key: cord-1006468-2avvntao
authors: Carbone, Michele; Lednicky, John; Xiao, Shu-Yuan; Venditti, Mario; Bucci, Enrico
title: Coronavirus Infectious Disease Epidemic (COVID-19): where we are, what can be done and hope for.
date: 2021-01-07
journal: J Thorac Oncol
DOI: 10.1016/j.jtho.2020.12.014
sha: 1962ead8931b40cde421d887d799d74abf8b733b
doc_id: 1006468
cord_uid: 2avvntao

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spreads mainly via aerosol (microdroplets) in enclosed environments where temperature and humidity are regulated via air-conditioning (A/C). About 30% of individuals infected with SARS-CoV-2 develop COVID-19 disease. Among them, ∼25% require hospitalization. In medicine “cases” identify those who become ill. During this pandemic “cases” has been used to identify those with a positive SARS-CoV-2 PCR test, including ∼70% asymptomatic; this has caused unnecessary anxiety. Individuals >65 and those affected by obesity, diabetes, asthma, immune-depressed cancer patients, etc., are at higher risk of hospitalization and of dying of COVID-19. Healthy individuals younger than 40 very rarely die of COVID-19. Estimates of the COVID-19 mortality-rate vary because the definition of COVID-19–related deaths varies. Belgium has the highest death-rate 154.9/100,000 persons, because it includes anyone who died with symptoms compatible with COVID-19, even those never tested for SARS-CoV-2. The US includes all patients who died with a positive test, whether they died because of, or with, SARS-CoV-2. Countries that include only patients in which COVID-19 was the main cause of death, rather than a co-factor, have lower death-rates. Numerous therapies are being developed and rapid improvements are anticipated. Because of disinformation, only ∼50% of the US population plans to receive a COVID-19 vaccine. By sharing accurate information, physicians, health professionals and scientists play a key role addressing myths and anxiety, help public health officials enact measures to decrease infections, and provide the best care for those who become sick. We discuss these issues.

extensive human exposure to bats and their excrements, it should be no surprise that every few years a new coronavirus jumps from bats to humans.

Measures taken to reduce the spread of COVID-19 critically depend on rapid and accurate identification of virus-infected individuals by the most sensitive and specific method available. Presently, the most reliable and commonly used test is real-time reverse transcriptase PCR (rRT-PCR), performed on upper respiratory tract specimens such as nasopharyngeal or throat swabs, or saliva. 17 SARS-CoV-2 vRNA levels are highest in the nasopharynx and oropharynx between 2 days pre and 4 days post onset of symptoms and remain detectable for a median duration of 15 to 18 days. [18] [19] [20] Bronchial alveolar lavage fluids are more frequently positive but are not routinely collected. 21, 22 Saliva testing is replacing nasopharyngeal and bronchial testing because it is as sensitive and it is not painful to administer, thus it is particularly helpful when testing children who can be given a straw and told to drool saliva in a test tube. SARS-CoV-2 remains viable in saliva for 4 days at room temperature, no chemicals need to be added and the sample can be mailed to a laboratory for RT-PCR testing or virus isolation (J. Lednicky unpublished observations). RT-PCR testing of stool may hold value to identify patients who recovered from infection that may shed apparently non-infectious viral particles for some time. 18, 20 Several RT-PCR tests have been developed, and the amplification targets vary, such as detection of SARS-CoV-2 envelope (env), nucleocapsid (N), spike (S) and RNA-dependent RNA polymerase (RdRp) genes. 17 The US Centers of Disease Control and Prevention (CDC) has developed two tests, the original version which tested for SARS-CoV-2 vRNA only, and a newer multiplex assay that also detects influenza A and B vRNs. 23 The analytical and clinical performance of seven commercial RT-PCR diagnostic kits from different manufacturers were judged suitable for routine diagnostics of symptomatic COVID-19 patients. 24 Several research teams have also developed their own tests. At the University of Florida (UF), for example, an rRT-PCR test previously developed by J. Lednicky to detect betacoronaviruses in bats is used in various research projects to detect SARS-CoV-2 vRNA in human and environmental samples. 25, 26 An example of a test run using the UF test for detection of the RdRp gene sequence with a J o u r n a l P r e -p r o o f human specimen (from a COVID-19 patient), positive control SARS-CoV-2 vRNA, and a negative control, is shown in Figure 1 . 27 While PCR-based tests detect active infections, serology is used to detect past (IgG) or ongoing infections (IgM and IgG). Individuals who were infected with SARS-CoV-1 developed neutralizing antibody responses that lasted for several years. If reinfection occurred, the outcome was usually a mild illness or an asymptomatic presentation. 28 Similarly, it has been assumed that individuals with antibodies against SARS-CoV-2 are protected from disease.

If individuals with SARS-CoV-2 antibodies are protected from disease, they could safely return to normal activities, help restart the economy and may also help take care of the most vulnerable population. A number of serological assays, such as ELISA and lateral flow assays, have been developed to detect SARS-CoV-2 antibodies. These assays may target the spike protein, the receptor binding domain (RBD) part of the spike protein, or the SARS-CoV-2 nucleoprotein. These assays are relatively inexpensive and can be handled in a BSL2 laboratory, making them preferable to classic virology neutralizing assays that require the use of a BSL3 laboratory. However, the sensitivity of the serological assays for SARS-CoV-2 has been questioned. Grandjean L et al. 29 , reported that the half-life of the SARS-CoV-2 nucleoprotein antibody -which is the target of most commercial ELISA assays-is only 52 days, and for the Spike protein 82 days. Therefore, ELISA assays may be reliable only for recently infected patients. A parallel paper by Fenwick C et al. 30 came to similar conclusion and reported that nucleoprotein antibodies wane post infection resulting in underestimation of the infected population and that tests using antibodies against the spike proteins are more sensitive.

SARS-CoV-2 infections are often referred to as "cases", a terminology that in other diseases identify those who became ill and require therapy. During the current pandemic, the term "cases" instead identifies those with a positive SARS-CoV-2 test, not the fraction (about 30% of infected individuals) who develop symptoms. This inaccurate J o u r n a l P r e -p r o o f terminology has caused confusion and has contributed to the anxiety that surrounds this infection. 31 To put this issue in perspective, about 80-90% of sexually active people in the US become infected with human papilloma viruses (HPV) during their lifetimes, but we do not identify them as "cases". Rather, cases are the 34,800 patients that develop HPVrelated carcinomas each year in the US, not the many millions with asymptomatic infections. 32 Testing varies in different countries, and within a country, by region: some perform many tests, some only a few. Except in China, testing has been largely limited to symptomatic patients who seek medical care and to their immediate contacts: asymptomatic healthy people are largely not tested. Therefore, most countries are underestimating the total number of infected people, improperly called "cases". In summary, as of December 12 2020 , there are about 70 million documented SARS-CoV-2 infections worldwide: this is an underestimation because asymptomatic individuals account for most infections and they are seldom tested.

The percentage, rather than the actual number of positive tests, is a more relevant way to follow the pandemic, although since positive patients are often tested multiple times, even percentages are not accurate as they include new and ongoing infections. In some places, for example in Wuhan during the initial phases of the outbreak, in Lombardia, in many US cities, etc., authorities tested almost exclusively those who were sick enough to seek hospitalization. This of course resulted in a much higher percentage of positives and among them, of COVID-19 cases (here the term is used in its correct form) which required hospitalization, than in places where testing was random and included healthy volunteers.

When most of the positive tests are from hospital testing, as at the beginning of the pandemic, mortality is being measured in the fraction of patients most severely affected, and thus will be higher than when measured across the population, which includes ~70% of asymptomatic individuals. The recent record numbers of infections in the US showed J o u r n a l P r e -p r o o f that the fraction of people who died because of SARS-CoV-2 infection is 1% or less, much smaller than previous estimates that had placed it at about 5-10%, percentages largely based on hospital testing.

The overall number of deaths attributed to COVID-19 are inaccurate and overall represent an overestimation -as of December 12, 2020, there were an estimated 1.6 million deaths worldwide attributed to COVID-19, ~296,000 of them occurred in the US. 33 Why are these numbers not accurate? At the beginning of the pandemic, mortality counts may have underestimated the actual number of deaths due to COVID-19, as they did not include those who died at home or who died in a hospital but were not tested for SARS-CoV-2. On the other hand, mortality will overestimate the number of deaths, if all people infected with SARS-CoV-2 are counted as COVID-19 deaths regardless of the underlying pathology and cause of death.

A well-written autopsy report distinguishes the "main cause of death" from underlying "contributing factors", from the "immediate cause of death". For example: mesothelioma (main cause of death) in an obese and diabetic patient (contributing factors), who developed bronchopneumonia as he was lying in bed (immediate cause of death). It is easy to understand how the number of deaths attributed to COVID-19 will vary greatly depending on how we count them. In the US, all patients who test positive for SARS-CoV-2 infection and die are counted as COVID-19 deaths, regardless of underlying disease. It would be much more accurate instead to specify if these patients "died with SARS-CoV-2 infection", and clearly distinguish them from those who died because of it "main cause of death", from those in which COVID-19 was a "contributing factor" or the "immediate cause of death" in an already terminally ill patient. Obviously, by using the current approach the US reports a higher number of deaths for COVID-19 than if we were to use the criteria we use for deaths caused by other diseases. 34 The Istituto Superiore di Sanità of Italy, the equivalent of the NIH in the US, investigated 4,942 death certificates and found that 89% of deaths attributed to COVID-19 were indeed caused by this disease: however, they did not distinguish whether COVID-19 was the "main" or the "immediate" cause of death. The remaining 11% of deaths were attributed to other causes in individuals infected with SARS-CoV-2 (passenger or co-factor). 35 As for why people J o u r n a l P r e -p r o o f with COVID-19 die, a recent paper reporting autopsy findings for 22 COVID-19 Italian cases (including 4 cases without comorbidities) found that COVID-19 caused multisystem pathology. The main and most common pathology was in the lungs and in the cardiovascular system. In addition, hepatic, kidney, splenic, bone marrow tissue damage, and microvascular injury and thrombosis were detected. 36

Cell entry requires binding of the SARS-CoV-2 spike protein to its cell surface receptor, angiotensin converting enzyme 2 (ACE2), which is present on several cell types, including epithelial cells in the upper respiratory tract and type II pneumocytes. [37] [38] [39] SARS-CoV-2 may spread through direct, indirect, or close contact with infected people through mouth and nose secretions. These include contact with secretion droplets (> 5 µm) and inhalation of droplet nuclei (aerosol, < 5 µm) or, perhaps of airborne particles in fecal clouds. 40 Droplets are expelled from the mouth when people talk, more so when they speak loudly or sing, and they fall to the floor or on objects within 1-3 feet from the source, thus the recommendation for "social distancing" and of hand washing. Although theoretically possible, this appears to be a rare source of infection. 41 Most infections are instead linked to inhalation of droplet nuclei (i.e., in aerosols) as they float (i.e., are suspended) in the air. In a room in which the windows are closed and temperature maintained via A/C, thus with low humidity, droplet nuclei can remain adrift for hours.

Since SARS-CoV-2 remain infectious for at least 16 hours in aerosols, the risk of infection is high in crowded, enclosed, spaces. 41, 42 Opening windows rapidly eliminates aerosol, 43 reducing or eliminating the risk of inhaling SARS-CoV-2. 42, 44 Many if not most SARS-CoV-2 infections go undetected. Poletti et al. 45 studied 5,484 individuals infected with SARS-CoV-2: 73.9% of them aged less than 60 years did not develop symptoms (95% confidence interval: 71.8-75.9%). The risk of symptoms increased with age: 6.6% of infected subjects older than 60 had severe disease, with males at significantly higher risk.

J o u r n a l P r e -p r o o f Infected individuals, regardless of whether they develop COVID-19, can spread the virus.

It has been difficult to pinpoint the exact length of time during which infected individuals can spread the virus, the so called "infectivity window" 46 ( Figure 2 ). He et al., studied 77 infectious-infected couples and proposed that the maximum infectivity occurs between 2 days before and one day after the onset of symptoms, and that 8 days after the first symptoms, infectivity decreases significantly. 47 The methodology of this is work, however, has been criticized, 48 although the authors made some corrections. 49 A more sensitive approach than relying on symptoms is to isolate viruses from patients (i.e., grow them in cell culture): if SARS-CoV-2 can be isolated from a nose or throat swab, or saliva, it is likely that the patient is infectious. Instead, an rRT-PCR test cannot establish infectivity. This is because rRT-PCR detects fragments of virus genomic RNA (vRNA), the corresponding sequences of which are present in viable ('live') and also in non-viable ('dead') virus particles. In other words, the rtPCR can be positive in: 1) exposed non-infected and/or non-infectious individuals who were in contact with the virus but resisted infection, as well as those who were infected but are no longer infectious and may release non-infectious viral RNA fragments; 2) infected individuals who did not develop COVID-19, i.e., asymptomatic infectious carriers; and 3) those who have COVID-19 disease and for which the term "cases" should be reserved. rtPCR cannot distinguish among these three categories.

Wolfel et al., studied 9 COVID-19 patients and found that it was not possible to reliably isolate SARS-CoV-2 from throat swabs 8 days past the onset of symptoms. 20 However, the estimated confidence intervals were large: 14 days from onset of symptoms, the probability of isolating SARS-CoV-2 varied between 0 and 20%. The authors proposed that when the viral load determined by PCR was <10,000 copies per reaction, the probability of isolating SARS-CoV-2 at a 95% confidence interval varied between 0 and ~30%. Therefore, by correlating the viral load with SARS-CoV-2 isolation, it may be possible to establish a threshold value below which the probability of a patient's being infectious is small.

Singanayagam et al. 50 , using a larger collection of samples, isolated SARS-CoV-2 up to 12 days from the initial symptoms; at day 14 post-initial symptoms SARS-CoV-2 isolation dropped to 0 to 9.4%, and at day 15, to 0 to 6.7%. They found no difference in the probability of isolating SARS-CoV-2 from symptomatic or asymptomatic individuals, and they found no difference in the viral load of symptomatic and asymptomatic infected individuals -something that the authors of this review find difficult to understand because it is contrary to most other viral infections. Singanayagam A very recent study showed that SARS-CoV-2 multiplies robustly in the oral cavity: this likely explains why COVID-19 patients express a range of oral manifestations such as ageusia and oral blisters. 51 To summarize: 1) Infectivity is higher immediately before and soon after the onset of symptoms; however infected patients remain infectious for about 2 weeks; 2) Ten days from the appearance of the initial symptoms, the risk that a patient is still infections varies between 1%-10% at a 95% confidence interval; 3) Infectivity is related to the viral load, but not to the development and severity of COVID-19; 4) Individuals with a low viral load, determined by Ct = or >35, may be infectious; 5) The window of infectivity varies in different individuals and some may be infectious for several weeks. These "long-term spreaders" represent a fraction of the infected population, probably too small to significantly affect the spreading of the virus, thus the quarantine length could ignore them. At lower levels of virus circulation, however, long-term spreaders may frustrate efforts to further curb the epidemic, if the quarantine length is not long enough to account J o u r n a l P r e -p r o o f for their prolonged infectivity window. Finally, and most importantly, asymptomatic individuals -who account for about 70% of infections-appear able to spread virus as well as those who become ill 50 : if this is true, it will be much more difficult to contain the further spread of this pandemic.

Public health measures initially focused on the role of respiratory droplets and fomites in the transmission of SARS-CoV-2. 52 However, recent data underscore the role of aerosol transmission of SARS-CoV-2 in enclosed spaces where air re-circulates as the main cause of the spreading of the pandemic. [53] [54] [55] One of this manuscript's co-authors isolated SARS-CoV-2 from an air sample from a hospital room with a COVID-19 patient, taken 16 hours after the patient had left the room. 26 In contrast, the risk of transmission via fomites seems minimal. 56 Qureshi et al. 57 noted that the notion that SARS-CoV-2 is spread by droplets or fomites was based on old information related to other viruses, not on SARS-CoV-2 science. It has been estimated that the risk of SARS-CoV-2 transmission via fomite contamination of surfaces is less than 5/10,000. 58 Person-to-person transmission of the virus in open spaces is also very rare. 59 The hypothesis that SARS-CoV-2 spread widely on airplanes was largely based on an older study on SARS-CoV-1 transmission in an airplane that revealed that 1 individual infected 22 passengers who became ill within 4 days from the flight, including some seated far away from the infected case. 62 Instead, spreading of SARS-CoV-2 in airplanes may be limited. First, there has not been a reported increase of SARS-CoV-2 infections among airplane hostesses, compared to the high rates of infections among health care workers. Secondly, the hypothesis that airline flight is relatively "safe" from infection is supported by a recent report of a flight from Tel Aviv to Frankfurt in March 2020, before any measures to prevent transmission, including wearing masks, had been introduced on commercial airlines. 63 were pre-symptomatic and one never developed any symptoms. Follow up testing of the other passengers revealed that only 2, both within two rows of an infected passenger had been infected. The low number of infections limited to nearby passengers, in spite of the long flight duration with no masks, suggests that the HEPA filters present in today's airplanes, and the circulation system that replaces air every 2-3 minutes in the cabin, are effective at preventing spread of aerosol containing virus throughout the whole cabin.

Bae et al., reported transmission from one asymptomatic carrier to a lady sitting 3 rows away on an evacuation flight from Milano to South Korea. 64 The infected woman, wore a N95 mask throughout the flight -as every other passenger-except during meals and when she used the toilet. We do not know whether improvements in the air circulation and filtration in the cabin during the past 17 years, or differences among SARS-CoV-1 and SARS-CoV-2, or chance, or maybe a combination of all these variables, were responsible for these differences.

As for the possibility that animals spread SARS-CoV-2, so far there have been reports of minks passing the virus to people. SARS-CoV-2 replicates poorly in dogs, pigs, chickens and ducks, but replicates well in cats and ferrets, as these animals are permissive to the infection: infected animals can infect other animals of the same species. 65, 66 Moreover, antibodies for SARS-CoV-2 were detected in cats in Wuhan, suggesting that humans can infect cats, raising the possibility that cats may infect humans. 67 SARS-CoV-2 related coronaviruses have recently being isolated from Malayan pangolins, suggesting that these animals that are sold in some wet markets in Asia could represent an additional source of infection. 68, 69 In summary, SARS-CoV-2 might be spreading undetected among some animals: whether this occurs and whether animals may contribute to some human infections remains to be investigated. Finally, SARS-CoV-2 causes a COVID-19-like disease in macaques, a good model to study this disease. 70

China is the only country -so far-that has been able to effectively block and apparently eradicate SARS -CoV-2 infection, by implementing very strict measures that require J o u r n a l P r e -p r o o f residents to give up any personal privacy. Initially to stop the spread of SARS-CoV-2, China authorities responded by locking down the city of Wuhan and by implementing a rapid multidisciplinary effort using all possible technologies, personnel and resources that was based on their previous experience with SARS infection 71, 72 . Presently, in China, in addition to ban on gatherings and the requirement to wear masks, everyone is "tagged" and traced on an app uploaded on their mobile phones. As people go about their lives, all those they meet and places they visit are identified and transmitted to the authorities by this app, so that if they are considered at-risk, are rapidly identified, tested and quarantined. All public places, airports, train stations, hospitals, require individuals to scan a bar-code displaying a "green" code (indicating no contact with at risk individuals) before admission is granted. Borders are sealed and foreigners are subject to a 14 days quarantine. This means they are locked in a room in designated hotels with security guards, meals are brought to the door, and they are not allowed out of their room for anything. With these strict control measures, the entire China is presently open for normal business.

Australia, New Zealand, and Taiwan have also been able to contain the infection by implementing very strict measures that are similar to those used in China. 73, 74 Australia, New Zealand (NZ) and Taiwan are islands and therefore, can more easily monitor their borders. Moreover, they acted in the early phases of the pandemic, when relatively few had been infected. In NZ the implementation of the lockdown was supported by a national state of emergency, declared on March 25, 2020, which, along with newly written law changes passed through Parliament, enabled special powers to address the pandemic. 75 Taiwan established a National Health Command Center in 2004 following the SARS epidemic. This agency was dedicated to responding to emerging threats, such as pandemics, and given the power to coordinate work across government departments and draw on additional personnel in an emergency.

Equally important, however, is the willingness of the citizens to follow orders and the willingness or ability of the authorities to implement the orders. The same measures adopted in Australia China, Taiwan, NZ, cannot be easily implemented in Western European democracies or even in the USA where, for example, many citizens continue to refuse to wear masks, do not accept to give up their privacy wearing an app that traces J o u r n a l P r e -p r o o f every step in their life, do not accept to seal the borders to refugees, do not accept bans on gatherings as shown -for example-by the many large demonstrations that occurred in the recent past in many US cities, France, Italy, Holland, etc. The culture is very different.

For example, Europe continued to accept thousands of asylum seekers from Africa during the past 12 months, some of them were infected with SARS-CoV-2 upon arrival. It would be illegal for European countries not to accept refugees. Australia, China, New Zealand, Taiwan, have a different, much tougher, approach and can seal their borders. 

About 30% of those infected develop COVID-19 and experience flu-like symptoms, but 25% of them may require hospitalization, and 1/3 of hospitalized patients may require treatment in the ICU. 76 Because of the large number of infections, the demand for ICU beds has exceeded capacity in some regions. 77 The concern that capacity may be insufficient has led many hospitals to shut down elective surgeries and other procedures that may require ICU treatment, which causes additional deaths.

Overall hospital mortality has been about 20% and up to 81% among patients requiring mechanical ventilation: most are older patients with pre-existing morbidities. [78] [79] [80] [81] [82] Men are much more likely to die and to require admission to ICU: in Lombardia, Italy, 82% of patients admitted in ICU were males. 80 Individuals older than 65 are at much greater risk of requiring hospitalization and death, as are those affected by obesity, hypertension, congestive heart failure, diabetes, asthma, chronic kidney disease, and those who are immune-depressed, including cancer patients. 83 These pre-existing diseases significantly increase the risk of hospitalization, ICU requirement and death upon SARS-CoV-2 infection, especially among older males. 84 Among pre-existing conditions, obesity stands out because of its frequency in the USA and its complexity and because it appears to be the most common co-factor in COVID-19 patients in ICU. 85 Because only 13/134 patients who met the criteria for admission to the ICU were actually admitted in the ICU, the authors suggested that reduced access to the ICU because of the COVID-19 pandemic might have influenced the high mortality. The data suggested that the type of systemic therapy, including immunotherapy and targeted therapies, did not influence survival of these patients. 91 A subsequent study conducted in Spain on 23 lung cancer patients who developed COVID-19, also found that the type of systemic therapy did not influence the incidence of COVID-19 or mortality. 92 These findings are still preliminary; however, they suggest that withholding or discontinuing therapy for lung cancer patients out of fear of COVID-19 might not be warranted.

Epidemiological studies have proposed an association between environmental pollutants measured as PM 2.5 concentrations in the air with severity of COVID-19. 93 Wu et al. reported that even a small increase in exposure to PM 2.5 leads to a large increase in COVID-19 death rate with the magnitude of increase 20 times that observed for PM 2.5 and all-cause mortality. 94 William et al, reported that 50% of the variance of 'predicted COVID-19' phenotype is due to genetic factors and may reflect inter-individual variation in the host immune response. 95 Lucas et al. reported that the immune-profiles of patients that easily recovered from COVID-19 were different from those who did not. 96 Zhang et al. found that loss of function at 13 human loci that regulate TLR3-and IRF7-dependent type-1 immunity, transmitted either in an autosomal dominant or recessive fashion, underlie susceptibility to life threatening COVID-19 pneumonia. They estimated that 3.55% of patients with life-threatening COVID-19 disease had genetic defects at 8 of these 13 loci. 97 In a parallel study, the same research team estimated that 12.5% of men and 2.6% of women who develop life-threatening COVID-19 disease have autoantibodies against interferon; thus their immune response against viral infections is impaired. 98 The presence of autoantibodies in the population was estimated at 0.33%, and patients with autoantibodies were 25 to 87 years old, half of them older than 65. Therefore, these studies identified a subset of individuals with genetic predisposition or acquired predisposition (autoantibodies) to develop severe COVID-19 disease. These findings help explain the higher prevalence of severe COVID-19 disease in men, and why although rarely, apparently healthy and young individuals succumb to COVID 19. In summary, genetic susceptibility in some individuals together with exposure to pollutants exacerbates COVID-19 along a model of Gene x Environment interaction. 99 As for a possible increased susceptibility of African-Americans to COVID-19, a recent study found that among patients treated in a hospital setting, mortality did not vary among white and blacks after adjusting for comorbidities and socio-demographic factors, suggesting that the higher prevalence of co-morbidities among African-American patients is responsible for the observed increased mortality in this ethnic group. 79 Accordingly SARS-CoV-2 mortality among blacks in Haiti is much lower than among African The risk of death for young and healthy people is instead very small, and deaths outside the high-risk groups are quite rare. 83 died. 100 Therefore, the reported average 1-3% infections-death-rate is, as many averages in medicine, a number of little relevance to the individual patient.

Regardless of the age group and comorbidities, men are at much higher risk than women to require ICU treatment and to die. This increased risk has been linked to genetic predisposition and to the presence of autoantibodies (see above refs. 97, 98 ) , and to testosterone. Hoffman et al. 101 discovered that the membrane-bound serine protease TMPRSS2, cleaves the spike protein allowing the viral membrane to fuse with the cell membrane and enter the cell. Infections could be blocked in cell culture by a clinically approved inhibitor of TMPRSS2. TMPRSS2 is produced in response to binding of testosterone to its receptor. Alimonti et al. 102 reported that men treated with androgen deprivation therapy (ADT) because of prostate cancer had a significant lower risk of being infected with SARS-CoV-2 and, when infected, to require intensive care or to die, than prostate cancer patients who were not on ADT. Subsequent studies supported that testosterone levels influence susceptibility to infection and COVID-19. 103 In a few of the children affected by Kawasaki's disease, their blood pressure drops and the child may go into shock. In these cases, steroid and immunoglobulin therapy are effective and children recover. 105 Overall the risk that children infected with SARS-CoV- 

The pathophysiological mechanisms underlying these conditions are complex. The upper respiratory tract epithelial cells and alveolar type II pneumocytes, and endothelial cells throughout the body, exhibit high densities of ACE2, the cell receptor for SARS-CoV-2 that allows viral infection. [106] [107] [108] Patients with higher risk for severe disease of fatal outcome do not show increased ACE2 expression. 39 Infected and damaged endothelial cells lead to vascular leakage, trigger blood clotting and cause inflammation and, at J o u r n a l P r e -p r o o f times, a lethal cytokine storm. 109 Histology of the lungs of patients with COVID-19 ( Figure 4) show diffuse alveolar damage and pneumocyte hyperplasia, extravasation of fibrin and other of proteins, focal patchy inflammatory infiltration, and massive congestion: the resulting thickened alveolar walls prevent oxygen exchange. 31, [110] [111] [112] Moreover, the endothelial damage leads to alveolar capillary micro-thrombi and neoangiogenesis. 113 The clinical spectrum of SARS-CoV-2 infection ranges from an asymptomatic condition to a multi-organ failure disease and includes life-threatening super-infections as well as long term sequelae. [114] [115] [116] Although the initial clinical manifestations are often those of an "Influenza-like illness", the infection is not limited to the lungs. SARS-CoV-2 causes viremia and binds the ACE2 receptors in the lungs, gastrointestinal tract, heart, vascular endothelium, kidneys, liver and brain. 117 The main symptoms include fever, cough, fatigue, myalgia, pharyngodynia, diarrhea, anosmia, and ageusia. [118] [119] [120] [121] [122] More severe cases show pneumonia, severe acute respiratory syndrome (SARS), embolisms, diffuse intravascular coagulation (DIC), and eventually death. 123 The early infection phase includes an asymptomatic incubation of 1-14 days followed by disease manifestations (Figure 5 ). Seven to 14 days after the onset of the symptoms, some patients may develop a severe clinical condition. This fraction of patients (estimated at ~ 5%, and as high as 20-40% among those admitted to a Hospital 119,120,124 ) includes mostly elderly patients and/or patients with pre-existing conditions-see above. [118] [119] [120] 124 Clinical clues of a more aggressive and potentially fatal outcome include fever >39°C, conjunctivitis, neurologic symptoms, evidence of a hyper-coagulation state such as ecchymosis of the fingers and toes, and patients who underwent cytoreductive chemotherapy within 4 weeks before the onset of the symptoms. 120,124-127 As the severity of COVID-19 symptoms increases, some patients develop dyspnea with hypoxia, and chest imaging shows the appearance of ground glass opacities in the lung that subsequently acquire a "crazy paving pattern" and may progress from single to multiple and confluent, ensuing in lung consolidation ( Figure 6A, B) . 114, 125, 128 In parallel the peripheral blood T and B lymphocytes may significantly decrease while laboratory markers of inflammation and organ involvement may either increase (C reactive protein, J o u r n a l P r e -p r o o f lactate dehydrogenase, IL 6, prothrombin time, D-dimer, ferritin, liver transaminases, high-sensitivity troponin T, N-terminal pro B-type natriuretic peptide) or decrease (albumin, fibrinogen, platelets count). [118] [119] [120] 124, 125, [129] [130] [131] [132] Clinicians must be aware that these laboratory markers indicate that these patients require immediate transfer to the ICU to prevent impending death. In fact, the clinical and laboratory findings outlined indicate that these patients may be developing an acute respiratory distress syndrome (ARDS), pro-thrombotic disseminated intravascular coagulation, septic shock and/or cardiac failure. The latter may be caused by acute myocarditis with or without arrhythmias, by acute myocardial infarction 133, 134 or, by pericardial effusion with tamponade. 127, 135, 136 Some patients may deteriorate suddenly, as a consequence of thromboembolism of large blood vessels, including pulmonary embolism. 137 In this setting, a some robust, though preliminary, evidence indicates that low molecular weight heparin helps preventing and treating this hypercoagulation syndrome. 138 To contrast the systemic inflammation cascade before it causes multiorgan failure and death, therapy hinges on the use of immunomodulatory agents. 125 In this phase it may be helpful to use corticosteroids 139, 140 possibly in concert with cytokine inhibitors, such as tocilizumab, sarilumab, or clazakizumab (IL-6 inhibitors), anakinra or canakinumab (IL-1 inhibitors), and baricitinib or ruxolitinib (Janus kinase inhibitors). 141 A retrospective study 142 , found that Tolicizumab (Roche) reduced the risk of death by 50% and reduced the requirement for mechanical ventilation in patients with COVID-19 pneumonia. Unfortunately, soon after a Roche phase 3 clinical study with Tocilizumab did not meet its primary endpoint of improved clinical status in adult hospitalized patients although reporting a positive trend in time to hospital discharge. 143 Recent data indicate that baricitinib has anti-viral and anti-cytokine efficacy against SARS-CoV-2 showing a 71% mortality benefit in a propensity score matched analyses of 166 patients with moderate to severe pneumonia 144 .

In vitro studies showed that baricitinib is a Janus kinase-1 inhibitor that interferes with SARS-CoV-2 infection, with viral replication and inhibits the cytokine storm. 144 The potential advantages of immunomodulatory therapy in improving symptoms, should however, be balanced with a likely increase of the risk of severe bacterial and fungal super-infections that may cause the patient's demise. [145] [146] [147] Recent reports underscore the J o u r n a l P r e -p r o o f risk of "CAPA" (Covid 19 associated pulmonary aspergillosis) which may be lethal in up to one third of patients that require mechanical ventilation (Figure 6 C, D) . 148, 149 Moreover, cross-transmission and life-threatening infections with multi-antibiotic resistant bacteria, such as carbapenem resistant gram negative bacilli and methicillinresistant staphylococci, may be frequent in some ICU where optimal adoption of infection control procedures may be hampered by the massive nursing workload required by intubated patients with SARS-CoV-2 infection. 147 A yet-to-be-defined fraction of patients who survive severe COVID-19 develops significant morbidity. These include pulmonary fibrosis, SARS-CoV-2 post-infective myocarditis, Kawasaki's disease, stroke and various neurodegenerative diseases, including sub-acute and chronic neuropsychiatric disorders ( Figure 5 ). [150] [151] [152] [153] [154] 

A better understanding of the disease and some initial improvements in therapy may have helped reduce the death toll of COVID-19 to about 1-2% from initial estimates in China and Northern Italy of a 5-30% mortality. However, the initial estimates were an over estimation as they were based on the fraction of patients that required hospitalization.

Remdesivir, a drug developed by Gilead, is a broad-spectrum antiviral nucleotide prodrug with potent in vitro activity against a range of RNA viruses including Ebola virus, Marburg, MERS-CoV, and SARS-CoV. 155 Based on preliminary evidence from three randomized clinical trials [156] [157] [158] , IDSA guidelines on the treatment and management of patients with COVID-19 159 were recently (September 9, 2020) updated, supporting therapy with this drug over no antiviral treatment for hospitalized patients with severe COVID 19 disease defined as those with SpO2<=94% on room air, on supplemental oxygen, mechanical ventilation or ECMO. In crisis capacity settings (i.e. limited drug supply) Remdesivir was recommended only for those patients with hypoxia not requiring mechanical ventilation or ECMO.

In 1901 Emil von Behring received the Nobel Prize for medicine for treating diphtheria with antiserum obtained from horses. Subsequently, convalescent plasma-therapy, using J o u r n a l P r e -p r o o f blood or plasma from recovered patients, has been used for over a century to treat infectious diseases, including the infamous Spanish influenza in 1918 and more recently, for Ebola virus infections. Shen et al. tried this approach during the initial epidemic in Wuhan. 160 Duan K. 161 Patients treated with plasma in the early phases of COVID-19, before they required ventilation, fared better than those that were not treated or treated once on a respirator. 163 This seems related to the inactivation of SARS-CoV-2 by antibodies during the early stages of the respiratory disease, before patients develop widespread COVID-19-related damage, including lung consolidation. In summary, plasma-therapy is considered safe, although side effects may occur; therefore, the Food and Drug Administration (FDA) has recently approved its use as emergency treatment for COVID-19 patients. However, the availability of convalescent plasma is limited, as each donation consists of about 690-880 ml of plasma, enough to treat only 1 or 2 patients. Moreover, the efficacy of plasma and the antibody titer changes from donor to donor. 163 This system will be used to specifically "chew up" the SARS-CoV-2 genome, hence limiting its ability to reproduce. 170 The rush to publish papers related to this pandemic has resulted in some inaccurate publications that have delayed progress and caused harm. In particular three papers, all of them based on clinical data assembled by Surgisphere, a company based in Chicago, were retracted in short order. One was published in the New England Journal of Medicine May 1, 2020 and claimed that therapy with ACE2 inhibitors did not increase the risk of death. A second one was published in The Lancet, May 22, 2020 and claimed that hydroxychloroquine treatment decreased survival in hospitalized COVID-19 patients. A third paper published as a preprint claimed that a widely-used anti-parasitic drug, "Ivermectin", significantly reduced mortality in COVID-19 patients. This paper has since disappeared from the portal, and thus it does not count as an "official" retraction.

Apparently the database collected by Surgisphere on which these three papers were J o u r n a l P r e -p r o o f based, contained a number of anomalies and upon questioning, Surgisphere declined to share the database, thus the data could not be verified and the papers were retracted. 171 The consequences of these retractions were significant: in South America some officials recommended the use of Ivermectin, creating a shortage of the drug and at the same time COVID-19 patients received a drug they did not need. 172 "Solidarity", the WHO organization that runs the COVID-19 trails, halted the recruitment of patients into the hydroxychloroquine arm. They anticipate that it will be difficult to re-start the trial.

Infected people develop antibodies that protect them from developing illness from the same virus. A recent paper studied the crew of a fishing boat of 122 fishermen, 104 of whom became infected with SARS-CoV-2 during the trip as shown by RT-PCR and seroconversion. 173 Prior to the trip 120/122 had been tested for neutralizing antibodies against SARS-CoV-2, and 3/120 were positive. When the boat came ashore because one sailor had become sick with COVID-19, none of these 3 tested positive for SARS-CoV-2 by RT-PCR or developed any COVID-19-related symptoms while 104/122 of the other sailors were infected (p=0.002) -the authors did not know if and how many of them developed COVID-19. This report provides the first strong evidence in humans that neutralizing antibodies are protective and supports the hypothesis that a SARS-CoV-2 vaccine should work to prevent disease-but not infection, see below. However, we do not know yet for how long those who have overcome SARS-CoV-2 infection are protected from developing disease, and therefore we cannot predict how long immunity will last.

Protective antibodies can develop "naturally" following viral infection, or in response to vaccines. Some have suggested that we should let the virus run its course through the population to allow the natural development of herd immunity. When enough peopleover 60%-are infected and develop antibodies, the so-called herd immunity protects the rest of the population, the epidemics slow down and eventually ends because the virus cannot easily find new victims to infect. Brazil and Sweden have adopted this approach assuming that a rapid aggressive course of COVID-19 epidemic in their region will in the end cause less harm than a long lasting one: time will tell if they were wise to do so.

So far mortality rate attributed to COVID-19 in Brazil and Sweden is 86.14/100,000 and 73.79/100,000 persons respectively. This compares favorably, for example, to 104.89/100,000 and 86.09/100,000 in Italy and France respectively, to 90.31/100,000 in the USA, countries that have adopted lockdowns and other measures to mitigate the spread of the pandemic (data as of Dec 12, 2020). 33 On the other hand the Sweden nearby countries of Finland and Norway have experienced much lower mortality rates, of 8.21 and 7.28/100,000 respectively. So the verdict is still out.

There are ~180 vaccines in production in the world: among them, several are being produced in the US, at least two in China, one by a joint European effort known as the "Oxford vaccine", etc. 174, 175 The Chinese SARS-CoV-2 vaccines are inactivated. One of them, (PiCoVacc) provided partial or complete protection in macaques without causing antibody-dependent enhancement of infection or detectable histological damage in any organ, and, therefore, is now being tested in human trials. 176 These data are encouraging.

The reason that there is no vaccine for SARS CoV-1 is that animals given the vaccine developed a worse disease when challenged by virus than those not vaccinated.

"Operation Warp Speed" is a 2 billion dollar US government-sponsored project that aims to test 3-5 potential vaccines the fall of 2020 and start massive vaccinations in January of 2021. The first two of these vaccines are RNA vaccines coding for the spike protein of SARS-CoV-2 produced by "Moderna" and by "Pfizer and BioNTech", the latter is known as "BNT162b2", presently being tested in a Phase 2-3 trials. These vaccines use a technical approach never tried before, therefore it will be very interesting to see if and how well they work as the results may impact all future vaccine preparations. Preliminary data from these companies suggest that they are 95% effective at generating neutralizing antibodies. They were largely tested in adult healthy volunteers younger than 55, and they appeared safe at least in the short term, although the BNT162b2 vaccine caused pain at the site of injection and headaches in >90 of volunteers. 177 These vaccines will soon become available for mass vaccination, and therefore could play a major role in halting among those assigned to placebo. Therefore, BNT162b2 was 95% effective in preventing Covid-19. The safety profile of BNT162b2 was characterized by shortterm, mild-to-moderate pain at the injection site, fatigue, and headache. These side effects were more pronounced in younger individuals and at the time of the second injection. The incidence of serious adverse events was low. There is, however, concern for possible allergic reactions; therefore, individuals with a history of anaphylaxis to a vaccine, medicine or food, are not candidates to receive the BNT162b2 vaccine. Moreover, in spite of alarming reports on the web, no causal relationship has been established between the vaccine and the two deaths reported among those who received this vaccine, nor the four Bell's palsy cases during the trial. Therefore, "BNT162b2" has been the first vaccine to receive approval for mass vaccination, in the UK first, and soon after in Bahrain, while BNT162b2 should be Clearly more vaccines need to become available to address the needs of the world.

Preliminary data from a Phase 3 trial of the Oxford vaccine from AstraZeneca (ChADOx1nCoV-19)-which should also be available soon for mass vaccination-suggest that it is safe, at least in the short term, although 60% of volunteers developed headache and 70% fatigue. This vaccine was 70% effective at inducing neutralizing antibodies. 175 Although apparently less effective than the Moderna and Pfizer vaccines, the ChADOx1nCoV-19 vaccine -that uses a genetically modified replication incompetent chimpanzee adenovirus vector which expresses the full wild-type spike protein-can be stored at room temperature, making distribution much simpler. The estimated cost of this vaccine is of 3 dollars/dose compared to 15 (BNT162b2) or 25 (Moderna) dollars/dose. All vaccines in clinical trials are delivered intramuscularly to produce IgG, therefore, they cannot produce IgA -which are instead produced by natural infections. For example, while ChADOx1nCoV-19 protected macaques that were challenged with SARS-CoV-2, there was no difference in SARS-CoV-2 nasal shedding from vaccinated and nonvaccinated infected macaques. 179, 180 This means that vaccinated subjects should be resistant from developing COVID-19 but they may still be infected in the nose, oral cavity, eyes and intestine, and spread SARS-CoV-2. This will raise the issue of whether vaccinated people can safely return to a normal life without endangering others.

A problem faced by these trials is that to verify their ability to protect from infection, they need to be administered in areas were infections are spreading; nd these are shifting.

For example China is testing their vaccines in Brazil where the infections are still spreading rapidly. The World Health organization (WHO) is setting up vaccination teams capable of rapidly relocating to the areas in which the epidemic spreads. 174 As for who should receive these vaccines, it can be argued that young people should receive it first, because they should tolerate eventual side effects better, and because they mount a stronger immune response. The opposite argument is that older people and those J o u r n a l P r e -p r o o f with pre-existing health conditions should receive the vaccine first, since they are at increased risk of developing serious disease if infected. Moreover, it may be ethically questionable to vaccinate with a yet to be proven safe vaccine children (and maybe young healthy people) who have a very small risk of becoming seriously ill and whose main reason to receive the vaccines is to protect high-risk groups.

We think that those who have already been infected with SARS-CoV-2 should not receive the vaccines because of the limited number of vaccines available versus the billions who need them. Moreover, based on all we know from other viral infections and the extremely rare frequency of documented SARS-CoV-2 re-infections, those who have been naturally infected should be as or more (as they develop both IgA and IgG protecting antibodies) immune to a second infection than vaccinated people -who can only develop IgG. Also, it is possible that SARS-CoV-2 vaccine side effects might be stronger in individuals already immune.

It has been estimated that if the vaccine is administered to about 20,000 in a region that has a 1% incidence of infection, it will take 6 months to validate its efficacy. Efficacy could be measured either as prevention of infection -but injectable vaccines do not induce IgA thus they cannot prevent infection,, a symptomless infection, or in an attenuated disease course: most trials have used the latter end-point easier to achieve. 174 An obvious problem is how to distribute vaccines to billions of people worldwide. The US Operation War Speed program aims to distribute the vaccines first to US citizens; instead, the Access to COVID-19 tools (ACT) accelerator sponsored by the WHO has raised 8 Billion and plans to distribute vaccines equally among rich and poor countries. 174 It is crucial to convince people to get vaccinated. The anti-vaccine movements in Europe and in the US have raised skepticism in the population about vaccines and up to 50% of the population in different countries does not plan to take a SARS-CoV-2 vaccine. 181 Physicians, health professionals and scientists shall play a critical role in educating the masses so that they understand the limited risks and large benefits of vaccination.

An additional issue to consider because it is attracting a lot of media coverage and it is causing widespread anxiety is whether vaccines or the natural immunity that follows infection, will provide protection against all strains or only some strains of SARS-CoV-2.

Recent papers showed that it is possible to be re-infected by a different strain of SARS-CoV-2. 182 However, considering that as of December 12, 2020 there have been about 70 million estimated infections and 1.6 estimated million COVID-related deaths worldwide, but only a few cases of documented re-infection, the risk that re-infection may pose a real public health problem seems unlikely.

In Wuhan, where the epidemic started in December 2019, the authorities stopped it in its tracks in 3 months. The government literally sealed the doors of the homes and prohibited people from leaving their residences ( Figure 3 ). They used teams to deliver food and medicine to residents and quite literally stopped all movement of citizens.

Before the Chinese government authorized the "re-opening" of Wuhan to the rest of the country, every single person in Wuhan -a city of about 11 million people-had to be tested for SARS-CoV-2 with a nasopharyngeal swab. The sample collection and testing were completed in a 14-day window! People who were positive were placed in continuous quarantine until retests were negative (Xiao SY, personal observations).

Northern Italy, where the first case of COVID-19 was diagnosed a month later than in China, experienced an exponential crisis for 4 months that continues at lower rate of infections up to now. Northern Italy implemented less restrictive measures than China did in Wuhan to lessen the negative economic impact, keeping so-called essential services open. Therefore the virus continued to spread, although less rapidly.

Based on this evidence, by shutting everything down the epidemics can be stopped. This is because the virus cannot "travel" on its own; it requires human-to-human transmission.

Once all movements are restricted, the epidemic ends. Although the option of shutting down a city or a region, like China did in Wuhan, was a viable option during the early stages of the epidemics, presently with ~ 70 million, December 12, 2020, infected throughout the world, this is no longer an option: it is not possible to paralyze the world J o u r n a l P r e -p r o o f without causing many more collateral deaths than SARS-CoV-2 could ever cause. In other words the pandemic can no longer be stopped with a "lock-down", because we should lock down the entire world for this measure to be effective. It is possible however, to slow down the rate of infections as we wait for more effective therapies to reduce the number of deaths, and eventually for an effective vaccine in sufficient amounts that can be delivered to the entire world population.

Until we find effective drugs, or effective vaccines for all become available, the only option to stop or mitigate the pandemic is to stop the virus in its tracks by stopping our own movements. It's that simple. However, in doing so we have to sacrifice our normal living routine, our jobs, our relations with friends and relatives, our religious functions, our passions, everything that defines our lives: we have done most or all of that for the past several months. We have gone so far to let the people we love die alone in the hospital and their corpse burned without a funeral, all this for fear of infection. Is it worth it? And did it help?

It has been estimated that 1.2 million children and 55,000 women will die in the third world because of these restrictions, as children will not receive vaccines -as schools were vaccines are administered are closed-and mothers will not receive gynecological and obstetrical care. The NCI estimated that public fear in engaging with health services and restricted access to diagnostic services, will be responsible, so far, for ~10,000 additional colon and breast cancer deaths because early cancers are not diagnosed as screening has largely been suspended. The NCI stated that this analysis is conservative because it does not consider other cancer types, it does not account for the additional non-lethal morbidity from upstaging and it assumed that all will revert to normal January 2021which is impossible. 183 A South Korean study found that the proportion of patients with advanced NSCLC significantly increased during the COVID-19 pandemic. 184 In the UK public health authorities estimated an additional 1372 lung cancer deaths because of delays in diagnosis caused by the pandemic which results in more patients presenting with advanced disease. 185 Therefore, reducing efforts to prevent and treat cancer and J o u r n a l P r e -p r o o f other critical diseases as we divert all our attention and resources to try to contain SARS-CoV-2 infections, may end up costing many more lives. 183 The price humanity is paying for implementing strict restrictive measures based on fear of contracting SARS-CoV-2 infection may out-weight any benefit of decreasing the rate of viral spreading.

So what can we do as we wait for effective therapies and for a vaccine?

Wearing facial masks, lockdowns, closing borders, etc., may mitigate SARS-CoV-2 transmission, but is not sufficient to significantly influence the pandemic in countries year long because the temperature is neither too hot nor too cold, it is very difficult to contain a viral pandemic during cold months -or in places where temperature and humidity are too high and thus uncomfortable-without imposing strict measures that cause collateral deaths from other diseases, cripple the economy, and limit civil liberties.

Soon we should have more effective drugs to treat those who develop COVID-19: the science supporting the efficacy of therapies with anti SARS-CoV-2 monoclonal antibody cocktails is strong, the very quick recovery of President Trump who received this therapy presently in clinical trial, makes us hope that this therapy will be a game changer as soon as it becomes widely available. And eventually, hopefully, there will be sufficient doses of effective vaccines, and we shall all go back to the life the way it used to be. 

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Effectiveness of convalescent plasma therapy in severe COVID-19 patients

Convalescent plasma treatment of severe COVID-19: a propensity score-matched control study

Factors Associated with Good Patient Outcomes Following Convalescent Plasma in COVID-19: A Prospective Phase II Clinical Trial

Studies in humanized mice and convalescent humans yield a SARS-CoV-2 antibody cocktail

Antibody cocktail to SARS-CoV-2 spike protein prevents rapid mutational escape seen with individual antibodies

Passive antibody therapy in COVID-19

Mesenchymal Stromal Cells: Clinical Challenges and Therapeutic Opportunities

Adipose-derived mesenchymal stromal cells for the treatment of patients with severe SARS-CoV-2 pneumonia requiring mechanical ventilation. A proof of concept study

Structure-based design of antiviral drug candidates targeting the SARS-CoV-2 main protease

Virus against virus: a potential treatment for 2019-nCov (SARS-CoV-2) and other RNA viruses

The pandemic's first major research scandal erupts

Latin America's embrace of an unproven COVID treatment is hindering drug trials

Neutralizing antibodies correlate with protection from SARS-CoV-2 in humans during a fishery vessel outbreak with high attack rate

Pandemic vaccines are about to face the real test

SARS-CoV-2 vaccines in development

Development of an inactivated vaccine candidate for SARS-CoV-2

Phase I/II study of COVID-19 RNA vaccine BNT162b1 in adults

Safety and Efficacy of the BNT162b2 mRNA Covid-19

ChAdOx1 nCoV-19 vaccine prevents SARS-CoV-2 pneumonia in rhesus macaques

DNA vaccine protection against SARS-CoV-2 in rhesus macaques

Officials gird for a war on vaccine misinformation

Evidence of Severe Acute Respiratory Syndrome Coronavirus 2

Reinfection After Recovery from Mild Coronavirus Disease

COVID-19 and cancer

Collateral effects of the coronavirus disease 2019 pandemic on lung cancer diagnosis in Korea

Lung cancer control in the UK hit badly by COVID-19 pandemic

We are grateful to Drs. Anna Nowak and Franco Vicario for critical discussion about COVID-19 in Australia and New Zealand.J o u r n a l P r e -p r o o f