COVID-19: Notes on its Etiology, Pathogenesis and Mediation

The novel severe acute respiratory syndrome coronavirus SARS-CoV-2 is an RNA virus with a surface arrayed with crown-topped protein spikes that project 24 nm outward from its lipid envelope (Figure 1). These proteins, labeled spike S proteins because of their shape, form the outer surface material that interacts with particular protein binding sites. This unusual virus interacts with the angiotensin converting enzyme (ACE) protein on human type 2 pneumocytes to elicit an infectious process having variable outcomes, ranging from moderate symptoms to lethal pneumonia. This virus is highly transmissable among humans and rapidly caused a worldwide pandemic and thus is a modifi cation of earlier known forms of coronavirus including CoV and MERS.


Introduction
The novel severe acute respiratory syndrome coronavirus SARS-CoV-2 is an RNA virus with a surface arrayed with crown-topped protein spikes that project 24 nm outward from its lipid envelope ( Figure 1). These proteins, labeled spike S proteins because of their shape, form the outer surface material that interacts with particular protein binding sites.
This unusual virus interacts with the angiotensin converting enzyme (ACE) protein on human type 2 pneumocytes to elicit an infectious process having variable outcomes, ranging from moderate symptoms to lethal pneumonia. This virus is highly transmissable among humans and rapidly caused a worldwide pandemic and thus is a modifi cation of earlier known forms of coronavirus including CoV and MERS.
The transmission electron microscopic image of intact viruses (lower photo) showing the protruding spike proteins were presented for the public by the NIAID Rocky Mountain Laboratory, Hamilton, Canada (April, 2020) available at: fi le:///C:/Users/RSauerheber/Documents/Novel%20 These viruses readily infect human alveolar cells, which biochemically replicate virus particles that destroy the infected cell and spread to infect additional cells. The virus has been found to spread into systemic circulation and has been isolated from several organs. Unlike the AIDS RNA virus (Figure 2) that also contains a lipid bilayer with protruding proteins that generate antibodies that do not neutralize infectivity, it is hoped that the protruding surface spike proteins on CoV-2 will be amenable to neutralization with a suitable vaccine antibody. while other coronavirus forms were not affected at this low fever temperature [2]. Further, merely lowering the pH from 7.4 to 7.0 changes the conformation of insulin suffi ciently to completely block the insulin stimulation of glucose transport in intact cells. This is attributed to changes in binding, where   DOI: https://dx.doi.org/10.17352/apm.000020 a 6 fold lower binding of insulin to its receptor occurs over a mere drop of 1 pH unit from 7.8 to 6.8 [6]. (Extracellular and arterial blood pH is tightly regulated by physiologic buffers and proper breathing to maintain the pH at 7.4).
Spike S proteins on coronaviruses are classed as type I fusion proteins and at least one type is irreversibly denatured at pH 8. The U.S. CDC has stated that, unlike the hepatitis virus ( Figure  5), there is no evidence the Cov-2 virus infection is transmitted by consuming foods. One possibility is that the spike protein is destroyed by digestive proteases or by the alkaline bicarbonate secretions in the small intestine.
The spike proteins undergo signifi cant conformational change upon binding to cell surface receptor proteins that may be sensitive to temperature. One spike protein form was not denatured during a brief fi ve minute exposure to 70-80 o C (158-176 o F) [7]. However, an important recent study [5] found that the SARS CoV-2 virus infection of human embryonic kidney cells was half inhibited after a two hour exposure to 43 o C (109 o F) and was completely obliterated at 48 o C (118 o F) for two hours. If the exposure does not permanently denature RNA or the spike protein, the treatment could nevertheless block binding of the virus to ACE protein. These fi ndings are consistent with measures of coronavirus viability as a function of time on surfaces exposed to various temperatures ( Figure 6).
Steam treatment of the face and the oral cavity have been used to cure acne and to treat bacteria causing bleeding gums (unpublished). A controlled study conducted on patients with lower respiratory tract infections, some with pneumonia, indicated substantial shortening of recovery time and lowering of hypoxia caused by steam inhalation in tents [7]. Steam has been recommended to open nasal ostia in cases of infectious sinusitis [8]. It is therefore hypothesized that the combination of heating and pH lowering of the free virus in bronchioles and alveoli prior to infection of lung cells might impair infection of lung tissue, and later in an infectious episode may mitigate further spread from virions present in nasal and bronchial airways. It is possible that inhaling steam or lemon juice acidifi ed steam coupled with nasal lavage with a "netty pot" containing sanitized pre-boiled lemon water cooled to a tolerable temperature may improve outcomes in individuals infected with the novel virus.
Although dry skin can be scalded at a liquid temperature of 155 o F (68 o C), moist tissue in the oral, nasal, and bronchial airway cavities withstand much higher temperatures. Warming airways to approximately 160 o F (71 o C) for several minutes a few times daily could be a useful practice for generally preventing viral infections of the upper respiratory tract. This temperature denatures the structure of insulin ( Figure 4) and blocks insulin function, and a 10 minute exposure is known to degrade RNA.

Results
Here reported is the temperature of steam as a function of height above boiling water, and also optimum conditions to inhale acidifi ed steam (see Figure 7 for the system used).
Organic acids in lemon juice can co-distill with water. Acidifi ed steam from boiling lemon juice treated water may provide additional benefi t. The pH of steam can be adjusted to a safe but effective level with properly diluted amounts of lemon juice (pH 2.5).  The time required to obliterate CoV-2 virus infectivity is shown as a function of temperature. Most of the points were from published values for virus survival on surfaces exposed to varying ambient temperature [4]. The third value however is from the Chinese study conducted in Wuhan showing conditions that obliterate the infection of human kidney cells in culture [5].
Citation: Sauerheber Figure 7A and the values are plotted in Figure 7B. In these studies the duration of time the RNA is exposed to these temperatures determines the extent of degradation. Proteins commonly become dysfunctional at 50 o C (148 o F).
Basically if one tested positive for the virus, a goal would be to inhale all the steam energy that could be safely tolerated in an attempt to denature the viral spike protein and RNA.
There are large discrepancies among the public statements made regarding the length of time that coronavirus-2 (SARS-CoV-2) remains infective upon residing on various surfaces. Published data indicate that the virus at moderate temperature is not effi ciently eliminated in infectivity until about 9 days. At  Figure 6). These results are fully consistent with the aforementioned fi nding that coronavirus infection of human kidney cells is obliterated at 48 o C (118 o F) for two hours. These comparisons are important because steam burns are usually not as severe as boiling water burns even though steam molecules contain more heat energy. This is because steam vapor is disseminated into a larger volume. So the close comparison between temperature and time exposures for both ambient air and incubation media that obliterate infectivity suggest that proper steam exposure might replicate this effect.

Discussion
These data taken together imply that one precaution anyone could take who suspects is infected, or is infected, would be to breathe steam at a proper temperature and time of exposure. This is a simple home treatment, breathing steam at a temperature that is tolerable above a pot of boiling water (212 o F, 100 o C). This could be done daily or in some cases at four hour intervals to help minimize the effects of the infection, where recent studies indicate viral infectivity is obliterated at 167 o F (75 o C) for 30 minutes [9]. A rule of thumb in thermodynamics is that a process may be accelerated by a factor of two for every For individuals with breathing diffi culty, or to ensure most effi cient penetration of steam into bronchioles and alveoli, steam could be administered through a nebulizer. These devices use a slight positive pressure to increase the penetration of inhaled medicines delivered as mists, most commonly for cases of asthma.   The long term survival of CoV-2 on surfaces at modest temperature is particularly troubling and may be an important feature of the high incidence of transmission, being an indirect route between people. Mailed packages can arrive quickly after being sent from infected locations or handled by infected people, and since asymptomatic people can transmit the virus which can last for so long on surfaces, one suggestion would be that mail generally could be sanitized on the outside or the contents could be opened several days after arrival.
Since coronaviruses are RNA based, drugs used that are FDA approved for treatment on the use of RNA-based AIDS virus should be considered as possible treatments. Recent studies indeed indicate signifi cant improvements in the condition of Covid-19 patients treated with remdesivir, a nucleoside analog that slows replication of the viral RNA. The widespread hope that hydroxychloroquine, the antimalarial that de-glycosylates the ACE protein, would be an effective treatment has been largely tampered. Although much evidence has been published that this agent has antiviral effects in vitro, it has been found that the coronavirus infection compromises heart function and this drug can prolong Q-T intervals on electrocardiograms. Indeed a clinical trial of this drug in Covid-19 patients in Brazil had to be halted for increased cardiovascular mortality during the trial. The largest study to date at the University of Virginia found that Covid-19 patients treated with the drug experienced 22% death rates compared to 11% without the drug. A similar fi nding was observed for the combined use of hydroxychloroquine and azithromycin. The FDA had little choice but to place warnings on the use of this agent in Covid-19. The largest controlled clinical trial done so far recently found no benefi t for use of the drug in Covid-19 patients. There will be no single treatment that would readily arrest an ongoing symptomatic infection, but the combined use of extracellular steam plus RNA replication medicines such as remdesivir, acting intracellularly, could be a possible approach, as well as agents such as dexamethasone that mitigate the cytokine storm [10].
Vaccines targeting various parts of the virus are being developed in various labs around the world. A vaccine that has shown to be effective in macaques has now been developed in the U.K. and in China [11]. The Oxford vaccine is a nonreplicating adenovirus containing the SARS CoV-2 spike protein which generated both cellular and humoral antibody in macaques and recently in man. Since the lethality of Covid-19 is argued to be due largely to an immune overreaction in a cytokine storm, vaccination for the condition may be problematic, but the data on macaques do not show evidence of such an overreaction while preventing the condition in inoculated animals and human volunteers. However, it remains possible that an immune exaggerated response might still be a problem after a later re-exposure to the virus, and this remains to be studied. Many vaccines include aluminum as an artifi cial adjuvant. It is hoped that any widespread use of a vaccine will not contain aluminum because the dose injected is larger than what would enter the circulation after ingesting an FDA allowed maximum amount of this metal ion in foods. And an unnatural stimulation of the immune response with adjuvants should not be considered viable when the cytokine storm and an overreaction is to be avoided.
It is expected that antibodies raised to the viral RNA in some studies would not be as effective since viral RNA would be released and exposed only inside cells. The RNA sequence [12] of this novel virus has become altered over time in the human population, causing a glycine to replace an aspartate at position 614 in the spike protein. This is a region where antibodies typically bind and one can only hope that antibody effectiveness is not reduced by this mutation. This amino acid substitution has been detected mostly in Europe and the Eastern U.S. and has been the predominant form found in those infected. This form appears far more infective than the original sequence. The Oxford vaccine directed against the virus spike protein induced both humoral circulating antibody and cellular immunity which destroys infected cells and this immune response has lasted for 3 months as of July, 2020 [13].
It is hoped that this particular vaccine will not require yearly vaccinations as do other coronavirus vaccines for the fl u. If steam is unavailable it is also possible to use a room space heater to generate heated air for breathing. The temperature could be measured as indicated in Figure 7A to ensure suffi cient heating for a given time to compare with the effect of steam inhalation. Heated air from a 1,500 Watt room space heater measured at a 20 cm distance was about 120 o F (49 o C). It is important to stress that in no case should heat be inhaled in such a manner that would cause discomfort.
Because the ACE protein in type 2 pneumocytes is highly expressed in patients treated with ACE inhibitors to mitigate high blood pressure, it has been widely suggested that these individuals might be much more sensitive to coronavirus infection. It is very possible that the increased level of this protein in the elderly may explain why Covid-19 lethality in the elderly is typically a much higher percentage of confi rmed cases. On the other hand, a recent study reported that the use  of ACE inhibitors in Covid-19 patients did not affect disease outcome [14]. One possibility is also that the use of these inhibitors might impair infection since the enzyme is inhibited, and that discontinuance of the drugs during an infection might worsen the condition due to expression of the more highly uploaded ACE protein. Moreover, it has been reported that an increased incidence of blood clotting occurs in Covid-19 patients. Additional studies might clarify this point.  Steam or heated air treatment would be expected to be most useful for asymptomatics who tested positive with a nasal, oral, or saliva test. Steam might mitigate subsequent infection of lung cells. In symptomatic stages where cells have been infected and virus particles have entered the blood, steam could be a mitigant to help slow infection of additional sites from the airways. In late stage illness with alveolar fl uid accumulation, steam use would be less useful, but steam has been used in cases of pneumonia and severe congestion from viral infections. As stated, one study found decreased time to recovery when using steam compared to controls.
Steam or heated air use is possible at home during self quarantine. Ideally instead of simple self isolation at home after a positive test, one could self-isolate with access to a heating unit to generate steam or hot air and sinus lavage procedures daily to improve the chance of preventing serious illness. Unsupervised steam inhalation by children has led to scalding and usually is discouraged, unless a carefully temperature controlled system is used. In adults, effective steam inhalation can be obtained by inserting a plastic or metal funnel cone into the appropriate steam column position to conduct steam into the oral cavity and thus avoid exposure of facial surfaces. Steam tents over the head could be used but must have an open side for ventilation.
The goal of steam or heated air inhalation is to prevent serious infection. In cases where exposure to the virus was expected but signifi cant symptoms have not yet appeared, it is not expected that this would require total irreversible denaturation of the virus particles, but rather structural alterations suffi cient to minimize infectivity and prevent the virus from producing serious or lethal symptoms. All virus particles are of differing size, from 70 to 90 nm, and thus require differing heating times to achieve a denaturing temperature. Proteins vary in temperature and time needed to achieve either functional block, permanent functional block, or complete irreversible denaturation. Baking to denature proteins in meat is complete at approximately 160 o F (71 o C) for safe consumption. Figure 10 shows more effi cient systems that could be used for steam production if one did not want to move into the steam fi eld to inhale and then leave the fi eld between breaths to avoid overheating facial skin. In these devices steam heat generation is extremely energetic so it is necessary to measure the temperature of the steam actually inhaled at the end of the mouthpiece straw tube, which must be adjusted to a height suffi cient to achieve a temperature of about 140-150 o F. for 30 minutes would achieve complete destruction, but again either lower temperatures or shorter times regularly could be suffi cient to minimize infectivity.
Steam inhalation should not be overdone to the point of causing unnecessary discomfort. Although hot steam is expected to inactivate virus particles in the open airway spaces, it would be prudent to exercise caution so that the speed with which steam is inhaled should be no greater than normal breathing, to avoid viral particles from penetrating more deeply in the airways. Heated air from a space heater, rather than fro a blower, would therefore also be preferred. Dry heated air has the advantage of being perhaps more effective at heating airway tissue, but the disadvantage of drying out secretions that help remove foreign particles. 15 minutes of dry heated air breathing could be followed with 15 minutes of steam to mitigate this. Note that the usual temperature range in a sauna bath is about 150-170 o F ( 66-77 o C).
The time and temperature required to destroy infectivity of the coronavirus in airways by inhaling steam may be estimated by again turning to Figure 6. Heating at a high temperature but too brief a time is insuffi cient to achieve total destruction, and heating for a long time but at too low a temperature is also insuffi cient. The time-temperature curve must be reached or exceeded to completely destroy virus infectivity. However, it is not necessary to achieve complete irreversible denaturation, but rather a minimization of infectivity. This curve is a guide, and is not necessarily strictly required to prevent serious infection. As promising as this discussion sounds, it must be emphasized here that although steam can destroy the coronavirus in vitro on external surfaces and could block infectivity of human cells in tissue culture, there are no studies of steam use in patients with Covid and any effectiveness is at this point not proven in clinical studies.
A simple but important action is to sleep upright, not lying down. This is because mucus secretions and pus when prone, due to gravity, causes inhaled air to simply fl ow atop the liquid which continues to accumulate and provide a growth medium for infectious agents. Sleeping upright causes fl uid to span an airway lining and force a cough which expectorates the material. Also regularly changing positions while sleeping helps prevent damage from fl uid buildup. These actions are the single most important an individual can do to combat the effects of respiratory infection.
Most water droplets released during human breathing are on the order of 1 um in diameter [15]. Coughing produces larger droplets that travel less distance than smaller particles and settle out of the atmosphere more readily also.   Memorial Day when many cities and states in the U.S. began to "reopen," spikes in incidence began again. In the month of June, while NY continued to decline in reported new cases, the U.S. incidence of new cases rose. This was associated with a % lethality decrease to 5.2% by June 22, with 120,225 total deaths out of 2,298,696 total reported cases. Coinciding with this drop, the world average also dropped to 5.2% with a large increase in reported cases, with 469,378 deaths out of a total of 9,015,582 reported cases. This effect could also be partly due to increased effi ciency of treating the condition, such as use of steroids and RNA replication blocking drugs, and to increased testing of people. The U.S. increased testing capacity signifi cantly after this date so the chart is ended here.
In South Korea the entire course of the pandemic may be mapped from inception to completion since rigorous controls were instituted to bring the incident to an end, including national wearing of masks, widespread testing using tests from the WHO, and contact tracing. Shown in Figures 12,13 are the cumulative confi rmed cases of infection and the deaths that occurred later during the course of the entire incident from February to July, 2020. Note that indeed deaths follow a few weeks behind any increase in incidence, and death reductions follow a lag after incidence reduction occurred. The has been attributed to widespread re-opening of society with new cases of infection rapidly increasing. But the phenomenon also appeared to occur generally in many countries around the world with lethality incidence also at 4.6% due to reported large increases in number of new cases (545,485 deaths among 11,892,382 confi rmed cases). Therefore it has been largely attributed to "quarantine fatigue" coupled with lack of complete squashing of the incidence curve, where people begin to resume more risky activities again. It was expected that the lethality % would again rise to near 5-6% in these countries since deaths of course lag behind new cases by a few weeks. As seen below however, the overall world lethality has remained    in each facility. Jails and prisons with people in close quarters also exhibit high incidence. And African Americans have a far higher incidence of lethality than Caucasian people. This is not only due to the 12% difference in high blood pressure incidence between these groups, but may be largely related to the higher incidence of vitamin D defi ciency which has been recently reported to be associated with higher Covid incidence [17].
The incidence on May 7, 2020 in the most populated state Citation: Sauerheber     On the other hand, principles of the Calculus, namely the fi rst and second derivatives of a function, applied to actual raw data here reveal whether the increasing number of daily deaths are occurring at an increased, or rather a steady or decreased, rate at any particular time. The concavity represents the rate at which the slope of the curve itself is changing over time. Figure   17 is a graph of the accumulated death total from   For example, if a large enough sample could be obtained then virus particles could be centrifuged or purifi ed through ultramicron fi ltration before extracting the RNA for analysis.
This would only detect intact virus particles and could assist health departments with contact tracing to control the spread of active virus, rather than spending resources on tracking non-infectious cases. On July 22, 2020 there were a leading nearly 4 million cases in the U.S., over 2 million in Brazil, over 1 million in India, and nearly 800,000 in Russia in this ongoing, highly fl uid, world-wide pandemic.

Summary
Thoroughly washing nasal passages with hot physiologic saline, and carefully inhaling mildly acidifi ed steam or even heatxed air for a suffi cient time and temperature may be of potential help in impeding the progression of COVID-19 infections.

Acknowledgments
Statements in this article do not necessarily refl ect the views of Palomar Community College or its staff. As a victim of advanced serious pneumonia contracted from direct inhalation of coughed droplets from an ill individual, RDS recognizes the benefi ts of proper steam heat use fi rsthand for ameliorating respiratory symptoms and in the cure of acne and pyorrhea of gums in the oral cavity. New York Governor Cuomo is thanked for the daily detailed press briefi ngs during the height of the pandemic on the East Coast.
As of September 22, 2020, the fi rst day of Autumn, the U.S. total deaths reached over 200,000 among nearly 6.9 million confi rmed cases (2.9% lethality), the fourth worst per capita incidence in the world. Total deaths in the world are 967,000 among 31 million cases (3.1% lethality). Next in line total deaths are Brazil at 137,000, India 89,000, and Mexico 74,000. The U.K. and Israel are re-instituting severe restrictions considered 'lockdowns' to help slow recent spikes in cases. The fact that the Covid-19 pandemic outbreak initially began within yards of a Wuhan laboratory, and has accidentally killed over 1 million people on earth, suggests that the practice of intentionally infecting human cell lines with wild viruses should be discontinued and considered unethical worldwide.