In December 2019, a new potentially pandemic Coronavirus made its appearance in the province of Wuhan, China. From there, the epidemic began to spread to the rest of China, then to Asia and all over the world. Today, cases are reported in over one hundred countries, in Asia, Europe, North America, South America, Africa and Oceania. The feared transmission of the virus from human to human has been confirmed in all these regions and in Europe, also by asymptomatic subjects. It is difficult to understand why these data have long been underestimated, above all in the West Countries. Only on March 11th 2020 the WHO declared the pandemic alarm. To date, April 13th 2020, the confirmed cases in the world are 1.844.863 and the confirmed deaths 117.021 (20.465 in Italy vs. 3.351 recorded in China and 222 in South Korea). The situation appears particularly serious in Northern Italy, and more recently also in UK (11,329 deaths), France (14,946 deaths), Spain (17,489 deaths) and above all United States of America (21,972 deaths), with the number of cases doubling every day in Madrid and New York city. Italy has currently recorded 16.400 infected healthcare workers and 116 medical doctors dead. In this paper, we will try to explain why Italy has become the second epicenter of the world epidemics after China, and why the containment strategies and preventive measures adopted so far by the Italian government still do not seem to be sufficiently adequate in slowing the expansion of the COVID-19 outbreak.

Introduction: Chronicles of a drama foretold

One of the most false claims that have circulated in these 40 dramatic days in Italy is that the drama we are experiencing was not foreseeable and preventable. This is not true. First of all, because for at least twenty years, from the first alarms on the avian flu and then on the SARS Coronavirus, we knew that the chances of a pandemic were high. Secondly, because those who had dealt with these problems in those years had tried in every way to warn the establishment of the impending danger, especially seeing how the Asian countries were reacting. It is true that only a few experts had been able to realize the danger of the virus very early, having the Chinese sequenced it in a record time and published the sequence on January 12th. But it is equally undeniable that the media from all over the world were full of images of what was going on in China. And it was evident that the announced drama was taking place, but also that China, Korea, Hong Kong, Taiwan and all Southeast Asia countries were well prepared and were reacting quickly and effectively. It is certainly possible to assert that the Chinese could have warned us earlier, given that at the end of December they knew what was going on. But, in all sincerity we have to admit that, seeing what happened in Italy and in other western countries, things would not have changed much. Because the inhabitants of the wealthy West did not believe that a pandemic in the 21st century would be a drama like that we are experiencing. Ordinary citizens did not believe it, politicians and intellectuals did not believe it, nor did many of the experts who should have organized the strategies in time to slow down the inexorable advance of the virus. Many of whom not only lacked specific expertise and experience, but as a well-known parasitologist from the University of Padua declared, they followed the pandemic on television. Instead of organizing in time: the information and training of citizens and health workers; the radical reorganization of the health system, in order to obtain the early recognition of patients; the active surveillance and local monitoring; the creation of alternative corridors for diagnosis and isolation of patients and their contacts; the strengthening of the hospital wards necessary to treat serious cases; the protection of healthcare professionals. If it is beyond doubt that Western countries did not react correctly, it is equally interesting to analyze their different reactions arising from their history and culture and the consequences of these. The countries of southern Europe, mainly Italy, have long underestimated the risks and risked to have their health systems overwhelmed, in the most affected regions. The northern European countries reacted in a more orderly and rational manner and were able to reduce the damage and the deaths. The Anglo-Saxon countries have perhaps more than all the other underestimated the virus, especially in the first phases of the pandemic, thinking in a very Darwinian way that it would have been better to take into account thousands of deaths among the weakest and oldest, rather than slowing down and hurting economy. Yet, the way the pandemic is spreading and its dramatic initial effects demonstrate the weakness of all these analyzes. Reflecting on some of the dramatic misunderstandings made in Italy, which had the misfortune of being the first western country hit hard by the pandemic, can be of great help for the future.

Some articles have already highlighted several significant aspects of the Italian outbreak. At this point, we should investigate why Italy has become the second epicenter of the world epidemic, wondering whether the extreme social restrictions and measures adopted so far by the Italian government will sufficiently slow the expansion of the epidemic. In an attempt to address this question, we may compare what happened in China, the country that first had to face the new pandemic and that efficiently managed to quickly curb its expansion, with what it is ongoing in Italy. The first observation that arises from our analysis is that, unlike their Chinese and Asian colleagues, - who had the opportunity to be alerted by the previous outbreaks caused by the SARS Coronavirus (SARS-CoV/2003) - European and Italian experts, in particular, did not believe in time that SARS-CoV-2/2019 could be the pandemic virus expected for over 20 years.

It is useful to remember that when facing a possible pandemic event, due to a pathogen that has made the species jump, it is necessary to consider three main factors:

1) the pathogen;
2) the reaction of the host immune response to the pathogen;
3) environmental factors and related containment strategies.

In this report we describe the critical errors that were made in addressing these factors according to our analyses of the phenomenon.

The first factor: The pathogen

The pathogen, which is the cause of the first pandemic of the third millennium, is the acute respiratory syndrome Coronavirus 2 (SARS-CoV-2), previously referred to as COVID-19, a single-stranded RNA virus, closely similar to another Coronavirus thought to originate from bats. Unlike previous pandemics, the sequencing of COVID-19 was accomplished in early 2020 very rapidly by Chinese researchers who had made it immediately available to the international scientific community. A few days later, the Pasteur Institute announced that it had also completed the sequencing from samples obtained from two patients (one in Paris the other in Bordeaux) suspected to be infected with this new Coronavirus. The two French patients completed sequences were filed on January 30 on the GISAID (Global Initiative on Sharing All Influenza Data) platform. Within 24 hours of isolation, the first Australian SARS-CoV-2 viral isolate (genetically almost identical to the Wuhan virus master sequence) was shared with national and international reference laboratories. The availability of these sequences, due to high-minded sharing of data by scientists, made possible not only the rapid identification of the new virus responsible for the several sporadic cases all around the world, but also, at least by induction, the immediate recognition of its contagiousness and virulence. The discovery could have provided a potentially huge advantage to face the global pandemic that was emerging. Unfortunately, this was not the case. Many eminent pulmonologists and infectious disease specialists continued to assert that the pathogen involved in the outbreak was a common Human parainfluenza virus (HPIV) and that the potential risks triggered by unfounded panic would be even greater than those associated with the virus itself.

The first avoidable risk factor: Inadequate attention to the virus

In addressing this first error, it is important to stress that the first assessment of the magnitude of risks associated with a new virus can be achieved starting from the genetic and phylogenetic analysis of the virus itself. It does not take more than 48-72 hours to reconstruct the phylogenetic rank of a virus starting from the sequences of the isolated strains. At this point, we must admit that in Italy sequencing and phylogenetic analyzes on the isolated strains have not been sufficiently timely or accurate. In particular, 15 days were lost to search for the supposed Italian zero patient, instead of trying to understand, on the basis of the genetic sequences, from where the virus had arrived and how it was spreading throughout northern Italy. In early February, the sequencing of the new virus was announced by the National Institute for Infectious Diseases Lazzaro Spallanzani in Rome. In early March, the phylogenetic analysis of the first 3 genomes obtained from the Italian SARS-CoV-2 isolates circulating in Lombardy and sequenced at the Luigi Sacco Hospital in Milan, demonstrated both the Chinese origin of the pandemic outbreak and their derivation from a cluster of genomes isolated in other European countries (in particular in Germany and Finland) and in Central-South America. The virologists who glanced at the viral RNA stunned. It was really a virus that had 96% of the genome of a bat-coronavirus, but also 8 mutations at the key points: the sequences coding for the spike protein, which would have made the virus terribly contagious and invasive for the human species.

The second avoidable risk factor: The delay of the pandemic alarm

It was therefore truly a pandemic virus, and not a normal parainfluenza virus, as unfortunately many expert infectious disease specialists, had repeatedly affirmed. This interpretation was the fundamental error that prompted politicians, health workers and ordinary people to underestimate the alarm for a long time, to waste precious time, to expose themselves without sufficient protection and to promote, first in Italy and then in Europe, the current almost uncontrollable spread of the virus. On the other hand, the scientific community and politicians waited to act that the WHO decided to declare the pandemic alarm, which this time arrived too late. How can we motivate this delay? It is useful to remember that in recent decades, some large avian outbreaks and repeated and widespread human clusters, mainly in China and Southeast Asia, led the WHO to launch some alerts for a possible "avian" pandemic, inappropriately criticized by many, owing to ideological and political, rather than scientific motivations. Furthermore, it is important to underline the detrimental role played by the social media, where innumerable fake news circulated, generally connected to conspiracy-type assumptions. It is not unreasonable to hypothesize that these criticisms negatively influenced WHO, when the feared pandemic actually occurred.

The second factor: The reaction of the new guest

The capacity to invade the host and to spread in organs and tissues, the contagiousness and ultimately the ability to transmit from human to human are determined by the genetic and molecular structure of a new virus. SARS-CoV-2/2019 acquired these properties in a very short time and the underestimation of these findings by many experts was one of the main reasons for the rapid expansion of the epidemic outbreak, particularly in Italy. Yet, some aspects of the host immune response and its diverse reaction modes need clarification. It is useful to recall that most viruses do not cause serious or even lethal systemic diseases. In the most serious and severe viral infections, it is the contribution of the host’s immune response that plays the most important determinative role. Paradoxically, it is an excessive immunological reaction or a dysregulated aberration of natural immunity with hyperproduction of pro-inflammatory cytokines, that results in the organ damage in the most serious viral infections, a phenomenon referred to as cytokine storm. In the great pandemics of the past and in recent outbreaks, the high lethality rates even among young subjects, were probably due to this mechanism, although in some, e.g., the Spanish flu, bacterial infection could have played a significant role. Both the data from China and from the most serious cases of the Italian outbreak seem in line with this proposed pathogenesis. The most typical and serious prototypic presentation seems to be Acute Respiratory Distress Syndrome (ARDS), with exceptionally rapid evolution towards pulmonary fibrosis and a hypercoagulable state inducing pulmonary and systemic microvascular thrombosis that may play a major role in the progression of the disease towards death. Another troubling possibility, which should not be overlooked, is that many of the subjects who recover from the ARDS will also have the sequelae of reduced respiratory function throughout their lives.

A recent report from the Lancet supported this proposed pathogenic mechanisms, and advocated that treatment of hyper-inflammation using existing, approved ant-inflammatory cytokine therapies of proven safety may be critical in addressing the immediate need to reduce the rising mortality of COVID-19 infection. Moreover, the application of heparin has been recommended to avoid the risk of disseminated intravascular coagulation and venous thromboembolism. It is also important to note, that the topic of high mortality in elderly subjects, carriers of serious chronic pathological diseases should not be used lightly, in support of the thesis that SARS-CoV-2/2019 would not be very different from the common flu and paraflu viruses. The difference also in this case is important: seasonal flu viruses act as a final cause in people with poor health, but they are not particularly dangerous for people living with them and for healthy and young people. On the contrary, pandemic viruses can cause serious and sometimes lethal pathological states even in healthy subjects and at a relatively young age. In this sense, even a hint to targeted molecular therapies can be illuminating. The drug that seems to have given the most promising results so far is Tocillizumab, a specific monoclonal antibody capable of blocking interleukin IL-6, interrupting or at least reducing the violence of the cytokine storm. Its effectiveness demonstrates that this one is the most important pathogenic mechanism in severe cases, proving, once again, that SARS-CoV-2 is a pandemic virus and not a trivial parainfluenza virus. It is, therefore, only partially true that the factor that determined the extreme gravity of the current situation in Italy, compared to what happens during the annual flu epidemics, is only the extreme rapidity of the spread of the virus, which caused the assault on intensive care units. This type of analysis would lead once again to underestimate the true nature of SARS-CoV-2/2019 as a pandemic virus, and this would be a very serious mistake, which could have dramatic repercussions both on health workers and on the health system itself, not only in the short term, but also and above all in the medium to long term.

The third factor in play: Environmental features and containment strategies

The third fundamental factor is the environment in which the virus emerges and spreads. This is not the place to deal with the immense problem of altered ecosystems and microbial systems, the precarious socio-economic and town planning conditions in some countries, the critical conditions of fast-food chains, the undoubtedly underestimated role of pollution: all factors playing an important role, above all in the genesis and the initial spread of a pandemic. Only with regard to pollution we must mention that at least in this initial phase of the epidemic in Italy the areas characterized by the highest lethality rates are among the most polluted of the country. It has long been known that atmospheric particulate matter is an effective vector for the transport of viruses and for the spread of viral infections. During the avian flu outbreaks it was even shown that the particulates had carried the fearsome H5N1 for long distances and that there was an exponential correlation between the quantities of cases of infection and the concentrations of PM10 and PM2.5. Not only a correlation between the presence of viruses in the particulate matter and epidemic outbreaks has never been proved, but it is increasingly evident that most of the infections occur by human contact and in closed and crowded environments (families, public places and unfortunately hospitals and healthcare residences). Any minimal quantities of viruses transported by the particulates do not seem to play a significant role in this context. Rather, it is the persistent air pollution rate that must be called into question and its effects on human health. Because of pollution, adults and in particular the elderly suffering from chronic diseases are affected by low grade persistent inflammation and systemic endothelial dysfunction, that appears to be the most potent predisposing and triggering factors for cytokine storm and thrombotic dysfunction. That’s why it is conceivable that prolonged exposure to ultrafine particulates, heavy metals and other atmospheric pollutants played a pro-inflammatory role in subjects leaving in the Po Valley, one of the most polluted regions in Europe. In fact, in the scientific literature the role of air pollution in chronic diseases (in particular neurodegenerative, respiratory, and cardiovascular diseases) has been demonstrated, and is very underestimated by official medicine. Furthermore, an ecological study has already documented a positive association between air pollution and mortality in the Chinese population during the SARS epidemic in 2003. To further verify these interesting correlations, however, it will be necessary to carefully evaluate the morbidity and lethality rates that will be recorded in the most polluted megacities of the world (New Delhi, Mexico City, Cairo), if they will be involved in the pandemic. An extremely controversial issue (certainly not to be overlooked) is that concerning the persistence of the virus in the environment and on certain materials rather than on others, evaluated, in some cases, even in many days. In any case, the personal and environmental hygiene rules have been largely and persistently reminded in these days. On the other hand, these are difficult data to interpret: above all, what is the "bioavailability" of viruses scattered on a sink or on the floor and in public places? In a recent study on influenza transmission, it has been shown that cough is not necessary for the emission of viruses and that nevertheless the exhaled infected aerosols essentially come from the lower respiratory tract. As already mentioned, the Chinese data in this case are very clear: the largely prevalent route of infection remains the traditional, direct, massive and prolonged one, via aerosols of respiratory droplets in closed rooms and in families.

Another aspect to be considered are the effects of the containment strategies put in place by China to stop the spread of the virus in the bud. Already from a summary analysis of the graphs, it is clear that in the first month, from early December until early January, COVID cases in China were very few. The increase began on January 21 (1500 cases in one day). Within 48 hours, the entire province of Hubei was closed: a decision not to be underestimated, considering that the region has almost the same number of inhabitants of Italy and France: about 60 million (on an area that is just over half of the Italian one and a third of France). The following day, January 23, another 15 cities were closed and as many the day after. Nevertheless, inevitably, the situation remained critical for two weeks, the whole country was placed under close surveillance and no further clusters were registered in the other regions. The increase in cases peaked around January 23-25 with 3000/3500 positive cases per day. The peak was followed by a short plateau of a few days and by a gradual reduction in cases which led to a very limited number in less than a month (300/day compared to over 3000/day at the peak moment). But how was all this achieved? Undoubtedly, the strength of the Chinese strategy was the overwhelming control of all the exposed population. For this purpose, a capillary monitoring system was organized through teams coordinated by experts, who interviewed all infected and positive people, and performed swabs not only on symptomatic subjects, but on all their contacts.

The Golden Rule: Pandemics must be stopped on the ground, not in hospitals

Only in this way was it possible to proceed not only with the immediate recognition and isolation of cases, but also with the quarantine of all close contacts. Strategies that worked thanks to a very high degree of acceptance and active collaboration by the population, much more informed and aware than in Western countries about the danger of such situations and the urgency and necessity of restrictions and containment strategies. The Chinese epidemiological data immediately confirmed the great effectiveness of such radical strategies: most of the cases and deaths had in fact occurred in the Hubei region alone, immediately put into quarantine (Fig. 1).


China

Fig. 1. The Chinese internal divide: Clinical characteristics and outcomes of hospitalised patients with COVID-19 treated in Hubei (epicenter) and outside Hubei (non-epicenter) (A Nationwide Analysis of China European Respiratory Journal 2020; DOI: 10.1183/13993003.00562-2020).

As for lethality rates, these too had been 4.5% in the Hubei region alone and less than 1% in the rest of the country, where the number of cases had remained very low. The early information concerning the immediate results obtained in China by closing entire regions and cities as soon as the first cases had arisen, should have shown the need to act immediately and radically, without waiting for the first clusters to manifest with dramatic evidence. Moreover, as early as mid-January, a considerable volume of news and images arrived in Europe showing thousands of disciplined Chinese walking, wearing their masks in the urban areas where the first cases had been detected, not to protect themselves, but mainly (despite being asymptomatic status) to avoid spreading the virus to others. Above all, it was immediately clear that only after the January 20 decision to set up places for the isolation of all the positives in ad hoc adapted buildings (i.e., gyms, barracks, exhibitions, etc.) did the first signs of epidemic appeared to slow down. The recognition of direct human to human spread of infection should have promptly led to the immediate closure of clubs and meeting places where the virus was likely to remain viable for a long periods and be easily transmitted, rather than the almost-prohibition of walking in the parks or in nature. Yet, above all, the absolutely fundamental data, which emerged from the WHO study, but already partially known through the international media, was that the Chinese immediately understood the necessity of adapting health facilities to the emergency. This included converting departments, increasing bed places, recruiting staff, building new healthcare facilities in record time, producing up to 1,500,000 tampons per week and above all, protecting medical and paramedical staff with adequate protective measures. Only in this way, would it be possible to prevent health facilities from becoming sites of the most dangerous and contagious places posing a clear and present danger for both health care personnel and for the whole country. In the meantime, many other Asian countries, in which the infection began to spread, reacted in an equally rapid and effective way. In particular, Japan, Taiwan, Singapore and Hong Kong took timely and drastic measures, obtaining the rapid containment of the epidemic quickly and with a negligible increase in cases. The most probable explanation for this, is that all these countries were perfectly aware of the enormous risks associated with the spread of a pandemic virus, for at least two reasons: because of decades of experience in the prevention of the numerous potentially pandemic outbreaks originating in Southeast Asia; owing to the recent, dramatic experience of SARS faced in 2003 and subsequently studied with extreme attention, in order to avoid possible new outbreaks.

Unfortunately, the same scenario did not occur in western countries and, in particular, in Italy.

The Italian drama

As for the Italian situation on April 17th, the data appear to be critically extensive. In the first 50 days of the epidemic, 172.434 cases (22,745 dead) were identified mostly (> 80%) located in the 4 major northern regions: Lombardy (64.135/11.851 dead), Emilia-Romagna (21,834/2,903), Piedmont (19,803/2,171), Veneto (15,374/1,026). These figures are beyond those normally considered worrisome. The trend of deaths since February 25 followed a strictly exponential trajectory. Although it is difficult to draw definitive conclusions for mortality rates from the current epidemiological data in this first phase of the epidemic lethality rates (calculated on the basis of cases identified by PCR tests) appear very high, although with considerable variability from region to region. The most dramatic scenario occurred in Lombardy, one of the richest regions characterized by a high-level health organization. Nonetheless, 10,627 currently hospitalized patients, probably many more real deaths than the almost 12,000 officially registered (with a lethality rate close to 20%) and still 971 cases in intensive care units (ICU) have been already recorded in Lombardy. Much more dramatic data than those officially reported in China, where the lethality rates quickly plateaued at 3.5%. Not much better are the data from Emilia-Romagna where the lethality rates are slightly lower than 15% and Piedmont where the lethality rates are approximately 10% (in any case 3 times greater than in China). Slightly better are the lethality rates (around 6-7%) in the Veneto region, the only region of Northern Italy that immediately underwent strict containment measures, in open contrast to official government rules, significantly slowing down the spread of the virus. Evidently, these are really dramatic data: 20/30 times higher than those due to the common seasonal influence. To which it is necessary to add the number of ICU admissions, many of which have ARD, and are doomed to death. Undisputed data are that throughout Italy over 10-15% of those affected so far have died or been hospitalized in intensive care.

A situation that seems to have no precedent except, perhaps, in the Spanish Flu. In that case, however, the retrospective computation of lethality data was very difficult. Recently, an agreement has been reached on these figures: approximately 50 million deaths and 500 million infected in 1.8-2 billion people. Which would mean lethality rates oscillating between 2 and 10%, but mortality rate around 2.5%. Moreover, we should consider that a century ago developing a cytokines storm and an ARD generally meant death. So, it is not unexpected that young people frequently died, especially in the second epidemic wave, which was much more lethal than the first: a most worrisome possibility for the current COVID-19 pandemic. As for Asiatic flu (1957), the lethality cases seem to have been much lower: probably around 0.5-1% and even lower those of Hong Kong flu (1968), despite the lack of current therapeutic possibilities. Yet, it is evident that something does not work in such evaluations. And above all, how can we explain the dramatic situation in Northern Italy with very high lethal rates and thousands of ICU patients and the much less severe one in central and southern Italy?

The third avoidable risk factor: The partial and late application of the Chinese and Asian strategies

Many have so far interpreted the aforementioned data as the classic tip of the iceberg, in relation to a probable wide circulation of the new virus in the general population and a very large number of asymptomatic subjects. It is in fact probable that, if the evaluations previously described are true and the virus has been circulating, at least in the northern regions, for almost 2 months, the subjects infected and capable of infecting others could already be hundreds of thousands in Italy. In this case, the very high lethal rates that are creating panic would be an almost artifact. Indeed, it is evident that screening only symptomatic subjects by PCR test and not ascertaining or monitoring their contacts, means selecting the most severely affected among the infected without considering all those subjects who have already encountered the virus and have overcome mild forms of the disease and are paucisymptomatic or asymptomatic. It is at least partly for these reasons that on the one hand in Italy lethality rates are much higher than in China, on the other hand the virus continues to circulate and expand freely.

Anyway, among the many important data that emerged from the WHO study in China, one does not seem convincing: that in most cases, those who meet the virus sooner or later become symptomatic. The data that appear every day in Italy and in other countries contradict this theory: the majority of people infected with the virus remain asymptomatic or paucisymptomatic and appear to be the most dangerous source of spread of the epidemic. And in fact, recently, researchers at Columbia University Mailman School of Public Health established that undocumented infections probably facilitated the rapid spread of the virus in Wuhan, especially before the restrictions. According to their study, published in Science, 86% of all infections had not been recognized and these subjects, although presumably less infectious compared to the symptomatic ones, would have been the source of 2/3 of all infections. If these assessments are truthful, in Italy another fundamental mistake was to focus exclusively on serious cases, while in China it was immediately understood that it was necessary to test and monitor all cases and in particular the mild ones (anyone who had symptoms of fever, asthenia and cough) and anyone who had direct contact, especially if protracted, with them. It should be clear that if we only focus on serious cases, characterized by high and prolonged fever, asthenia, cardiovascular symptoms, high pressure, neurological and respiratory disorders, which according to Chinese data should be only 5% of the total, an early diagnosis will not be possible. And, above all, the dissemination of the virus, essentially occurring through the infected patients who are still asymptomatic, will not stop. Relying on these criteria, reserving testing to serious cases was a serious mistake, which the Asian countries did not make.

A drama in the drama, in Italy, concerns health professionals: according to the data released by the ISS, in Italy since the beginning of the epidemic, at least 17,000 health professionals have contracted the COVID infection (equal to 10% of the total number of people infected!) and 130 medical doctors deceased. These data are enormously worse than those of the Chinese cohort (3300 infected, 3.8% of the total number, and 23 deaths) reported in a study published in JAMA. It is increasingly evident that these events would have been largely avoidable if specific hospital/diagnostic paths had been set, and if health workers would have been properly informed and furnished with "sufficient protective equipment". A very serious fact not only on the moral and juridical level, but also for the consequences it will have. And this not only in Italy, but with increasingly dramatic evidence, in all Western countries.

Finally, what happened in China, but also in other Asian countries, demonstrates the importance of timely and correct information and the proactive and convinced participation of the population. The accurate and rapidly implemented surveillance also made it possible to make predictions on the evolution of the epidemic outbreak that proved to be accurate. After setting the starting point of the epidemic on December 8, the date of the first case diagnosed in Wuhan by the famous doctor Li, who unfairly censored unfortunately died, Chinese experts calculated that the peak would be reached in a few weeks; that the plateau would have been short, reaching around 85,000 total cases; that the outbreak would decrease and then shut down after about 100 days. At this point it will be difficult to predict what will happen in Italy and in the other western countries, where the restrictions have been implemented too late and gradually, without the accuracy of the Chinese and above all, as mentioned, only considering severe cases and significant clusters. As we can see (Fig. 2), the very first divide in epidemiological data concerns, on the one hand, Asian countries which, for the above-mentioned reasons, were able to cope drastically and effectively with the epidemic, on the other hand Western countries which having underestimated the pre-pandemic alarm and the virus itself were found unprepared.


Deceased

Fig 2. The global divide: Asian versus Western Countries. The diffusion patterns of SARS-CoV-2 deaths number growth in different countries are outlined. Cumulative number of deceased is considered from the first day with 100 recognized cases. South Corea is taken as example of a country accustomed to dealing with this type of emergency and “sensitized" by SARS/2002 related pandemic warnings. Taken from COVID Time Series Test.

As for Italy, a similar epidemic gap is evident between the northern and southern regions. Indeed, the fact that the southern regions could benefit of a longer latency time between the first cases and the spread of the virus played an important role. We hypothesize that the fact of having been able to reduce the inflow of infected people in hospitals made the difference (Fig. 3).


Italy

Fig. 3. The Italian divide. Cumulative growth of COVID cases number in three North Italian regions (Veneto, Piedmont, Emilia) and three South regions (Campania, Puglia, Sicilia) starting from the first case registered in Veneto. The six areas have a similar population size. The institution of the red zone was established 17-18 days after the tenth case in North Italy and 6-11 days after the tenth case in the South.

Unfortunately, as the days go by, it becomes more and more evident that many other western nations are destined to follow the fate of Italy. Starting from Spain, which in the last 20 days has gone from 39,670 cases/2696 deaths to 177,633 cases/18,579 deaths). Followed by France, which in the same period went from 22,025 cases/1100 deaths to 105,155 cases/17,146 deaths. And again: United Kingdom from 8081 cases/422 deaths to 98,480 cases/12,868 deaths. And finally, USA from 51,914 cases/673 deaths to 604,070 cases/25.871 deaths. And the rule becomes increasingly evident: a pandemic unfortunately accelerates inexorably, in countries that do not implement rapid and decisive containment strategies.

The fourth avoidable risk factor: Insufficient information and protection of the operators and the health system

The fourth error, which unfortunately is about to manifest itself in Italy and in all western countries all its dramatic relevance, derives directly from the first three and in particular from the underestimation of the pathogenic potential of a pandemic virus. It essentially consists of the insufficient information about the risks associated with a direct (and therefore massive) exposure to the new bug. Neither ordinary people, nor especially health workers, have been warned in time and adequately protected. Furthermore, our requests to quickly adapt to the emergency the National Health System and in particular hospital facilities were not taken into consideration.

In fact, because of the "Public Health Emergency of International Concern" (PHEIC) announced by the World Organization the New Coronavirus Emergency had already been announced, for six months, on 31 January, in The Official Journal of The Italian Republic, by a Decree of the Council of Ministers. Yet, the correct measures did not start even after the beginning of the outbreak. The golden standard for trying to stop a pandemic is to face it on the territory, safeguarding hospitals, as Asian countries have done (preparing for these emergencies for 30 years). We should have arranged alternative pathways to prevent the virus from entering hospitals through the emergency rooms: by organizing military hospitals and other alternative facilities for positive quarantine; by testing and monitoring interpersonal contacts; adequately protecting health professionals assigned to SARS CoV2 control; organizing hospital wards and in particular intensive care units only for COVID. Neglecting these basic rules, you risk turning hospitals into virus sanctuaries. After all, some article has indirectly recognized the possible role of hospitals in amplifying and perpetuating the epidemic. While the great part of health workers usually protect themselves from observable droplet transmissions, they are often unaware that asymptomatic transmit the virus even more often than symptomatic. Moreover, fomite transmission is frequently overlooked in hospitals. It has been proven that a very careful control of the correct management of the fomites plays an important role in the control of the pandemic. Unfortunately, western countries have shown not to be ready to face such events. Although the danger of a pandemic had been known for 20 years, a pandemic virus has been circulating in Europe for at least 2 months, without taking adequate precautions. Neither ordinary people, nor especially health workers, have been warned in time and adequately protected. Furthermore, our reiterated requests for to quickly adapt to the emergency the National Health System and in particular hospital facilities were not taken into consideration.

As regards the urgent and inevitably profound and articulated adaptation of the health system, a first reorganization proposed by us and uselessly solicited on several occasions, consists in the establishment of alternative corridors and dedicated medical areas that should be able to operate in coordinated succession:

A) in each region or province, a single extra-hospital center should be equipped primarily for initial triage, early diagnosis and immediate isolation of positive cases, characterized by mild symptoms (presumably about 80% of cases). Obviously, in this first center, the adequate protection of all the medical personnel assigned is already mandatory. It is extremely important to understand that this center will have to replace any other private and public structure with regard to the immediate approach to suspicious cases that must absolutely not go to private medical offices and hospital facilities. Equally important will be (as in Asian Countries) the research, the correct information and the monitoring of the contacts of all the positive subjects;

B) secondly, wards and hospital or extra-hospital structures should be organized, capable of administering supportive care to cases of medium severity (probably about 15%) needing, in particular, protracted (3/6 weeks), non-invasive oxygen therapy (NUV-Non Invasive Ventilation). Even in these cases, particularly accurate and protracted monitoring will be essential, because the sudden evolution of some towards more serious and acute forms does not seem rare;

C) In this way, only 5% of cases should reach the intensive care units (ICU), requiring intubation and assisted ventilation. In a situation such as the current one, it will be necessary not only to urgently strengthen the current intensive care units, but also to transform some wards normally used for long-term hospitalization, into wards adequate to cope with the emergency.

Lessons to be learnt

We started writing this article a month ago, in the belief that a correct analysis and evaluation of the mistakes made in Italy, the first western country hit by the pandemic, could have prevented the drama from spreading quickly to other countries. But in the 21st century pandemics spread through highways, super-fast trains and international flights and there is not enough time to imitate effective reactions (if you are not prepared in time), or to learn from the mistakes of others. At this point, the analysis of the mistakes made must be extended to all western countries if we do not want to risk being caught unprepared by a second wave of pandemic and in the face of other increasingly probable pandemic outbreaks.

In a nutshell, too many western experts underestimated the pandemic alarm and therefore the virus, which like all "new viruses" has recently gained both contagion/spreading modalities, and pathogenic mechanisms very different from the viruses known for some time to the human immune system. As a result, they did not look for suspicious cases from the beginning and when the first case was diagnosed it was already too late, since the virus was probably circulating in many countries at the end of December. However, it is clear that timely and effective choices would have been possible only if China had raised the alarm in time, rather than hiding the first cases. Nonetheless, we have to admit that western countries would still have found it difficult to react efficiently, due to the lack of experience and real experts in this area. In Italy, at least, this lack of experience has been very evident and harmful. Otherwise, would symptomatic cases be identified in time; the viral genomes of the ascertained cases sequenced; the phylogenetically probable path of the virus reconstructed, avoiding the wrong perception (unfortunately rapidly becoming international) of an almost indigenous, sudden and difficult to interpret "Italian drama". Especially since many experts, have continued to say that 2019nCoV/SARS-CoV-2 was a common flu virus, which in most cases favored/accelerated the death of the elderly and debilitated subjects.

Based on these misunderstanding, many Italian experts (and consequently politicians) did not understand that it was necessary to immediately close, as in China, not only the areas of the first clusters, but entire regions, scrupulously checking the exposed population, monitoring and isolating the infected and their contacts, and above all preventing the circulation of the asymptomatic carriers of the virus. It is evident that the situation is critical today precisely in the areas of the first clusters and the first dissemination. In some cities of Lombardy, such as Bergamo and Brescia, the virus spread hurriedly, in the absence of any perception of the risk and even minimal precautions. This provoked the collapse of the system and the spread of panic, which probably facilitated, in turn, immuno-inflammatory reactions.

Yet, the main mistake that has produced the most painful consequences of the COVID-19 epidemic in Italy was the insufficient information and protection of health personnel and the failure to adapt the National Health System to an emergency that seems to be only at the beginning. It would be important, at this point, to take the correct precautions, to predict and adjust western sanitary services to the "Worst possible scenario", which with reference to modern pandemics is represented by the Spanish Flu of 1918-20, where the expansion of the pandemic progressed through sequentially more deadly steps. After a relatively massive beginning, partly explained and perhaps underestimated due to the concomitant First World War in the first months of 1918, the second, truly devastating wave reached at the end of summer and in less than a year resulted in the death of 40-100 million men, women and children. It is from here that we must start: faced with a situation that could last for months and reappear in an even more dramatic form at a later date, it would not be sufficient to maintain the current lockdown conditions for a long time, simply waiting for the epidemic to subside. It would be necessary to understand that containment measures can serve to slow down the spread of a pandemic, but must be integrated with a rapid and effective reorganization of the entire health system to address this and other future increasingly probable pandemic alarms. What China and other Far Eastern countries effectively accomplished has yet not happened neither in Italy nor in the rest of the Western world.

Thanks to doctors of medicine Justina Claudatus and Catherine Delplanque for the help in the revision and translation of texts in English.

Disclosures
Authors declare no conflict of interests.

Authors' contribution
Ernesto Burgio conceived and designed the paper.
Joseph Bellanti, Giancarlo Di Renzo, Enzo Grossi, Rodolfo Guzzi, Giuseppe Remuzzi revised the manuscript, and integrated it with contributions and graphics.

Corresponding Author
Ernesto Burgio, European Cancer and Environment Research Institute (ECERI), Square de Meeus, 1000 Bruxelles.
Joseph Bellanti, Director, International Center for Interdisciplinary Studies of Immunology (ICISI), Georgetown University Medical Center.
Gian Carlo Di Renzo, Director, Centre for Perinatal and Reproductive Medicine, University of Perugia, Professor, IM Sechenov First State University, Moscow, Russia.
Enzo Grossi, Scientific Director Villa Santa Maria Foundation, Tavernerio, Italy.
Rodolfo Guzzi, Optical Society of America Emeritus, Rome.
Giuseppe Remuzzi, Direttore Istituto di Ricerche Farmacologiche Mario Negri IRCCS.

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