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Asymptomatic Patients and Immune Subjects
Sheila Veronese * and Andrea Sbarbati
Department of Neurosciences, Biomedicine and Movement Sciences, Verona University, 10 Sq. L.A.Scuro,
37134 Verona, Italy; andrea.sbarbati@univr.it
* Correspondence: sheila.veronese@univr.it
Definition: An asymptomatic patient is someone who contracts a disease but shows no symptoms.
An immune subject is a person who is free from virus infection. Both of these categories of people
experience the limitations of government imposed by a pandemic situation, with one important
difference. Probably only the first subjects contribute, in spite of themselves, to the spread of the
disease and to the contagion of the people most susceptible to the virus. This implies that their
detection is essential to limit infections. Therefore, knowing the characteristics of these people and
those immune to the virus can be extremely useful in mitigating the effects of the disease and/or
defeating it.
Keywords: natural immunity; asymptomatic subjects; sickle cell disease; obesity; population density;
age; gender
1. Introduction
The spread of a disease in a country can depend on the effectiveness of the measures
put in place to contain it and on the characteristics of the health system of the country itself.
In the case of COVID-19, a disease resulting from a new virus, the whole world reacted by
taking drastic measures, such as repeated total lockdowns during peaks of contagion.
Citation: Veronese, S.; Sbarbati, A. The analysis of the data on infections, hospitalizations, and deaths showed that the
Asymptomatic Patients and Immune
virus has had very different effects from country to country. Overall, an immediate attempt
Subjects. Encyclopedia 2022, 2,
was made to identify and protect the people who could be at increased risk of contracting
109–126. https://doi.org/10.3390/
this disease. It was quickly realized that the most severe forms of COVID-19 affected people
encyclopedia2010008
over the age of 60 and/or with health conditions, such as lung or heart disease, diabetes,
Academic Editor: Stephen Bustin or conditions affecting the immune system [1]. However, country-to-country differences
emerged on the groups of people at greatest risk.
Received: 15 November 2021
This is the case, for example, of people with diabetes, who were listed in second place
Accepted: 7 January 2022
Published: 11 January 2022
in the top 10 groups of people at risk of developing severe and life-threatening forms of
COVID-19 by the European Union’s European Center for Disease Prevention and Control
Publisher’s Note: MDPI stays neutral (ECDC) of the European Union [2], while they ranked eighth among people who could be
with regard to jurisdictional claims in most at risk of serious illness by the Centers for Disease Control and Prevention (CDC) of
published maps and institutional affil-
the United States of America [3].
iations.
It should be emphasized that the containment measures adopted by the different
countries have been different. The peaks of contagion occurred at different times, resulting
in non-coincident lockdown periods in adjacent countries. The same political choices of
Copyright: © 2022 by the authors.
the moment of initiation of the individual lockdowns, of their duration, and of the number
Licensee MDPI, Basel, Switzerland.
of people authorized to continue essential work activities could have influenced both the
This article is an open access article contagion and mortality rates. The health protocols implemented in the various hospitals
distributed under the terms and could also have played a decisive role in this regard.
conditions of the Creative Commons These considerations lead to the conclusion that people with a certain pathology could
Attribution (CC BY) license (https:// be more at risk in some countries than in others. However, there may be other pre-existing
creativecommons.org/licenses/by/ factors that may have made some people more or less susceptible to the disease than
4.0/). others, leading to the development of mild forms of infection. Furthermore, it should
Encyclopedia 2022, 2, 109–126. https://doi.org/10.3390/encyclopedia2010008 https://www.mdpi.com/journal/encyclopediaEncyclopedia 2022, 2 110
not be forgotten that, as with all viruses, even for SARS-CoV-2 there can be people who
are immune.
Immune subjects have undergone all forms of containment, to no effect, but this can
be considered an acceptable price given the gravity of the situation.
Patients who have developed mild forms of COVID-19, paucisymptomatic or asymp-
tomatic, are instead those who have probably contributed, in spite of themselves, to the
spread of the disease and to the contagion of the most susceptible people.
Perhaps early characterization of both of these two groups of subjects could have
mitigated the effects of SARS-CoV-2 and could, however, still be useful in explaining its
spread dynamics.
Taking all these considerations into account, we analyzed the contagion and mortality
data from Italy, relating to the first wave of infections, in order to identify which people were
less susceptible to the virus. The characteristics of these people were then also observed on
a global scale to understand whether the data found for Italy were general or specific for
this country.
2. Italy
2.1. First Wave of Infections
Why Italy? Because Italy is the first country in Europe where SARS-CoV-2 spread.
Probably also for this reason it is the country that has suffered the greatest damage, pre-
senting both a diffusion rate and a mortality rate among the highest, both in the European
continent and in the whole world [4].
Italy is divided in three parts: north, center, and south. These areas are not geographi-
cally divided, and there is a high mobility between the different regions, both for business
reasons and for tourism factors. The first generalized lockdown in Italy took place in the
period of 11 March–3 May 2020 [5,6]. Although the characteristics of this country did not
hinder the spread of SARS-CoV-2, the first wave of COVID-19 in the various Italian areas
was not homogeneous, and there was a greater spread and aggression, especially in the
north compared to southern Italy (Table 1).
Table 1. Epidemiological data in northern and southern Italy.
Infections in the Infections in the
No. 1 of No. 1 of Southern No. 1 of No. 1 of
Northern Italy Total Population Total Population
Cases Deaths Italy Cases Deaths
[in %] [in %]
Aosta Valley 1223 146 0.973 Abruzzo 3662 472 0.279
Emilia-Romagna 31,094 4458 0.697 Apulia 5119 555 0.127
Friuli Venezia
3651 348 0.300 Basilicata 505 28 0.090
Giulia
Liguria 10,683 1571 0.689 Calabria 1408 97 0.072
Lombardy 98,545 16,857 0.980 Campania 5976 442 0.103
Piedmont 32,440 4143 0.745 Molise 511 23 0.167
Trentino-South
7925 697 0.739 Sardinia 1859 134 0.113
Tyrol
Veneto 22,190 2107 0.452 Sicily 4091 286 0.082
Total 260,407 30,327 0.697 ± 0.232 23,131 2037 0.129 ± 0.067
Deaths [in %] 11.65 8.81
1 No., number. COVID-19 data available as of 25 August 2020 [4].
From the beginning of the pandemic to 25 August 2020, the date of full resumption of
socio-economic activities, keeping the prevention measures active, the spread of the disease
was more than ten times higher in the north than in the south (mean = 0.697, sd = 0.232,Encyclopedia
Encyclopedia 2022,
2022, 2,
2, FOR
FOR PEER
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Encyclopedia 2022, 2 111
disease
disease was
was more
more than
than ten
ten times
times higher
higher inin the
the north
north than
than in
in the
the south
south (mean
(mean == 0.697,
0.697, sd
sd ==
0.232,
min
0.232, min
= 0.300,= 0.300,
min = max max
= 0.980
0.300, = 0.980
max =in0.980 in the
the north north
in thevs. mean
north vs. mean
vs.=mean =
0.129,=sd0.129, sd
= 0.067,
0.129, = 0.067,
sd =min min
= 0.072,
0.067, = 0.072,
min =max max
= 0.279
0.072, max
=in
= 0.279 in
in the
the south)
0.279 south)
the(Figure (Figure
south)1a). The 1a).
(Figure 1a). The
death death
rate
The was rate
death 15 was
ratetimes 15
15 times
was higher in higher
times in
the north
higher in the
the north
than in thethan
north in
south,
than in
the
the south,
with with
with the
the death-to-infection
the death-to-infection
south, ratio higherratio
death-to-infection higher
in the
ratio northin
higher the
the north
in(Figure 1b)(Figure
north [4].
(Figure 1b)
1b) [4].
[4].
(a)
(a) (b)
(b)
Figure 1.
Figure 1.
Figure COVID-19
COVID-19 data
1. COVID-19 as
data as
data of
as of 25
of 25 August
25August 2020.
August2020. (a)
2020. (a) Number
(a) Number
Number ofof cases.
ofcases. (b)
cases. (b) Number
(b) Number of
Number of deaths.
of deaths. Both
deaths. Both
Both
graphs
graphs show
show the
the greatest
greatest severity
severity in
in northern
northern Italy,
Italy, particularly
particularly in
in the
the Lombardy
Lombardy
graphs show the greatest severity in northern Italy, particularly in the Lombardy region.region.
region.
What
What caused
What caused these
caused these differences?
these differences?
differences?
Northern
Northern
Northern andand southern
andsouthern Italy
southernItaly have
Italyhave different
havedifferent demographic
differentdemographic
demographicand and socio-economic
andsocio-economic
socio-economic char-
charac-
char-
acteristics.
teristics.
acteristics.
Compared
Compared to to the
thesouth,
the south,the
south, thenorth
the northhas
north hasaa higher
has ahigher number
higher number
number of
of inhabitants
of (27,746,113
inhabitants
inhabitants vs.
(27,746,113
(27,746,113 vs.
20,597,424) and aa greater population 22
vs. 20,597,424)
20,597,424) andand a greater
greater populationdensity
population density(202
density (202vs.
(202 vs. 140
vs. 140 inhabitants/km
140 inhabitants/km2)) )(Figure
inhabitants/km (Figure 2).
(Figure 2).
There no doubt that, in the areas with the highest population density,
There is no doubt that, in the areas with the highest population density, the contagion is
is the contagion is
more
more widespread,
widespread, even protection
even ifif protection and
protectionand prevention
andprevention measures
preventionmeasures
measuresare are adopted.
areadopted.
adopted.
Figure
Figure 2.2.
2. Italian population
Italian population density
populationdensity (updated
density(updated
(updatedto to 2019).
to2019). Some
2019).Some regions
regionsofof
Someregions central-southern
ofcentral-southern
central-southern Italy
Italy have
have
Figure Italian Italy have a
aa high
high population
population density
density which,
which, in
in reality,
reality, is
is linked
linked to
to the
the presence
presence of
of large
large urban
urban centers
centers (such
(such as
as
high population density which, in reality, is linked to the presence of large urban centers (such as
Rome
Rome inin Lazio
in Lazio and
Lazio and Naples
and Naples in
Naples in Campania).
in Campania).
Campania).
Rome
Furthermore,
Furthermore, in
Furthermore, in percentage
in percentage terms,
percentage terms, the
terms, the population
the population is
population is older
is older in
older in the
in the north
the north than
north than in
than the
in the
in the
south
south [7].
[7]. The
The greater
greater number
number of
of inhabitants
inhabitants and
and the
the difference
difference in
in age
south [7]. The greater number of inhabitants and the difference in age distribution meanage distribution
distribution mean
mean
that
that in
that in the
inthe north
thenorth there
norththere
thereareare 2.2
are2.2
2.2 million
million
million more
more
more inhabitants
inhabitants
inhabitants aged
agedaged >> 64
> 64 64 years
years years (Figure
(Figure
(Figure 3).
3). Given
Given
3). Given the
the greater
the greater
greater susceptibility
susceptibility
susceptibility to SARS-CoV-2
to SARS-CoV-2
to SARS-CoV-2 of people
of people
of people aged >aged
aged > 60 years,
> 60 years,
60 years, these
theseare
these data data
data are
are com-
com-
compatible
patible
patible
with thewith
with the
the greater
greater greater severity
severity severity highlighted
highlighted
highlighted in
in northern
in northern Italy [4],Italy
northern even[4],
Italy [4], even ifif they
evenare
if they they are
are not
not suf-
not sufficientsuf-
to
ficient
ficient to
explain to explain
explain
the the
huge gap huge
the huge
betweengap between
gapthe
between the two areas.
the two areas.
two areas.Encyclopedia 2022,
Encyclopedia 2022, 22, FOR PEER REVIEW 4
112
(a) (b)
Figure
Figure 3.
3. Distribution
Distribution of
of the
the Italian
Italian population
population aged
aged >> 64
64 in
in percentage
percentage (a)
(a) and
and absolute
absolute (b)
(b) terms
terms
(updated to 2019).
(updated to 2019).
Another
Another peculiarity
peculiarity of of COVID-19
COVID-19 in in Italy
Italy concerns
concerns thethe gender
gender difference.
difference. ItIt quickly
quickly
emerged
emerged that although infections affected men and women at the same rate [8], the
that although infections affected men and women at the same rate [8], the death
death
rate was lower
rate was lowerfor forthe
thelatter
latter [9].
[9]. These
These data
data havehave
been been tracked
tracked overover
timetime and were
and were still
still valid
valid as September
as of 17 of 17 September
2021. 2021.
The
The national
nationalpercentage
percentagedistribution
distributionofof thethemale andand
male female
femalepopulation
populationindicates ho-
indicates
mogeneity
homogeneity throughout
throughout thethe
territory,
territory,with
witha apresence
presenceofofonly
only2.63%
2.63% more
more females
females than
males. These
These data,
data, however,
however, mainly concern the population >> 64 64 years,
years, in
in which
which there
there are
are
2.97% more women than men. This percentage is higher
This percentage is higher in in the north than in the south
(3.20% vs. 2.53%)
2.53%) andand implies
implies that, inin the
the north
north compared
compared to the the south,
south, there
there are
are 1.3
1.3 million
million
more women
women thanthan men
menandandaatotal
totalofof0.9
0.9million
millionmoremore women
women than
than men
men agedaged
> 64> 64 years
years [7]
(Figure
[7] 4). 4).
(Figure
(a) (b)
Figure
Figure 4.
4. Distribution
Distribution of
of the
the male
male and
and female
female populations
populations in
in Italy,
Italy, overall
overall (a)
(a) and
and only
only for
for the
the age
age
group > 64 years (b) (updated to 2019).
group > 64 years (b) (updated to 2019).
The graphs in
The graphs in Figure
Figure44are aresimilar
similartoto thethe graphs
graphs in in Figure
Figure 1 on1 SARS-CoV-2
on SARS-CoV-2 preva-
prevalence
lence and COVID-19 mortality. This seems to be in contrast to
and COVID-19 mortality. This seems to be in contrast to the higher male mortality figurethe higher male mortality
figure
because because
wherewhere
there there are more
are more females,
females, fewerfewer deaths
deaths should
should bebe expected. Given
expected. Given that
the
the number
numberof ofinfections
infectionsisisequally
equallydistributed
distributedbetweenbetween the
thesexes,
sexes,although
although thethe
number
number of
females
of females is greater,
is greater,cancan
it beit assumed
be assumed thatthat
females are less
females are susceptible than than
less susceptible malesmales
to con-to
tracting the virus, and therefore female mortality is lower than
contracting the virus, and therefore female mortality is lower than male mortality? male mortality?
Another characteristic aspect aspect of Italy is food, and there is a clear difference between
north andand south
southininterms
termsofofculinary
culinary culture,
culture, a difference
a difference which
which is reflected
is reflected in weight
in weight prob-
problems.
lems. FromFrom the Italian
the Italian population,
population, 46.3%46.3% have weight
have weight problems.
problems. Furthermore,
Furthermore, 35.4%
35.4% of peo-
plepeople
have ahavebodyamass 2 ),
of bodyindex
mass(BMI)
indexwithin
(BMI) the limits
within theoflimits
overweight (BMI = 25–29.9
of overweight (BMI = kg/m
25–29.9
and 10.7% are obese 2
Kg/m 22), and 10.7% are(BMI
obese > (BMI
30 kg/m> 30 ).Kg/m
The22).population of northern
The population Italy appears
of northern to be
Italy appears
to
in be in better
better physical
physical condition
condition than than
that ofthattheofsouth.
the south. Compared
Compared to the
to the national
national value,
value, all
thethe
all southern
southern regions
regionsexcept
except Sardinia have
Sardinia havea higher percentage
a higher percentage of problems,
of problems,while all the
while all
northern
the northern regions
regionspresent lower
present values
lower values[10].[10].Encyclopedia 2022,
Encyclopedia 2022, 22, FOR PEER REVIEW 5
113
The figure worsens
worsens considering
consideringonlyonlythetheadult
adultpopulation
population(>18 years).
(>18 The
years). regions
The regionsof
northern
of northernItaly have
Italy lower
have overweight
lower overweight percentages
percentages thanthan
the the
regions of southern
regions Italy,Italy,
of southern ex-
cluding
excludingSardinia. ThisThis
Sardinia. trendtrend
is alsoisvalid
also for the for
valid datathe
relating
data to obesity,
relating towith the exception
obesity, with the
of Veneto,ofFriuli-Venezia
exception Giulia, and
Veneto, Friuli-Venezia Emilia-Romagna,
Giulia, which have
and Emilia-Romagna, obesity
which have rates
obesitysimilar
rates
similar
to thosetoofthose of the southern
the southern regionsregions
(Figure (Figure
5). 5).
(a) (b)
(c)
Figure 5. (a)
Figure 5. (a) Total percentages of
Total percentages of weight
weight problems
problems in
in the
the individual
individual regions,
regions, considering
considering the adult
the adult
population only. (b) Percentage of overweight adults in the various regions. (c) Percentage of obese
population only. (b) Percentage of overweight adults in the various regions. (c) Percentage of obese
adults in the various regions.
adults in the various regions.
Overweight
Overweight rates ratesincrease
increaseasaspeople
peoplereachreach74.74. From
From thetheageage of 75,
of 75, the the
trendtrend reverses
reverses and
and rates decrease. The number of overweight males is greater
rates decrease. The number of overweight males is greater than the number of overweightthan the number of over-
weight
females,females,
and over and
64 over
years64 ofyears of age,
age, the the difference
difference (overweight (overweight males—overweight
males—overweight females)
females) is 12%. Obesity
is 12%. Obesity rates also rates also increase
increase with people’s
with people’s age up age to 64 upyears.
to 64 years.
From the From agetheofage
65,
of
the65, the changes
trend trend changes
and ratesandfall.
rates fall. Males
Males are moreareobese
more than
obesefemales
than females
up to 74 upyears
to 74of years
age.
of age.the
From From
agethe agethe
of 75, of percentage
75, the percentage
of obeseofmales
obeseandmales and females
females is the
is the same same [10].
[10].
Comparing
Comparing data data on the prevalence
prevalence and death rates of COVID-19 with data
and death rates of COVID-19 with data onon BMI,
BMI,
an almost surprising inverse relationship emerges. During the first phase of the infection
in Italy,
Italy, COVID-19
COVID-19was wasmoremoreprevalent
prevalent andandmore
more lethal
lethalin areas
in areaswhere
wherethe population
the population had
lower BMI BMI
had lower rates.rates.
People aged aged
People > 74, for whom
> 74, overweight
for whom rates decline,
overweight and people
rates decline, aged >
and people
64,
agedfor>whom
64, forobesity
whom ratesobesitydecline,
rates were
decline,thewere
most the
affected
mostby the virus
affected by and had the
the virus and worst
had
disease
the worst outcomes. Does this mean
disease outcomes. Does that excessthat
this mean visceral
excessadipose
visceral tissue maytissue
adipose be a protective
may be a
factor against
protective SARS-CoV-2?
factor against SARS-CoV-2?
However, malesmalesaged aged> >6464 with
with moremoreweight
weightproblems
problems thanthan
females had higher
females mor-
had higher
mortality
tality rates.rates.
Can Can excess
excess visceral
visceral fat protect
fat protect a person
a person fromfrom contracting
contracting the disease,
the disease, but but
ag-
aggravate
gravate symptoms
symptoms if he/she
if he/she becomes
becomes infected?
infected?
The last
last two
twoaspects
aspectsthatthatweweconsider,
consider, looking
lookingfor for
a correlation
a correlationwithwithCOVID-19
COVID-19 in Italy,
in
are theare
Italy, blood group group
the blood and theand pathological states related
the pathological to the levels
states related to theoflevels
iron inofthe blood
iron in thein
the different geographical areas.
blood in the different geographical areas.
A link between blood groups and susceptibility susceptibility to to COVID-19
COVID-19 has has already
already been
been de-de-
scribed, and
scribed, and blood
bloodgroup
groupAAwas wasmore
more susceptible
susceptible to to
thethe disease
disease thanthan group
group O, which
O, which ap-
appears to be more immune [11]. These data are in line with what has already beenEncyclopedia 2022, 2, FOR PEER REVIEW 6
Encyclopedia 2022, 2 114
pears to be more immune [11]. These data are in line with what has already been demon-
strated for other diseases, such as Helicobacter pylori and norovirus infections, and for
demonstrated
cholera for other
and malaria diseases,
[12,13]. In hissuch as Helicobacter
work, Anstee (2010)pylori
statesand
thatnorovirus
protectioninfections, and
against these
for cholera and malaria [12,13]. In his work, Anstee (2010) states that protection
infectious diseases derives from the inheritance of polymorphisms in the genes that en- against
theseand
code infectious
regulatediseases derives of
the expression from
ABHtheand
inheritance of polymorphisms
Lewis antigens in the [12].
in body secretions genes that
Cool-
encode and regulate the expression of ABH and Lewis antigens in body secretions
ing (2015) highlighted the possible protective mechanisms deriving from the gene poly- [12].
Cooling (2015)
morphism highlighted
of blood the possible protective mechanisms deriving from the gene
groups [13].
polymorphism
In Italy, the most common[13].
of blood groups blood group is group A. North and south differ in the
In Italy,
diffusion ratethe most common
of group A, whichblood group
is double is group
in the northA. North and
compared south
to the differ
south in the
(Table 2)
diffusion rate of group A, which is double in the north compared to the south (Table 2) [14].
[14]. This evidence could help explain COVID-19′s lower southern spread.
This evidence could help explain COVID-190 s lower southern spread.
Table 2. Distribution of blood groups in Italy.
Table 2. Distribution of blood groups in Italy.
Blood Group Northern Italy Southern Italy
Blood Group Northern Italy Southern Italy
A [in %] 44 19
OA[in
[in%]
%] 4044 19
41
O [in %] 40 41
Another aspect seems to be linked to the greater spread of SARS-CoV-2 in the north
and less in theaspect
Another south:seems
pathologies relatedtotothe
to be linked iron levelsspread
greater in the blood. Southern in
of SARS-CoV-2 Italy
theisnorth
part
of
andthe thalassemia
less prevalence
in the south: pathologiesarearelated
[15,16],toand
ironinlevels
general,
in theanemia
blood.isSouthern
more common
Italy is here
part
than in northern Italy [17,18]. Thalassemia is present in the north almost
of the thalassemia prevalence area [15,16], and in general, anemia is more common here exclusively in
southern Veneto and northern Emilia-Romagna, up to 20% of population
than in northern Italy [17,18]. Thalassemia is present in the north almost exclusively in [15,16,19]. Of
the peopleVeneto
southern with anemia, 80% are
and northern of predominantly
Emilia-Romagna, up Sicilian
to 20% of origin and from
population SouthernOfItaly
[15,16,19]. the
[17].
people with anemia, 80% are of predominantly Sicilian origin and from Southern Italy [17].
Figures 6a, bshow,
Figure 6a,b show,respectively,
respectively,the
thedistribution
distributionof of thalassemia
thalassemia and
and anemia in the
different areas of Italy.
Italy. Figure 6c represents
represents thethe distribution
distribution of of hemochromatosis
hemochromatosisin inItaly.
Italy.
(a) (b)
(c)
Figure
Figure 6.
6. (a)
(a) Thalassemia
Thalassemia distribution.
distribution. (b)
(b) Anemia
Anemia distribution.
distribution. (c)
(c) Hemochromatosis
Hemochromatosis distribution.
distribution.
Hemochromatosis
Hemochromatosis and and other
other iron
iron overload
overload diseases
diseases are
are more
more common
common in the north
than
than in southern
southern Italy. In particular, the spread of these diseases decreases from north to
south [20–27].
There is a clear similarity between Figures 1 and 6 of the areas where COVID-19 had
the least impact and the areas with the highest rates of people with thalassemia and anemia.Encyclopedia 2022, 2, FOR PEER REVIEW 7
Encyclopedia 2022, 2 115
There is a clear similarity between Figures 1 and 6 of the areas where COVID-19 had
the least impact and the areas with the highest rates of people with thalassemia and ane-
mia. That similarity is also present between areas where COVID-19 had a significant im-
That similarity is also present between areas where COVID-19 had a significant impact and
pact and areas with higher percentages of people with iron overload disease.
areas with higher percentages of people with iron overload disease.
How can these data be explained? Why is the amount of iron in the blood important
How can these data be explained? Why is the amount of iron in the blood important
for SARS-CoV-2?
for SARS-CoV-2?
In the rest of the chapter, we will explore the complex aspect of anemic forms, and as
In the rest of the chapter, we will explore the complex aspect of anemic forms, and
regards iron overload diseases, we can hypothesize that they can favor the contagion and
as regards iron overload diseases, we can hypothesize that they can favor the contagion
negative outcome of COVID-19 because they are generally associated with other diseases,
and negative outcome of COVID-19 because they are generally associated with other dis-
such as diabetes, hepatic dysfunction, and cardiac dysfunction [26,27], which are all mor-
eases, such as diabetes, hepatic dysfunction, and cardiac dysfunction [26,27], which are all
bidities considered
morbidities riskrisk
considered factors forfor
factors thethe
development of of
development severe forms
severe ofof
forms COVID-19 [1–3].
COVID-19 [1–3].
2.2. 17
2.2. 17 September
September 2021
2021
After the
After the first
first wave
wave of of infections,
infections, there
there were
were two
two more
more waves
waves of of COVID-19
COVID-19 in in Italy
Italy
until 17
until 17 September
September 20212021 [28–31],
[28–31], and
and SARS-CoV-2
SARS-CoV-2 has has continued
continued toto mutate
mutate [32].
[32]. Did
Did the
the
considerations made on the basis of the analysis of the data relating to the first
considerations made on the basis of the analysis of the data relating to the first wave remain wave re-
main valid over
valid over time? time?
Figure 7 presents the
Figure the situation
situation ofofinfections
infectionsand
andthe
thenumber
numberofofdeaths in in
deaths Italy, as as
Italy, of
1717
of September
September 2021,
2021,after
after three
threewaves
waves ofof
infections, with
infections, withrelative
relativelockdowns,
lockdowns,and andafter
after6
6months
monthsfromfromthethestart
startofofthe
thevaccination
vaccinationcampaign.
campaign.
(a) (b)
Figure 7.
Figure 7. COVID-19
COVID-19 data
data as
as of
of September
September 17,
17, 2021.
2021. (a)
(a) Number
Number of
of cases.
cases. (b)
(b) Number
Number of
of deaths.
deaths. Both
Both
graphs show that Lombardy and northern Italy continue to be the areas most affected by this dis-
graphs show that Lombardy and northern Italy continue to be the areas most affected by this disease.
ease.
In some regions of southern Italy, such as Campania, Apulia, and Sicily, the levels of
In some
contagion regions
have of southern
increased Italy, such
significantly, as Campania,
reaching Apulia, andto
similar percentages Sicily,
somethe levels of
regions of
contagion have increased significantly, reaching similar percentages to some
northern Italy. However, if we compare the number of infections and deaths with respect regions of
northern Italy. However, if we compare the number of infections and deaths with
to the total population of the different areas, we note that northern Italy continues to be respect
to theaffected
more total population of theItaly
than southern different areas, we note
[4]. Furthermore, thethat northern
number Italy among
of deaths continues to be
patients
more affected than southern Italy [4]. Furthermore, the number
seems to show a lower aggressiveness of the virus in the south (Table 3).of deaths among patients
seemsTheto disease
show a lower
spreadaggressiveness
model reflectsof the
the virus in theofsouth
percentages (Table 3).
population density, especially
considering the large cities of southern Italy. There is also a notable similarity between
Table 3.7Epidemiological
Figure and Figures 3b data
andin northern
4, with and southern
regards Italy.
to the age and sex characteristics of the
population. The Infections
considerations
in inherent to these two aspects are therefore Infections
confirmed,inas
are No.
those 1 of
related to BMI, blood Southern
groups, andIt-
diseases related to No.
the 1 of
concentration of iron in
Northern Italy No. 1 of Cases the Total Pop- No. 1 of Cases the Total Pop-
the blood. aly
DeathsIt should be noted, in particular, that in the regions ofDeaths
southern Italy that have
ulation [in %] ulation [in %]
reached a number of infections similar to that of the northern regions, both the percentage
Aosta Valley 12,071 473 9.61 Abruzzo 80,556 2535 6.14
of infections in the total population and the percentage of deaths (in the total population,
Emilia-Roma-
419,717 and in the total of infections)
13,427 9.41 are lower than the same
Apulia 266,881variables in6764
the north (Table 4).
6.63
gna
Friuli Venezia
112,817 3813 9.28 Basilicata 29,708 607 5.28
Giulia
Liguria 111,775 4395 7.21 Calabria 81,857 1369 4.20Encyclopedia 2022, 2 116
Table 3. Epidemiological data in northern and southern Italy.
Infections in the Infections in the
No. 1 of No. 1 of Southern No. 1 of No. 1 of
Northern Italy Total Population Total Population
Cases Deaths Italy Cases Deaths
[in %] [in %]
Aosta Valley 12,071 473 9.61 Abruzzo 80,556 2535 6.14
Emilia-Romagna 419,717 13,427 9.41 Apulia 266,881 6764 6.63
Friuli Venezia
112,817 3813 9.28 Basilicata 29,708 607 5.28
Giulia
Liguria 111,775 4395 7.21 Calabria 81,857 1369 4.20
Lombardy 878,526 33,979 8.73 Campania 452,471 7853 7.80
Piedmont 376,475 11,742 8.64 Molise 14,437 495 4.72
Trentino-South
124,259 2557 11.59 Sardinia 74,619 1624 4.55
Tyrol
Veneto 464,283 11,736 9.47 Sicily 291,964 6673 5.84
Total 2,499,923 82,122 9.24 ± 1.22 1,292,493 27,920 5.65 ± 1.20
Deaths/cases
3.25 ± 0.68 2.38 ± 0.63
[in %]
1 No., number. COVID-19 data available on 17 September 2021 [4].
Table 4. Spread and mortality in the regions of southern Italy with the highest number of infections.
% Cases/Population % Deads/Population % Deads/Cases
Apulia 6.63 0.17 2.53
Campania 7.80 0.14 1.74
Sicily 5.84 0.13 2.29
COVID-19 data available on 17 September 2021 [4].
3. What Can Be Concluded by Observing the Italian Situation?
From the data considered, it seems to emerge that, in Italy, despite the spread occurring
throughout the national territory, the highest rates of contagion occurred in areas with
greater population density, where there was also a greater number of elderly people. In
the areas of southern Italy, less affected by the first wave, the spread took place in the later
stages. However, the number of infections and mortality rates indicate a lower severity of
the disease. An excess of visceral fat accumulation, within the limits of overweight (not
obese), seems to have mitigated the effects of the disease. This is also the case with the
presence of thalassemia and forms of anemia, while iron overload diseases appear to have
worsened the outcome of the disease.
4. Rest of the World
Extending the research done for a small country to the rest of the world may seem
pretentious. Each country has its own peculiarities that can tip the balance, in this case, in
the number of infections and in the number of deaths from COVID-19.
Given that the aspects examined for Italy are general socio-demographic aspects, the
extension of the survey is possible and may prove useful.
The spread of the COVID-19 pandemic to the rest of the world has not been uniform.
As of 17 September 2021, American states have been particularly affected, both in terms
of the number of infected and the number of deaths. To this date, the United States and
Brazil alone accounted for 27.71% of cases and 26.95% of deaths worldwide. Both of these
countries had a higher contagion rate than Italy (12.72% for USA and 9.99% for Brazil vs.
7.83% for Italy), and while Brazil had approximately the same rate of lethality (Brazil 2.79%Encyclopedia 2022, 2 117
Encyclopedia 2022, 2, FOR PEER REVIEW 9
vs. Italy 2.81%), the United States had a much lower lethality rate than Italy (only 1.60%) [4].
What made the difference?
India, the second country in the world for the number of infections, had an infection
India, the second country in the world for the number of infections, had an infection
rate of 2.43% and a lethality rate of 1.33% [4]. This means that despite the large number of
rate of 2.43% and a lethality rate of 1.33% [4]. This means that despite the large number of
infections and deaths linked to the total number of inhabitants of this country, the virus
infections and deaths linked to the total number of inhabitants of this country, the virus
here seems to have failed to spread and manifest itself in a serious manner. Given the
here seems to have failed to spread and manifest itself in a serious manner. Given the
situation in this country, however, it is necessary to use the conditional because it is not
situation in this country, however, it is necessary to use the conditional because it is not
possible to
possible to be
be sure
sure that
that all
all cases
cases have
have actually
actually been
been registered.
registered.
The
The values,
values, however,
however, underline
underline how
how the
the pandemic
pandemic has has evolved
evolved extremely
extremely differently
differently
on the American and Asian continents.
on the American and Asian continents.
Considering
Considering African
Africancountries,
countries,thethelowest
lowest number
number of of
infections in the
infections world
in the was was
world rec-
orded
recorded here, despite this continent presenting the highest mortality rate comparedthe
here, despite this continent presenting the highest mortality rate compared to to
rest of the
the rest of world (2.52%
the world vs. 2.05%).
(2.52% The latter
vs. 2.05%). figurefigure
The latter is undoubtedly linkedlinked
is undoubtedly to health prob-
to health
lems and the
problems andvery low low
the very levellevel
of assistance available
of assistance on this
available continent.
on this It is striking
continent. that
It is striking
South Africa alone, the most European of African countries, accounts for
that South Africa alone, the most European of African countries, accounts for 35.32% of 35.32% of infec-
tions and 41.83%
infections of deaths
and 41.83% on itson
of deaths continent. If the data
its continent. If therelating to this to
data relating country are added
this country are
to the data relating to Morocco and Tunisia, two other countries that have
added to the data relating to Morocco and Tunisia, two other countries that have numerous numerous in-
teractions with Europe, we obtain that the three countries alone represent
interactions with Europe, we obtain that the three countries alone represent 55.17% of 55.17% of infec-
tions and 60.47%
infections of deaths
and 60.47% in Africa
of deaths [4]. [4].
in Africa
The question arises whether
whether the virus in the first variant that spread in Europe was
more aggressive and lethal than the one that arrived in Africa at a later time. There is also
the possibility that not all cases from the latter continent are known, and, therefore, it is
only possible to estimate the severity of COVID-19 in Africa. There There is also, however, the
possibility that the population here actually contracted the virus less and developed less
severe forms of the disease.
The number of infected and deceased people is shown in Figure Figure 8.
8.
(a) (b)
Figure
Figure 8.
8. COVID-19
COVID-19 data
data as
as of
of 17
17 September 2021. (a)
September 2021. (a) Number of cases.
Number of cases. (b)
(b) Number of deaths.
Number of deaths. Both
Both
graphs show the extremely variability in the diffusion and severity of this disease.
graphs show the extremely variability in the diffusion and severity of this disease.
Considering
Considering the
the population
population density
density in
in the
the world,
world, the
the highest
highest values
values are
are recorded in
recorded in
Europe and Asia. The areas of the world with the lowest population density are Russia,
Europe and Asia. The areas of the world with the lowest population density are Russia,
Canada, and some
Canada, and some African
African states
states (Figure
(Figure 9)
9) [33,34].
[33,34].
In terms of gender and age of the population, overall, there are a total of 51.6 million
more males than females in the world. Up to the age of 54, there are more males than
females (143.9 million). Over the age of 54, the trend reverses with 92.3 million more women
than men. There are more males than females in Asia and in many North African states,
considering both the overall population and the population aged > 64 [35]. People live
longer in European countries, Canada, Oceania, and Japan than in African countries [33],
and mean age values align with survival rates [33,35]. From this it follows that, in these
countries, there are more people aged > 64 years (Figure 10).
Figure 9. World population density (updated to 2000) [34].(a) (b)
Figure 8. COVID-19 data as of 17 September 2021. (a) Number of cases. (b) Number of deaths. Both
graphs show the extremely variability in the diffusion and severity of this disease.
Considering the population density in the world, the highest values are recorded in
Encyclopedia 2022, 2 118
Europe and Asia. The areas of the world with the lowest population density are Russia,
Canada, and some African states (Figure 9) [33,34].
Encyclopedia 2022, 2, FOR PEER REVIEW 10
In terms of gender and age of the population, overall, there are a total of 51.6 million
more males than females in the world. Up to the age of 54, there are more males than
females (143.9 million). Over the age of 54, the trend reverses with 92.3 million more
women than men. There are more males than females in Asia and in many North African
states, considering both the overall population and the population aged > 64 [35]. People
live longer in European countries, Canada, Oceania, and Japan than in African countries
[33], and mean age values align with survival rates [33,35]. From this it follows that, in
Figurecountries,
these
Figure 9. World
9. World population
population density
there are density
more (updated
people aged
(updated to2000)
to 2000) [34]. (Figure 10).
> 64 years
[34].
(a) (b)
Figure
Figure 10.
10. (a)
(a) Distribution
Distribution of
of the
the World
World population aged >
population aged > 65
65 as
as aa percentage.
percentage. (b)
(b) Distribution
Distribution of
of the
the
male and female population in the World [33].
male and female population in the World [33].
The
The statistics
statistics on
on the
the age
age ofof the
the population
population in in Italy
Italy and
and in in the
the rest
rest ofof the
the world
world are
are in
in
line
line with
with the
the spread
spread of COVID-19, which
of COVID-19, which is is lower
lower in in countries
countries where
where the the average
average ageage isis
lower
lower (e.g.,
(e.g., Africa)
Africa) [33,35].
[33,35]. AA different
different trend
trend isis found
found only
only in
in South
South Asia,
Asia, where
where the
the spread
spread
is
is high
high compared
compared to to Europe
Europe [4], despite the
[4], despite average age
the average age of the Asian
of the Asian population
population being
being
lower than that of the European population [33]. However, However, the death rate in Asia is lower
than in Europe [4].
The fact
fact that
thatininthe
theworld
world there
thereis aisgreater
a greaterpresence
presenceof women
of womenagedaged> 64 years com-
> 64 years
pared
comparedto males, and that
to males, andthethatnumber of infections
the number is the same
of infections is the between males and
same between females,
males and
while it should
females, while itbeshould
higherbe for women
higher for(who
women are(who
in greater
are innumbers), supportssupports
greater numbers), the hypoth- the
esis that women
hypothesis are moreare
that women immune or develop
more immune COVID-19
or develop more frequently
COVID-19 than males
more frequently in
than
asymptomatic or paucisymptomatic
males in asymptomatic forms, forms
or paucisymptomatic thatforms
forms, are not detected.
that are notData on theData
detected. higheron
death rate death
the higher for males than
rate for for females
males than for[36] seem[36]
females to confirm a tendency
seem to confirm for females
a tendency to de-
for females
to develop
velop less severe
less severe formsforms
of theofdisease.
the disease.
Analyzing data
Analyzing dataon onthe
theweight
weight of of
thethe population
population in world,
in the the world, the obesity
the obesity rate israte
high-is
highest
est in theinUnited
the United
StatesStates and Saudi
and Saudi Arabia. Arabia. The problem
The problem of obesity
of obesity is more is relevant
more relevant
in the
in the American
American states, states, in Europe,
in Europe, in Australia,
in Australia, and inandthe in the countries
countries of theof the Mediterranean
Mediterranean area.
Problems of malnutrition, on the other hand, are more common in AfricaAfrica
area. Problems of malnutrition, on the other hand, are more common in and inand in the
the coun-
countries
tries of South
of South Asia Asia [37] (Figure
[37] (Figure 11). 11).
While in Italy the number of infections and deaths seems to indicate excess weight
as a protective factor against SARS-CoV-2, the data in the rest of the world do not seem
to match. It should be noted that the number of cases of serious and morbid obesity is
much lower in Italy than in many other countries of the world [38]. In the United States,
where the obesity problem is most severe [37], obesity is listed among the top eight risk
factors for COVID-19 [3]. In Europe, where obesity problems, although present, are less
prominent than in America, obesity ranks eleventh on the list of risk factors [2]. The spread
could affect more obese people in countries where there are actually more obese people.
Obesity could, therefore, become a risk factor only when it exceeds a certain degree, such
(a) (b)while it should be higher for women (who are in greater numbers), supports the hypoth-
esis that women are more immune or develop COVID-19 more frequently than males in
asymptomatic or paucisymptomatic forms, forms that are not detected. Data on the higher
death rate for males than for females [36] seem to confirm a tendency for females to de-
velop less severe forms of the disease.
Encyclopedia 2022, 2 Analyzing data on the weight of the population in the world, the obesity rate is high- 119
est in the United States and Saudi Arabia. The problem of obesity is more relevant in the
American states, in Europe, in Australia, and in the countries of the Mediterranean area.
Problems
as to induce
Encyclopedia 2022, 2, FOR PEER REVIEW of malnutrition, on thestates,
other pathological otheras
hand,
it is are more
easier forcommon in Africa
people aged and intothe
> 60 years coun-
develop11
tries
theseof South
[39]. Asia
There is [37]
little(Figure
data on11).
the impact of obesity on COVID-19 severity [40].
Figure 11. (a) Percentages of obese adults in various countries. (b) Percentages of overweight adults
by country [37].
While in Italy the number of infections and deaths seems to indicate excess weight as
a protective factor against SARS-CoV-2, the data in the rest of the world do not seem to
match. It should be noted that the number of cases of serious and morbid obesity is much
lower in Italy than in many other countries of the world [38]. In the United States, where
the obesity problem is most severe [37], obesity is listed among the top eight risk factors
for COVID-19 [3]. In Europe, where obesity problems, although present, are less promi-
nent than in America, obesity ranks eleventh on the list of risk factors [2]. The spread could
(a) (b)
affect more obese people in countries where there are actually more obese people. Obesity
could, therefore,
Figure 11. become
(a) Percentages of aobese
riskadults
factorinonly when
various it exceeds
countries. a certain degree,
(b) Percentages such adults
of overweight as to
induce other
by country [37]. pathological states, as it is easier for people aged > 60 years to develop these
[39]. There is little data on the impact of obesity on COVID-19 severity [40].
As far as haematological
haematological characteristics
characteristics are are concerned,
concerned, blood
blood group
group O O is the most
widespread
widespread in in the
the world
world and
andisisfound,
found,in inparticular,
particular,ininAmerica,
America,Africa,
Africa,and
and eastern
eastern Rus-
Russia.
sia.
GroupGroup
A isAmore
is more common
common in Europe,
in Europe, Australia,
Australia, and and thenorth
the far far north of America.
of America. GroupGroup
B is
B is the
the leastleast widespread
widespread in the
in the world
world andandis is foundininAsia,
found Asia,Eastern
EasternEurope,
Europe,and,
and, to
to a lesser
extent, Africa (Figure 12) [41].
(a) (b)
Figure
Figure 12.
12. (a)
(a) Distribution
Distribution of
of blood
blood group
group A.
A. (b)
(b) Distribution
Distribution of
of blood group O
blood group O [41].
[41].
In Italy, the different distribution of blood groups between north and south confirms
the greater susceptibility
susceptibility toto COVID-19
COVID-19 in in people
people with
with blood
blood type
type A compared to people
with blood
bloodtype
typeO. O.The
Theprevalence
prevalence ofofblood
bloodgroup
groupO and
O andnotnot
A inAChinese, American,
in Chinese, and
American,
African populations
and African seems
populations to explain
seems why,why,
to explain despite the high
despite the number of infections,
high number the mor-
of infections, the
tality rate rate
mortality is relatively low low
is relatively [42].[42].
All the considerations
considerations made so far far do
do not
not explain
explain why
why SARS-CoV-2
SARS-CoV-2 affects more men
and older people. The The data
data relating
relating to
to the
the incidence
incidence ofof hemochromatosis
hemochromatosis in northern
northern Italy
Italy
anemia and
and anemia and thalassemia
thalassemia inin the
the south
south seem
seem toto answer
answer this
this question
question [15–17,19,21–27].
[15–17,19,21–27].
In Europe, the countries of the Mediterranean area, where anemic forms prevail among
the population
population [43,44],
[43,44],record
recordlower
lowermortality
mortality rates than
rates thanthethe
countries of Northern
countries Europe,
of Northern Eu-
wherewhere
rope, iron overload diseases
iron overload are more
diseases are frequent (Figure
more frequent 13) [23–27].
(Figure 13) [23–27].Encyclopedia 2022,
Encyclopedia 2022, 22, FOR PEER REVIEW 12
120
(a) (b)
(c)
Figure 13. (a)
Figure 13. (a) Anemia distribution [42–44].
Anemia distribution [42–44]. (b)
(b) Thalassemia
Thalassemia distribution [45]. (c)
distribution [45]. (c) Hemochromatosis
Hemochromatosis
distribution [23–27,42,46].
distribution [23–27,42,46].
This
This isis despite
despite the the fact
fact that
that the
the rates
rates ofof contagion
contagion among
among the the population
population are are some-
some-
times
times higher
higher in in the
the countries
countries of of the Mediterranean area
the Mediterranean area than
than in the countries
in the countries of of northern
northern
Europe
Europe [4].[4]. Here,
Here,on onthe theother
other hand,
hand, hemochromatosis
hemochromatosis andandironiron overload
overload diseasesdiseases
are moreare
more frequent [46]. For these diseases, the incidence decreases
frequent [46]. For these diseases, the incidence decreases progressively in non-Hispanic progressively in non-His-
panic whites,
whites, NativeNative Americans,
Americans, blacks,blacks,
PacificPacific Islanders,
Islanders, up to up to Asians,
Asians, in which
in which they aretheyprac-
are
practically
tically absent absent
[47].[47]. Conversely,
Conversely, Asians,
Asians, particularly
particularly fromthe
from thesouth-east;
south-east;Africans;
Africans; and
populations of of the
theeastern
easternMediterranean
Mediterraneanarea areaarearemore
more prone
prone to to
diseases
diseasessuch as thalas-
such as tha-
semia
lassemiaand andforms
forms of of
anemia
anemia [42–45].
[42–45].Even
EvenininAmerican
Americancountries,
countries,data dataon on blood
blood group
distribution
distribution [41] and incidence of iron overload disease [25] and forms of anemia [43,44]
appear to be related to a reduced death rate from from COVID-19
COVID-19 [4]. [4].
Hemochromatosis
Hemochromatosis causes causesexcessive
excessiveabsorption
absorptionofof iron
iron bybythethe intestine,
intestine, resulting
resulting in
in the
accumulation
the accumulation of this metal
of this in other
metal organs
in other and tissues.
organs Males
and tissues. showshow
Males muchmuch moremorefrequent
fre-
and more
quent severe
and more symptoms
severe symptoms thanthan
women,
women, with thethe
with first manifestations
first manifestationsofofthe the disease
between the ages of 40 and 50. In women, before menopause, the clinical picture is ten
times less frequent than in men due to the loss of iron during menstruation and during
pregnancy. Therefore, women develop signs and symptoms of hemochromatosis-related
approximately 10 years after men [48]. This
organ damage approximately This could
could really be linked to the
greater severity
greater severity of of COVID-19
COVID-19 in in males,
males, more
more prone
prone toto pathological
pathological forms forms linked
linked to to the
the
accumulation of
accumulation of iron
iron inin the
the body.
body.
Extremely interesting
Extremely interestingisisthe therelationship
relationship that
that seems
seems to exist
to exist between
between the levels
the levels of
of iron
iron present in people’s blood, both in terms of deficiency and
present in people’s blood, both in terms of deficiency and in terms of excess, and the se- in terms of excess, and
the severity
verity of COVID-19.
of COVID-19. ManyMany viruses viruses have shown
have been been shown to hijack
to hijack cells cells for replication,
for replication, and
and efficient replication requires an iron-filled host [49,50]. Indeed,
efficient replication requires an iron-filled host [49,50]. Indeed, iron-filled cells turn iron-filled cellsout
turn
to
outgood
be to besites
good forsites for viruses.
viruses. Conditions Conditions
such as such as hemochromatosis
hemochromatosis or iron overload
or iron overload disease,
disease,
in whichinthe which
serum theiron
serum ironislevel
level is increased,
increased, compromise
compromise host defenses
host defenses and increase
and increase sus-
susceptibility to various infectious diseases [50]. In populations
ceptibility to various infectious diseases [50]. In populations where the incidence of he- where the incidence of
hemochromatosis is high, a virus such as SARS-CoV-2 could
mochromatosis is high, a virus such as SARS-CoV-2 could find a perfect environment to find a perfect environment
to live
live in, in, causing
causing thethe disease
disease to spread
to spread widely.
widely. In thalassemic
In thalassemic andand anemicanemic subjects,
subjects, on theon
the other hand, the proliferation of the virus would be more difficult,
other hand, the proliferation of the virus would be more difficult, in the former due to in the former due toEncyclopedia 2022, 2 121
cyclic blood transfusions (15–20 days) associated with chelating agents (to eliminate the
abnormal accumulation of iron in the organs) which is commonly used as a therapy and
causes blood purification [42], and in the latter due to the absence of iron.
The data in the literature seem to confirm these observations [51,52]. However, ane-
mic patients are not immune to COVID-19 and, if infected, their picture is immediately
severe [53]. On the other hand, the inflammatory state induced by SARS-CoV-2 [54],
which worsens with the duration of the disease [55], is often accompanied by systemic
hypoferritinemia [56,57]. This obviously strongly compromises an already anemic patient.
The particular link between COVID-19 and blood, and the iron contained in it, really
seems to explain why women have a lower death rate than men, but also why children are
less affected than adults. In fact, in children, the rates of anemia are very high [43,44]. It
is, however, mandatory to use the conditional, since this disease can be defined in many
ways, except simple, the greater or lesser mortality in a country is not attributable to a
single factor.
It should be emphasized that the resistance of anemic subjects to COVID-19 has been
observed by other researchers. Particular attention was paid to sickle cell disease (SCD),
which we analyze below.
5. Sickle Cell Disease and COVID-19
There are several forms of anemia dependent on different causes. There may be
anemia due to excess bleeding, such as in the case with pregnancy and breastfeeding, some
surgeries, and trauma. There may be sickle cell anemia and hemolytic anemias due to
excessive destruction of red blood cells. There can be aplastic anemias due to reduced
or impaired production of red blood cells and hemoglobin, as in the case of nutritional
deficiencies (iron, vitamin B12, and folic acid) or diseases (which induce poor absorption of
iron, vitamin B12, and folic acid), such as Crohn’s disease or celiac disease.
SCD is particular because it is a genetic disease. If people with SCD were truly immune
to COVID-19, then we would have a favorable genetic condition against this disease. Some
genetic diseases are known to show resistance to some infectious diseases [58], and in this
case, the term heterozygous advantage is used. SCD already presents the heterozygous
advantage over falciparum malaria [59,60]. Could it be that it also has this advantage
against COVID-19?
We analyzed the data available in literature on the incidence and lethality of COVID-
19 for subjects with SCD. We performed a literature search on the PubMed database,
considering all the works published from the beginning of the pandemic until March 2021,
one year after the diffusion of COVID-19 in Italy. For the research, we used the terms “sickle
cell,” “COVID-19,” and “SARS-CoV-2.” Non-English articles, articles that did not contain
patient numbers, and articles for which full text could not be obtained were excluded.
With the literature research, we identified ninety-two articles, and, applying the exclusion
criteria, we selected 43 articles. Among these, 28 studies were single case or case reports
with a limited number of patients (≤10 patients).
Of particular interest is the study of de Sanctis et al. [51], conducted on 9499 patients
with hemoglobinopathies, followed in 17 centers in 10 different countries. Only 13 patients
contracted SARS-CoV-2, with an incidence of 0.14%. Other studies in adults [61–64]
and children [62,64,65] showed a favorable outcome of COVID-19, with milder clinical
presentations than the general population had [61–63,66]. The published data are such as
to raise the question of whether SCD really increases the risk of SARS-CoV-2 infection [67]
or, conversely, may be a protective factor against COVID-19 [62,68–70].
Opinions contrary to the previous observations were found in Minniti et al. [71], and
Panepinto et al. [72], which reported a worsening of the course of COVID-19 in patients
with SCD, and in three other studies [73–75], which reported no differences in either
symptomatology or outcome between subjects with and without SCD from COVID-19.You can also read
