1 COVID-19 : New disease and chaos with panic , associated with stress

COVID-19 (coronavirus disease – 2019) caused by SARSCoV-2 (also known as 2019-nCoV) is a new infectious disease by etiology, but in manifestations it has some similarities with SARS (Sever Acute Respiratory Syndrome) that ravaged several countries of the world around 2003. Coronaviruses are RNA containing microbes that ‘hijack’ mammalian cells to replicate themselves intracellularly, just to be released in large quantities. SARS-CoV-2 fi rst replicates in the upper respiratory tract, as opposed to SARS-CoV viruses in the ‘old’ SARS that attack the lower respiratory tree, especially the lungs and cause severe pneumonia. About 80% of COVID-19 patients are mild, some of them are even asymptomatic and only about 10-20% require hospitalization because of pulmonary edema and rapidly developing bronchopneumonia that often leads to multiorgan failure, especially in older patients with chronic comorbidities or immunocompromised system (e.g., obesity, diabetes mellitus, cardiovascular diseases). The overall worldwide mortality is about 1-2%, but some of the genetic variants of the virus caused 4-6% mortality, especially in densely populated areas, like Northern Italy, New York city, Spain. In the most severe cases a ‘cytokine storm’ (a massive release of cytokines) have been described that aggravate the initial damage in the lungs and heart. Epidemiologically, the true incidence and prevalence of COVID-19, most likely, will never be known because of uneven testing in most of the countries for the viral RNA and/or for the developed IgM and IgG antibodies against the virus. From public health perspectives, the hardest hit areas of the world are those that were not prepared, had a poorly organized or underfunded public health service, and/or did not follow the preventive measures such as social distancing, isolation and frequent hand washing. The poor organization of public health services, especially if associated with initial denial of the rapid spread of the disease lead to chaos, panic and, predictably, sever distress in many people.

COVID-19 (coronavirus disease -2019) caused by SARS-CoV-2 is the subject of lot of scientifi c rapid publications and of news media coverage, because of its rapid, pandemic spread. The name of the virus originates from a similar coronavirus which caused the also pandemic SARS (Sever Acute Respiratory Syndrome) around 2003, and as we will see below, there are some similarities and diff erences between the old SARS and the new COVID-19. One of the best examples of urgency and the need for rapid distribution of objective scientifi c information is the fact that a recent issue of Science, one of the best scientifi c journals in the world, dedicated the cover page and most of its content to COVID-19. The other best weekly scientifi c journal Nature also Праці  This short review article is written at the beginning of April 2020, i.e., within about two months after the declaration of pandemic by the World Health Organization (WHO) and since only a few peer-reviewed scientifi c papers have been published in reputable journals, I also quote data from credible news organizations, such as the BBC, daily Guardian, Japan Times, The New York Times, Washington Post and Wall Street Journal. The review is divided into sections on the etiology, i.e., the new virus, then to new disease COVID-19 and its epidemiology, followed by the ensuing chaos and panic that was bordering on hysteria, associated with stress in several countries.

The etiology: SARS-CoV-2
Viruses are virtual 'cells', or nuclei without cytoplasm. This defi nition implies that viruses cannot live long and multiply without entering mammalian cells, essentially hijacking the cell genetic material and its endoplasmic reticulum in the cytoplasm. Then they multiply in the animal or plant cells, just to be released in a large number, often destroying their host cells that helped the virus to survive and multiply.
Viruses can be classifi ed by many criteria, but probably the most useful distinction is dividing them into DNA and RNA-containing viruses [1]. SARS-CoV-2 is an RNA virus, the 7th coronavirus so far identifi ed ( Table 1). The name of coronaviruses originates from their protein-containing corona-like nuclear membranes. As the SARS-CoV-2 picture on the cover page of Science ( Fig. 1) shows, out of viral membrane protein spikes are T able 1.

Human Coronavirus Types
Coronaviruses are named for the crown-like spikes on their surface. There are four main sub-groupings of coronaviruses, known as alpha, beta, gamma, and delta. Human coronaviruses were fi rst identifi ed in the mid-1960s. The seven coronaviruses that can infect people are:  Праці НТШ Медичні науки 2020, Том 59, № 1 ISSN 2708-8634 (print) Proc Shevchenko Sci Soc Med Sci www.mspsss.org.ua ISSN 2708-8642 (online) 2020, Vol. 59, 1 Огляд Review protruding and serve as the invasion tools for coronaviruses. Namely, these can attach to the ACE-2 (angiotensin-converting enzyme 2) receptor in our cells and after endocytosis, the virus can access the intracellular machinery of the mammalian cell. The receptor attachment and endocytosis are the fi rst steps in the viral hijacking of our cells and the process is best illustrated in a fi gure published in the Science Times supplement of the New York Times [2].
Since discoveries in basic sciences are often not accepted and appreciated, it's worth mentioning that the fi rst coronavirus was discovered in the 1960s by virologist June Almeida, who grew up in Glasgow, UK and left school at age 16, but subsequently mastered electron microscopy as a lab technician and went on to obtain a Ph.D. Her discovery could have been recorded even sooner: an earlier paper featuring her images was rejected as "just bad pictures of infl uenza" [3].
SARS-CoV-2 is remarkably similar not only to the initial SARS-inducing coronavirus from 2003, but also to RNA viruses that caused the Middle East Respiratory Syndrome (MERS) a few years ago, and the seasonal common cold ("fl u"). These coronaviruses mutate very rapidly, and this is one of the main reasons why it is so diffi cult to develop long-lasting vaccine against infl uenzas, i.e., almost every year new mutations occur, hence new vaccines need to be produced. A recent issue of Science published not only the molecular structure of the SARS-CoV-2 (also known as 2019-nCoV), the virus genome but also the structure and composition of protein-membrane and the protruding spikes [4] (Fig. 2) It should be also acknowledged that coronaviruses are the etiologic factors in zoonosis, i.e., diseases when the pathogens jump from wild or domestic animals. SARS-CoV-2 in Wuhan, China apparently jumped from bats to other animals (e.g., civets, cats, wild dogs) that are sold as delicatessens in 'wet markets' that are so popular in China. New studies also indicate that animals exposed to severe or frequent environmental stressors, like temperature extremes, starvation, overcrowding (in farmed or domestic animals), shed the viruses much easier to other animals and humans, than healthy and well-bred animals [6]. It is also interesting that coronaviruses that are pathogens to us, do not make the host animal sick. And these zoonoses are becoming more frequent with global warming, adding one more example of environmental stressors aff ecting human health.

The new disease: COVID-19
It is interesting that the etiologic virus is new, actually novel, and the disease it creates is also new and unusual. Although it has a few similarities with other viral respiratory diseases, it also demonstrated major diff erences. The original SARS virus in 2003 attacked mainly the lower respiratory tract, especially the lung, and created severe bronchopneumonia that was exceedingly diffi cult to treat. The SARS-CoV-2, on the other hand, attaches mostly to the upper respiratory tract, e.g., nose and nasopharynx [7]. This diff erential target specifi city is the main reason that COVID-19 starts with a dry cough, often before the detectable fever, within 3-5 days after exposure.
Then, depending on the immune status of the infected person, the clinical progression may include the spread of the virus to the   The rapidly developing pulmonary edema is the reason for shortness of breath, and the need for respiratory ventilators in severely ill COVID-19 patients. If increased vascular permeability and edema, which are the fi rst stage in any acute infl ammation, not treated early, the cellular stage of infl ammation is ensuing when infi ltration of leukocytes in the next response to early tissue damage. This may progress to mild or severe bronchopneumonia that is the cause of death in the minority of COVID-19 patients. Fortunately, in about 80% of patients, the symptoms are mild or moderate, and only in 10-15%, the outcome is death. But the main concern from the public health point of view is that 5-20% of the infected people remain asymptomatic, i.e., unknowingly they may spread the virus, especially if they do not wear appropriate masks [14,15].
Comorbidities and pathogenesis of COVID-19: -Another important clinical and public health pattern is emerging that seems to be consistent from the very early reports from China to the most recent cases in Italy, Spain & USA: the hospitalized patients who suff er the most severe outcome are those who have other underlying chronic diseases, such as diabetes mellitus (DM), obesity, hypertension, chronic lung and cardiovascular diseases ( Fig. 3) and/or naturally compromised drug-induced immune suppression [16,17]. The underlying mechanism is not clear, but a few elements in the pathogenesis of very severe COVID-19 are emerging, e.g., nonre-  sponsive or poorly responsive immune system and the already existing tissue damage in the lungs and heart. It may be like the obesity-DM type 2 connection: obesity leads not only to non-responsive insulin receptors but also to sluggish immunity which allows the proliferation and dissemination of coronaviruses in the body. New reports are also emerging indicating "multi-organ failures" in a deadly form of the disease: infl ammation in heart muscle, especially around the conduction system in the heart resulting in fatal cardiac arrhythmias. The existing atherosclerotic plaques become more prone to rupture that will lead to, often occlusive, thrombus formation, which is aggravated by abnormal blood coagulation, as fi rst reported in patients from Wuhan, China [17]. In patients with COVID-19-related pneumonia, 10% had venous thromboembolism that contributed to their death. Almost half of COVID-19 patients have blood or protein in their urine, indicating kidney damage. Gastrointestinal (GI) symptoms and signs (e.g., nausea, vomiting, diarrhea) have also been reported and the GI signs may precede or follow the upper respiratory manifestations [18].
Very recent data and publications indicate that the multi-organ involvement and pathogenesis of COVID-19 is more complex and detrimental than initially thought. This is very nicely integrated and illustrated in a very recent review article in Science [19] (Fig. 4). It confi rms that although the initial target in the pathogenesis is the respiratory tract, including the lungs, with direct damage to the alveolar epithelial and endothelial cells, other organs are also involved, especially in the minority of very severe cases. In this sequence, damage to the liver, kidney and the GI tract has been documented, but lesions in the heart, blood vessels, and brain are the major contributors, in addition to pulmonary edema, to the cause of mortality in very ill COVID-19 patients. The fi gure also includes the recently identifi ed early sign and symptoms in this disease: the loss of smell because of viral proliferation in the nose in some of the infected people.
Thus, regarding the frequently discussed question "how SARS-CoV-2 kills" certain patients, i.e., by direct organ damage or via "cytokine storm" (reviewed in the next section), we could probably state that by both pathways [20].
The 'cytokine storm' -Among the complications of COVID-19, a new syndrome, the 'cytokine storm' is emerging. 'Cytokine storm' is a massive release of infl ammatory cytokines, in a second wave of secondary cytokines ( Fig.  5) in response to SARS-CoV-2 or infl uenza virus, i.e., when the release of defensive cytokines is much larger and last longer than in the usual infl ammatory response to microbial or viral invasion [20]. The 'storm' may occur during the clinical course of COVID-19 and rarely in infl uenzas, and it often kills the patient… Even worse, it may develop 3-5 days after recovery in healthy-looking individuals and may exacerbate pulmonary edema, pneumonia, and cardiac complications.
Very recent studies started to shed light on the molecular mechanisms of 'cytokine storm'. Namely, during infection, our T-lymphocytes are activated to release cytokines which trigger additional T-lymphocytes to be made, which release more cytokines. Among the proliferating lymphocytes, cytotoxic T-cells roam the body and kill infected cells to stop the increased production of viruses that cause COVID-19 [20]. Normally, cytotoxic T-lymphocytes target only infected cells, but when the immune response goes into overdrive, these cytotoxic T-cells and the massive release of cytokines damage or kill healthy cells in our organs, especially in the lungs and heart. This storm is the major cause of mortality in about half of the 20% of hospitalized COVID-19 patients. Fortunately, it is relatively easy to diagnose the 'cytokine storm' by laboratory tests that show elevated serum ferritin level (the usual 200 ng/ml goes up to 500-800 ng/ ml), accompanied by also increased serum D-dimer proteins and lactate dehydrogenase enzyme, originating from liver and heart [20].
Because of the clinical importance of 'cytokine storm', recent intensive research revealed an additional molecular/biochemical pathway: "glucose metabolism pathway [is] critical to the dysregulated immune response that kills many infectious disease patients, including those with COVID-19" [20]. The other main culprit is the transcription factor interferon regulatory factor 5 (IRF5) which is critical for pro-infl ammatory cytokine production, and if it is genetically deleted in mice, the animals are protected against infl uenza-induced cytokine storms. During the   infl ammatory response to infections, glucose metabolism is upregulated, in part to provide an energy source to our immune cells. The specifi c glucose metabolism pathway now identifi ed is the hexosamine biosynthesis pathway which leads to the production of uridine diphosphate N-acetylglucosamine (UDP-Glc-NAc)-pronounced UDP-GlickNack (Fig. 6). This nucleotide sugar is sometimes added to proteins in a process called O-GlcNAcylation. Namely, O-GlcNAcylation of IRF5 is necessary for the cytokine-producing activity of transcription factor IRF5 [21]. The research team also showed that patients infected with infl uenza coronavirus have higher blood glucose levels and more O-GlcNacylation of IRF5 than healthy controls. Furthermore, blood glucose levels correlated tightly with levels of infl ammatory cytokines [19].

Tests for COVID-19 detection.
-The growing number of approved tests around the world (so far more than 25 tests have been approved by the USA FDA), the confusion, as well as intentional and unintentional misinformation, is also spreading in the news and social media, often even in the scientifi c literature. Thus, it is important to clarify some facts and to distinguish the two types of tests so far available in most of the countries: • Direct detection of SARS-CoV-2 (the new offi cial name of the virus) which causes COVID-19: These tests detect the viral RNA fragments in the mucus secretion (obtained by upper respiratory tract swabs that are inherently prone to error) or in the blood (more reliable and accurate). These biochemical methods usually involve PCR (polymerase chain reaction) tests that could be performed, until recently, only in specialized molecular pathology labs. At the end of March 2020, the FDA approved a very rapid PCR test that can be performed in offi ce/desktop type "ID NOW" instruments produced by Abbott Labs. These instruments are in common use to detect infl uenza and other viral or bacterial products. With this technique, positive qualitative results can be seen in 5 mins, negative ones in 13 mins. To measure the viral levels of RNA in the blood, samples still must be sent to specialized labs. A very recent study, in part originating from China indicates that "throat washing outperforms nasopharyngeal swabs for coronavirus detection" [22].
• Measuring the antibodies against SARS-CoV-2 in the plasma, obtained by centrifugation the venous blood samples: Recently approved methods use only saliva or a drop of blood, obtained after needle pick of fi ngers, as source material for the qualitative detection of specifi c IgG and IgM. Thus, these tests do NOT detect the virus, only our antibodies that develop in a few days or weeks after the exposure, irrespective if a person is sick, or asymptomatic. Positive results may also indicate that the patient is immune to this virus. This is the medical reason why people with the defective or drug-suppressed immune system are so susceptible to COVID-19, i.e., since they cannot develop antibodies against the virus.
It's also important to understand that there is no such thing as "drive through testing" -only drive-through sample collection (of swabs) that need to be sent to specialized labs, where the results may be ready in 2-4 days.
Prevention and treatment. -As with any infectious disease, the best medical approach to COVID-19 caused by the SARS-CoV-2 is to eliminate, kill the bug… But since there is no truly aff ective, FDA-approved antiviral drug for this disease, we must rely on our own immune system. Naturally, our immune cells, mostly B-lymphocytes and plasma cells develop IgG & IgM antibodies against virtually all pathogenic bacteria and viruses. If a patient recovers from an infectious disease, these antibodies can be recovered and concentrated from their plasma. The purifi ed or synthetic antibodies may then be administered to severely ill patients and this has been the standard of medical care for more than 100 years before antibiotics became available following World War II.
During the COVID-19 pandemic, this kind of natural plasma transfusion has been used successfully and several companies, as well as government agencies, are rushing to synthesize large quantities of eff ective IgG & IgM antibodies. But until these antibodies will become commercially available, we may use other natural products. Among these, our fi rst line on nonspecifi c defense against almost any type of cell & tissue injury is the antioxidant system which protects against oxidative stress in our body: • Vitamins C and E are the best known -but we have to take them in higher doses than the 'daily recommended amount'. The water-soluble vitamin C need to be ingested in 1-2 grams/day (e.g., 1 g or 1000 mg tablets in the morning and evening). The lipid-soluble vitamin E, if taken as 400 IU (180 mg), is probably enough every other day. • Selenium (Se) is an essential trace element for animals and humans that need to obtain selenium from dietary sources. Plants convert selenium mainly into Se-methionine & selenocysteine which are potent antioxidants. Furthermore, glutathione peroxidase (GPx) is a selenium-containing antioxidant enzyme & the GPx/glutathione system is a major defense against oxidative tissue damage (stress). Since the about 30 selenoproteins are also immunomodulators, we need to consume at least 200 micrograms of organic selenium tablets, obtained usually from yeast (the inorganic selenium present in 'multivitamins & multimineral' tablets is not absorbed from our gut). • Zinc is not a direct antioxidant and no COVID-19 magic bullet but has shown to help with other coronaviruses that also cause common cold. There zinc lozenges helped to shorten the misery phase (e.g., running nose, soar-throat) of common colds.
Since the COVID-19-inducing virus accumulates and proliferates in the upper respiratory tract, i.e., nose and nasopharynx/throat (as opposed to SARS-inducing coronavirus which attacks the lower respiratory tract, like lungs and lower bronchi), based on experience with zinc lozenges in common cold, the natural alcohol (22% ethanol) present in Listerine-like lozenges may also be helpful in the current pandemic (e.g., some of us use Listerine gargles several times a day…) Nevertheless, let us keep everything in perspective: all these are temporary measures until vaccine and new, specifi c antiviral drugs will become widely available.
It should be emphasized that we are referring here only to chemical means of prevention, and this should be parallel or preceded by physical means of prevention, such as frequent handwashing with soap and water, wearing masks ( Fig. 6) in public spaces as well as a social distancing of at least 2 m. Be aware that not all masks created equal: the most eff ective ones are the N95 masks that exclude 95% of the very small, tiny particles (i.e., 0.3 microns, in comparison the human hair is about 70 microns). (Fig. 6). The next best masks the medical/surgical ones that have 3-ply of special material and protect against 60-80% of small particles.
Another important dictum of public health and preventive medicine is that 'if primary prevention fails, we have to start secondary prevention', i.e., treatment. As stated before, there is no approved drug treatment for COVID-19 in any country of the world, -but there is the emerging pipeline of potentially other medicines that proved to be eff ective in other viral or bacterial diseases [23]. Among these, apparently, the most eff ective seems to be is remdesivir which was used successfully again Ebola virus, and several controlled clinical trials are now on the way with this drug around the world; University of California Irvine (UCI) Medical Center, under the leadership of Dr. Alpesh Amin was the fi rst to start clinical trial with remdesivir. Other drugs in the pipeline are chloroquine and hydroxychloroquine which have long been used for treatment of malaria, rheumatoid arthritis and lupus, but these drugs have a narrow therapeutic window and people who used these for COVID-19 prevention without medical supervision often died because of cardiac toxicity [19,20]. Chloroquine derivatives block the attachment of SARS-CoV-2 virus spikes to ACE-2 receptors on human cells. Colchicine is an FDA-approved anti-infl ammatory drug to treat gout and pericarditis but now applied to mitigate the 'cytokine storm' in severe COVID-19 patients, along with or independently from the also potent anti-infl ammatory glucocorticoids. A group of researchers at the Montreal Heart Institute and the University of Montreal aggressively investigate to stop the overproduction of immune cells and cytokines that damage the lungs in the 'cytokine storm', resulting in acute respiratory distress and multi-organ failure (19,20). But as much as these drug trials and investigations are important now, these are not replacement for the intensive research to fi nd specifi c antiviral drugs and vaccines to treat or prevent COVID-19, respectively.

COVID-19 epidemiology and public health
If we learned anything so far from the pandemic of this new disease is the importance of public health that my former dean at the Harvard School of Public Health Dr. Howard Hyatt defi ned 'our patient is the nation'… Most countries of the world neglect the funding for public health, dismantle, diminish, or under-fund national surveyance and preventive programs.
The USA is one of the worst examples in this and now we are paying have a price for it (Fig.  7). Most of the nation-states of Eastern Europe do not even have modern schools/faculties of public health at university levels… Even worse is the almost total lack of education of our children about the basic principles of public health and epidemiology in our elementary and high schools. Should we then be surprised that people accept misinformation about the  One of the fi rst principles of epidemiology is that we should not look only at the total number of cases, but rather the ratio of cases per unit of population or percent (%) of the total population in the state or county/ region or city. For example, as I am fi nishing this review article in the middle of April, the total number of COVID-19 positive cases world-wide has been 2,243,512, with 154,209 deaths, while the USA had on April 17, 2020, 701,475 cases and 37,054 deaths (24). If we look at these numbers as a ratio, e.g., per 100,000 or millions of people, we get a very diff erent and more realistic picture wherein both the number of COVID-19 cases and the number of deaths in Spain, Switzerland, and Italy show the worst statistics (Fig. 8). It is interesting that some of these statistical comparisons, originating from Europe and USA, do not include Chinese data -in part, because by numerous experts believe that the 'Chinese data are suspect', they keep changing, e.g., even in the middle of April 2020, the Chinese death toll suddenly jumped, apparently due to their initial underreporting thousands of cas-es in some parts of China… Nevertheless, as the colored world map indicates (Fig. 8), it is probably safe to assume that the number of COVID-19 patients in China was not as prevalent as in some countries of Europe or in some states of the USA.
Another scary example of lack of epidemiologic insights and public health perspectives is not being able to distinguish the prevalence (total number of cases in a population) from incidence (new cases per day or week or month) and reporting these numbers only in daily totals. In California, we have seen the daily deluge of TV news and other news/social media reporting the TOTAL numbers that enhance the anxiety, bordering on hysteria in some segments of the society. Surely, every new case and death are a tragic example of our inability to save lives, but if we look at these numbers as PERCENT changes, the most recent data indicate much rosier, almost encouraging picture (Fig. 9). Namely, the percent changes in both new cases and deaths in California are dropping and started to 'fl atten the epidemiologic curve', most likely because California was the fi rst (on March 15, 2020) state, among the 50 states of the in the USA, to order a strict 'stay at home order' and closing all public gatherings, including sport events, schools, restaurants, bars, and non-essential businesses.  Bending the curve and case fatality ratios. -'Flattening the curve' is frequently used term during this pandemic both in the scientifi c literature and in the lay press. It also refers to fl attening the peak in the rapidly rising incidence of new cases that may overwhelm the capacity of the healthcare system in any community. The underlying logic is that if we slow the occurrence of new cases, e.g., by social distancing, contact tracing, and isolation, the slow rise of new COVID-19 cases could be handled by the available outpatient clinics and hospital beds. Epidemiologically, it refers to the decreasing the daily incidence of new cases or COVID-19 deaths, eventually reaching a pick, then starting a decline. As shown in Fig.  10, most of the countries started this decline, except the USA, due to multiple reasons, as we will see later in this review.
Another important epidemiologic and public health parameter is the 'case fatality ra-  tio' that refers to the ratio between confi rmed deaths and confi rmed clinical cases (Fig. 10).
In this COVID-19 pandemic, in the case fatality statistics, unfortunately, Italy is on the top of the curve, much above the world average, while Germany, South Korea, and Iceland are below the world average. Iceland, in this case, deserves special attention… Probably because it is a relatively small, isolated country, led by enlightened public health and political leaders, the majority of the population was tested, a few cases have been detected, then traced and isolated. Then it should not be surprising to all of us that from the public health point of view, Iceland is the best country in the world, especially in this pandemic.
This brings us to another surprising, sad conclusion: we should not blame only China since most of the declared "new cases" are unreliable since it depends on what part of the population has been tested either for SARS-CoV-2 RNA fragments or antibodies against it… The USA is probably one of the worst examples in this, since test kits, despite all the promises and predictions are still lagging… How can we then tell what the REAL incidence of disease is if we do not test the majority of the population? Even worse (and only a public health-trained pathologist can say or write this), we can only count death bodies with great certainties. This is one of the reasons that we have this surprising distribution of COVID-19 confi rmed cases vs. deaths per million population (Fig. 11): African countries (in the lower let of the distri-bution) have low death rates because they don't test the majority of the their populations, while wealthy countries of Europe that try to test most of their inhabitants have the highest rates of confi rmed COVID-19 cases of death rates per millions of their population (Fig. 11). Sadly, we will never know the real prevalence and incidence, because the large parts of the population were not tested (25), either because of the non-availability of test kits or poor organization of public health services or for other reasons. More concerning is what the recent results and estimates in California indicate: the more realistic prevalence of COVID-19 cases maybe 40-50 times higher than the current infection rates indicate…

Comparison of COVID-19 calamities vs.
other pandemics. -When we are in the middle of the public health crisis, it is natural to assume that it is terrible, we have never seen something similar or never lived through, but we have to put this pandemic in perspective… The best example is probably the infl uenza epidemic that returns almost every fall or winter and it is caused by another coronavirus: when a lot of people are panicking about COVID-19, they forget that they may get "fl u" more likely than the new disease… The prevalence of "fl u" is almost 10 times higher than that of COVID-19, but fortunately, 'fl u' mortality is lower (0.1 % vs. 1-2 % of COVID-19). But, despite lower mortality of 'fl u', because of its much higher prevalence, more people die of infl uenza than that of COVID-19.  Another useful comparison is to compare deaths in each country with other main causes of mortality. In the USA, the CDC (Center for Disease Control and Prevention) This season CDC estimates that, as of mid-March, between 29,000 and 59,000 have died due to infl uenza illnesses. Add to that the misery of hundreds of thousands of fl u-related hospitalizations and millions of medical visits for fl u symptoms this season. This is like the current COVID-19 deaths of more than 37,000 in the USA. This year's fl u season will be possibly less severe than the 2017-2018 season when 61,000 deaths were linked to the virus. Globally, the World Health Organization (WHO) estimates that the fl u kills 290,000 to 650,000 people per year, vs. the COVID-19-related more than 155,000 deaths until now [26].
Comparison with other seasonal infectious diseases may give us some hope since most of the other seasonal diseases show a clear pattern of waxing and waning over the years (Fig. 12) [27]. The incidence of these diseases decreases for several reasons, one of these being the warm weather, like with infl uenza… Population density is another major factor for the rapid spread and high prevalence of infectious diseases (Fig. 13). Expert opinions are sharply divided with COVID-19; some predicting a drop in new cases during the summer, but others, especially some of my alumni at the Harvard School of Public Health doubt that. New data on the prevalence and incidence of new COVID-19 cases in hot Brazil and Australia indicate that this new disease may persist even during the hot and wet summer months… There are also pessimistic predictions that the second wave of COVID-19 cases might be much worse than the initial prevalence.

COVID-19: Chaos, panic and stress
Chaos and anxiety are often seen in epidemics, especially when it grows to a pandemic level. As a recent article stated, "crisis response has always been chaotic" (Fig. 14) which might be an exaggeration but citing the example of 'Spanish fl u' (1918) and the Great Depression (1933) in the USA, the article quips "we start with inertia, bestir ourselves with hubris, move on to bungling, and spice things with venality" [28]. These articles also analyze the mistakes and lessons learned from the 1918 pandemic, com-  . Cities that shut down public gatherings, closed shops, factories, and schools very early in the 1918 pandemic had a much lower number of infl uenzas cases and mortality, in comparison with those that reacted late or initially denied the existence of any danger [29].
But we do not even have to go back to the early 20th century -we have examples of disorganized or unresponsive leadership in the COVID-19 pandemic: "Where Germany had success in fi ghting coronavirus, Britain failed: "Johnson proclivity for wartime bravura rings hollow in the midst of a public health emergency" [30]. UK has performed about 350,000 tests and almost completely dropped any attempt of contact tracing -leading to chaos, panic and anger in their population and healthcare sector. Germany, on the other hand, gave itself a head start in testing that resulted in much better public health outcomes.
In the Americas, Brazil and the USA are bad examples when and how to react to a pandemic like the COVID-19 storm… Although the WHO announced the pandemic on January 30, 2020, when it was obvious that the new virus was rapidly spreading around the globe, the USA did nothing in the entire month of February; no testing, no suggestions for social distancing or other preventive measures… In some circles, COVID-19 was considered just 'another fl u-like disease that will disappear with warmer weather'… It was only the State of California that on March 15 fi rst announced the state-wide stayat-home order, closures of schools, shops, and all non-essential businesses… Other states followed that a few days or weeks later.
No wonder then that some segments of the population were bewildered, confused and angry -that lasts until the present days. Furthermore, that led to panic buying of food, toilet papers, sanitizing tools, followed by a rush on face masks, bordering on hysteria. If we combine these stressors and add home isolation, loneliness, depression, and anxiety, the predictable outcome is a stress reaction, i.e., distress. All this could have been prevented by good planning, 'prepare for the worst, -hope for the best', and follow the basic tenets of public health and preventive medicine. i.e., test/ detect the disease, isolate the infected person, followed up with contact tracing.
The stress of COVID-19. -As stated above, the distress was almost predicable in this pandemic, also illustrated in Figs. 14&15. "Stress is the nonspecifi c response of the body to any demand made upon it", as we stated and discussed in our recently published book on Stress [31]. By defi nition, stress should be caused by diff erent factors (stressors) eliciting similar neuroendocrine changes, like the rapidly released catecholamines and sustained, elevated levels of secreted glucocorticoids [31]. The multifactorial etiology is almost given in a pandemic like this, e.g., anxiety about what the future may bring, depression, isolation, family arguments in closed quarters, real or perceived food shortages, unemployment, (temporary) loss of income, all culminating in increased domestic violence and suicides. The more psychological, societal, and physical stressors hit us, the more serious is the resultant distress reaction [31,32].
The distress may involve all segments of the population, but the most severely aff ected are the healthcare workers (e.g., emergency room and intensive care unit doctors and nurses), and contact tracers. The additional stress on healthcare workers, besides almost all the other factors that hit any segment of the society, are the long hours they must put in, in part because of the shortages of doctors and nurses, lack of suffi cient personal protective equipment, triaging patients that cannot be saved either due to lack of respirators or hospital beds, seeing dying patients… No wonder then that in some hospitals nurses and others demonstrate (Fig. 15), demand improvements or a few refuses to work to protect themselves and their families from potential exposure to the new virus. All this is compounded by the fact that thousands of doctors and nurses died worldwide, apparently in a much larger percentage than any other segment of the population.
Another unappreciated and stress-prone profession are the contact tracers [33] who are doing a critical, often very stressful job in the initial stages of epidemiology: after detecting a virus-positive, symptomatic or asymptomatic patient, they have to speak to the patient, often in their home. Sometimes, they don't let the contract tracers in, or if the patient agrees to speak, s/he may deny that they are in danger and refuse to reveal who they were with during the preceding week, since the contacts may also need to go to self-isolation for at least for two weeks, losing potential income for a few weeks… Then, the contact tracers must speak to all the people whose names were revealed to them, going through the same, often unpleasant conversation as with the initial patient. And this could be repeated 10-15 times a day… Thus, that it's not surprising that thousands of contract tracers are needed in the USA, and only after their entry salaries were substantially increased, like in Massachusetts [34], candidates showed up in throws, despite the distress they may face, since the stressful job may relax the fi nancial burden in their families… We should also mention a few remedies in the pandemic stress, and fortunately, the social media and lay press are full of stress-reduction exercises, diets, and other measures. Among these ones of the simplest, science-proven intervention is meditation, yoga and the easy, seven-minute workout (Figs. 15, 16). All these should be preceded or associated with a healthy diet (with a lot of vegetables, minimal carbohydrates, and salt), plenty of hydration with regular tap water, daily exercise (at least 30 min of walking), breathing exercise, and (if available) plenty of sunshine… If none of these steps help, to avoid going into a deep depression or alcoholism, or domestic violence, obtaining professional help from licensed mental health experts is crucial! Lessons learned and planning for the future. -Despite all the challenges, chaos, panic and stress associated with the COVID-19 pandemic, we should extract some benefi cial lessons. Although there are pessimistic predictions (e.g., 'end of globalization' -actually, we need coordination and cooperation in response to pandemics like the new coronavirus), and truly futuristic musings on 'how pandemic could reshape civilization', a rational, multidisciplinary global plan should emerge.
Among the fi rst things we should be ready to accept that zoonoses, disease caused by viruses jumping from animals to humans, are becoming more prevalent, and these viruses mutate very frequently [5]. This makes very diffi cult to develop new vaccines and specific antiviral drugs. Next, we should be vigilant that these zoonoses may linger long time, especially in rural areas and if the fi rst symptoms are very nonspecifi c or fl u-like, and they may be detected too late. Also, we must be ready that the new infectious diseases usually 'explode' in densely populated areas of any country. This was the case with COVID-19 which started in the huge, congested city of Wuhan, China, just to be reincarnated a few months later in the densely populated and industrialized Italian north. The rapid spread of COVID-19 in the USA confi rms that, since it 'exploded' in New York city and its surrounding areas that are densely connected by public transportation (e.g., buses, subways, trains, ferries) (Fig. 13). Chicago, Detroit and Seattle have smaller populations, but they heavily relay on public transportation where social distancing is almost impossible to practice and enforce. The high prevalence of cases in New Orleans is apparently caused by the fact that the city ignored the early warnings in middle of February and allowed the hugely popular Mardi Grass street-city wide celebrations and gatherings that actually lasted several days… This population-density theory of epidemiologic spread of respiratory infectious diseases may also explain the relatively small case number in the huge cities of California, (e.g., Los Angeles County, with its more than 10 million people is like New York City; and San Francisco with the Bay Area, with its 6 million inhabitants) had relatively low prevalence of COVID-19 cases (Fig. 13). These big California cities have minimal public transportation since people traditionally use personal cars, resulting in almost daily, notorious traffi c congestions when people sit in their idling cars, well isolated from each other… The other factor is the previously mentioned fi rst state-wide shutdown that the governor of California fi rst introduced in the nation on March 15, 2020.
As with COVID-19, the "asymptomatic transmission is the Achilles' heel" (14) of any existing or emerging epidemic. That is one more reason to rush with the development of new vaccines, but that may take about a year, just for early testing of its eff ectiveness… Then the mass-production of the vaccines usually requires 2-4 years.
Last, but not least, one of the most important lessons should be that cities, states and regions around the world should not neglect, underfund and underplay the importance of public health, where 'nation is the patient'. This should in- clude establishing new, modern schools of public health, especially in eastern Europe, and increase the support for existing schools, along with investing in public health education and research. After all, the best treatment of any disease as its prevention, which makes sense even economically. We owe this not only to the current, post-COVID-19 generation, but also to our children and grandchildren.