Covid 19 report commissione salute Lincei

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Accademia Nazionale dei Lincei
Commissione Salute
COVID-19: An executive report
Maurizio Cecconi, Guido Forni, Alberto Mantovani
in alphabetical order
Acknowledgments: For suggestions we wish to thank: Gianni Bussolati, Univ. Torino; Silvio
Garattini, Ist. Farm. Mario Negri, Milano; Jacopo Meldolesi, Univ. Scienza-Salute San Raffaele,
Milano; Stefano Schiaffino, Univ. Padova; Paolo Vineis, Imperial College, London, UK; Zhigang Tian,
The Key Lab. Innate Immunity and Chronic Diseases, Chinese Academy of Sciences, Hefei, China.
March 25, 2020

22
1. Premise
At a time when Italy and all world is dramatically faced with the challenge of the SARS-Cov-2
infection, hitting many aspects of human civilization, Commissione Salute of the Accademia
Nazionale dei Lincei felt that it is part of its social responsibility to provide the society at large with
an Executive Summary of the current status of understanding of origin, pathogenesis, and
treatment of COVID-19 pandemic.
This Report is not a comprehensive review of the state-of-the-art of the field but rather snapshot
of a field undergoing rapid evolution, with a daily flood of scientific publications and non-peer
reviewed reports. Preparing a digest is per se a risky endeavor and the extensors of this report are
well aware of their own limitations.
With the limits of the metaphor, we are experiencing wartime medicine and wartime scientific
research. We are called to respond to the drama of patients at times with empiric approaches. Yet
rigorous assessment remains a must and striking a balance between emergency and
methodological stringency represents a major challenge 1
.
Hopefully, with the above mentioned cautionary notes, this report will provide provisional tools to
understand and cope with the unprecedented challenge we are facing.
2. SARS-CoV-2
The virus. Coronavirus disease 2019 (COVID-19) is caused by the infection of the SARS-CoV-2 virus,
a coronavirus. Coronaviruses are a large family of viruses that cause illness ranging from the
winter common cold to more severe diseases such as Middle East Respiratory Syndrome (MERS-
CoV), Severe Acute Respiratory Syndrome (SARS) and COVID-19. The capside of SARS-CoV-2 is
made by four structural proteins: Spike, Envelope, Membrane and Nucleocapsid. The Spike
protein that forms a sort of crown on the surface of the viral particles acts as an anchor allowing
virus attachment, fusion and entry inside the host cells through the binding of Angiotensin-
Converting Enzyme 2 (ACE2) receptors 2
.
Virus infection. COVID-19 starts whit the arrival of SARS-CoV-2 virions on respiratory mucosal
surfaces. Epithelial cells that line the mucous membranes and the mucus secreted by goblet cells
form a first effective barrier. When the virus manages to overcome it, a rapid release of danger
signals activates the reaction of innate immunity. We do not know yet if and how many SARS-CoV-
2 viruses are eliminated by this initial inflammatory reaction, however it is reasonable to assume
that the effectiveness of the immune reaction mechanism may play a crucial role in determining
whether the infection will be benign or will have major consequences. Once the virus has entered
the target cell, viral RNA is immediately translated by the host cell that die by releasing millions of
new viruses.

33
Virus spreading and containment. Coronaviruses are zoonotic, meaning they are transmitted
between animals and people. In the past twenty years a coronavirus has made the so-called "inter-
species jumps” three times, passing from its natural host to humans: in 2003 in China the SARS
virus; in 2015 the MERS virus in the Middle East; in late 2019 in Wuhan, back in China, the SARS-
CoV-2. It is probable that, as already happened for the other coronaviruses, even in the case of
SARS-CoV-2 the original host was the bat. There are 1,200 species of bats which are the 20% of the
mammalian species: a huge virus reservoir. The passage to humans is believed to require an
intermediate host: in the case of SARS it was the civet, for MERS the camel, unknown, but
probably the pangolin for the SARS-CoV-2. Pangolins are an endangered species commercialized
for its keratin scales used as an ingredient in traditional Chinese medicine while the meat is
considered a delicacy in China and Viet Nam3
.
During 2019 fall, a pneumonia of unknown cause was diagnosed in individuals connected with the
seafood and wet market in the city of Wuhan, Hubei province, China. The new variant beta-
coronavirus (SARS-CoV-2) was then isolated from the bronchoalveolar lavage fluid from these
patients and the virus genome was quickly sequenced and made public by Chinese scientist 4
.
SARS-CoV-2 outbreak was declared a Public Health Emergency of International Concern on 30
January 2020 5
.
On February 20th
a patient in his late thirties with no risk factors for SARS-CoV-2 was found
positive to the virus while already admitted in an Intensive Care Unit in Codogno, Lodi, Italy. The
following day 36 cases with no link to an index case were found. The discovery of this secondary
transmission cluster marked the beginning of the largest SARS-CoV-2 outbreak outside China. In
the following weeks clusters emerged in most Western Countries.
On March 11 2020, the World Health Organization (WHO) upgraded the status of the disease
caused by SARS-CoV-2 infection (COVID-19) from epidemic to pandemic. To try to limit COVID-19
spread, first China, then South Corea, Italy and, progressively many countries of the world have
imposed lockdowns and closed borders 5, 6
. The largest quarantine in the history of mankind is
taking place.
Currently Europe appears to be the epicenter of this pandemic: Case counts and deaths are
soaring in Italy, Spain, France, and Germany. While the quick pace of the progression of the
pandemia along with different approaches adopted by the various countries to detect the disease
limit a real comparison, Italy appears to be hardly hit by COVID-19.
3. Strategies to control COVID-19 spread.
With some delay compared with the initiation of COVID19 spread, on January 23, 2020, Chinese
government isolated and locked tens millions people of Hubei province. People were barred from
working or going to school and all shops were closed except those selling food or medicine.
Following lockdown, new cases began to slow down. On March 19, 2020, no new cases were
reported in Hubei province5
.

44
Following Chinese experience, lockdowns of various degree are currently applied in several Asian
and European countries, UK and US. The purpose of lockdown is to reduce the Rt number, i.e. the
number of healthy people contaminated by each SARS-CoV-2 infected person. The Hubei
experience shows that in this way the suppression of virus spread is obtained in a short term 7
. The
effective case reduction obtained through the lockdown allows a better care of the patients and a
reorganization of the health care system. As we will report later, COVID-19 can present in a
significant percentage of cases as a very severe acute respiratory syndrome, requiring Intensive
Care Unit (ICU) admissions. In most countries in the world ICU beds are a limited resource.
In Italy there were roughly 5,000 ICU beds open before the outbreak. Recent data shows that 12%
of SARS-CoV-2 positive cases require ICU admission. In practice if 42,000 people are infected at the
same time the total ICU capacity of the country would be saturated. While ICU beds availability
varies between countries, no healthcare system in the World could sustain an unlimited surge in
ICU patients. For this reason, in order to get ready for a COVID-19 outbreak increasing surge of the
ICU capacity alone would not be sufficient and containment manoeuvres must be in place not to
overwhelm the capacity of the healthcare system.
However, what can be expected to happen when the lockdowns are lifted? The rebound of new
cases that may take place when lockdown interventions are relaxed may impose the
reintroduction of subsequent and perhaps periodical lockdown. The political and economic cost of
a prolonged and repeated lockdowns is very high and opens complex social problems 7,8
.
The perspective of less drastic measures to mitigate the probability of person to person virus
spread has also been evaluated in UK and other countries 7,8
. In this context, the high-tech South
Korea approach appears quite interesting since an effective control of COVID-19 spread was
obtained without locking down entire cities or the whole country. The particularly well-organized
Korean testing and tracing programs allowed to isolate infected people and quarantine their
contacts. While new clusters of infection may emerge, so far, the South Korean lesson is that high
tech preparedness may play a central role in the control of COVID-19 spread9
.
In summary, as of today, three containment scenarios can be envisaged, complete lockdown
(suppression), mitigation or a mix of the two. Suppression is the current approach, currently
underway in Italy and elsewhere. Mitigation consists of milder interventions such as those initially
adopted UK and others countries. These interventions reflect different stages of the epidemic
spread.
Following the resolution of the current dramatic emergency situation in northern Italy, a stop-and-
go suppression and mitigation may be foreseen to address societal needs and face future waves of
the epidemic.
4. Immunity
Innate immunity. Innate immunity represents a first line of resistance against microbes and
evidence suggests that it handles over 90% of encounters with pathogens. Information on innate
immunity in COVID-19 is scanty. Lymphocyte number decreases (lymphopenia) while neutrophils

55
number increases. Inflammatory cytokines (e.g. IL-6, TNF, chemokines) generally increase. SARS-
CoV and MERS-CoV infect macrophages and lymphocytes, but this may not be the case with SARS-
CoV-2. These viruses suppress the production of Interferons, a group of anti-viral cytokines of
crucial importance11
. These findings have clinical implications as discussed below.
Adaptive immunity. As far as adaptive immunity is concerned, although results are scanty and
largely based on SARS and MERS 12
, evidence suggests that, as generally true for antiviral
resistance, a Th1 orchestrated protective immunity 13
. Antibody responses were identified in SARS,
MERS and COVID-19 patients and there is evidence for antibody-mediated neutralization of the
virus12
.
Coronaviruses are professionals at suppressing various mechanisms of immunity protective
against viruses14
. They do so by suppressing Interferon production in macrophages and by
downregulating antigen presentation via Class I and Class II HLA glycoproteins.
A key issue with policy and public health implications, is the occurrence and duration of
immunological memory. Evidence suggests that infection with coronaviruses including SARS-CoV-2
elicits memory. Ralph Baric recently stated that immunity and resistance should cover at least 6-12
months 15
. Hard data on COVID-19 are badly needed.
5. Clinical presentation
SARS-CoV-2 infection presents with a variety of symptoms. It can be completely asymptomatic or
present with severe symptoms. Data from Italy, the country with the highest daily incidence of
cases while we write this report, shows that about 67% of the infected persons present with mild
symptoms. About 30% of the infected persons show more severe symptoms, requiring hospital
admission.
The most common symptoms are fever and cough. A minority of cases reports gastrointestinal
symptoms before the beginning of the respiratory symptoms 16
.
Initial reports from China showed a rate of ICU Admissions of about 5% with invasive mechanical
ventilation rates being below 3%15
. Recent data from Lombardy in Italy showed that the rate of
ICU admissions is much higher, in the range of 12% of all positive cases, or 16% of all hospitalized
cases17
.
Case fatality rate (CFR) varies among different Countries. In Italy, the overall CFR is 8.5%. CFR
varies significantly across age groups. With almost no reported death until the age of 29, CFR goes
from 0.3 % to 24.1% in the over 90 y old. Patients with comorbidities are more likely to be severely
affected and die17
.
6. Diagnostics tests: Virus and Antibodies
SWABS. The cornerstone of diagnostic tests is represented by PCR-based assays to detect viral
RNA in nasal swabs. The current test requires specialized personnel and approximately 4 hours. It
suffers from serious limitations with for instance negative nasal swabs and positive

66
bronchoalveolar lavages in advanced patients, false negatives in non-symptomatic patients etc 18
.
In addition, at the time of writing swabs which inactivate the virus are not anymore available at
least in Lombardy.
A 1 hour PCR-based assay (DiaSorin, Italy) has just been approved by US FDA and this may improve
the diagnostic output 19
.
In the US “home tests” have been approved by FDA: Kits are shipped at home along with detailed
instructions. Then the swab inserted it into a protective vial is mailed to one Everlywell diagnostic
lab for PCR analysis 20
.
Antibodies. The search for antibodies is an invaluable source for the diagnostics of infectious
diseases at the level of individuals and for accurate epidemiological studies. At the time of writing,
commercially available antibody assays have not been validated and compared with the PCR
assays. A recent non-peer reviewed report from academic institutions provides encouraging
results 21
.
Generation of reliable, validated assessments of the occurrence and significance of antibodies will
be of paramount importance for diagnosis, epidemiology, assessment of immunological memory
and provision of information to individuals returning to work following the suppression
approaches described above.
7. Therapy
General introduction. A wide range of therapeutic approaches have been tested under
uncontrolled conditions. These range from antiretroviral and antiviral agents, to Chinese
traditional medicine preparations. A detailed discussion of all compounds and strategies is beyond
the scope of this executive report. As stated in the Introduction, while we understand the
challenge of emergency medicine, we concur with the New England Journal of Medicine (“…rapidly
initiated high quality clinical trials are possible in epidemic situations, even in the trying
circumstances that prevailed in Wuhan”) and Journal of American Medical Association editorials
calling for high quality rigorous clinical trials 1, 22
.
Since several drugs are claimed to be effective without high quality clinical trials, quite recently the
WHO announced a large global trial, called SOLIDARITY, to find out whether any of those can be
really effective. This is an unprecedented effort to collect robust scientific data including many
thousands of patients in dozens of countries 23
.
The pillar of treatment: respiratory support and organ failure. Currently, there are no SARS-CoV-2
specific therapies. Supportive therapy is what can buy time for patients to recover their baseline
function. In the context of Severe Acute Respiratory Failure, supportive therapy could mean invasive
mechanical ventilation and or non-invasive support (in the form of high flow oxygen, continuous
positive airway pressure or non-invasive ventilation).
Patients that require invasive mechanical ventilation are usually very sick, require resource-intense
care, both in terms of nursing and doctor’s time and technology. Many of these patients develop a

77
form of acute respiratory failure called ARDS (Acute Respiratory Distress Syndrome). One of the
cornerstones of ARDS treatment is the so-called “protective lung strategy”. This strategy consists of
using the least possible ventilator’s pressures and volumes necessary to oxygenate the blood
without causing harm to the lungs with the ventilator itself.
In some cases, prone positioning is used as a therapy to maximise the gravity effect of blood flow
towards the better-aerated parts of the lungs.
While protecting the lungs and allowing them time to heal, particular attention has to be made to
support the other organs too. Vasopressors may be required to maintain adequate perfusion
pressure; fluids have to be carefully titrated to avoid both hypovolemia and fluid overload. In
some cases, acute kidney injury develops, and renal replacement therapy may be necessary.
In the most severe cases of ARDS, extracorporeal membrane oxygenation (ECMO) can be used to
temporarily substitute the gas exchange function of the diseased lungs. This technique is very
invasive, resource intense and particularly challenging to perform during a pandemic in which the
volume of critically ill patients to treat is particularly high.
Currently, there is no convincing evidence for any other drug in COVID-19 patients with acute
respiratory failure. Despite this, several clinical protocols have been developed using antivirals,
chloroquine, anti-inflammatory drugs just to name a few. We will review rationale and evidence.
Selected antivirals
• Lopinavir/ritonavir. This is a combination of agents used in the treatment of HIV and has
been widely used. However, a recent randomized study in advanced patients showed no
benefit 24
. Further carefully controlled adequately powered studies are needed to assess
the potential of this combination in early disease.
• Remdesivir. This agent has potent antiviral activity in vitro and in animal model of MERS. Its
potential in COVID-19 is undergoing clinical evaluation25
.
• Chloroquine and hydroxychloroquine. Chloroquine and hydroxy- derivative have anti-viral
activity as well as the capacity to suppress inflammation (see below). Its potential for the
treatment of COVID-19 needs to be investigated.
• Interferons. The rational for considering interferon therapy, systemic or via lung aerosol, is
mentioned under 3. It has been used in Ebola and SARS26, 27
. It will be important to assess
its potential in COVID-19 in subsets of patients based on cytokine and immune cell profiles.
The four most promising therapies that will be included in the above mentioned WHO SOLIDARITY
global trial are remdesivir; cloroquine and hydroxychloroquine; lopinavir and the same
combination plus interferon-beta23
.
Inhibition of excessive inflammation. There is a strong rationale that an uncontrolled immune
response and excessive inflammation may play a role in amplifying tissue damage in SARS and
possibly in COVID-19. The high levels of inflammatory cytokines (e.g. IL-6, TNF, IL-1, chemokines)
and the prognostic significance of IL-6 levels provide a rational for these strategies 28
. These
include monoclonal antibodies anti-IL-6 or anti-IL-16R (e.g. tocilizumab), anti-IL-1 (e.g.

88
canakinumab); a recombinant IL-1 receptor antagonist (anakinra); complement targeting
strategies; inhibitors of cytokine signaling pathways (JAK1,2) (e.g. baricitinib).
It should be mentioned that chloroquine, proposed as antiviral drug, has immunosuppressive and
anti-inflammatory activity. Incidentally, the speculation that usage of chloroquine as an
antimalarial underlies the apparent resistance of Africa to COVID-19 does not take into account
the fact that this agent has long and largely been abandoned in malaria.
Tocilizumab, an anti-IL-6 receptor humanized monoclonal antibody is to the best of our knowledge
the one agent in this field for which there is more available data. The rational stems from its
limited use in rheumatoid arthritis and, most important, in controlling the cytokine release
syndrome in CAR-T cell therapy. To the best of our knowledge, Professor Haiming Wei in Hefei
conducted the first experimental administration of tocilizumab in a limited series of patients
followed by widespread usage and recommendation in guidelines issued on 13/02/2020 in
China29
. It should be noted that studies are now ongoing in China and elsewhere, including Italy
under the auspices of AIFA.
Therapeutic Antibodies. Since the early days of immunology, plasma from recovered patients has
been used as a source of antibodies. Plasma from recovered patients has been used in China and
elsewhere, including Italy, as a source of antibodies, as already done for Ebola although the
therapeutic efficacy of this approach remains to be established.
Several academic and industrial laboratories are at various stages of development of human
monoclonal antibodies against components of SARS-CoV-2 virions, such as the Spike protein30, 31
.
It should be noted that both with SARS and with other viral infections, under selected conditions,
antibodies can enhance viral entry (Antibody-Dependent Enhancement, ADE)32
and tissue damage
33
. Therefore, as emphasized above, rigorous clinical assessments will also be mandatory for
antibody-mediated therapies.
8. Anti SARS-CoV-2 vaccines
Rationale. The hope and hype that the media and ordinary people are placing on having as soon as
possible a vaccine that protects against COVID-19 arise from the great triumphs that vaccines have
had and are having in the control of infectious diseases12
.
Caveats Vaccines do not always protect well. We still have a long series of serious infectious
diseases towards which vaccines are only partially effective and we then have a series of
sensational defeats. In effect, each disease is an immunological problem in itself: even today, with
all the data we have, it is difficult to predict whether and which vaccine can be truly effective. This
difficulty is accentuated in the case of COVID-19, a young disease on which studies implemented in
labs all over the world are leading new data day by day. In addition, RNA viruses generally have a
high mutation rate. This is one reason why it is difficult to make effective vaccines to prevent
diseases caused by RNA viruses.

99
Preliminary issues.
• As for COVID-19 vaccine is concerned it is essential to know if the patients who
have recovered from COVID-19 are protected against a second infection.
• If these patients develop immunity, how long does it persists? 34
• it is fundamental to establish whether the immune protection against COVID-19
mainly rests on the anti-virus antibodies or on the reaction of the killer T
lymphocytes.
In many cases, healing from a viral disease is the result of the combined action of antibodies in the
biological fluids that neutralize viral particles and the killer activity of lymphocytes that track down
and kill the body's cells infected with the virus, which are turning into factories of millions of new
viral particles. But there are viral diseases whose healing depends mainly, if not exclusively on the
antibody response and others in which the destructive action of the killer lymphocytes is
fundamental. Which is the case with COVID-19?
Role of CEPI. On January 2017, during the World Economy Forum in Davos, Coalition for Epidemic
Preparedness Innovations (CEPI) was established, an international organization to promote the
development and storage of vaccines against those microbes that could cause new frightening
epidemics: a significant amount of funds was paid by the Bill & Melinda Gates Foundation, the
Welcome Trust and the governments of numerous countries. The major multinational drug
companies have announced their collaboration. And it was precisely CEPI that, together with
numerous other private and public initiatives, during the very early stages of the epidemic,
activated and coordinated numerous and different programs for the preparation of vaccines
against COVID-19 following very different conceptual and technological strategies. This
diversification appeared essential precisely because, for many diseases, but mainly in the case of a
new disease as COVD-19, it is difficult to predict which type of immune response and therefore
vaccine will be more effective 35
.
RNA vaccines. On March 17, 2020, Dr. Michael Witte administered to volunteers the first shot of
an RNA vaccine against the SARS-CoV-2 virus prepared by Moderna, a biotech firm from
Cambridge, MA36
. RNA vaccines have been developed precisely in order to be produced in a very
short time. The RNA specific for a particular protein is brought into cells by virus-like particles or
into liposomes or bound to nanoparticles. Once the RNA is inside the body’s cells, the cells use its
genetic information to produce the target protein.
DNA vaccines. Other companies, including TAKIS Biotech, from Castel Romano, are experimenting
DNA vaccines against SARS-CoV-2 on animals. DNA vaccines, too, are based on the possibility of
making the body cells to temporarily produce the protein against which an immune response
should be induced. DNA vaccination induces the production of antibodies but can also favor the
development of killer T lymphocytes. RNA and DNA vaccines have not yet specifically tested in
elderly persons who are the ones who need them the most 37
.

1010
Protein vaccines. In addition to RNA and DNA innovative vaccines that are faster and cheaper to
produce, other laboratories as those of Queensland Univ. in Australia are preparing COVID-19
vaccines using the Reverse vaccinology technique developed by Rino Rappuoli, GSK in Siena.
Starting from the virus RNA sequence, the proteins of the surface of the SARS-CoV-2 virions are
identified. Crucial fragments of these proteins, produced in the laboratory with recombined DNA
technology, associated with new adjuvants of synthetic origin that most effectively induce an
optimal immune response in the elderly.
Other laboratories are following more traditional strategies, which take longer to develop.
Vaccine assessment. The administration of the new vaccine on a limited number of volunteers, as
is happening with the vaccine developed by Moderna, allows us to understand if the vaccine
induces a good antibody response and / or a response of the T killer lymphocytes and if its
administration is associated with evident adverse events. Subsequently, the true assessment of
the effectiveness of the new vaccine will be based on randomized controlled trials that will
compare the incidence of COVID-19 in groups of vaccinated and unvaccinated people. Only the
extension of this evaluation to larger and larger groups and for longer periods will show whether
one, all or none of the new COVID-19 vaccines protects effectively or only marginally and if its
administration is associated with important collateral events. However, there is so much urgency
of the vaccine that in order to quickly verify its efficacy a human “vaccine – SARS-CoV-2 challenge
study” has been proposed38
.
Caveats associated to fast track vaccine evaluations. It is likely that in the face of the enormous
pressure made by the COVID-19 pandemic, surrogate markers are initially used, such as the
evaluation of the amount of antibodies or the intensity of the reaction of the T killer lymphocytes
induced by the vaccine on the volunteers to decide whether initially the new vaccine could
reasonably be used for vaccination. However, the administration of the new vaccine should always
be carefully associated with the study of its safety. Since a vaccine is not a drug for people at risk
of dying but a treatment given to those who are well to prevent the risk of getting sick, the
evaluation of its safety assumes particular importance39
.
The race for a COVID-19 vaccine is not only justified but absolutely necessary. However, it must
not push to tak e the necessary time to evaluate the dangers and risks that may arise from a new
vaccine. In some cases, vaccines prepared against other coronaviruses or other viruses have
accentuated the dangerousness of the disease39
and inducing Th2-type immunopathology 40
.
These issues must be carefully evaluated and excluded before new COVID-19 vaccines are
employed to combat the pandemic or its subsequent reappearances.
Production and economic issues. Subsequent problems will be related to the production and
distribution of millions of doses of the new COVID-19 vaccine. Complex technological,
organizational, regulatory and economic problems will have to be addressed to produce and
distribute million doses of new COVID-19 vaccines. It may be difficult to create hundred million

1111
doses of a RNA vaccine, and each dose may be relatively expensive as it may require a fair amount
of RNA, in particular to immunize an elderly person 37
.
Hence the indications that the COVID-19 vaccines, if effective, will be very difficult to be
commonly available before a few years. This long interval raises another problem of crucial
importance: what if in one or two years the new COVID-19 vaccines no longer crucial or will be
exploited by only a small population in a particular area of the world? In fact, today we cannot
predict what the evolution of COVID-19 will be, if the pandemic will end, if the epidemic will
continue to hit massively, if it will only spread in some areas of the world or if, periodically, it will
give rise to new epidemics.
Recommended vaccines and BCG. At present, no reliable data are available concerning the impact
of seasonal influenza vaccination and anti-pneumococcus vaccines on the incidence and clinical
progression of COVID-19. However it should be emphasized that we concur with the general
recommendation of anti-pneumococcal vaccination in the elderly because of its own merit, its
protection against super-infection by pneumococcus in the course of viral infections and its impact
on reducing the appearance of bacteria resistant to antibiotics.
Lastly, somewhat connect with vaccines, it is of interest to mention the hypothesis that the old
anti- tuberculosis the Bacillus Calmette Guerin (BCG) vaccine may reduces the risk of SARS-CoV-2
infection. A team in the Netherlands will start a clinical trial with 1,000 health care workers.
Similar trials in other countries will evaluate whether BCG vaccine increases resistance to SARS-
CoV-2 in elderly people41
. A discussed above (see 4, Innate Immunity) innate immunity plays a key
role in controlling the first stage of SARS-CoV-2 infection. Therefore, strategies which increase
innate immunity (“training strategies”) need to be carefully evaluated by epidemiologists and in
carefully controlled clinical studies.
8. Preparedness
In the face of the enormous tragedy of death, suffering and social disaster brought by COVID-19
pandemic, it is inevitable to ask how much the world as a whole, and Italy in particular were or
should have been prepared.
According to the “2010 Global Health Security Index ranking” 42,43
, Italy does not appear to have
been particularly aware of the problems posed by the spread of infectious diseases. Is this
judgement justified? In Italy, in a few weeks over 50 doctors and 50 nurses have lost their lives
due to the pandemic and even a greater number have been placed in isolation because they are
infected. This is a very serious loss that Italy will never have to afford again. Certainly, much more
could have been done in many aspects and a few of them even relatively simple 44,45
. On the other
hand, many other countries and even international agencies took action in a little coordinated and
sometimes contradictory way.
We must consider, however, that only a few months ago the allocation of energy and resources in
order to be better prepared for a possible, but still hypothetical pandemic would not have a
chance to overcome indifference, skepticism, anti-scientific attitudes and suspicions of hidden

1212
obscure interests and bribery. Italy, a country where it is difficult even to convince a high portion
of its population of the importance of basic childhood vaccinations, would not take into
consideration to allocate a significant share of resources in order to be prepared for a never seen
event such as a new pandemic.
Almost all countries in the world are facing this kind of difficulty, declining it differently on the
basis of their own culture46,47
.
An assessment of how Italy and the world could have been better prepared can only be made
when the pandemic is over. In the future, preparedness is likely to be much more in the focus of
public health policy 43
.
The lesson on the dangers of anti-scientific attitudes and errors in the allocation of resources that
Italy and the world are facing is complex and very hard, so hard that today we cannot even have a
clear idea of the after that is waiting for us.
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