Richard Stein

and 5 more

Conspiracy theories, omnipresent in traditional and modern societies [1], span demographic strata and political differences [2] and have fascinated people for ages [3]. While many conspiracy theories are harmless and may even be entertaining, the ones related to medical and public health topics can be particularly dangerous for the individual and collective well-being [3]. This second category includes misinformation and conspiracy theories related to COVID-19, which is likely one the most significant pandemics of our lifetime. Compounding the challenges that it opened for the economy, social and political sciences, and biomedical, translational, and clinical research, COVID-19 also propelled discussions about conspiracy theories and media health literacy to the forefront of public health in ways that were nearly impossible to predict.Situations of crisis, fear, and uncertainty increase the likelihood of conspiratorial thinking [4]. A key difference between COVID-19 and the 1918 flu pandemic, which is sometimes used as a reference, is that a highly interconnected world, to a great extent on social media, is setting the stage for distributing information and misinformation about COVID-19 [5]. In the short time since the beginning of the pandemic, the number of COVID-19-related conspiracy theories increased and propagated on social media. According to some metrics, online sensationalist and conspiratorial sites and articles generate more user engagement than more reputable sources such as the World Health Organization and the US Centers for Disease Control and Prevention [6] or mainstream news media such as the BBC and New York Times [7].An important way in which misinformation related to COVID-19 differs from misinformation that impacts other health-related topics is its multi-layered nature, in the sense that it concomitantly targets multiple facets of the pandemic. These include misinformation and conspiracies casting doubt on the very existence of the virus, minimizing the value of long-proven preventive strategies, and questioning the safety, efficacy, and potential ulterior motives of a vaccine that is not even available yet, and not sure it will ever be. In the wake of COVID-19, an ocean of misinformation [8] that spans all these domains has accumulated faster than for many other health-related topics. As a result, mutually incompatible and contradictory conspiracy theories were sometimes being endorsed and circulated together [9]. Misinformation and disinformation during the pandemic contributed to the demonization of health care workers [10]. As patients avoided hospitals or had difficulties making appointments in the wake of the pandemic, they experienced delays in accessing healthcare for various medical conditions [11-14]. An increased mortality from acute heart disease was reported in several countries [15]. In this context, ambiguous messages about the pandemic endanger the delivery of healthcare in virtually all clinical areas and can place patients at a heightened risk of complications.Some conspiratorial claims include assertions that COVID-19 is a hoax, arguments that the virus was created artificially [16, 17] and spread on purpose [18] as a bioweapon [19], or allegations that governments are using the emergency situation to pursue their anti-democratic goals [20]. As early as in January 2020, social media stories contained claims that 5G technologies either caused or accelerated the spread of the pandemic [21, 22]. Other conspiracies argued that people in power are taking advantage of the pandemic as a plan to inject microchip quantum-dot spy software and monitor people [8]. Videos or articles perpetuating these theories were viewed by millions of people on social media platforms. Another conspiracy theory, circulating in several languages, claimed that the swab test reaches the back of the nasopharynx and damages the blood brain barrier, and urged people to refuse testing [23, 24]. Yet another conspiracy theory, spread thousands of times on social media, claimed that testing itself infects people with the coronavirus and urged them to refuse testing [23].The use of face masks has become a passionately debated topic [25, 26], even though many studies support their benefit against SARS-CoV, SARS-CoV-2, MERS-CoV, [27, 28], flu, and seasonal coronaviruses [29]. Some people wearing masks have faced alienation or discrimination [30]. Claims on social media that the virus crosses the masks, and therefore the mask is useless, have been circulating together with claims that the virus persists on the surface of the mask and wearing a mask would, therefore, infect people, or that the mask could “activate the virus” [31]. Other social media claims include warnings that masks may cause fungal or bacterial pneumonia [32] or oxygen deprivation and carbon dioxide poisoning [33], an especially worrisome complication for children and pregnant women, despite evidence that no differences exist in heart rate and oxygen saturation between pregnant and non-pregnant women wearing N95 respirators for a short period of time [34].Most recently, warnings on social media advised people of the dangers of having their temperature checked upon entering closed spaces, based on the false claim that infrared light damages their pineal gland, when in reality infrared thermometers detect radiation emitted by the body [35, 36]. Other pseudoscientific claims advanced unproven therapies, including homeopathic arsenic-based products or colloidal silver solutions [22], advocated for prophylactic vitamin megadoses [37], promoted vitamin C and garlic as miracle remedies [38], and recommended ginger, hot pepper, and lemon to limit the impact of the pandemic [39].A vaccine is highly anticipated but not yet available, and it is uncertain which of the several vaccines that are currently pursued will succeed, if any. As of late July 2020, ~200 vaccine candidates were under active development and 15 were in human clinical trials [40]. Prior to the widespread use of social media and crowdsourcing to obtain medical information and advice, the spread of infectious disease outbreaks was usually limited to confined geographic locations; now, the availability of misinformation widens the footprint of its harm. Vaccine-related misinformation on social media is rampant. In late April 2020, a false story that circulated claimed that one of the first volunteers in the UK during a COVID-19 vaccine trial died from complications [41]. Another conspiracy theory claimed that the vaccine will be used to establish a global surveillance network [42]. Additionally, various social media posts are already providing advice on how to avoid the vaccine. A WebMD poll in late July 2020 found that if a COVID-19 vaccine was available, fewer than one-third of the respondents would take it in the first 90 days, and fewer than one-half of the people would take it in the first year [43].Each of these conspiracy theories may be destructive in itself. While it is challenging to demonstrate the direct influence of any given conspiracy theory on an individual’s behavior, there are some suggestive trends. In the wake of the misinformation linking 5G technologies to the pandemic, attacks were perpetrated against telecommunication masts on several continents, and engineers were subjected to verbal and physical abuse [44]. Between April 2-6, 2020, it was estimated that at least 20 phone masts were damaged in the UK. This included a hospital in Birmingham, UK, whose phone mast was set on fire [21]. There are previous examples to illustrate the heavy price of denial and misinformation in the wake of an infectious disease crisis. During the HIV/AIDS pandemic, claims that the virus does not exist or that it does not cause AIDS were incredibly harmful [38]. When the South African government, in its widely criticized denialist approach [45], withheld lifesaving drugs and promoted non-tested alternative solutions instead [46], the public health damage was incalculable and estimated to have claimed >330,000 lives [47-49].Anti-vaccination rhetoric and conspiracies are not new. They existed since Edward Jenner’s time, when some rumors claimed that vaccination will make people grow horns [50, 51]. The themes have been strikingly similar across time, and include distrust of the medical establishment or governments mandating vaccination; revulsion at the idea of introducing unknown substances into the body; accusations that the ingredients are harmful; or suspicion that the real motives behind vaccines are to make people sick or to control the population. Like many conspiracy theories, some worries over history have been rooted in a kernel of truth. Such examples include the Tuskegee Syphilis Study, where the government and the medical establishment have abused their power at the cost of people’s health [52-54]; the rare cases when contaminated vaccines caused harm [55-57]; or instances when vaccination was used as a cover for intelligence operations [58]. During the Zika virus epidemic, some of the conspiracy theories claimed that the disease was caused by vaccines, and an Australian anti-vaccination Facebook group emphasized that the vaccine used to prevent diphtheria, tetanus, and pertussis in pregnant women was introduced in Brazil only months before the Zika outbreak [59-61]. This makes it understandable, to a certain extent, why some people continue to view vaccines with suspicion.A paradox in the vaccination debate seems to be the fact that even though vaccines have well-known and widely-reported adverse effects [62-64], most conspiratorial discussions focus on false claims about adverse effects that were never linked to vaccines, while the actual adverse effects, that scientists and regulators are attempting to address and avoid, are rarely discussed, if ever. What makes the COVID-19 vaccine refusal so different is that the debates are directed against a vaccine that was not even manufactured yet. Amidst these multiple layers of misinformation and conspiratorial discourse, the potential for damage is unpredictable, poignant, and difficult to manage, and the challenges associated with bringing the pandemic under control adopt a new, amplified, and more acute perspective.On the bright side, overall, social media harbors a larger volume of accurate information than misinformation [65]. The sobering news is that misinformation seems to be more popular [65], become more prevalent over time [66], and spread faster, farther, and deeper [67, 68]—though whether this is true of health emergencies is less clear [69]. Several studies found that COVID-19 conspiracy beliefs negatively correlate with COVID-19 health-protective behaviors [70, 71], and individuals who support COVID-19 conspiracy theories are less likely to accept the advice of public health experts [72].Even though social media made it easier to disseminate misinformation, it is not clear to what extent it causes more people to believe in them. Surveys of public opinion around conspiratorial beliefs, particularly during an ongoing global event such as the current pandemic, should be interpreted with caution. The responses to such surveys depend on the questions asked. As noted, conspiracy theories often make a multitude of specific, sometimes mutually contradictory claims; COVID-19 conspiracy theories are no exception. As a result, it is difficult for a single survey to cover all variants of any given conspiracy theory. While research suggests that endorsement of one conspiracy theory predicts the endorsement of others, general conspiratorial ideation has been found to be relatively weakly predictive of general conspiracy claims about COVID-19, and even more weakly predictive of a plethora of specific claims [71]. Even more basic aspects of survey design such as the wording of available response options can have a substantial influence on responses [73]. The extent to which such surveys over- or underestimate true engagement with conspiracy theories is therefore unknown. It must also be noted that misinformation constitutes only a small fraction of people’s news consumption, and that news consumption itself is only a small fraction of people’s overall information diet [74]. The nuances of public opinion around conspiracy claims should receive increased attention in the years to come, as they have the potential to directly impact public health.Even though initial surveys indicate that many people would hesitate to adopt a coronavirus vaccine, it is important not to over-extrapolate, as responses to hypothetical questions may reflect many unstated assumptions and variables. However, the link merits increased focus over the coming months and years. We also need to recognize that hesitancy does not necessarily suggest that someone is a conspiracy theorist, or that they won’t actually seek vaccination should it become a reality with demonstrated safety and efficacy. A lot remains to be understood about people’s attitudes towards vaccines, and we should support this topic to further develop in the years to come.As we are exploring the best way forward during the COVID-19 pandemic, an ongoing challenge and a critical task will be to understand how to limit the rapid spread of misinformation, for which the term “infodemic” was coined to reflect its amplitude and extent [75-77]. Prompt, effective, and targeted interventions that seek to delegitimize misinformation emerge as an important strategy to reduce its impact. It was suggested that social media users should take advantage of the mechanisms available to report misinformation on the respective platforms [21]. More extensive efforts need to be dedicated to advance and promote media and social media literacy, and to interrogate the impact of misinformation, disinformation, and conspiratorial thinking on the different facets of this pandemic and of other public health emergencies. For sure, the road ahead will be long and tortuous.

Richard Stein

and 1 more

Since the beginning of the 21st century, three coronaviruses have crossed the species barrier and caused serious human disease: severe acute respiratory syndrome coronavirus (SARS-CoV) in November 2002 [1, 2], Middle-East respiratory syndrome coronavirus (MERS-CoV) in 2012 [3, 4], and SARS-CoV-2 in 2019 [5, 6]. SARS-CoV-2 [7], initially called 2019-nCoV, is the etiological agent of COVID-19, a highly contagious infectious illness that was first reported in December 2019 in Wuhan, China and subsequently spread globally [8]. As of May 24, 2020, COVID-19 has caused >5,370,000 infections and >343,000 deaths worldwide [9].Unfortunately, nearly 20 years after the SARS outbreak, and despite many attempts for vaccines and therapeutic agents directed against SARS and MERS, no approved prophylactics or therapeutics exist. As a result, the management of COVID-19 largely relies on supportive care [10, 11] and on hopes surrounding compounds that appeared promising against previous coronaviruses [12, 13]. This lost opportunity, in itself, offers a valuable lesson for current and future outbreaks, and the need for new experimental rationales to accelerate discovery.The cellular entry of coronaviruses is fairly conserved across members of the Coronaviridae family and is mediated by the transmembrane spike (S) glycoprotein [14], a homotrimer [15, 16] that is often heavily glycosylated [17] and protrudes from the viral surface. Each of the three monomers of the spike glycoprotein consists of two functional subunits, S1, involved in membrane attachment, and S2, required for membrane fusion [15, 18]. In many coronaviruses, the spike glycoprotein is cleaved at the S1/S2 interface by host cell proteases [19]. Within the S1 domain, the receptor binding domain (RBD) attaches to the cellular receptor, which in the case of both SARS-CoV and SARS-CoV-2 is the angiotensin-converting enzyme 2 (ACE2) [19-21]. Another cleavage site, S2’, is located within S2 [17, 19]. The spike glycoproteins of SARS-CoV and SARS-CoV-2 share 76% identity at the amino acid level [22, 23], although biophysical assays indicate that SARS-CoV-2 binds their common receptor, ACE2, with a 10-20 fold higher affinity than SARS–CoV [14].As we contemplate the dynamics of COVID-19 and the development of prophylactic and therapeutic interventions, one of the key considerations is the emergence and potential relevance of viral mutations. In the short time since the pandemic started, several missense mutations have been observed in various SARS-CoV-2 isolates [24]. One of these, the 23403A>G variant, substitutes the aspartic acid at position 614 of the viral spike glycoprotein with glycine (D614G), and is frequently documented in European countries but rarely observed in China [25].In the current issue of the IJCP , Becerra-Flores and Cardozo interrogate the impact of this mutation on pathogenicity and offer a structural correlate for their findings [26]. Their analysis includes confirmed COVID-19 cases and deaths as reported by the European CDC during the first week of April 2020 and examines the viral spike genomic sequences deposited in the GISAID database over that period, correlating the prevalence of the D614G mutation with fatality rates in the same regions. The authors then use cryo-electron microscopy data andin silico mutagenesis of this key residue to predict conformational preferences of the two variants of the spike protein.The analysis indicates that viruses isolated from European patients predominantly expressed a glycine at position 614 of the spike glycoprotein, while a high percentage of the isolates collected from Far East patients favored aspartic acid at the same position. The proportion of viral isolates having a glycine at this position significantly correlated with higher average and median case fatality rates across geographic areas. Interestingly, their data also imply a rationale for divergence in the behavior of the disease between the East and West coasts of the United States, based upon the provenance of the viral ‘founders’ in these regions, from the European and Asian variants, respectively.Surprisingly, the authors’ molecular modeling indicates that the presence of a glycine at position 614 diminishes binding to the cellular receptor when replacing the aspartic acid at that residue, mainly by reducing the spike protein’s occupancy of the “up” or liganded state, when it is most amenable to receptor interaction. While seemingly counterintuitive, this finding opens at least two fascinating scenarios. As the authors hypothesize, a spike glycoprotein that harbors glycine at this position might be better protected from immune recognition, elicit the production of harmful antibodies, flood the host with ineffective antibodies, or some combination of all three. A delay in immune recognition may impact viral transmission by delaying symptomatic presentation or allowing unfettered infection without effective immune response. An aberrant response, suited to the viral conformation at large but not the infective conformation, could equally allow for an increased—but poorly targeted—inflammatory cascade. The possibility of a harmful immune response is particularly thought provoking, as antibody-dependent enhancement, the phenomenon by which antibodies facilitate viral entry into host cells that do not necessarily have viral receptors [27, 28], has been reported for many viruses, including coronaviruses [27, 29], dengue virus [30, 31], feline infectious peritonitis virus [32] , Ebola virus [33], and HIV [34]. Another possibility, not mutually exclusive, is that the D614G mutation creates or exposes a novel cleavage site in the spike glycoprotein.Delving into these molecular mechanisms with confirmatory in vitro studies will hopefully reap the benefits of decades of scientific strides while simultaneously highlighting deficiencies in key areas that can guide our approach to the current pandemic. One of the immediate questions involves the impact of this and other mutations on vaccine efficiency and the potential need to develop multiple candidate vaccines that cover a range of epitopes and their variants. In all likelihood, there is a lengthy and tortuous road ahead, but characterizing significant variants will allow us to better understand many elusive aspects of this virus’ success – the latent/incubation period, immune evasion and hyper-response, variable receptor binding, replication dynamics, and organ-specific pathogenesis—and discover host vulnerabilities that mutations such as D614G seem to exploit.The D614G mutation appears to become more common as the pandemic unfolds [35]. That this phenomenon is simply the result of a founder effect is possible but unlikely, and rather may be explained by this variant’s selective advantage allowing more efficient spread. Whether this advantage is conferred by infectivity, immune evasion, or pathogenicity—or some combination of these—is yet to be understood. Interestingly, this mutation is now known to travel simultaneously with other mutations, including one that affects the RNA-dependent RNA polymerase, with implications for proofreading, replication efficiency (and thus viral titer), and the emergence of drug-resistant viral phenotypes [36].Addressing these molecular questions relies heavily on widespread efforts to assemble accurate and comprehensive data on population infection rates and mortality, and frequent sampling of the genotypes of circulating isolates on a global basis. So far, this feat has been challenging and continued deficiencies will translate into missed singular opportunities to link molecular findings with population-level consequences, ultimately leaving us less prepared to address both this and future pandemics.The valuable and timely experimental strategy used by Becerra-Flores and Cardozo serves as an important analytic model that should be employed routinely to understand the ‘molecular strategy’ of this virus in the context of the evolving pandemic. This approach will also prove to be an indispensable instrument if also employed routinely at the onset of future outbreaks, which are all but guaranteed in the coming years, given the only recently appreciated ease of global spread of viruses in the modern world. In summary, this set of tools allows us to perform active surveillance, monitor the emergence of deleterious mutations prior to their widespread distribution, and use informed in silico and structural data to make informed decisions guiding molecular research and epidemic preparedness.

Richard Stein

and 1 more

In To Have or to Be? , psychoanalyst Erich Fromm writes about pursuit after domination of nature, material abundance, and unlimited happiness, which made modern society become more interested inhaving than in being . Income, in his view, should not be as accentuated as to create different experiences of life for different groups [1]. Of the concepts that Fromm presents, the domination of nature, which facilitates zoonotic spillover events by increasing the overlap between the habitat of various species with that of humans [2-5], and the gap between the rich and the poor, which recently has become the widest in years [6], become particularly relevant in context of the COVID-19 pandemic.Even though susceptibility to COVID-19 does not know socioeconomic boundaries, a critical and worrisome finding is emerging from preliminary data and may re-shape infectious disease outbreak management strategies for the future. An early analysis of COVID-19 data from several jurisdictions in the United States found that counties with a majority of African American residents had three-times higher infection rates and six-times higher mortality rates than counties with a majority of Caucasian residents [7]. Another analysis, of March 2020 COVID-19 hospitalization data from 14 states in the United States, found more African American individuals among hospitalized patients whose race or ethnicity was recorded [8]. These and other findings reveal a disproportionately higher risk of serious or fatal COVID-19 in minorities. What makes these observations remarkable is that hypertension, diabetes, and obesity, which are risk factors for more severe or fatal COVID-19 [9-13], are exactly the chronic conditions that have long been recognized as disproportionately affecting racial/ethnic minorities and socioeconomically disfavored individuals and groups [14].Obesity affects minorities and low-socioeconomic-status groups disproportionately at all ages [15], a finding that was reported in several countries [16-19]. Some of the risk factors that account for disparities in obesity include low socioeconomic status [20], food insecurity, restricted access to healthy diet and recreational facilities [21-24], residence in areas with fast food restaurants [25], a high neighborhood density of small grocery stores [26], distance to a store [27], exposure to obesogenic environments [28, 29], shift work [30] and irregular sleep patterns [31-33].Obesity increases the risk for other chronic diseases [12], including diabetes and hypertension [34]. African American adults in the United States have among the highest rates of hypertension worldwide [35]. Several factors were implicated in disparities in hypertension, including socioeconomic status [36], differences in awareness [37], residence in a food desert [38], chronic stress [39, 40], fewer healthcare resources [41], and income [42]. Disparities for diabetes were described in minority populations in terms of increased prevalence [43, 44], worse management and control [45, 46], and higher rates of complications [45, 47]. Over the past three decades the socioeconomic disparities for type 2 diabetes have widened [48].Racial, ethnic and socioeconomic disparities also shape inequities in the access to mental health care [49-52]. This is very relevant for COVID-19, in context of the quarantine that was implemented in many countries in various forms, including school closures, allowing non-essential personnel to work from home, closure of mass transit systems, cancellation of public events, and restrictions on the assembly of groups of people [53-55]. Social isolation negatively impacts mental health and, with > 70% of the young people and adults not receiving adequate mental health treatment from health care personnel worldwide [56], the implications in the wake of COVID-19 are extensive and far-reaching. The 2002-2003 SARS pandemic revealed that a substantial proportion of the quarantined individuals may display PTSD and depression symptoms, with longer duration of the quarantine being associated with more severe PTSD [57]. During the same pandemic, hospital employees from Beijing who were quarantined had higher PTSD levels than those who were not, even three years later [58]. Among individuals from South Korea isolated for two weeks during the 2015 MERS outbreak, anxiety and anger were still present 4-6 months after the quarantine [59].The disproportionately higher suffering of socio-economically disadvantaged individuals at a moment of crisis is, unfortunately, nothing new. In the 14th century, in the Black Death pandemic, the poorest populations were also the most extensively impacted ones in terms of mortality [60, 61], and low-income individuals had a considerably worse outcome after the 1918 flu pandemic [62]. The disproportionate effect on socio-economically disadvantaged individuals was also apparent in the wake of natural disasters, such as Hurricane Katrina [63] or the Deepwater Horizon oil spill [64]. One aspect that makes COVID-19 different is that several segments of the population become more vulnerable not simply due to socioeconomic disparities, but as a result of chronic medical conditions that these disparities have at least partly fueled over decades. The partial overlap between the risk factors for these two groups of diseases is reminiscent of debates on whether the broad classification of diseases into non-communicable and communicable ones is a meaningful one, considering that the two groups often overlap and interact markedly with one another [65-67]. Another aspect that sets COVID-19 aside from other pandemics in recent history is the extent and the duration of the quarantine and the resulting increase in unemployment rates [68, 69], which only promise to prolong and exacerbate the extent of social inequities and the burden of chronic diseases.COVID-19 provides a steep and perplexing learning curve that underscores the imperative need to envision infectious diseases not simply from a biomedical perspective, but as part of a complex framework that incorporates ethnic, socioeconomic, and political dimensions. Racial/ethnic and socioeconomic disparities are conducive to the development of chronic medical conditions that could increase the risk of severe COVID-19, widening the disparities and accentuating the chronic disease burden and, as a result, further marginalizing already vulnerable individuals and groups. The implications of this positive feedback loop for individuals, groups, and society, extend beyond COVID-19 and beyond infectious diseases in general. The current pandemic eloquently demonstrates, albeit at a high cost, that societies function on the basis of a social contract, as described by Jean-Jacques Rousseau and, undoubtedly, offers an important moment to reflect on the profound, far-reaching, and multi-layered consequences of disparities in society.References1. Fromm E. To Have or to be. Continuum: New York 1977;
As Dr. Thomson eloquently notes in his valuable letter [1], underlying respiratory diseases appear to be less of a risk factor for poor outcome in COVID-19 patients than either underlying cardiovascular disease or diabetes. This intriguing finding emerged from several studies that examined underlying medical conditions in COVID-19 patients.In a single-center retrospective analysis of critically ill adults admitted to the intensive care unit of a hospital from China between late December 2019 and January 26, 2020, 22% of the non-survivors had cerebrovascular disease, 22% had diabetes, and 6% had chronic respiratory disease [2]. The analysis of data from patients with laboratory-confirmed COVID-19 from hospitals in China through January 29, 2020 found that 16.2% of those with serious disease had diabetes, 23.7% had hypertension, and 3.5% had chronic obstructive pulmonary disease [3]. A study of electronical medical records of COVID-19 patients admitted between January 16 and February 3, 2020 to a hospital from Wuhan found that hypertension and diabetes mellitus, the most common comorbidities, were present in 37.9%, 13.8%, of the patients with severe disease, respectively, but only in 3.4% of the patients with chronic obstructive pulmonary disease [4]. Finally, an analysis of all COVID-19 cases reported through February 11, 2020, extracted from the Infectious Disease Information System in China, found that case fatality rates in individuals with cardiovascular disease, chronic respiratory disease, and diabetes were 10.5%, 6.3%, and 7.3% respectively, as compared to 0.9% among patients with no comorbidities [5]. In a case series of COVID-19 patients hospitalized in Wuhan, China, ICU patients were more likely to have underlying diabetes than patients that did not receive ICU care (22.2% vs 5.9%) [6].The studies mentioned above did not stratify patients by therapies they were receiving. However, one commonality between cardiovascular disease and diabetes is that they are often treated with angiotensin-converting enzyme (ACE) inhibitors and angiotensin II type-I receptor blockers (ARBs), widely used to inhibit the formation and action of angiotensin II.ACE shares 42% amino acid identity with ACE2 [7], a membrane-bound aminopeptidase [8] extensively expressed on type II human alveolar cells [9]. The genes encoding these two proteins are thought to have emerged by duplication [10]. ACE2 is distributed on many tissues and shows highest expression levels in the heart, kidney, lung, small intestine, and testis [11]. On the apical surface of polarized respiratory epithelial cells, ACE2 is a crucial and primary receptor for the cellular entry of SARS-CoV, the virus that caused the 2002-2003 SARS outbreak [12-16]. SARS-CoV binding to ACE2 mediates entry into human or animal cells [17]. ACE2 is also the receptor for SARS-CoV-2, the etiologic agent of COVID-19 [18]. Structural analyses indicate that SARS-CoV-2 binds the ACE2 receptor with a 10-20-fold higher affinity than SARS-CoV [19, 20].The entry of SARS-CoV and SARS-CoV-2 into their target cells is mediated by the viral spike (S) glycoprotein, which is located on the outer envelope of the virion [21]. The S glycoprotein has two functional subunits, S1, which binds the cellular receptor, and S2, which contains domains required for the fusion between viral and cellular membranes [22, 23]. Viral binding and membrane fusion represent the initial and critical steps during the infection cycle of the coronavirus [24] and the first step in establishing the infection [25, 26]. Binding is followed by internalization of ACE2 and down‐regulation of its activity on the cell surface [27-29].SARS-CoV binds ACE2 through a region of the viral S1 subunit called the minimal receptor-binding domain (RBD) [17]. RBD is the most important determinant of the SARS-CoV host range, and studies about the “species jump” during the 2002-2003 SARS outbreak revealed that changes of only one or two amino acids in this region were sufficient to make the virus “jump” to a new host [26, 30, 31].ACE and ACE2 are two members of the renin angiotensin system that negatively regulate each other [32, 33] and are distinct in their substrate specificity and function [34]. ACE converts angiotensin I to angiotensin II and mediates aldosterone release, vasoconstriction, sodium retention, cell proliferation, and organ hypertrophy [35]. ACE2 cleaves a single residue from angiotensin I to form angiotensin-(1-9), and a single residue from angiotensin II to form angiotensin-(1-7). In humans, ACE2 has a 400-fold higher catalytic efficiency when it uses angiotensin II as a substrate as compared to when it uses angiotensin I [36]. ACE2 and angiotensin-(1-7), through the Mas receptors, oppose ACE and mediate vasodilation and anti-proliferative, anti-hypertrophic, cardioprotective, and reno-protective effects [8, 35, 37]. ACE2 has physiological and pathological importance [25] and its dysregulation was implicated in heart disease, hypertension, and diabetes [36, 38-40]. ACE2 is not inhibited by ACE inhibitors [32] and several studies indicate that the ACE2/Angiotensin-(1-7)/Mas axis has anti-inflammatory effects [41, 42].It was recently hypothesized that treatment with ACE inhibitors and/or ARBs may lead to ACE2 overexpression and this could increase the risk of severe COVID-19 [43], possibly by increasing the internalization of SARS-CoV-2. Several lines of evidence indicate that pharmacological manipulation of the renin-angiotensin-aldosterone pathway could affect ACE2 receptor levels. In animal studies, the selective blockade of angiotensin II synthesis or activity increased cardiac Ace2 gene expression and activity [44, 45], and treatment with ARBs increased the levels of cardiovascular ACE2 receptors [46-49]. While this link is thought-provoking as a possibility, there isn’t currently sufficient evidence to contemplate changing patients’ existing therapeutic regimens in order to minimize their risk of COVID-19 complications. The first clinical evidence exploring this link indicated that the use of ACEI and ARBs appear to improve the clinical outcome of COVID-19 patients with hypertension [50]. We will only learn about any possible associations, along with their magnitude and direction, from carefully conducted and adequately powered clinical trials.It is also important to consider that an increase in ACE2 levels does not necessarily entail a negative impact for the course of COVID-19. ACE2, by forming angiotensin-(1-7) from angiotensin II, could diminish the deleterious effects of angiotensin II and, consequently, it is also possible that ACE inhibitors or ARBs could, in fact, lower the risk of complications [51]. However, increased ACE2 and the formation of angiotensin-(1-7), by inhibiting COX-2, could exert anti-inflammatory effects [52, 53], underscoring the multitude of possible effects and the need to conduct studies to interrogate these connections. Finally, it is not known whether an increase in the expression of ACE2 would also lead to an increased shedding and increased levels of soluble ACE2, which could act as a decoy receptor and lower viral entry into cells [54]. In support of this, recombinant human ACE2 ameliorated the lung injury induced by the avian influenza H5N1 virus in mice [55]. It is also important to consider that from the relatively limited amount of human data, plasma ACE2 activity does not appear to be statistically different between individuals taking ACE inhibitors or ARBs and those not taking these medications, but these results do not reflect the levels of cellular receptors [56]. Structural analyses indicate that the binding of the SARS-CoV spike protein to ACE2 does not occlude the catalytically active site of the receptor [26, 57], and it was hypothesized that angiotensin II binding to ACE2 could induce a conformational change in the receptor, which will no longer be favorable for SARS-CoV-2 binding [54]. The mining of existing datasets, preclinical studies, and clinical trials will help shed light on these complex and sometimes conflicting scenarios.A decrease in the number of ACE2 receptors appears to be involved in acute lung injury and cardiovascular pathology [58, 59], and may be detrimental during coronavirus infection. A mouse Ace2 knockout developed severe cardiac contractility defects and increased angiotensin II levels, and the additional deletion of Ace rescued this phenotype [60]. In acute lung injury models, the loss of Ace2precipitated severe acute lung failure, and this was attenuated by the exogenous recombinant human ACE2 in both Ace2 knock-out and in wild-type mice [59]. Attenuation of the Ace2 catalytic function perturbed the pulmonary renin-angiotensin-aldosterone system and increased inflammation and vascular permeability [61], and Ace2 overexpression decreased lung inflammation in an animal model of acute lung injury [62]. In vitro and in experimental animals, SARS-CoV and the SARS-CoV spike protein downregulated ACE2 expression [12, 28]. In mice with lung injury, injection of the SARS-CoV spike protein worsened the acute lung failure and caused lung edema, increased vascular permeability, and decreased lung function, and this pathology was attenuated by blocking the renin-angiotensin-aldosterone pathway [12]. Thus, animals infected with SARS-CoV or treated with the spike protein resemble Ace2 knockout animals [12]. It is relevant that a pilot study of patients with acute respiratory distress syndrome reported the accumulation of angiotensin I and the decrease of angiotensin-(1-9), indicating decreased ACE2 activity, among non-survivors [63]. Thus, SARS-CoV and SARS-CoV-2 might contribute to severe respiratory symptomatology partly because the viruses, by binding the ACE2 receptors, also deregulate protective pathways in the lungs.Thus, either increased or decreased numbers of pulmonary ACE2 receptors may be detrimental during SARS-CoV or SARS-CoV-2 infection, most likely for distinct reasons. An increased number of ACE2 receptors may lead to a higher viral load and more severe clinical disease. Diabetes increases ACE2 expression, as shown in several experimental models, and the resulting increased viral load might explain the more severe course of COVID-19 in diabetic patients [64, 65]. Interestingly, in a rodent model of diabetes, ibuprofen inhibited the ACE/angiotensin II/angiotensin type 1 receptor axis and enhanced the ACE2/angiotensin-(1-7)/Mas receptor axis [66]. Too few functional ACE2 receptors, which decrease even more as a result of high viral loads and enhanced receptor internalization [67], might exacerbate acute lung injury, increase angiotensin II levels, and alter the balance between pro- and anti-inflammatory responses. It is relevant that in a study on twelve COVID-19 patients from China, plasma angiotensin II levels were markedly elevated as compared to healthy control individuals, and linearly associated with the viral load and with the lung injury [68]. The animal studies that documented an age-dependent decrease in ACE2 expression in the lung and the aortic might also explain, at least in part, the age-dependent increase in the risk of serious COVID-19 complications [69, 70].SARS-CoV can also bind cells through alternative receptors that include the C-type lectins DC-SIGN (dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin) and/or L-SIGN (liver/lymph node-SIGN) [14, 71-73]. It will be critical to understand the potential involvement of the same, or alternative receptors in the pathogenesis of COVID-19.It has been less clear why SARS-CoV and SARS-CoV-2 lead to severe lung disease [57], in contrast to other, previously known coronaviruses, which usually result in mild upper respiratory infections and cause pneumonia only rarely, mostly in newborn, the elderly, and immunocompromised individuals [74-77]. One of the possibilities advanced for SARS is that the burden of viral replication and the immune status of the host may both shape the severity of the infection [57, 78, 79]. The same might be true for COVID-19, and further exploring the link between viral burden, chronic medical conditions, long-term medication usage, and the severity of the infection will be critical.An important lesson from SARS and MERS is the association between the incubation period and disease severity. For any infectious disease, the incubation period varies among individuals, even for the same outbreak, and depends on the initial infective dose, the speed of pathogen replication within a host, and host defense mechanisms [80]. During the 2002-2003 SARS outbreak, a study in Hong Kong revealed that patients with shorter incubation times developed more severe disease [81]. The same was found in MERS patients from South Korea, where longer incubation times were associated with a lower risk of death [82]. Interestingly, during the SARS outbreak in Hong Kong, healthcare workers, who have a higher infecting dose, had 34% shorter median incubation times than non-healthcare workers [83]. It will be interesting to examine whether the same is true for SARS-CoV-2, and whether the incubation period is different in COVID-19 patients when they are stratified by age, coexisting morbidities, and therapies they receive for chronic diseases. While the association between the incubation period and mortality might simply indicate that the disease was confirmed earlier in patients with longer incubations, and reflect earlier treatment opportunities [82], it is also plausible that high viral loads might mediate the link between the two.Two factors decisive for the successful control of outbreaks are the ability to isolate asymptomatic individuals and the ability to trace and quarantine their contacts [84, 85]. Several studies reported asymptomatic shedding of SARS-CoV-2, indicating that asymptomatic carriers, or individuals with very mild symptoms, may sustain transmission [86-89]. For example, nearly 18% of the passengers who tested positive for SARS-CoV-2 on the Diamond Princess cruise ship were asymptomatic [88]. Another valuable finding that emerged from the COVID-19 outbreak analysis in Singapore, and has a strong impact on infection control, is that after becoming asymptomatic, some patients continued to shed the virus for up to several days. In one instance, a patient continued to have detectable respiratory shedding, as shown by PCR, for eight consecutive days after becoming asymptomatic [90]. Another study revealed that several children with COVID-19 persistently tested positive for viral RNA on fecal swabs after their nasopharyngeal cultures became negative. Even though replication-competent virus was not detected in the fecal swabs, this finding leaves open the possibility of SARS-CoV-2 fecal-oral transmission [91]. These findings illustrate the challenges in understanding SARS-CoV-2 transmission and in identifying infected individuals, tracing their contacts, and implementing preparedness plans. One of the absolute requirements, to clarify these questions and overcome these obstacles, is ensuring the prompt and large-scale testing of symptomatic individuals and of their asymptomatic contacts. This, together with the social distancing measures, are currently our only available assets in facing a pandemic that, even though it was preceded by multiple warnings in recent years, is unlike any other infectious disease that we experienced in modern history.