARS-CoV-2 are the key in viral entry to the host cell and in the induction of neutralizing-antibody and T-cell responses [167]. Blocking the S-spike protein with a polyclonal antibody is one of the promising prophylactic neutralizations of the possible viral penetration [168]. Various peptides, antibodies, organic compounds, and short interfering RNAs are also other anti-SARS-CoV therapeutics targeting the S protein [167], developing a vaccine for the prevention of the infection. The S-block, together with the inhibition of the main gates of cellular entries like ACE2 and BSG could be a successful strategy in the early infection period.

2.2. Challenges of the Immune Regulation and Control

The patient-oriented approach involves the detailed measure of the personal patient features, taking care of their individual character. Patients are different in their homeostatic control. Their pre-set “trained” immunity and complete regulatory system depend on the environmental conditions, modified by the diets and habits, as well as the recognized or hidden comorbidities. Every living organism has intrinsic self-time defined by their individual features [169] [170]. One study compared the host immunity of SARS-infected patients directly at the time of admission for care [171]. Differences in host immunity were found when the patient developed mild or severe disease. Host values for ferritin, lactate dehydrogenase, and D-dimer increased as patients develop harsh conditions during care.

Conversely, the absolute number of CD4+ helper T-cells and CD8+ killer T-cells and B cells decreased significantly, and NK cells increased substantially with increasing infection intensity. At the same time, their share-percentage did not change so markedly. The CD4/CD8 cell ratio did not change, while the CD4+ and CD8+ T cell activation markers (HLA-DR and CD45RO) increased, and the costimulatory CD28 decreased as the disease worsened. The percentage of natural regulatory (suppressor) T-cells (Tregs) decreased in the patients’ extreme conditions. The rate of interferon-gamma (IFN-γ), a soluble cytokine essential for innate and adaptive immune reactions, is produced predominantly by NK cells and promotes the development of CD8+ and CD4+ T-cells, increases with the development of the illness. Cytokines IL-2R, IL-6, and IL-10 all increased in host immunity in patients who developed extremely severe conditions. Activation of dendritic cells (DC) and B cells decreased in extremely severe stages from the patients. Interestingly, patients’ age in severe and extremely severe disease stages did not have a significant influence. Another notable observation is that CD4+ and CD8+ T-cells are involved in the pathogenesis of an extremely severe viral infection [164]. Genetic diversity studies show that mutations interact with host CD8 and CD4 T-cells and could cause simultaneous infections with different genetic compositions [172].

The SARS-CoV-2 virus down-regulates the ACE2 by developing the infection, reducing the anti-inflammatory role of this enzyme. The early lymphopenia observed was possibly associated with a reduction in CD4+ T-cells and some CD8+ cells, which could delay or suppress the immune response and viral shedding. Macrophages and hyper-stimulated neutrophils can produce uncontrolled amplification of cytokine production [173]. Excessive autoimmune reactions worsen symptoms and could lead to a critical condition. A positive side of the inhibition of ACE2 proteins is that their limited availability typically reduces the autoimmune effect [174] and suppresses the cytokine storm, and contributes to alleviating the disease in this way. From this point, the cytokine storm’s critical state is highly dependent on the additional expression of bradykinin, regulated by the KKS system as a counteraction of the RAS imbalance.

Most patients who are transferred to the ICU have severe cytokine storm. The storm is an attempt to regulate body homeostasis that reacts to hyper inflammation induced by the SARS spike protein’s active binding to ACE2 [175]. The high concentration of various pro-inflammatory interleukins such as IL-1β, IL-4, IL-5, IL-6, IL-17, IL-18, IL-21, IL-22, IL-23, etc. together with chemokines (such as CCL2, CCL3, CCL5, CXCL8, CXCL9, CXCL10 etc.) [176] and GM-CFS is released into the extracellular matrix and into the bloodstream. Due to attempts to regulate weak physiological control, anti-inflammatory cytokines (such as IL10, IL-13, M-CSF, etc.) are produced [177], but their presence is insufficient to rebalance severe inflammatory overload. The situation, together with the blocked ACE2, could lead to pneumonia and associated edema. SARS-CoV-2 develops pulmonary [178] and laryngeal [179] edema associated with pneumonia, also seen in SARS-CoV-1 infection [180]. However, the SARS-CoV-2-induced edema and pneumonia differ from standard high-altitude pulmonary edema (HAPE) [181] [182], even though they both meet the criteria for ARDS [183]. The difference is the vascular endothelial cell injury [184] that the COVID-19 infection presents diffuse alveolar damage and airways inflammation. Medium and small vessels dilate accompanied by perfusion abnormalities in the lung [185]. Both types of ARDS have the risk of being lethal, but HAPE, for the most part, does not need ICU treatment, whereas the consequence of COVID does, frequently developing multiple organ failure [186], even heart failure [187]. Endothelial cells’ role is essential in SARS-CoV-2 infection [188], characterizing COVID-19 as an endothelial disease [189].

Another side of the complexity shows the production of cytokines and chemokines. A subclass of cytokines, interferons (INFs, named for their interfering actions) again have double-sided activities. On the one hand, IFNs are usually active in antiviral defenses. IFNs are communication molecules between cells to activate protective [190]. The automatic physiological control releases IFNs by the cells infected “alarming” neighboring cells and prepares them for possible viral invasion, helping the immune system destroy pathogens [191]. IFNs can activate natural killer cells and macrophages, and promote antigen presentation by increasing major histocompatibility complex (MHC) antigens. While IFNs are perfect communicators that help organize a defense against viral infection, it upregulates inflammatory symptoms (fever, muscle pain, flu symptoms) that are also commonly present in COVID-19. The molecular basis for the frequently observed progression of pulmonary fibrosis due to SARS-CoV-2 infection is not yet fully clarified. It is most likely due to multifactorial causes [192]: direct viral effects, immuno-dysregulation, cytokines (MCP-1; IL-6, IL-8, TGF-β, TNF-α) and increased oxidative stress [193]. IFNs along with IL-1, IL-6, IL-15, IL-17, and tumor necrosis factor (TNF) are pro-inflammatory agents that orchestrate various signaling cascades that lead to the induction of chemokines and, what is more important, they trigger the production of other cytokines, which could cause an emergency in the advanced stage of COVID infection.

Consequently, inhibiting these pro-inflammatory proteins could be one of the winning strategies in the severe phase of COVID, when ARDS formation appears as the number one danger [194]. On the other hand, many cytokines, such as IL-1, IL2, TNF, and colony-stimulating factor (CSF), can also enhance IFN production [195]. Other problems appear to be that type I INF (IFN-I) produces fibroblasts and monocytes, which could favor fibrotic processes in the disease’s severe phase. On the other hand, the immediate and efficient production of the same IFN-I helps the viral clearance in a mild or moderate state of COVID-19, and its impaired production and weak activity lead to viral existence and further development of the disease. Homeostatic feedback is also active here. The production of IFN-α type I could be inhibited by IL-10. IL-12 acts directly on CD4+ T-cells to enhance the priming of type II IFN (known as IFN-γ, as immune IFN) [196], which could inhibit viral replication [197]. On the other hand, IFN-γ can spread intravascular coagulation and decrease serum protein, maintaining the balance glucocorticoids regulate, inhibit IFN-γ [198].

The regulatory system completely overlaps, and complex feedback signaling maintains dynamism in balance in healthy homeostasis [199]. Patients’ whole blood profile in COVID-19 indicates triggering of the highly dynamic immune response even in early stages [200]. The starting disease dynamically induces most the pro-inflammatory genes, causing a well detectable inflammatory response on the SARS-CoV-2. The T cell involvement is likely while CD4 and CD8 are expressed as a part of the pro-inflammatory response, which could worsen the disease or prolong the infection [200]. These findings could help to make prognosis in the early stages and develop patient-oriented, host-directed therapies.

The interaction of several effects also has consequences in diagnostic strategies, where complexity must be considered adaptively depending on the disease [201] [202]. When we act on one side of the scale, this complex system could be so seriously disturbed that it could not find dynamic equilibrium again through the interaction of negative feedback loops’ mechanisms. In this way, the system will be out of regulatory range, out of control, as if shown in the case of IL-17 inhibition [203]. For example, a drug such as azithromycin decreases the expression of BSG. It increases the levels of interferons and interferon-stimulated proteins [203], which are effective antiviral inhibitors in the early phase of infection but could cause a storm of severe cytokines in the second phase. Managing inflammatory processes could be the critical issue in the different stages of the disease, again showing a complex tissue response behavior, requiring an adaptive adjustment of therapies [204].

Interestingly, there is a cross-immunity that had been observed between the rhinovirus and SARS-CoV-2 [172]. Rhinovirus infection could prepare the immune system’s mechanisms against other viral [205] [206] diseases. While possible prevention against common cold coronavirus (CCC) infection was shown more than 30 years ago [207], this research was abandoned. It became a hot topic to investigate again only today whether it has a possible cross-immunity connection with SARS-CoV-2 [208]. The idea of CCC protection had been reexamined, and it was hypothesized that pre-existing immunity in COVID-19 was primarily determined by previous CCC infection [209]. The research could contain exposure to cold without viral load, which was expected to also prepare the immune system for better performance against the viral infection [210] [211]. An exciting idea emerges that the Bacillus Calmette-Guerin (BCG), an attenuated strain of Mycobacterium Bovis, applied against tuberculosis for a century could decrease the mortality rate of COVID-19 [212] [213]. The cross-immunity assumption goes even further. There are assumptions that other live vaccines may have a role to prevent COVID-19 [214]. The mixed injection against measles, mumps, rubella (MMR) or Polio vaccine [215] may be a practical addition to avoid the worst developments of COVID-19 [216]. These theories and ideas well characterize how complex the infection and its consequences, and how much these depend on various personal and conditional factors. Even the oxytocin hormone level, which usually has a social and emotional bonding role, may have part in the prevention [217].

3. The Hypothesis

We propose to apply electromagnetism to defeat coronavirus infection. This idea fits well with the request to lock processes rather than remove some products [70]. The suggested new technology is physical so that it could avoid the pitfalls of the chemical approaches.

The conventional heating could affect the SARS-CoV. However, there is a further challenge: This virus is heat resistant even at higher temperatures, while other coronaviruses are heat sensitive. Complete inactivation of the virus requires a reasonably high temperature, [218], with a phenomenon similar to a phase transition at 56˚C, which is well above the physiological limit of body temperature. Nevertheless, the rising temperature could partially inactivate the viral infection by a long-lasting fever. Fever could alter the complex homeostatic regulation of the human body [219] [220].

We propose to use modulated electrohyperthermia (mEHT, trade name in oncology “oncothermia”) [221] as a physical method complemented with appropriate immunostimulants in oncology [222] [223]. This method is not simple heating. It has a double role, heats and excites by absorbed energy of the electric field. The mEHT process has already demonstrated its ability to elicit tumor-specific and selective immune effects [224] and is widely applied in clinical oncology [225]. It has only some contraindications [226] and its adverse effects are minor [227]. The widely published preclinical and clinical [228] results on tumors clearly show healing processes driven by specific immune functions, [229]. To our knowledge, we also expect successful treatment for viral infections [230]. When the procedure is not effective in a particular virus-infected case, our current experience suggests that we do not harm the patient. It does not increase the intensity of the infection process at any stage. This implies that we expect mEHT treatment to be extremely safe. However, since the method was applied to viral infection by HIV/cancer [230] [231], the transposition of the results of malignancy in COVID cases is hypothetical, although the processes listed confirm the practical applicability of the hypothesis. Technical details discussed elsewhere [232], as well as the practical issues, are shown in detail in protocols [233] [234].

The main task of cellular treatment is to select infected cells without damaging healthy ones. The selection of mEHT uses biophysical differences between malignant and healthy cells [235]. Specialties of the SARS-CoV-2 infection cause the biophysical differences presenting the selection possibility. The metabolic rate of cells loaded with the virus remarkable grows because it needs extra energy to support the replication process [236]. The “hijacking” of the energy resources of the host cell [237] [238] makes recognizable the infected cells from the uninfected ones. The higher metabolic rate needs an intensive exchange of ionic species, frequently forcing the cells to direct glycolysis. This accelerated ATP production makes only two ATPs from the glucose. Still, this quick and straightforward process delivers more ATP in a unit of time than the more complicated citrate (Krebs) cycle in the mitochondria with its 36 ATP/glucose. The result is a high concentration of lactate and other ions near virus-infected cells. This makes the microenvironment of infected cells more conductive, recognized by well-chosen radio frequency (RF) current flowing through the tissues. The distinguished flow increases the electric current around the targeted cells and could excite some transmembrane proteins (Figure 12 ).

Figure 12. The primary selection of virus infected cells by RF-current, flowing through the tissue. (a) The microenvironment of infected cells is highly conductive due to the high metabolic rate of the cells. (b) The cellular membrane is an isolator (condenser) so the well-chosen current will flow mainly in the extracellular electrolyte. (c) The selected cells are excited by their transmembrane proteins, including the virus-entry points.

The method is centered on electromagnetic action, which synergistically combines the heat and electromagnetic bio-effects on the targeted cells [239], like it is proven and widely used in the similar conditions of malignant cells [240] [241]. Conventional heating also has a general antiviral impact with its thermal effect [242]. The challenge that it heats the tissue equally, but the temperature alone is not selective. However, mEHT is certainly heterogeneous by the non-isothermal electrothermal effect, [243], which precisely attacks only the microenvironments of the target cells [244]. The absorbed electromagnetic energy on selected target cells partly heats them up while the electric field extrinsically excites various signals. The cells’ heated microenvironment will increase their conductivity, promoting the selection process in a positive feedback loop. The applied bioelectromagnetic concept chooses the cells that are out of the homeostatic regulation, recognizing where the dynamic equilibrium of homeostatic control is changed. The combination of temperature-dependent and independent factors could provide optimal treatment [245] [246]. Importantly, the lung’s intensive cooling with breathing does not modify the process due to the low dependence on the thermal factors.

The relatively low electrical impedance of infected cells’ microenvironment allows selection deeply in the body (Figure 13 ); as occurs in cases of malignant neoplasms [247] too.

Cell membranes contain numerous transmembrane proteins, which are connected to the cytoskeleton on one side and act as receptors or intercellular connections (cadherins, junctions) between cells. Some of the transmembrane proteins with the interaction of membrane lipids clump together and form a clustered group. The combination of glycosphingolipids, cholesterol, and protein receptors is organized into lipid microdomains of glycolipoprotein. These clusters (lipid rafts) in the plasma membrane have various functions [248], including signal transmission by group receptors [249], and play an important role in membrane dynamics [250]. Instead of chemical reagents to excite or block the receptors, mEHT targets the selected cells’ lipid rafts directly [251]. The membrane

(a) (b)

Figure 13. The electric field directs the radiofrequency current which selects the infected cells. (a) the current flows to the volume where the overall average conductivity is higher (b) the selection could be multilocal, the current flows the electronic rules.

rafts absorb most of the electromagnetic energy (Figure 14 ). It works in nano targeting of the natural nano-units, the rafts [251].

Precise in silico models well describe the special energy absorption of the membrane rafts of selected cells [252] (Figure 15 ).

In this way, the mEHT has a double-action (Figure 16 ): the thermal part of mEHT [253] locally heats the membrane rafts of the target cells in the depth of the body, [254], which could cause changes in their structure [255]. It is essential to highlight that the lipid rafts of the cell membrane are involved in the cellular invasion of SARS-CoVs [256] [257] [258], and could have an active reduction of the infectivity of SARS-CoV-2, inhibiting the dependent binding of lipids to host cells [259]. The viral surface’s weak temperature dependence could be an additional factor of mEHT action on the selected cellular microenvironments, where the temperature could be locally high [243]. Measurements of viral load in sputum show a small partial inactivation of viral load at 42˚C for 15 min, [260]. Although the virus can recover from severe mechanical disturbances and is unusually resistant to temperature, its surface is progressively stripped of spikes

Figure 14. The excitation process in steps: it starts with the transmembrane protein groups (lipid rafts) which absorb more energy than the non-conductive lipid membrane, the proteins are excited in the chosen rafts and at the end the death receptor and its complex molecular set start the apoptotic process.

(a) (b) (c)

Figure 15. The energy absorption can be calculated in silico, (ECM in upper, cytoplasm in lower parts of the figures divided by the membrane, with a raft in the center: (a) the electric field; (b) the current density; (c) and the specific absorption rate values.

Figure 16. The mEHT uses double effects. The absorbed electric field makes excitation non-thermally, while the absorbed energy heats the absorber, and gives optimal condition for the excitation process.

with thermal exposure. Its dynamism is reduced as measured by atomic force microscopy [261]. Therefore, both the infectivity and the thermal sensitivity of SARS-CoV-2 depend on the stenosis of the superficial peak and dynamics of the virus, and so the growing temperature could decrease the replication speed. The heat affected virus and the observed thermal aggregation may be one reason for the suppressed activity of the SARS-CoV-2 virus by heat [262]. In addition to the effects of the outside temperature, the infection process also generates heat. The infection uses several metabolic pathways in the host, using large amounts of energy, while ATP’s amount decreases as early as 3 hours after invasion [263]. This intensive consumption of ATP in a short time causes a sudden increase in temperature, which could reach approximately 4˚C - 5˚C of the host cells [258], which, together with the increase in ionic concentration in the neighboring extracellular electrolyte, decreases impedance also supporting the mEHT selection mechanism.

When cells are exposed to heat shock, they develop protective proteins (heat shock proteins, HSP [264] ) in response to exposure to stressful conditions. These proteins also have very complex functions in the cell-life. It was discovered as the protection of cells against thermal stresses [265]. Many HSPs are “chaperones” to stabilize new proteins that fold properly or help to refold proteins damaged by various cell stresses and are found in almost all living organisms. In general, any stress develops HSP [266], including electromagnetic interactions without thermal effects [267]. Under healthy conditions, cell survival modulated by the essential activity of HSP70, repairing the stress damages.

HSPs are very conservative proteins, which are part of general protection at the cellular level. HSPs are involved in stress-induced damage repair mechanisms and are also involved in multiple signal pathways, including many apoptotic signal transmissions. Various HSPs (indicated by their molecular weight in kD) operate to correct the various stress consequences. The most important HSP members are the 60, 70, and 90 kD proteins (HSP60, HSP70, HSP90). These chaperones are widely used in medicine [268]. Like heat stress induces most of HSP70 [269]; respiratory hyperthermia induces a cytoprotective response to heat shock in vesicular stomatitis virus [270] and rhinovirus-infected cells [271]. The main functions of HSPs as chaperones help repair misfolded or unfolded polypeptides, protect cells from various types of toxic stress, and present immune and inflammatory cytokines that support immune regulations. Merely speaking, HSPs are the guardians of the real dynamic status quo of the system.

Viral infection generally triggers apoptosis or programmed cell death of the infected cell [272]; the cell automatically activates its pathways for programmed cell death [273]. As the oldest cellular immune defense, the natural self-destruction of cells selected by apoptosis can be a significant point to eliminate the virus-infected cells. Despite the normal cellular reactions that induce apoptosis, the “hostile behavior” of HSPs disrupts apoptotic processes, blocks the signal pathways that keep infected cells active [274]. HSP70 has a belligerent activity in viral infection with their protective functions, it cooperates with numerous viruses [275], keeping the host cell alive during the virus’s replication and exit. The intrinsic mitochondrial pathway of apoptosis in cells infected with SARS-CoV-2 is positively correlated with the induction of viral pathogenesis of apoptosis and virus replication [276] [277]. The caspase-dependent mitochondrial apoptosis is active in viral pathogenesis [278]. We hypothesize that the complex cellular heat shock and electrical shock presented by mEHT will aid [279] apoptosis of infected cells and induce protective chaperone expression against viral invasion in uninfected cells. The main action of apoptosis by mEHT uses an extrinsic apoptotic pathway, exciting TRAIL (DR) death receptors on the surface of the membrane selected cells [280]. The TRAIL can induce apoptosis in virus-infected cells and can promote immune defense against viral infections [281]. On the other hand, there is evidence of the complexity of the feedback-controlled function of TRIAL in the immune system, helping to kill virus-infected cells or promoting their survival [282], showing the complexity of this effect. Furthermore, the TRAIL is an IFN-dependent mediator. The balance of the IFN/TRIAL signaling response has complex modulation and is essential to balance viral disease promotion or suppression [282]. The IFN-γ could help to develop antitumor immunity in malignancies [283]. The mEHT therapy induces IFN-γ proven in vivo [284]. It was measured, that the number of IFN-γ-secreting CD8+ T-cells in mice that were co-treated with DC and mEHT significantly exceeded the corresponding numbers in mice that were treated with DCs alone. The development of IFN-γ supports the systemic abscopal effect of mEHT [285] and helps to avoid the growth of the rechallenged tumor in the animal [284], and so it works like a vaccination. The mEHT developed IFN-γ could promote the appropriate immune-response at the early stages of the viral infection too.

The TRIAL induced extrinsic apoptotic signal goes through caspase (CAS) dependent (CAS-8 → CAS-3, or mitochondria → CAS-9 → CAS-3) and also independent (apoptosis-inducing factor, AIF) pathways [286]. The different apoptotic processes could usefully suppress viral replication, including the c-Jun N-terminal kinases (JNK) as the dominant factors to induce apoptotic cell death in mEHT [287]. Importantly the radioresistant cells could be forced for apoptosis with mEHT [288] The apoptosis is such a basic feature of mEHT, that its dose could be measured by apoptotic rate [289].

The complex regulation of dynamic equilibrium of homeostatic regulation is active in the role of HSPs too. Their guardian function is a double-edged sword. Processes could express the HSPs on the cell membrane, [290] or release of HSP to the ECM, or secreted in exosomes [291]. The HSPs’ function turns to the opposite direction when they are outside of the cytoplasm. In this situation, protection of the “status quo” by HSP activity takes on an opposite meaning outside the cytoplasm: it supports systemic integrity and aids apoptosis of infected cells. The selective stress of the mEHT method expresses HSP70 in the cell membrane and releases these proteins to the ECM [292], well-proven in malignant cases [293]. On this way, the HSP70 out of cytoplasm in oncology induces apoptosis signals and promotes immune effects [294], as well as immune-mediated systemic effects (abscopal) [295] and increases tumor-specific adaptive immune activity [224] in addition to apoptosis. The beneficial immunogenic actions of HSPs could be a helpful tool against COVID-19 too. HSP70 in ECM carries out a transfer of information essential for the specific immune action against the virus. HSPs are crucial components of antigen presentation [296] formed by antigen-presenting cells (APC) and also cross-presentation [291] and autophagy [297]. MEHT induces a complex process that creates a “damage-associated molecular pattern” (DAMP) in ECM [294]. As is usual for all complex regulators, the DAMP has a two-sided behavior: it could be antiviral, causing apoptosis, inhibit virus reproduction, or it could be a promoter of the consequences of infection by enhancing the process of severe inflammation [298]. The DAMP created by mEHT includes calreticulin (CRT), “high mobility group box protein 1” (HMGB1), 70 kDa heat shock proteins (HSP70), and ATP. The members of the pattern that appear in the ECM are separate information carriers: HSP70 carries the genetic information, CRT is the “eat me signal” [299], HGMB1 is the “danger signal” [300], and ATP provides the “find me signal”. These pieces of information form a set of spatially and temporally harmonized immune processes in the ECM [301], orchestrated primarily by CDs’ maturation to APC [302]. Note the possible shift in DAMP’s regulatory direction from suppressor to a promoter, because all the effects of the molecular components have connections embedded in complex ways, and our positive actions could easily be reversed when the system is out of balance. We have to apply mEHT in the mild or moderate phase of the disease when the inflammation and cytokine production promote immune activity and do not lead to an emergency cytokine storm condition. Recurrent in the “double-edged sword” phenomenon also characterizes all elements of DAMP, shown for CRT [303] [304] and for HMGB1 [305] and in HSP70 [275]. ATP as an energy source for dynamic changes could also support viral infection through its energy supply function. DAMP induces immunogenic cell death (ICD) generating APC [306], with the maturation of DCs [307]. The APC formed by ICD carries specific information about the infected cell and could produce virus-specific killer (CD8+) and helper (CD4+) T-cells (Figure 17 ). An interesting observation in cancer experiments, that mEHT treatment enhances the γδT-cell migration towards tumor cells even as low temperature as 38˚C [308]. The γδT-cells link the innate and adaptive immune systems, [309], so could have effective participation in the developing of immune defenses against SARS-CoV-2 invasion.

The virus uses the cell cytoskeleton for all its invasion, movements in the cytoplasm, and leaving the cell for replications [310]. The cytoskeleton components provide a dynamic framework for viral trafficking in the cytoplasm. They are involved in the entire process of the virus in the host, providing efficient elimination, replication, and egress exit [311]. In the first step, the spike protein binds to the cell surface. The docking strategy is universal; it works for all mammals. The binding process rearranges the cytoskeleton in one hour [312]. After this initiation, the intracellular transport of the virus involves both the cytoskeletal filaments of actin and tubulin and their dynamic components dynein, kinesin, and myosin [313]. After transport to the perinuclear region, the coronavirus replicates. With the active promotion of microtubules, the virion is transported to the plasma membrane, “hijacking” the host’s cytoskeletal system [314] and helping the viral replication exit. The applied electric field of mEHT also affects intracellular components. The rearrangement of the cytoskeleton by the modulated electric field signal suppresses the viral replication by limiting the intracellular transport by modifying the necessary polymerizing components for viral replication [315]. The structural reorganizing of the microtubules and actin filaments and also limiting the dynamics of cytoskeletal “motors” dynein, kinesin, and myosin [316] distract the correct transports for virus replication.

The hypoxemia caused by the low oxygen availability in later stages of the viral infection help many viruses replicates more easily. Hypoxia leads to inflammation and endothelial activation [317]. Cells adapt to hypoxia and induce cell survival and specifically endothelial cell adaptation (migration, growth, differentiation)

Figure 17. The immunogenic process has a systemic feedback from the local excitement. The clue is the immunogenic action, which makes the genetic information available for the immune-system. The “trained” immune mechanism produces adequate cells (killer cells) to attack and kill the virus infected cells in all over the body.

[318]. The developing hypoxemia in COVID-19 upregulates the hypoxia-inducible factor-1 (HIF-1α), increases the ACE protein expression, while counterbalancing downregulates the ACE2 enzymes [319]. Due to the possible bradykinin overload, the process produces cytokine storm, evolving the patient state to critical.

On the other hand, the hypoxia at the onset of the COVID-19 helps avoid serious infections because ACE2 is the main target of SARS-CoV-2 in pulmonary epithelia. Clear epidemiologic fact among highlander populations supports the positive role of hypoxemia in preventing the COVID-19 [320] [321]. This well emphasizes the double-faces of HIF-1α which could help in prophylactics in early infection stages [322], but oppositely active during development of the disease. A variety of viral pathogens may activate the HIF-1α, as well as the glycolytic supported high metabolic rate, which is induced with viral infection in the host cell, which promotes inflammation, and facilitates viral replication [323]. Suppression of HIF-1α [324] is an additional advantage of mEHT against the development of the symptoms.

Other factors involving mEHT to COVID-19 treatments are that both mEHT and bradykinin promote the activation of TRPV1 receptors [325], which can trigger additional regulatory mechanisms and reduce pain sensation. Although TRP channels have no role in healthy lung function, repair processes use them to promote endothelial permeability, inducing inflammation for immune action, which are normal helper processes. Still, again their activation could become pathological [326], involved in asthma, COPD, and pulmonary fibrosis [327] and pulmonary edema [328].

The KKS induced overregulation of bradykinin due to the RAS disbalance is caused by dysfunctional or downregulated ACE2. This process can be partially corrected by mEHT, producing vasodilation [329] without RAS control. This bradykinin-free action would be a helpful option for the vasocontraction challenge, which additional advantage could be essential in the treatment of patients in the ICU.

Fibrotic processes dangerously risk the survival of the patient and could cause serious harm and reduce the quality of life of the patient even chronically after successful antiviral therapy as well. Those who survived treatment the applied aberrant and excessive treatment in the ICU, sometimes have hardly reversible or irreversible lung damage and fibrosis, resulting in functional disability and a significantly reduced quality of life [330] [331]. The worsening of symptoms could also become chronic without further viral infection. The fibrotic damage in patients during and after a viral infection may cause acute lung injury (ALI), releasing fibrosis mediators [332]. The epithelial-mesenchymal transition (EMT) [333] promotes fibrotic processes [334] [335] derailing the epithelial-fibroblastic crosstalk [336]. The mEHT is feasible for treating fibrotic states due to its electric field effect, which could moderate the EMT [337], so we consider it to treat certain fibrotic conditions. The successful anti-fibrotic effect of mEHT is proven for patients with fibrosis of the penis (Peyronie’s disease) [338], and fibrosis of the palm (Dupuytren’s contracture) [339]. Furthermore, mEHT treatment in malignant fibrosarcoma also showed a great benefit to the patient [340]. Note that RF current is widely used for cellulite fibrosis [341], and skin laxity [342], but only for areas near the surface. MEHT is active in deeply located tissues of the body [247], so therefore the usual activity against fibrotic structures is expected anyway. Due to its repairing action, the mEHT therapy could be in the healing process or also in the rehabilitation period when the infection does not appear. Still, its consequences (primarily pulmonary fibrosis) need care.

Further possible impact of mEHT on fibrosis is developing HSP, which suppresses the fibrotic processes [343], like this is shown in wart healing [344] [345]. Additionally, the positive impact of high-dose vitamin-C [346] may inhibit fibrosis complementing with mEHT, using its intensive attack of viral infected cells’ membranes. Clinical study shows successful complementary treatment for lung cancer with high dose vitamin-C [347]. Lung effusion is also one of the patient’s remaining negative states cured of the SARS-CoV-2 viral disease. mEHT also offers a solution to this problem [348].

The above effects present the complex behavior of mEHT therapy. Low-frequency modulation mEHT on a high-frequency carrier [232] allows penetration into the entire lung, attacking the virally infected cells in. The demodulated signal promotes the restoration of the cells’ homeostatic balance by loading the redistribution. It forces the process to maintain equilibrium [349] forms multiple regulation loops to support the homeostatic control of the body (Figure 18 ).

4. Discussion

Like we learned in malignant diseases, the SARS-CoV-2 coronavirus infection exhibits a complex phenomenon by upsetting the healthy homeostatic balance. It means that the processes in developing conditions are stochastic (probabilities of events dependent on time). They have promoters and suppressors, and their equilibria decide the fate of the infection. The cumulative dose of viral exposure and the efficacy of the local innate immune response (natural IgA and IgM antibodies, mannose-binding lectin) form the most important equilibrium in the first 10 - 15 days of infection. When the virus can block the primary innate defense immunity, it could rapidly spread from the upper respiratory tract to the alveoli, replicating without local protection. This phenomenon causes pneumonia and clinically induces a high antigen concentration. The delayed and strong adaptive immune response (high-affinity IgM and IgG antibodies) that follows causes unstoppable inflammation and generates a cytokine storm, which requires mainly intensive care and is fatal in some cases [176]. Balancing physical activity also affects: low or moderate physical activity can be helpful, but extreme action can facilitate the virus’s shedding. The same problem could arise in the case of oral respiration with hyperventilation during the incubation processes. The virus bypasses the immune barrier and determines the rapid development of the disease. This well-presented spatio-temporal harmony (balance of the viral load, repetitive infection, timing of immune actions, concurrent effects of personal

Figure 18. The complexity of mEHT is its two balancing and interaction branches of actions. The conditional heating (depends on square of the field strength) prepares the physiological and cellular conditions, while the electric effects (linearly proportional with field strength) act on molecular level supporting the immune processes.

immune regulations, etc.) of the development of infection decides the fate of the patient.

Consequently, understanding the complex process of infection development is essential for the medical care, prevention, treatment, and rehabilitation of patients. The COVID-19 disease has many unusual aspects compared to other respiratory viral infections. The severe lymphopenia, which causes a deficiency in the immune regulation processes, and a cytokine storm with extensive activation of cytokine-secreting cells with innate and adaptive immune mechanisms, is special, leading to acute respiratory distress syndrome and multiple organ failure [350]. Laboratory evidence from clinical patients showed that a specific T-cell response against SARS-CoV-2 is essential for recognizing and destroying infected cells [351], and the measurement of these could inform the design of prophylactic vaccines and immunotherapy for the future.

Most of the current drug developments are strongly connected to some chosen molecular products. My current proposal opens a new approach with the bioelectromagnetic method. It supports the complex processes of regulation and control and the restoration of the natural homeostatic balance. This proposed paradigm shifts from current drug-focused developments to bioelectromagnetics. Besides, the change proposes a shift from the product-oriented to the process-oriented approach. This strategic objective has historically been proven in the fights against dangerous enemies. The winning strategy seeks out and attacks the weak side of the “enemy” and avoids having too much confrontation with their strong positions. Applying in the COVID-19 fight case, we must attack the infection’s weak side (violation of collective regulation), instead of the viral force (reproductive capacity). My new strategy proposal is biophysical. The mEHT which composes novel advantages:

1) It “rides” the high-frequency carrier, which carries this information in depth, which would not be possible only with this low frequency through the insulating layers, including the tissues, applicators, and boluses.

2) The applied modulation uses appropriate time-fractal series, which promote the correct signal processes in cells after the plasma membrane demodulates the signal. The time-fractal represents the spatio-temporal complexity of healthy homeostasis, maintaining the necessary systemic equilibrium, despite the disturbing local balances.

These novelties, as I described above, could solve many problems connected to the complex control. The homeostatic balance of the immune system is essential. The flexible adaptability of SARS-CoV-2 avoids any homeostatic regulations that make it complex indeed. Our task is supporting the natural processes to find a way of repairing the lost control. The in situ generated ICD provides genetic information for APC and forms CD8+ T-cells may be one of the solutions. The transferred information is specific to the actual infected cell and, regardless of the mutation, serves as a feedback mechanism to destroy it. This is an opportunity to target and try to kill cells infected by viruses. Through this mechanism, mEHT treatment could interrupt or at least slow down the rate of viral replication, the delay of which may be essential in preparing for adaptive immune defense. Slower replication activity can retain mild disease does not evolve to severe stages. The complex cooperation of mEHT with the innate and adaptive immune system causes a systemic effect (abscopal) from the local treatment site throughout the body [352]. The method had shown preclinically [353] and clinically [225] eliciting an adaptive immune response in oncology. DAMP induces targeted apoptosis leading to ICD by creating molecular clusters and systemic effects (tumor vaccination, patented [354] ). And expectedly could lead to vaccination against viral infection, as occurs in malignant cases.

The inhibitory effect of mEHT against COVID-19 is hypothesized due to its immunological and biophysical selection of cells that create apoptotic signal transduction in infected cells. The process uses bioelectromagnetic effects and takes into account complex regulatory needs. The actions of mEHT in the later stages help the complex fight for healing. The method we propose can generate a virus-specific immune response electromagnetically in situ.

Challenges of the Therapeutic Paradigm and Management of the Therapy

The clinical management of the disease is complex and needs right-time decisions about the applied treatments [355]. The adequately sequenced treatment series could synergistically increase the patient’s chance of cure. This is also related to the fact that when the treatment starts in the early stages of infection, it may significantly slow down the infection’s exacerbation, which can provide sufficient time to develop an adaptive immune response, which can be aided by DAMP-ICD processes.

At the time of development, infection with the SARS-CoV-2 virus can be divided essentially into two phases, separated by basic immune processes [350]. The two phases, innate and adaptive immune reactions [356], occur superimposed and accompanied by cytokine waves [357]. The applied mEHT must be adjusted to the treatment periods (Figure 19 ). It is sometimes performed successfully when the patient remains asymptomatic, or the symptoms are so mild that the patient does not recognize them.

The clinical intention is to prevent the development of a severe disease even in the first phase when the patient still shows mild symptoms. A problem arises when the viral load dose is too high or the innate immune response is too weak to exceed that dose. Then rapid progress of shortness of breath dominates the symptoms [358]. When the disease worsens in the second stage, the adaptive immune system’s activity will be decisive [356]. The immune-activated high cytokine production in the second wave typically creates a cytokine storm that primarily requires active medical attention and sometimes treatment in the patient’s ICU [359]. Leukocyte-mediated antiviral responses again need a balance in a dual role, as they can help counter the effects of the SARS coronavirus and cause severe pneumonia. The dose of the virus and the timing of the processes can be crucial in preventing infection, which again requires only dynamic stochastic considerations. The direct way considers the complex dynamism of using the different drugs in their regulation of equilibrium. When the therapy uses them in the appropriate time sequences and taking care of homeostatic regulation and its temporal factors, success will not be lacking.

The INF-mediated immunological dynamics became the guiding factor [360] to find the optimal and adaptive treatment. The favorable balance of DAMP in antiviral activity requires close monitoring and patient adjustment. The dose to form the various immuno-active molecules must be adjusted to cytokines’ concentration, which helps avoid over-regulation, leading to a septic storm. Developing fibrotic processes is one of the clinically most problematic tendencies. In the intermediate stage of viral infection (weeks 2 - 5), fibrosis signs are already shown: fibrin deposition and infiltration of inflammatory cells and fibroblasts in the epithelial cells of the alveolar parts. In the later stage (weeks 6 to 8), the lung tissue becomes very fibrotic with collagen deposits.

The fibrosis treatment could be artificial respiration in case of shortness of

Figure 19. The distribution of the various characters of SARS-CoV-2 infection and treatment possibilities during the infection. Note the distributions are probabilistic, do not cover individual cases. The individual conditions depend on various factors, including the dose of the viral load, the patient’s environment, the habits and diets, the “prepared” protection of the immune system, etc. Due to the considerable individual differences, the distributions are normalized as much as was possible. The intervals are approximate like the distributors are also estimates. Distributions are composed in their most probable form using the results [199] [355] [361] - [369]. The disappearance of antibodies against SARS-CoV-2 was also measured [370], but others measured the opposite; the antibody protection exists for at least two years [371].

breath. In less severe cases, this is done simply by intubation with tubular dosing of oxygen, but in more severe cases with mechanically forced ventilation, “positive end-expiratory pressure” (PEEP) is applied [372]. Although this procedure saves lives, strong mechanical interaction can cause serious side effects [373]. Lung damage caused by mechanical ventilation can develop into additional ALI [332]. These changes’ underlying mechanisms may be an epithelial-mesenchymal transition (EMT), and the release of profibrotic mediators caused by cell stretching and mechanical ventilation [335]. Aggravating ALI could also induce pulmonary fibrosis. In the period of infection, the SARS-CoV-2 virus progressively replicates in the upper respiratory tract. Extensive mechanical ventilation can facilitate the direct penetration of high concentrations of the SARS-CoV-2 virus from the URI into the lower respiratory tract, eliciting the effects of neutralizing possible antibodies on the mucosa. Intensive PEEP may be associated with strong functional effects; hyperinflation, and significant hypercapnia (hypercarbia) caused by ventilation of dead parts and occurs to reduce hypoxia [374]. With ventilation, the risk of lung injury is high; most mechanically ventilated patients develop severe ARDS [375]. The detrimental effects of mechanical ventilation can further exacerbate the patient’s condition, which is mediated by cellular, molecular mechanisms involved in mechanical stress-induced lung damage. However, patient selection for PEEP treatment is also not straightforward, as the additional extent of viral lung injury limits patients’ choice. In contrast, pulmonary hypertension is usually not a clinically relevant factor in the screening process, causing physiological problems during treatment.

Due to the possible damages, the use of “preventive” PEEP is not recommended [376]. Use it only in case when it is necessary indeed. After intubation oxygen supply, an assisted breathing associated with intubation should be used. In this phase, the patient could be treated by mEHT to ease the symptoms by freeing the airways with dilatation and painless relaxing. Accordingly, PEEP mechanical ventilation should only be used in insufficient critical respiration and should be used as carefully as possible. The adverse effects of PEEP could be severe, leading to worsening the patient’s condition. The risk/benefit ratio of PEEP-induced lung injury may be higher than without this mechanical support. The strategy has to be well adapted to the patient [377]. When necessary, the PEEP treatment must be kept to the minimum, which enough for patient breathing. The analysis of data shows attention to the technical data shows. This usually means that the application of PEEP is airway occlusion pressure P0.1 < −4 cm H2O or the expected pressure generated by respiratory muscles Pmus > 15 cm H2O, or expected transpulmonary respiration > 17 cm H2O) [149]. The position of the patient is also an important factor to evaluate in the actual case and stage. The proposed prone position [378] needs to be applied in the proper time-course [379]; otherwise, it could cause damages [380].

Approximately one-third of the patients experienced persistent lung abnormalities after being cured of SARS-CoV-1 and MERS’ acute disease. Furthermore, approximately one-third of patients infected with SARS-CoV-2 develop acute idiopathic pulmonary fibrosis (IPF) even after improvement and discharge from the hospital [381] [382]. Consequently, strict follow-up observation is necessary after 3 - 6 months of the healing process completed in the hospital to warn of the potential hidden risk of developing IPF. Post-treatment care should prevent, cure, or at least block the further development of the disease’s consequences, mainly the problems of fibrotic processes. The antifibrotic treatment of mEHT, like we shown above, could be considered during, as well as it could be a useful approach in post-cure time (Figure 20 ).

In the second wave of the pandemic, more and more patients have relapsed with persistent symptoms, especially myalgia, intense fatigue, a sensation of fever, shortness of breath, chest tightness, tachycardia, headaches, and anxiety [383]. Regardless of the severity of the disease, avoiding permanent ARDS, the damage could significantly reduce the patient’s quality of life. The 8 - 12 weeks after hospitalization complains are pretty common. 74% of patients had persistent symptoms (notably breathlessness and excessive fatigue) [384] in the UK. In an observational cohort study, 78% of patients who had recovered from COVID-19 had abnormal findings on cardiovascular MRI (median of 71 days after diagnosis), and 36% reported dyspnoea and unusual fatigue [385]. The three or more weeks of primary care after the presence of symptoms have proposed guidelines [386]. Nevertheless, the research on the reasons for the long-term care is warranted, together with the rising questions about the consequent morbidities like diabetes, metabolic disorder of interstitial lung-disease [387].

The reinfection of cured patients is also possible [388], so follow-up is reasonable. Returning to the analogy of military strategy: the possibility of winning a war lies in the new technologies, the new weapons that are beyond the enemy’s

Figure 20. The possible rehabilitation treatment of mEHT. The treatment may be used successfully for the convalescent period against the remaining fibrosis and edema.

expectations. Chemical machinery is embedded and regulated in complex ways in living objects, developed and optimized by evolution over millions of years. We have to use those effects and technology against COVID, which is above specially chosen chemical reactions. We need a deductive (holistic) approach, which considers the system, and deduces the details from the complete unit [389]. Our presented hypothesis below gives a proposal to solve this challenge.

5. Conclusions

The human system has a complex regulatory mechanism controlled by various homeostatic actions to maintain the dynamic balance of the living organism. The self-similar structuring [76] develops an intrinsic self-time [169], regulating any developmental process’s complex effects in the organism. Responses must consider this complexity, taking care of events’ timing and the formulation of a balance. The balance determines the immune/autoimmune developments, the viral dose’s effect concerning the immune developments, and the dangerous cytokine storm. The mEHT method, with its fractal physiology considerations, could help you find the best treatment option. I am convinced that the complexity of the treatment could only manage the disease’s complexity. Expectations about a “miraculous” and unique curative effect are not realistic.

According to our recent knowledge except us nobody presented bioelectromagnetic treatment proposal to treat the COVID-19 and its consequences in convalescent period of time.

The mEHT method seems to be an optimal complementary treatment for SARS-CoV-2 infection and its consequences. It has special bioelectromagnetic steps to select for virus-infected cells, based on their markedly changed impedance in their cellular microenvironments. Excitation of membrane rafts and receptors induces transmembrane signals that choose apoptotic pathways and form DAMP and ICD, which develop virus-specific immune responses. An appropriate time fractal amplitude modulation attempts to balance the unusual systemic regulations. Time-fractal modulation drives processes in the direction of healthy homeostatic balance, promoting the immune system for vigilance [390]. Allometric fractal considerations help solve structural and metabolic problems of SARS viruses [81]. Mechanistic investigations of the effects of mEHT in related pulmonary fibrotic animal models can be effectively performed using in vivo molecular imaging outcomes [391], and X-ray computed tomography fractal dimension analysis [392]. The mEHT acts on the fractal complexity [393]. It uses an allometric approach [394] for the self-similarity [76] of homeostatic systems [59] [395], providing additional support for its action against the formation of IPF.

The mEHT is a possible and feasible treatment to manage the complexity of the therapy. It could be used for three purposes, encompassing all medical activities used in the epidemic. The method could be applied:

1) as prophylactics, when the infection is recognized, but symptoms have not developed or only weakly developed yet;

2) for the treatment of patients suffering from mild and severe symptoms;

3) for the recovery period, when the individual is discharged from the hospital but needs rehabilitative care.

Our proposal is to use an adequate electromagnetic treatment, which can solve numerous challenges in the SARS-CoV-2 viral infection and its consequences, based on the results obtained by the mEHT applications that have proven to be successful in malignant diseases [396]. We propose the application of a broad set of mEHT actions for the treatment of SARS-CoV-2 infection and its post-treatment syndrome.

Conflicts of Interest

The author declares no conflicts of interest regarding the publication of this paper.

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