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Citation: Hromi´c-Jahjefendi´c, A.;
Barh, D.; Ramalho Pinto, C.H.;
Gabriel Rodrigues Gomes, L.; Picanço
Machado, J.L.; Afolabi, O.O.; Tiwari,
S.; Aljabali, A.A.A.; Tambuwala,
M.M.; Serrano-Aroca, Á.; et al.
Associations and Disease–Disease
Interactions of COVID-19 with
Congenital and Genetic Disorders: A
Comprehensive Review. Viruses 2022,
14, 910. https://doi.org/10.3390/
v14050910
Academic Editor: Manuela Sironi
Received: 30 March 2022
Accepted: 25 April 2022
Published: 27 April 2022
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viruses
Review
Associations and Disease–Disease Interactions of COVID-19 with
Congenital and Genetic Disorders: A Comprehensive Review
Altijana Hromi´c-Jahjefendi´c 1, *,† , Debmalya Barh 2, 3, *,† , Cecília Horta Ramalho Pinto 4,‡, Lucas Gabriel
Rodrigues Gomes 3, ‡, Jéssica Lígia Picanço Machado 5 ,‡, Oladapo Olawale Afolabi 6,‡ , Sandeep Tiwari 3,
Alaa A. A. Aljabali 7, * , Murtaza M. Tambuwala 8,Ángel Serrano-Aroca 9, Elrashdy M. Redwan 10,11 ,
Vladimir N. Uversky 12 and Kenneth Lundstrom 13, *
1Department of Genetics and Bioengineering, Faculty of Engineering and Natural Sciences,
International University of Sarajevo, Hrasnicka Cesta 15, 71000 Sarajevo, Bosnia and Herzegovina
2
Institute of Integrative Omics and Applied Biotechnology (IIOAB), Nonakuri, Purba Medinipur 721172, India
3Department of Genetics, Ecology and Evolution, Institute of Biological Sciences,
Federal University of Minas Gerais
, Belo Horizonte 31270-901, Brazil; lucasgabriel388@gmail.com (L.G.R.G.);
sandip_sbtbi@yahoo.com (S.T.)
4Department of Biochemistry and Immunology, Institute of Biological Sciences,
Federal University of Minas Gerais, Belo Horizonte 31270-901, Brazil; ceciliahrp@gmail.com
5Department of Bioinformatics, Institute of Biological Sciences, Federal University of Minas Gerais,
Belo Horizonte 31270-901, Brazil; jessicaligia.pm@gmail.com
6Department of Physiology and Biophysics, Pharmacology, Institute of Biological Sciences,
Federal University of Minas Gerais, Belo Horizonte 31270-901, Brazil; afolabi.oladapo9@gmail.com
7Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Yarmouk University,
P.O. Box 566, Irbid 21163, Jordan
8School of Pharmacy and Pharmaceutical Science, Ulster University, Coleraine BT52 1SA, UK;
m.tambuwala@ulster.ac.uk
9Biomaterials and Bioengineering Laboratory, Centro de Investigación Traslacional San Alberto Magno,
Universidad Católica de Valencia San Vicente Mártir, c/Guillem de Castro 94, 46001 Valencia, Spain;
angel.serrano@ucv.es
10
Department of Biological Science, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia;
rredwan@gmail.com
11 Therapeutic and Protective Proteins Laboratory, Protein Research Department, Genetic Engineering and
Biotechnology Research Institute, City for Scientific Research and Technology Applications,
New Borg EL-Arab 21934, Alexandria, Egypt
12
Department of Molecular Medicine and USF Health Byrd Alzheimer’s Institute, Morsani College of Medicine,
University of South Florida, Tampa, FL 33612, USA; vuversky@usf.edu
13 PanTherapeutics, Route de Lavaux 49, CH1095 Lutry, Switzerland
*Correspondence: ahromic@ius.edu.ba (A.H.-J.); dr.barh@gmail.com (D.B.); alaaj@yu.edu.jo (A.A.A.A.);
lundstromkenneth@gmail.com (K.L.)
† These authors contributed equally to this work.
‡ Are students of Postgraduate Transversal topic III, course “Personal Genome and Precision Health”
(NAP 802) 2021 of ICB/UFMG.
Abstract:
Since December 2019, the COVID-19 pandemic, which originated in Wuhan, China, has
resulted in over six million deaths worldwide. Millions of people who survived this SARS-CoV-2
infection show a number of post-COVID complications. Although, the comorbid conditions and
post-COVID complexities are to some extent well reviewed and known, the impact of COVID-19
on pre-existing congenital anomalies and genetic diseases are only documented in isolated case
reports and case series, so far. In the present review, we analyzed the PubMed indexed literature
published between December 2019 and January 2022 to understand this relationship from various
points of view, such as susceptibility, severity and heritability. Based on our knowledge, this is the
first comprehensive review on COVID-19 and its associations with various congenital anomalies
and genetic diseases. According to reported studies, some congenital disorders present high-risk for
developing severe COVID-19 since these disorders already include some comorbidities related to the
structure and function of the respiratory and cardiovascular systems, leading to severe pneumonia.
Other congenital disorders rather cause psychological burdens to patients and are not considered
high-risk for the development of severe COVID-19 infection.
Viruses 2022,14, 910. https://doi.org/10.3390/v14050910 https://www.mdpi.com/journal/viruses
Viruses 2022,14, 910 2 of 34
Keywords:
COVID-19; congenital anomalies; disease incidence and association; genetic diseases;
genetic susceptibility
1. Introduction
Birth defects, also known as congenital diseases, can be inherited, or caused by envi-
ronmental circumstances, leading to physical, intellectual, or developmental disabilities
(https://www.who.int/news-room/fact-sheets/detail/congenital-anomalies accessed on
9 December 2021). Some birth defects can be fatal if they are not detected and treated
early enough. Thousands of distinct birth abnormalities have been uncovered. Accord-
ing to the Centers for Disease Control and Prevention (CDC), birth defects are the most
significant cause of death for newborns in the United States. In general, there are two
categories of birth defects: structural and functional. Structural disorders relate to struc-
tural abnormalities of particular body parts. Cleft lip and palate, heart defects such as
missing or misshaped valves, deformed limbs such as clubfoot, neural tube defects such
as spina bifida, and issues related to the brain and spinal cord growth and development
are just a few examples. Problems with the way body parts or systems work are referred
to as functional or developmental dysfunctions. These problems often lead to intellec-
tual and developmental disabilities (IDDs). They can include nervous system or brain
dysfunctions, sensory problems, metabolic disorders, and degenerative disorders. Muscu-
lar dystrophy and X-linked adrenoleukodystrophy, which affect the nervous system and
adrenal glands, are examples of degenerative illnesses. Both structural and functional prob-
lems are present in some birth malformations (https://www.nichd.nih.gov/health/topics/
birthdefects/conditioninfo/causes accessed on 9 December 2021). Genetic or chromoso-
mal problems, exposure to certain medications or chemicals, or certain infections during
pregnancy can all cause birth malformations (https://ug1lib.org/book/5586785/4989ce
accessed on 9 December 2021). According to the CDC, one out of every 33 newborns
in the United States has birth defects. Birth abnormalities can occur at any time dur-
ing pregnancy; however, some pregnancies are at a higher risk than others due to a
shortage of folic acid, alcohol and tobacco use, drug addiction, and numerous diseases
(https://www.nichd.nih.gov/health/topics/birthdefects/conditioninfo/types accessed
on 9 December 2021).
Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) is a highly transmissi-
ble and deadly coronavirus that first appeared in late 2019. It triggered a pandemic of an
acute respiratory disease known as coronavirus disease 2019 (COVID-19), which poses a
hazard to global public health and safety [
1
]. The SARS-CoV-2 pandemic has been in focus
since 2019. Studies have reported an association between viral infection and pre-existing
congenital disorders. On the other hand, most instances, however, concern the implications
of SARS-CoV-2 infection in patients who already have a congenital disorder [2].
Pre-existing (comorbid) medical conditions are associated with the severity of
COVID-19
,
and more than 50 long-term effects of COVID-19 have been described [
3
]. It has also been
reported that the COVID-19 related risk is increased with age, several comorbid conditions,
cyanotic heart disease, and Body Mass Index (BMI) [
4
]. However, the association of COVID-
19 with various congenital conditions has either been neglected or not frequently studied.
This review tries to map the association between congenital and genetic disorders and their
association with COVID-19.
2. Methods
For this mapping, we mainly used two approaches. In the first approach, we searched
the PubMed (www.pubmed.ncbi.nlm.nih.gov accessed on 7 March 2022) literature database
from December 2019 to January 2022 using an advance search option (keywords in title)
with the following keywords: (congenital [Title]) AND (COVID-19 [Title]), (Thalassemia
[Title]) AND (COVID-19 [Title]), (Down Syndrome [Title]) AND (COVID-19 [Title]) etc.,
Viruses 2022,14, 910 3 of 34
like more than 2980 congenital anomalies/genetic disorders from birth defect surveil-
lance Toolkit of CDC (https://www.cdc.gov/ncbddd/birthdefects/surveillancemanual/
resource-library/manual.html accessed on 7 March 2022). The number of articles with the
name or synonym of congenital anomalies or genetic diseases and COVID-19 in the article’s
title was recorded. The conditions showing more than five articles were first considered, to
understand which anomalies or diseases are more frequently associated with COVID-19
(Figure 1). Once this mapping was completed, abstract level selection and curation was
carried out following the PRISMA method to identify the articles having direct association
and disease–disease-interactions with COVID-19.
Viruses 2022, 14, x FOR PEER REVIEW 4 of 35
Figure 1. Congenital anomalies and genetic diseases associated with COVID-19 based on the Pub-
Med literature search. Conditions having more than five PubMed hits are mostly considered in this
review.
Figure 2. PRISMA flow diagram of the literature search and article selection to develop the key
sections (direct association and disease–disease interactions between a congenital anomaly or ge-
netic disease and COVID-19) of this review.
Figure 1.
Congenital anomalies and genetic diseases associated with COVID-19 based on the PubMed
literature search. Conditions having more than five PubMed hits are mostly considered in this review.
In the second approach, we tried to identify those congenital anomalies and genetic
diseases associated with COVID-19 as predicted by Barh et al., 2021 [
5
], but were not
reported in the supporting primary literature at that time. We considered the work of
Barh et al., 2021, as it was the first bioinformatics-based prediction to show association and
disease–disease interactions between congenital or genetic disorders and COVID-19 with
high precision.
3. Literature Search Results
In the PubMed search, we found a total of 547 articles describing various congenital
anomalies and genetic diseases and their associations with COVID-19. Based on analysis
of these 547 publications, we found that congenital heart disease, cystic fibrosis, autism
spectrum disorder, Downs’s syndrome etc., were the most reported cases associated with
COVID-19 (for details, see Figure 1). Following the methods, finally a total 68 articles
describing direct association and disease–disease interactions between the congenital
anomaly or genetic disease and COVID-19 were considered to develop the main sections of
the review (Figure 2). Additional references were used to describe various pieces of basic
information on congenital anomalies or genetic diseases.
Viruses 2022,14, 910 4 of 34
Viruses 2022, 14, x FOR PEER REVIEW 4 of 36
Figure 1. Congenital anomalies and genetic diseases associated with COVID-19 based on the Pub-
Med literature search. Conditions having more than five PubMed hits are mostly considered in this
review.
Figure 2. PRISMA flow diagram of the literature search and article selection to develop the key
sections (direct association and disease–disease interactions between a congenital anomaly or ge-
netic disease and COVID-19) of this review.
Figure 2.
PRISMA flow diagram of the literature search and article selection to develop the key
sections (direct association and disease–disease interactions between a congenital anomaly or genetic
disease and COVID-19) of this review.
4. Most Frequently (>10 PubMed Hits) Associated Congenital and Genetic Disorders
with COVID-19
4.1. COVID-19 and Congenital Heart Disease (CHD)
Congenital heart disease (CHD) showed a total of 75 PubMed hits in our litera-
ture search (Figure 1). Heart disease was identified as a risk factor for mortality in the
early stages of the COVID-19 pandemic [
6
]. Adults with CHD, which affects more than
1.5 million
people in the United States [
7
] and 2.5 million in Europe [
8
], are recognized as
a high-morbidity population, susceptible to a variety of cardiovascular deterioration and
dysfunction. As a result, these individuals are widely seen as high-risk, and they must
adapt to a highly limited lifestyle and career choices. A recent clinical study involving
105 patients has indicated that patients with congenital cardiac defects such as cyanotic
lesions, and unrepaired cyanotic defects (Eisenmenger syndrome), were at much higher
risk if infected by SARS-CoV-2 [
4
]. The ACE2 receptor has been demonstrated to have a
greater affinity for SARS-CoV-2 than for SARS-CoV. This, along with the presence of ACE2
on myocardial cells, may help explain how COVID-19 impacts the cardiovascular system
(CVS) by accessing these cells and causing direct toxicity.
Studies have indicated that COVID-19 patients with pre-existing cardiovascular dis-
ease (CVD) have a higher mortality rate than those with chronic obstructive pulmonary
disease (COPD) [
9
]. The exact mechanism by which SARS-CoV-2 harms cardiomyocytes is
unknown. It has been claimed that it could happen due to COVID-19-generated cytokine
storm [
10
]. Another suggested explanation is that during acute respiratory distress syn-
drome (ARDS), the increased oxygen demand of cardiomyocytes occurs in a condition of
hypoxia, resulting in oxidative stress [
10
]. Although there is no evidence to show how
COVID-19 affects CHD patients, present research implies that they may be at an elevated
risk of cardiovascular problems and intensive care unit (ICU) admission. The majority of
cardiovascular problems occur in CHD patients with confirmed COVID-19, rather than
suspected COVID-19 cases, with heart failure (55%), arrhythmias (22%), and stroke (22%)
Viruses 2022,14, 910 5 of 34
being the most common [
11
]. There has been no research reported on CHD repair surgery
and the risks of perioperative COVID-19. However, a recent study of postoperative mortal-
ity in patients with perioperative SARS-CoV-2 infection found that overall mortality was
34% and that 94.1% of patients undergoing cardiac surgery had pulmonary problems. Male
gender, age 70 or older, physical status classification system (ASA) grades 3–5, surgery
for malignant disease, emergency surgery, and major surgery were all identified as risk
factors [
12
]. Another study, focusing on children, recommends a surgical priority classifi-
cation depending on the type of congenital cardiac abnormality. There are three types of
operations: emergency (24–48 h), urgent (one–two weeks), and elective (more than two
weeks) [
13
]. In conclusion, CHD patients of an advanced age with obesity and multiple
comorbidities are at an increased risk when infected with SARS-CoV-2 [
4
], although the pe-
diatric population is mainly protected. However, as the hazards are unknown, consenting
these patients for surgery must be carried out cautiously [9].
4.2. COVID-19 and Cystic Fibrosis (CF)
In our literature search, Cystic fibrosis (CF) was the second most common genetic
disease associated with COVID-19 described in 67 PubMed articles. CF is the most frequent
fatal genetic illness in North America and possesses a classic Mendelian autosomal recessive
trait [
14
]. The inheritance of two defective copies of the CF transmembrane conductance
regulator (CFTR) gene has been linked to CF. Abnormal salt and water transport across
epithelial surfaces is associated with abnormal CFTR. It presents itself in the lungs as
mucus build-up and an inability to remove or clear inhaled organisms, leading to persistent
infection and inflammation, which causes airway remodeling and illness. CFTR is also
important in bicarbonate transport; abnormalities in its function cause the pH of the airway
surface fluids to drop [
14
]. The recent COVID-19 pandemic has had an impact on patients
with comorbidities. However, it is unclear if individuals with CF are more susceptible to
COVID-19 or its negative repercussions. The role of recurring respiratory virus infections
in disease perturbation and pulmonary exacerbations has made this a hot issue [
15
]. A
search of the literature published between 28 April and 10 December 2020, was conducted
using EMBASE and MEDLINE [
16
]. The goal of this search was to find publications that
documented COVID-19 outcomes in people with a history of CF, who were infected by
the virus. The incidence of SARS-CoV-2 infection was 0.07 percent in a global cohort
study of 40 people with CF from eight countries, which is almost half of the 0.15 percent
prevalence reported in the general population [
17
]. This evaluation included six studies that
reported on a total of 339 people with CF who developed COVID-19. The European Cystic
Fibrosis Society Patient Registry (ECFSPR) also contributed data on SARS-CoV-2 infections
in 1236 individuals with CF from 30 countries (https://datawrapper.dwcdn.net/uQ1iZ/1/
accessed on 4 January 2022). Partial information was available from 946 (77%) of the cases.
The most common age group was 18–29 years, with 56% having a FEV
1≥
70 (Forced
Expiratory Volume). Increased cough, fever, and exhaustion were the most prevalent
symptoms. There were 582 persons with reported severities, with 550 (95%) being moderate
or asymptomatic, 23 (4%) severe, and 9 (2%) catastrophic cases. In terms of treatment,
217 people (23%) were admitted to hospital, of which 30 (14%) were placed in the ICU.
At the time of reporting, 866 (92%) of those infected had totally recovered, 39 (4%) were
still infected, and 13 (1%) had died [
16
]. Although persons with CF are at risk for acute
exacerbations of chronic lung disease, which are frequently caused by respiratory tract viral
infections, available research suggests that SARS-CoV-2 infection rates in CF are lower than
in the general population [
16
]. Nevertheless, there is evidence that specific subsets of the
CF population, such as those who have had a transplant, may have a particularly severe
clinical course. The low incidence of SARS-CoV-2 infection in the CF community is likely
due to a combination of variables, including appropriate physical and social separation and
the efficient application of established infection control concepts and practices emphasized
as part of standard CF therapy [16].
Viruses 2022,14, 910 6 of 34
4.3. COVID-19 and Autism Spectrum Disorder (ASD)
Autism spectrum disorder (ASD) emerged as the third most common congenital
anomaly with 61 articles suggesting an association between ASD and COVID-19 (Figure 1).
ASD is a neurodevelopmental disease marked by communication and social interaction
difficulties and confined and repetitive patterns of behavior and interests. In 1943 Leo
Kanner initially identified autism as a disease in youngsters with difficulties connecting
to others and a high sensitivity to changes in their environment [
18
]. The Fifth Edition
of the Diagnostic and Statistical Manual of Mental Disorders [
19
] introduced the broad
diagnosis of ASD in 2013, combining four formerly distinct disorders: Autistic Disorder,
Asperger’s Syndrome, Childhood Disintegrative Disorder, and Pervasive Developmental
Disorder, which are some of the most common developmental disorders [
19
]. Families
have had to alter their lifestyles as a result of the COVID-19 epidemic, including social
isolation and parents working from home. The long-term effects of prolonged confinement
on one’s mental health are unknown [
20
]. Changing routine can be difficult for children
with ASD [
21
], and as a result, families with ASD children are more likely to experience
anxiety and mental abnormalities during quarantine. A cross-sectional, observational, and
analytical investigation was conducted.
A total of 99 parents of school-aged children volunteered to participate in a study in
April 2020 [
22
]. Parents of children with ASD and parents of children without neurode-
velopmental conditions (control group; online form) were contacted by phone or email.
An anonymous questionnaire with a total of 24 sets of questions was used to investigate
the children’s demographic and clinical features, and the influence of social isolation at
home during COVID-19 quarantine on various areas of the children’s and parents’ daily
lives [
22
]. Of the 99 questionnaires collected, 43 were from children with ASD and 56 were
from children who were not diagnosed with ASD. The age of children in the study was
10.75
±
3.13 years old, with 68.7% of them being male. The majority of parents of children
with ASD reported changes in their children’s behavior (72.1%), whereas most parents of
children in the control group reported no changes (67.9%); the differences between the
two groups were statistically significant (p= 0.05). Anxiety (41.7%), irritability (16.7%),
preoccupation (11.1%), anger (5.6%), and impulsivity (2.8 %) were the most common causes
of behavioral change indicated by parents of children with ASD. Parents of both groups felt
that quarantine had more of a negative influence on learning than a favorable one (46.5%
vs. 14% in the group of children with ASD and 50% vs. 19.6% in the control group) with
no statistically significant differences between the two groups (p= 0.572). In addition, no
statistically significant variations in the influence on cognitive development (p= 0.518)
or familial ties (p= 0.298) were found [
22
]. The difference in the impact of quarantine on
emotion management between the two groups was statistically significant (p= 0.02), and
most parents of children with ASD reported a negative impact on emotion management
(55.8%), in contrast to the parents of the control group. The latter mostly reported a positive
or null impact on emotion management (71.4%). The greatest obstacles for children with
ASD during this time were social isolation (41.4%), not being able to play outside (13.1%),
changes in routine (11.1%), boredom (9.1%), and online education (7.1%), according to
their parents.
To summarize, there is strong evidence that children with ASD are more likely to ex-
perience anxiety, which can aggravate ASD symptoms and lead to more serious behavioral
difficulties. Children with ASD experienced the most behavioral alterations throughout
the school closure time in our study, while most children in the control group maintained
their pre-quarantine conduct. Furthermore, anxiety, anger, preoccupation, hostility, and
impulsive traits traditionally linked with this condition were indicated by parents as the
causes of this behavioral change [22].
4.4. COVID-19 and Autoimmune Hemolytic Anemia (AIHA)
Hemolytic Anemia (AIHA) and COVID-19 gave 45 hits in our PubMed search (
Figure 1
).
Anti-erythrocyte autoantibodies with or without complement activation induce an increase
Viruses 2022,14, 910 7 of 34
in the destruction of red blood cells (RBCs) in AIHA [
23
]. It can manifest itself in various
ways, from asymptomatic to severe versions with catastrophic effects, and it can be idio-
pathic or due to the presence of another condition [
23
]. The first incidence of COVID-19
was reported in an AIHA patient in Sri Lanka [
23
]. A 23-year-old woman, who had been
sick for three days with fever and cough, was treated in the Emergency Treatment Unit.
Her COVID-19 quick antigen and PCR tests were both positive; thus, she was treated for a
moderately severe SARS-CoV-2 infection in the ICU with non-invasive ventilation and high
flow nasal oxygen (HFNO). Her COVID-19 exit PCR came back negative on day 20, and she
was moved to the general medical unit to continue her treatment. She suffered significant
weariness and shortness of breath while recovering from a moderate to severe COVID-19.
Closer examination showed that she displayed a significant pallor, and tachycardia, and
she was oxygen-dependent where her arterial blood gas showed no symptoms of hypoxia.
Her ECG revealed a normal sinus rhythm, and she tested negative for troponin I. Initial
blood tests indicated an abrupt reduction in hemoglobin from her normal level of 11 g/dL
to 5.1 g/dL. The white blood cell and platelet levels were within normal ranges. There was
no additional indication of heart or respiratory problems. The D-dimers were within an
acceptable range, and the transthoracic echocardiography revealed normal left ventricular
function with no signs of pulmonary embolism [
23
]. Her thyroid status was also normal.
There was no sign of internal or external bleedings after a thorough examination. There
was no history of hematological malignancy or connective tissue problems in the family.
In summary, before she acquired COVID-19, she was generally healthy with no risk
indicators for AIHA. Her first blood tests revealed hemolysis, as evidenced by a high
reticulocyte count, lactate dehydrogenase (LDH), and indirect hyperbilirubinemia. A
blood smear established the existence of severe hemolytic anemia. The direct antiglobulin
test was positive [
23
]. She was successfully treated with red blood cell transfusions and
corticosteroid medication. After five days of therapy, the hemoglobin level had increased
to 10 g/dL. Over three months, she was gradually weaned off prednisolone, and her
hemoglobin was steady during the follow-up.
COVID-19-induced hemolysis has already been described in two articles. The first
publication described a lady who needed steroids to treat her warm AIHA as she had
underlying congenital thrombocytopenia [
24
]. The second study [
25
] included seven
individuals who had symptomatic COVID-19 and exhibited warm or cold hemolysis
symptoms nine days after arrival at the hospital. All of them required steroid therapy or a
blood transfusion. In conclusion, AIHA coexistence with COVID-19 is a recently reported
phenomenon that should be recognized in patients with unexplained or chronic anemia
who have a current or recent history of COVID-19. Steroids showed a good response in
the treatment of the first case of COVID-19 in the AIHA patient, which could be continued
even after the COVID-19 acute phase had ended [23].
4.5. COVID-19 and Hematophagocytic Lymphohistocytosis (HLH)
Hematophagocytic lymphohistocytosis (HLH) is the fourth most frequent condition
associated with COVID-19 (Figure 1). Hyperinflammation, cytokine storm, and secondary
HLH (sHLH) are potential aggravating factors [
26
] for SARS-CoV-2 infections. Both non-
COVID-19 and severely sick COVID-19 patients have shown significant sHLH death rates
(about 40%) and viral infections are known to trigger sHLH (approximately 65%) [
26
].
Immunosuppression has been proposed as a therapeutic option, and preliminary findings
are encouraging [
27
]. More data on the clinical treatment of sHLH in COVID-19 patients
is critically needed in this scenario. Between April and May 2020, three patients were
brought to an ICU in Vienna, Austria, according to the case report [
26
]. Real-Time qPCR
was used for the detection of SARS-CoV-2 in pharyngeal and tracheal respiratory speci-
mens. Repeated testing revealed positive results (Ct value > 35). The HScore was used to
diagnose sHLH: Core temperature, hepato- and/or splenomegaly, number of cytopenias,
triglycerides, fibrinogen, ferritin, and ASAT levels, history of immunosuppression, and (if
possible) the presence of bone marrow hemophagocytes were all evaluated. For HLH, a
Viruses 2022,14, 910 8 of 34
positive result showed a sensitivity of 93% and specificity of 86%, and immunosuppressive
therapy for sHLH was performed in a stepwise manner [
28
]. All three COVID-19 patients
had cytokine storm, and their clinical course matched the clinical (fever, hypoxia, delirium)
and laboratory (hyperferritinemia, lymphopenia, elevated IL-6, and CRP) characteristics
of critically ill COVID-19 patients in general, as well as those with severe cardiac injury
or coagulopathy [
26
]. The major cause for multiorgan failure is a rush of inflammatory
cytokines, which leads to hyperinflammation and tissue destruction [
27
]. This shows that
a significant number of severely ill COVID-19 patients have sHLH, which, if untreated,
might explain the high fatality rates. Diagnosis of sHLH is difficult due to frequent mis-
diagnosis [
26
]. There are currently no randomized-controlled studies for sHLH therapy
regimens, and evidence is poor even among non-COVID-19 patients. Immunomodulation
has been proven to be effective in lowering death rates, and it was also recommended for
COVID-19 treatment [
27
]. Immunosuppressive drugs like tocilizumab (IL-6 receptor mono-
clonal antibody) and anakinra (IL-1 receptor antagonist) may help against a cytokine storm.
Furthermore, the data demonstrate that combining corticosteroids and immunoglobulins
can help patients with severe COVID-19 [
26
,
27
,
29
]. In a case study for three patients, all
patients had all of the symptoms of sHLH and were given a three-step treatment plan
for sHLH induced by COVID-19 [
28
]. However, the identification of sHLH occurred too
late for patients 1 and 2, but there was a favorable outcome for patient3—comparable to
previously described results [
26
]. Routine screening for sHLH in COVID-19 patients using
the HScore appears appropriate; patients who have a poor reaction to shock may be partic-
ularly vulnerable. A sequential therapy strategy using corticosteroids, immunoglobulins,
and anakinra, as well as immunoadsorption, may help to mitigate the consequences of
cytokine storms and may lower mortality [28].
4.6. COVID-19 in Adult Patients and Children with Down Syndrome (DS)
Down Syndrome (DS) or Trisomy 21 (T21) gave 37 PubMed hits and was the fifth most
frequent congenital anomaly associated with COVID-19 (Figure 1). DS is the most prevalent
chromosomal defect in humans. T21 causes immune dysregulation, which predisposes
the individual to autoimmune disorders, as well as anatomical differences in the upper
respiratory tract, such as a smaller trachea, enlarged adenoids/tonsils, glossoptosis, upper
airway narrowing, and tracheal bronchus airway malacia, which all predispose the individ-
ual to a high frequency of respiratory diseases [
30
–
32
]. Despite the increased likelihood
of respiratory infections, there has been no evidence of an increased risk of SARS-CoV-2
infection in DS patients. A case report of two COVID-19 cases in adult Caucasian patients
with DS, who tested positive for SARS-CoV-2 without any respiratory coinfections after a
nasopharyngeal swab (NFS), and a chest computer tomography (CT) scan revealed bilateral
interstitial pneumonia [
33
]. A 59-year-old female, who had previously been diagnosed
with congenital hydrocephalus, epilepsy, and hypothyroidism was the first case, while the
second case involved a 42-year-old female who had hypothyroidism [
33
]. The clinical spec-
trum of DS is complex, with varied aspects affecting most organ systems. Various genetic
processes may contribute to the phenotype of DS, and more than 80 clinical characteristics
have been reported in DS, ranging in number and severity [
34
]. Case 1 had a more complex
clinical DS with congenital hydrocephalus and epilepsy, while case 2 had a less complex
clinical DS with hypothyroidism. The first patient was nearing the end of her DS lifespan,
and an older adult is usually thought to present an additional independent risk factor for
a poor outcome of SARS-CoV-2 infection. At the time of admission, both patients had
lymphopenia. The first patient had a stable course of disease for ten days until provoked,
requiring low-flow oxygen supplemental therapy but no substantial inflammatory index
changes. The second patient’s inflammatory indexes and need for oxygen supplementation
increased over time, requiring CPAP assistance and mechanical ventilation [
33
]. The labora-
tory parameters (leukocytes, lymphocytes, C-reactive protein, aspartate aminotransferase,
alanine transaminase, total bilirubin, gamma-glutamyl transferase and D-dimer) were
followed for both patients [33].
Viruses 2022,14, 910 9 of 34
The cytokine release syndrome is frequently associated with severe respiratory im-
pairment in COVID-19 patients, which is caused by an increased immunological response
to the virus [
35
]. Those with severe COVID-19 experienced lymphopenia and high lev-
els of circulating proinflammatory cytokines when compared to patients with moderate
COVID-19 illness. Type I and III interferons (IFNs) appear to be involved in SARS-CoV-2
cytokine production, which is followed by immune cell infiltration and activation, cytokine
hyperproduction, worsened immunological activation, and deterioration of progressive
respiratory function [
36
]. In DS, studies have revealed an interferonopathic hallmark char-
acterized by dysregulation of IFN-inducible cytokines, resulting in persistent inflammation
and broad responsiveness to IFN activation across the immune system [
37
]. The first patient
did not get immunomodulating medication since it was not yet available at the time of
admission. However, the second patient was given sarilumab, the monoclonal antibody
against IL-6, and her respiratory function gradually improved over the next few days until
she recovered. Furthermore, it has been suggested that there may be mutations in other
type I IFN–related genes in other patients with life-threatening COVID-19 pneumonia and
the administration of type I IFN may be of therapeutic benefit in selected patients, at least
early in the course of SARS-CoV-2 infection [38].
In COVID-19 patients, elevated levels of the inflammatory cytokine IL-6 were linked
to a higher risk of death in retrospective studies, suggesting that it may operate as a
crucial mediator for respiratory failure and shock [
39
]. Finally, due to the high number
of comorbidities, structural changes in the upper respiratory tract, and immunological
dysregulation, people with DS have a higher risk of respiratory infections and a poor
prognosis. It is critical to recognize the therapeutic importance of DS in the treatment of
COVID-19.
Additionally, two incidences of SARS-CoV-2 infection in children with DS have been
reported [
40
]. The first case was a 14-year-old Caucasian girl with DS who had no cardiac
abnormalities but was overweight (BMI 36) and had obstructive sleep apnea (OSA), which
is prevalent in DS and can lead to pulmonary issues. In the second case, a 34-month-old
North African child was diagnosed with DS and bilateral interstitial pneumonia, which
needed
15 days
of hospitalization and treatment with external oxygenation and antibiotics
(ceftriaxone and azithromycin) [
40
]. She was readmitted after two weeks with high fever
and skin rashes, which lasted three days, and antibiotic treatment with cefotaxime was
started. She began to show signs of Kawasaki disease on the third day. Treatment be-
gan according to the Italian Society of Pediatrics’ standards, which included intravenous
immunoglobulin, oral steroids, and high doses of aspirin, as well as a second dosage of
immunoglobulin given due to a persistent fever. After this treatment, the fever went down,
and aspirin administration was continued for another six weeks. SARS-CoV-2 serology
(IgM, IgG) was positive. Follow-up visits revealed no problems in the heart or other
organs [40].
Previous coronavirus epidemics have shown that these viruses have a lower proclivity
for affecting youngsters. Only 6.9% of patients infected during the 2003 SARS-CoV outbreak
were minors, and there were no fatalities among those under the age of 18. Furthermore,
children were discovered to have a milder variant of the disease. Only 2% of the patients in
the Middle East respiratory syndrome coronavirus (MERS-CoV) outbreak, which began
in 2012 and is still ongoing, were youngsters [
41
,
42
]. Children appeared to be compara-
tively spared at the start of the COVID-19 pandemic, but later studies from multiple sites
revealed a likely COVID-19-related severe multisystem inflammatory syndrome in children
(MISC) and young adults [
43
,
44
]. The literature on COVID-19 in DS patients is still sparse,
however, DS should be considered as a risk factor [
45
]. Children with DS have a distinct
cardiovascular disease profile. Furthermore, anatomical abnormalities of the airways are
substantial risk factors for respiratory infections in individuals with DS [40].
Viruses 2022,14, 910 10 of 34
4.7. COVID-19 and Thalassemia
Thalassemia ranked the sixth most frequent genetic disease associated with COVID-19
(Figure 1). Patients with pre-existing chronic morbidities are more likely to be impacted
by SARS-CoV-2 infection, but no data on Thalassemic Syndromes (TS) is available. TS
and hemoglobin variations are one of the most common causes of anemia, affecting more
than 7% of the global population, according to the WHO [
46
]. Thalassemia is divided
into two types: transfusion-dependent thalassemia (TDT) and non-transfusion-dependent
thalassemia (NTDT). Infections, primarily caused by bacteria, are a significant cause of
death and morbidity in TS patients. Stress erythropoiesis, iron excess, splenectomy, and
adrenal insufficiency are just a few of the factors that might enhance infection suscepti-
bility [
47
]. In the study reported by Motta et al., an electronic Case Report Form (eCRF)
survey in Italy was conducted to analyze the impact of SARS-CoV-2 infection on TS. Eleven
cases of TS with COVID-19 had been collected as of 10 April 2020 [
48
]. The average age
was 44.11 years (range 31–61 years), with females accounting for 55% (6/11). There were
ten TDT patients and one NTDT patient. All patients had thalassemia-related comorbidi-
ties, eight had splenectomies, and one had sildenafil-treated pulmonary hypertension. In
55% (6/11) of patients, the likely source of infection was identified: two had contact with
COVID-19 positive people, and four had occupational exposure (e.g., hospitals). Three of
the patients had no symptoms. One patient was hospitalized with high fever, bone mar-
row hypoplasia, lymphopenia, and agranulocytosis (on deferiprone medication), where
the third swab came back positive. Six of the eleven people were admitted to hospital,
although none of them required mechanical breathing. The patient who required more
intensive breathing support with continuous positive airway pressure (CPAP) had a history
of diffuse large B-cell lymphoma (DLBLC), treated with chemotherapy a year earlier and
is currently in complete remission. Only three of the six patients brought to hospital got
purportedly COVID-19-specific treatment: one hydroxychloroquine (HCQ), one HCQ plus
ritonavir/darunavir, and one HCQ plus anakinra [
48
]. Due to simultaneous amiodarone
medication and a higher risk of life-threatening arrhythmia, one patient did not receive
HCQ. The clinical program lasted from 10 to 29 days. Ten patients have recovered clinically
and were receiving daily phone calls for follow-up. The presence of splenectomy in eight
of eleven individuals did not appear to alter the clinical outcome. Except for the patient
with myelosuppression, there was no increase in blood demand. When the NTDT patient’s
luspatercept therapy was stopped, his hemoglobin dropped from 110 to 82 g/L, identical
to the pre-luspatercept period. Death, severe SARS-CoV-2, or symptoms of cytokine storm
were not found in these eleven participants, which is remarkable given their average age
and the prevalence of significant comorbidities. Although early, these findings show that
COVID-19 severity is not elevated in TS patients. More cases must be studied to determine
the impact of SARS-CoV-2 and its outcome in these vulnerable people [48].
4.8. COVID-19 and G6P Dehydrogenase Insufficiency
The seventh most frequent condition associated with COVID-19 in our literature search
was glucose-6-phosphate dehydrogenase (G6PD) insufficiency (Figure 1). The varied vul-
nerability to infection is one disconcerting characteristic of COVID-19. Some exposed
individuals were asymptomatic, while others showed mild to moderate symptoms, and
still others became critically ill and died. Hospitalization rates rose with age, and over 90%
of hospitalized patients had underlying medical problems [49]. G6PD insufficiency is one
issue to consider. Around 400 million individuals worldwide are affected by this X-linked
recessive condition with multiple allelic variations, showing a higher frequency in Africa,
the Mediterranean area, and Asia [
49
]. Decreased G6PD synthesis caused nicotinamide
adenine dinucleotide phosphate deficiency and reduced glutathione, resulting in oxidative
stress and red blood cell death [
49
]. Patients can develop hemolytic anemia due to some
infectious agents and drugs, even if they are asymptomatic. There is evidence to imply an
association between G6PD deficiency and greater susceptibility to SARS-CoV-2 infection,
as well as the severity of the illness [
50
]. G6PD deficiency might increase the susceptibility
Viruses 2022,14, 910 11 of 34
to coronavirus infection. For example, G6PD-deficient cells infected by human coronavirus
229E showed considerably enhanced coronavirus gene expression and viral particle gen-
eration [
51
]. Furthermore, elderly people with G6PD deficiency are more likely to have
red blood cells with lower G6PD levels, lower glutathione levels, and increased red blood
cell turnover [
52
]. This may predispose older G6PD deficient patients to a lower threshold
for hemolytic crises after exposure to a triggering event such as coronavirus infection.
Chloroquine (CQ) has been observed to cause hemolysis in G6PD-deficient individuals,
therefore it should be used with caution [
53
]. Its molecular variant, HCQ, an antimalarial
medicine, has also been evaluated as a potential COVID-19 therapeutic. However, a recent
study documented an acute hemolytic event in a COVID-19 patient with G6PD deficiency
treated with HCQ [
53
]. In COVID-19 patients with G6PD deficiency, HCQ may enhance
oxidative stress, potentially triggering hemolytic anemia [
53
]. More research is needed to
clarify whether there is an association between G6PD deficiency and COVID-19 in increased
susceptibility to infection and disease severity. This is significant for several reasons. First,
it will enable the identification of a subgroup of COVID-19 patients, who will require
intensive monitoring and supportive care. Second, some therapies, such as HCQ, may be
contraindicated in these individuals. Third, the discovery of this link might lead to the
development of new treatments for COVID-19, such as the use of antioxidants. Finally,
those with known G6PD impairment will need this knowledge to guide their decisions and
activities in order to avoid SARS-CoV-2 infections.
4.9. COVID-19 and Agammaglobulinemia
According to the CDC, patients with primary immunodeficiency diseases are prone
to severe COVID-19. One case study [
54
] described a 28-year-old man diagnosed with
X-linked Agammaglobulinemia (XLA), who had received a septic hip at the age of one year.
B-cells were completely absent, and XLA was detected by flow cytometry. His medical
history included a persistent multifocal cellulitis of his leg caused by a helicobacter species,
which had been effectively treated without recurrence in 2019. His infectious history was
otherwise normal, and he never received sequence confirmation of the Bruton’s tyrosine
kinase gene, even though his diagnosis of XLA was highly suggestive based on his clinical
history of early-onset infections and the lack of B-cells. He received 10 g of subcutaneous
immunoglobulin (SCIG) on a weekly basis. He had a one-week history of fever, chills,
hyposmia, and increasing productive cough and dyspnea when he arrived at the hospital.
Prior to his arrival, he tested positive for COVID-19 by RT-PCR from a throat sample [
54
].
The patient was tachycardic, tachypneic, and required 2 L of oxygen through nasal prongs
when admitted. A chest X-ray revealed bilateral airspace opacities, which might indicate
pneumonia. Hyponatremia, leukopenia, thrombocytopenia, transaminitis, and increased
inflammatory markers were also present in his blood. Despite these interventions, the
patient’s hypoxia and breathing effort continued to deteriorate. He needed 5 L of oxygen
via nasal prongs by day four and had a respiratory rate of 22. He was subsequently
started on a five-day remdesivir regimen. On the fourth day, he self-administered his
SCIG dosage. He was moved to the ICU on day five after requiring 60% oxygen via
a high-flow nasal cannula. He was then given 500 mL of convalescent plasma. The
patient began to show symptoms of clinical improvement on day nine, and his oxygen
needs had decreased. He returned to the ward and was subjected to daily chest X-rays
to monitor the development of a pneumothorax. He was weaned off oxygen by day 11,
and the pneumomediastinum had cleared. On day 13, he was released [
54
]. Although
it is hypothesized that patients with primary immunodeficiencies are at an increased
risk of more severe infections due to COVID-19, few studies in the literature cover these
situations [
55
]. Two individuals with Agammaglobulinemia (one with XLA) and five
patients with common variable immunodeficiency (CVID), who tested positive for COVID-
19 were documented in an early investigation [
55
]. Patients with Agammaglobulinemia
had a much milder course than those with CVID. A second study of two XLA patients,
who recovered quickly after being infected with SARS-CoV-2 and did not require critical
Viruses 2022,14, 910 12 of 34
care, backs this up [
56
]. According to international research, B-lymphocytes may be
directly engaged in COVID-19-related inflammation, and their absence may result in
lesser illness. When paired with the recent case series, the reported case [
54
] supports
the idea that individuals without B-lymphocytes can nevertheless generate a significant
inflammatory response to SARS-CoV-2 infection. In contrast to previous case reports, this
study showed that XLA patients are still at risk of serious consequences from SARS-CoV-2
infection. Antibodies may be critical for viral neutralization, based on the quick recovery
reported in XLA patients after receiving convalescent plasma. While the effect of remdesivir
cannot be discounted, the patient’s quick response to convalescent plasma implies that
humoral immunity is a key aspect in recovery from COVID-19. More research is needed to
ascertain if the observed response to convalescent plasma is unique to individuals lacking
B-lymphocytes [54].
4.10. COVID-19 and Polycystic Ovary Syndrome (PCOS)
Polycystic ovary syndrome (PCOS) is the 12th most common condition associated
with COVID-19 (Figure 1). Women suffering from PCOS have lately been identified as an
underserved and possibly high-risk group for COVID-19 [
57
]. PCOS is a lifelong metabolic
disorder that is most commonly linked with androgen excess, infertility, and polycys-
tic ovarian morphology based on ultrasound [
58
,
59
]. Insulin resistance is connected to
low-grade chronic inflammation and androgen excess in PCOS, both of which influence
adipocyte biology and metabolism. Owing to androgen excess in women with PCOS,
the gender advantage due to estrogen’s preventive impact against COVID-19 appears to
be lost [
60
]. In women with PCOS, insulin resistance with excess insulin or proinsulin
promotes steroidogenesis. The Health Improvement Network (THIN) database was used to
conduct a population-based retrospective closed cohort analysis to estimate the incidence
risk of SARS-CoV-2 infection in women with PCOS compared to those without PCOS. THIN
is a longitudinal primary care electronic medical records database including anonymized
data from 365 current general practices in the United Kingdom [
61
]. The major question
was whether the primary care physician categorized COVID-19 as suspected or confirmed.
To calculate unadjusted and adjusted hazard risks (HR) of SARS-CoV-2 infection in women
with PCOS compared to women without PCOS, the authors used a Cox proportional haz-
ards regression model with stepwise inclusion of explanatory variables (age, BMI, impaired
glucose regulation, androgen excess, anovulation, vitamin D deficiency, hypertension, and
cardiovascular disease) [
61
]. The researchers found 21,292 women with a coded diagnosis
of PCO/PCOS and chose 78,310 age- and practice-matched control women at random. In
women with and without PCOS, the crude COVID-19 incidence was 18.1 and 11.9 per
1000 person-years
, respectively. Women with PCOS have a 51% greater risk of COVID-19
than women without PCOS, according to age-adjusted Cox regression analysis (HR: 1.51
(95% CI: 1.27–1.80), p< 0.001). HR was lowered to 1.36 (1.14–1.63)] after correcting for age
and BMI, p= 0.001. Women with PCOS had a 28% higher risk of COVID-19 (aHR: 1.28
(1.05–1.56), p= 0.015) in the fully adjusted model [
61
]. According to the study, women with
PCOS have a higher risk of cardio-metabolic illness, which has been identified as a risk
factor for COVID-19, and they should be urged to follow infection control measures during
the COVID-19 pandemic [61].
5. Congenital and Genetic Conditions with Five to Ten PubMed Hits
5.1. COVID-19 and Hereditary Angioedema (HAE)
Hereditary angioedema (HAE) is the top condition associated with COVID-19 among
conditions with less than ten PubMed ID hits (Figure 1). HAE, due to C1 inhibitor (C1INH)
deficiency (HAE-C1INH), is a rare autosomal dominant and potentially life-threatening
disease, clinically characterized by swelling attacks of the subcutaneous (SC) tissue and
mucous membranes due to dysregulation of the plasma kallikrein-kinin system with
enhanced generation of bradykinin [
62
]. In HAE-C1INH, the incidence and consequences
of COVID-19 remain unclear. As ACE2, a key receptor protein involved in SARS-CoV-2
Viruses 2022,14, 910 13 of 34
infectivity, also degrades kinins and bradykinin excess, it has been hypothesized to play a
pathologic role in the severe respiratory complications of COVID-19 and individuals with
HAE-C1INH have been hypothesized to be at increased risk for SARS-CoV-2 infection and
complications [
63
]. The data for the reported study [
64
] came from online surveys, in which
people and their families self-reported SARS-CoV-2 infection, complications and morbidity,
were asked to fill out an online questionnaire. HAE patients with C1 inhibitor (C1INH)
deficiency (HAE-C1INH), HAE patients with normal C1 inhibitor (HAE-nl-C1INH), and
household controls were among the participants (controls). The effects of HAE medicines
were investigated [
64
]. A total of 1162 individuals participated in the survey, including
695 persons with HAE-C1INH, 175 persons with HAE-nl-C1INH, and 292 healthy persons.
The incidence of reported COVID-19 cases was not statistically different between normal
controls (9%) and HAE-C1INH (11%) participants but was considerably higher in HAE-
nl-C1INH (19%) subjects (p= 0.006). Obesity was shown to be positively associated with
COVID-19 in the general population (p= 0.012), with a similar but non-significant trend
in HAE-C1INH patients. Comorbid autoimmune illness was found to be a risk factor
for COVID-19 in HAE-C1INH patients (p= 0.047). The severity and consequences of
COVID-19 were similar across all groups. COVID-19 levels were lower in HAE-C1INH
patients, who were treated with prophylactic subcutaneous C1INH (5.6%; p= 0.0371) or
on-demand icatibant (7.8%; p= 0.0016). When compared to normal controls, persons with
HAE-C1INH, who were not taking any HAE drugs had a higher incidence of COVID-19
(24.5%; p= 0.006) [
64
]. The findings revealed that participants with HAE-C1INH, who did
not use HAE drugs, had a considerably higher risk of reported COVID-19 than normal
controls, albeit no significant increase in COVID-19–related complications were found. SC
pd–C1INH and icatibant usage were linked to a substantial decrease in COVID-19 levels in
HAE-C1INH patients [
64
]. The participants with HAE-nl-C1INH reported more COVID-19
symptoms than the controls, but HAE medicines did not affect the likelihood of infection.
All these findings suggest that the traditional complement and tissue kallikrein systems are
involved in SARS-CoV-2 infection [64].
5.2. COVID-19 and Parsonage-Turner Syndrome (PTS)
Parsonage–Turner Syndrome (PTS) showed eight PubMed hits in our literature search
(Figure 1). PTS, also known as idiopathic brachial plexopathy or neuralgic amyotrophy, is a
rare illness with a documented overall incidence of 1.64 per 100,000 persons [
65
]. Young
people are usually most affected, while incidences have been observed in children as young
as three months old and in persons as old as 75 years of age. PTS is marked by sudden
onset of significant shoulder discomfort, usually unilateral, that can spread to the arms
and hands [
65
]. The clinical history/symptoms and physical examination results are used
to diagnose PTS. Additional diagnostic testing, such as imaging and electromyography,
may help confirm the diagnosis of PTS by ruling out alternative causes [
65
]. PTS has
been documented in the postoperative, postinfectious, and post-vaccination settings, even
though the origin and pathogenesis are unknown. As PTS variations are hereditary, there
might be a genetic component. PTS has been linked to autoimmune diseases such as
systemic lupus erythematosus, temporal arteritis, and polyarteritis nodosa [
65
,
66
]. Two
possible explanations have been reported for PTS. Either a viral disease directly affects the
brachial plexus or an autoimmune reaction to the viral infection or the viral antigen takes
place [
67
]. Various viral, bacterial, and fungal diseases have been linked to PTS, but only
two cases of SARS-CoV-2 infection have been confirmed.
The first case was a 17-year-old female patient who had been experiencing shortness
of breath and joint discomfort for several weeks and had no substantial medical or surgical
history. She claimed her symptoms started three months earlier, when she had fever, chills,
and other upper respiratory infection symptoms for approximately a week [
68
], until they
went away without treatment. A few weeks later, the patient complained of a new onset of
multifocal joint discomfort, mostly affecting the left shoulder and left hand. The discomfort
was described as persistent. However, it got worse by movement. Her symptoms improved
Viruses 2022,14, 910 14 of 34
dramatically after seeing her primary care physician and she was briefly treated with oral
steroids. However, the patient began to feel increasing abdomen discomfort, shortness of
breath, palpitations, and joint pain shortly after, prompting her to seek medical help [
68
]. A
physical examination showed that her serum inflammatory indicators were significantly
enhanced, and a SARS-CoV-2 RT-PCR test from a nasopharyngeal swab was negative, but
serum IgG antibodies for SARS-CoV-2 were positive, indicating past infection/exposure.
The supraspinatus, infraspinatus, teres minor, teres major, and trapezius muscles all showed
uniformly elevated T2 signal on MR of the left shoulder, which was consistent with PTS
diagnosis [
68
]. Although the patient’s history and physical examination are important for
the diagnosis of PTS, imaging is typically used to rule out other etiologies for a patient’s
symptoms and confirm a suspected diagnosis of PTS. The imaging method of choice for
evaluating PTS is MRI [68].
The second case included a 61-year-old man, who had significant pain and paralysis
in his left shoulder after contracting COVID-19. The patient was taken to the hospital with
hemoptysis after two days of increasing cough prior to his first visit to the orthopedic
clinic [
69
]. The patient was subjected to a lung CT scan on arrival at the emergency
department. This revealed a minor, acute pulmonary embolism, and a tiny infiltration
with lymphadenopathy in the right upper lobe. At the time, laboratory values were mostly
normal. The patient was tested for COVID-19 due to his symptoms and was confirmed to be
positive. After receiving remdesivir, he was discharged three days after his arrival in stable
condition, with his respiratory status gradually improving. Several weeks later, the patient
went to the emergency room with a gradual development of acute shoulder discomfort and
major restrictions in active range of motion. A physical examination revealed deep forward
flexion weakness and significant weakness with external rotation [
69
]. The rotator cuff on
the MRI was found to be fully healed. Mild edema and atrophy of the supraspinatus and
deltoid were the only notable findings. At that moment, the focus shifted to a neurologic
cause for his extreme weakness [
69
]. EMG was also requested. This revealed a left brachial
plexopathy that mainly affects the upper trunk, and continuous denervation. The activation
of the infraspinatus, deltoid, and, to a lesser extent, the biceps brachii were severely reduced,
with accompanying fibrillations [69].
Physiotherapy was started along with a domestic workout program. Both at rest and
during action, his discomfort was kept minimal. Unfortunately, eight months after the
beginning of symptoms, he was having severe difficulty in performing activities above
shoulder height. The patient had neuralgic amyotrophy as a result of SARS-CoV-2 infection.
He was first diagnosed with migrating neuralgia, which led to an emergency room visit
for the acute shoulder pain resistant to oral and intravenous pain medicines and was
accompanied by weakness and loss of mobility. The patient gradually improved over
the course of a year, albeit he still had chronic weakness in his upper body at his last
check-up [
69
]. The use of EMG investigations can aid in the identification of the illness as
well as the delineation of healing. MRI tests may reveal edema inside the muscular bellies
of afflicted muscles, which can help rule out associated disease. Recovery might take a long
time, so cautious waiting is usually the best option, along with physiotherapy to encourage
mobility [69].
6. Congenital and Genetic Conditions Less Frequently (<5 PubMed Hits) Associated
with COVID-19
6.1. COVID-19 and Prader–Willi Syndrome (PWS)
Prader–Willi syndrome (PWS) is a multisystem illness with an incidence of 1 per
10,000–30,000 persons
. Unless eating is externally managed, it is characterized by severe
hypotonia with poor sucking and feeding problems in early infancy, followed by ex-
cessive eating and progressive development of morbid obesity in later infancy or early
childhood [
70
]. In most cases, hypogonadism manifests itself as genital hypoplasia, poor
pubertal development, and infertility in both males and females. A common reason of low
stature is a lack of growth hormone (GH). Sleep disruption and type II diabetes mellitus
Viruses 2022,14, 910 15 of 34
are more common, as are unusual facial characteristics, strabismus, and scoliosis [
70
]. In
contrast to the vast literature on the role in the development of severe COVID-19, there
is no published data on the progression of COVID-19 in PWS, the most common form
of syndromic obesity, which affects about 1 in 21,000 infants [
71
,
72
]. Early results were
unexpected, considering that persons with PWS frequently have comorbidities, which
significantly impact COVID-19 outcomes [
71
]. Furthermore, patients with PWS have diffi-
culties in communicating their concerns and have a lower temperature when an infection
begins, leading to a delay in diagnosis [
73
]. Finally, as many persons with PWS live in a
community structure and social distancing might be problematic in adults with IDDs, the
risk of SARS-CoV-2 infection is higher among them. Between March 2020 and January 2021,
288 adults participated in a study in France, with 38 of them diagnosed with COVID-19.
The average age of the adult cohort was 34 years, and 58% of the participants were female,
89% were Caucasian, and 53% of patients were reported to have 15q11-q13 deletions [
74
].
The majority of patients (82%) were obese, with 55% suffering from severe obesity [
74
].
COVID-19 symptoms were widespread, but only one adult experienced anosmia, and
37% were asymptomatic. At the time of infection, 60% of patients were taking vitamin D
supplements. Three adults were admitted to hospital with proven pneumonia; however,
all symptomatic patients showed rapid, full recovery [
74
]. A poll was also conducted for
239 minors (young population), 13 of which had COVID-19. The average age was 9.6 years,
with 38% of the participants being female, 85% Caucasian, and 62% reported having 15q11-
q13 deletions. Obesity affected three children (23%), and two had sleep apnea syndrome.
At the time of infection, all youngsters were living with their families at home. The majority
(85%) were taking vitamin D supplements, and only one was on psychotropic medication
(neuroleptics). The most notable conclusion of this study is that, despite multiple comor-
bidities, including obesity and diabetes, there was no severe form of COVID-19 in adults.
The youthful age of the patients (mean age of 34 years) may explain this observation, as
age is the most well-known risk factor for severe COVID-19 [
71
]. Another explanation for
the absence of severe COVID-19 in adults with PWS could be the beneficial role of oxytocin
(OXT), which appears to have special functions in immunologic defense: it suppresses
neutrophil infiltration and inflammatory cytokine release, activates T-lymphocytes, and
antagonizes the negative effects of ACE2 and other key COVID-19 pathological events [
75
].
The OXT system is defective in most individuals with PWS, and high plasma levels of
OXT in people with PWS (perhaps due to overcompensation of a brain impairment) may
provide a protective role against COVID-19 [
75
]. Furthermore, most of the patients were
given vitamin D, which has been shown to protect against COVID-19 [
76
], even if there
is no consensus on how to reduce the risk of severe COVID-19 development in individu-
als without a deficiency [
77
]. Furthermore, antidepressants were taken by a third of the
individuals with PWS in the cohort, which may have aided in the course of COVID-19 [
78
].
Finally, in three studies [
79
–
81
], ten adults with diabetes (83% of people with diabetes) took
Metformin, which reduced the mortality of hospitalized patients with COVID-19 and type
II diabetes. However, it is difficult to know whether Metformin contributed to less severe
diabetes or has a specific effect on COVID-19 in these studies. Despite multiple risk factors
for severe COVID-19, such as obesity and diabetes, persons with PWS showed only mild or
moderate COVID-19 in this study. The key explanations are their youthful age (
34 years
)
and possibly additional defensive mechanisms yet to be discovered. Therefore, PWS cannot
be regarded as a risk factor for severe COVID-19.
6.2. COVID-19 and Lysosomal Storage Disorders
Lysosomal storage disorders (LSD) are a group of 70 metabolic illnesses that are
hereditary. While they are uncommon individually, they occur in 1 per 5000 live births as a
group [
82
]. Affected people have multi-systemic involvement, which varies in severity and
rate of illness development depending on the condition. Some LSDs have well-established
therapies, including stem cell transplantation, parenteral enzyme replacement therapy
(ERT), oral substrate reduction therapy or chaperone therapy. Furthermore, all affected
Viruses 2022,14, 910 16 of 34
individuals require supporting therapy, such as physiotherapy, among other things. Both
ERT and supportive therapy are outpatient therapies that can be given in hospitals, in
outpatient clinics or at home [
83
]. A study was conducted in Israel to evaluate the impact
of the COVID-19 pandemic limitations on LSD patients [
83
]. Secondary goals included
determining the influence of mood and behavioral changes on treatment adherence and
determining the link between mood and cognitive and behavioral changes. A total of
48 patients
were treated at four different medical institutions in Israel. The patient group
included 29 men (60%) and 19 females (40%) with ages ranging from one to 42 years, with
46 patients (95%) under the age of 18 and a median age of 6.5 years. The participants
had the following disorders: 27 patients (56%) with mucopolysaccharidosis (MPS): one
with MPS type I (Hurler syndrome), two with MPS type II (Hunter syndrome), eight with
MPS type IIIA (Sanfilippo A syndrome), 14 with MPS type IVA (Morquio syndrome), two
with MPS type VI (Maroteaux–Lamy syndrome); seven with Pompe disease (15%), six
with Niemann Pick type C disease (12%); two with Gaucher type 1 disease (4%); two with
neuronal ceroid lipofuscinosis (NCL) (4%; where one had NCL5 and another had NCL6);
one with Niemann Pick type A disease (2%); one with cystinosis (2%); one with I cell
disease (mucolipidosis II) (2%); and one with Lysosomal acid lipase deficiency (2%) [
83
].
The SARS-CoV-2 infection was detected by PCR in four individuals, all of whom had been
diagnosed with Sanfilippo A, and of which two were siblings. In terms of underlying
treatment, 26 patients (55%) received intravenous ERT, 15 patients (31%) were on various
oral medications such as chaperone therapy or supportive care, and seven patients (14%)
received no treatment at all [
83
]. Before the COVID-19 outbreak, 24 patients (92%) were
receiving intravenous infusions at the hospital regularly, while two patients (8%) were on
home-therapy. Two more patients were sent home due to the epidemic. Thirty-one of the
38 patients (82%) who received regular therapy did not miss any of their appointments.
Five patients (20%) experienced treatment disruptions while receiving ERT in the hospital
setting: three patients missed an intravenous infusion due to their parents’ fear of going to
the hospital, one patient missed an intravenous infusion due to logistic issues in his medical
center and one patient missed an intravenous infusion due to low adherence, despite the
COVID-19 pandemic. Seven of the 48 patients (14.5%) reported mood abnormalities and
cognitive and physical impairment during the home quarantine. This cohort included
14 Morquio patients (29%), of which two patients missed one ERT infusion (14%), and
one patient was not on ERT for reasons unrelated to COVID-19. Due to the difficulty in
obtaining these services, nine Morquio patients (64%) reported missing physiotherapy
treatments throughout the quarantine period. However, as these patients’ compliance
with extra therapies was already low before the onset of COVID-19, this had no significant
impact on them. As the subset of patients who missed ERT was small (n = 7), these
findings should be interpreted cautiously and confirmed in larger cohorts [
83
]. Patients
with worsened mood were 76 times more aggressive, 37 times more cognitively impaired,
and 12.8 times more motorically impaired (all with p-value < 0.001) [
83
]. Despite severe
psychological stress as shown by aggression, cognitive function decrease, and motoric
function degradation that were connected to general worsened mood, this research on LSD
patients demonstrated rather undisturbed treatment throughout the COVID-19 epidemic
in Israel [
83
]. Compared to prior investigations on LSD patients, such as those conducted
on Sanfilippo individuals [
84
,
85
], it is difficult to determine whether aggressiveness or
cognitive deterioration were accelerated by the psychological stress associated with the
lockdown or were simply part of the disease’s natural history. The standard therapy of
individuals with uncommon inborn metabolic defects with multisystemic involvement is
complicated and burdensome for patients, especially during a worldwide pandemic [83].
6.3. COVID-19 and Hereditary Spherocytosis (HS)
Hereditary spherocytosis (HS) is a hemolytic condition that manifests itself in various
ways, ranging from asymptomatic to chronic hemolysis. Due to genetic abnormalities
in plasma membrane proteins, the membrane-cytoskeleton interface of red blood cells
Viruses 2022,14, 910 17 of 34
becomes unstable, increasing the likelihood of hemolysis induced by stress such as fever,
hypoxia, or viral infections [
86
]. Due to the splenic evacuation of damaged red blood cells,
which causes anemia, patients are treated with supportive transfusions or, splenectomy
in the most severe cases [
87
]. Severance et al. described a case of a four-year-old boy who
arrived in the hospital with two days of cough, congestion, and subjective fever and had
a history of mild HS and sickle cell trait without prior splenectomy [
88
]. His oral intake
was reduced with the presence of yellow discoloration in his eyes. The patient’s mother
experienced similar symptoms. There were no known SARS-CoV-2 exposures. Upon
admission at the emergency room, the patient was febrile and tachycardic, but otherwise
hemodynamically stable. He had a palpable spleen tip slightly below the rib edge and
scleral icterus, but no additional abnormalities were discovered. Furthermore, the chest
X-ray was normal [
88
]. An acute hemolytic process was the cause of the anemia. His
metabolic profile was adequate. A COVID-19 nasopharyngeal PCR test was conducted due
to the fever, cough, and congestion. He was hospitalized and given a packed red blood
cell infusion of 10 mL/kg (pRBCs). Fever prevented the completion of the transfusion,
and he only got 6 mL/kg of cells as a result [
88
]. The fever that developed during the
transfusion was thought to be caused by COVID-19 rather than a transfusion response.
Due to his continually low hemoglobin, he was given a second transfusion, which he
handled well. His hemoglobin levels improved, and his hemolysis indicators were on
the mend. Hemoglobin levels were unchanged six hours later, indicating no additional
hemolysis. He was sent home with orders to quarantine for 14 days. With cellular stress
and splenic clearance, hereditary spherocytosis increases the risk of hemolysis. While
hemolysis is a well-known consequence in individuals with HS and viral infections, it
has only been documented in the setting of HCQ toxicity in COVID-19 patients [
89
]. In
the case of COVID-19, this patient underlines the need to monitor individuals at risk
of hemolysis regularly. There have been reports of SARS-CoV-2 infection in sickle cell
disease patients, but none have addressed the danger in individuals with hemoglobin
membrinopathies [
88
]. The need to monitor hemoglobin and hemolytic indicators in
individuals with red blood cell membrane abnormalities and SARS-CoV-2 infection is
highlighted in this case. Children with positive COVID-19 test findings and underlying
hemolytic diseases should be examined for hemolysis if extensive COVID-19 testing is
implemented. The degree of hemolysis in HS varies, and the initial hemolytic episode
might happen in the context of a SARS-CoV-2 infection [88].
6.4. COVID-19 in Patients with Spina Bifida (SB)
Spina bifida (SB) is a congenital birth condition that is caused by the failure of the
embryonic neural tube to close properly [
90
]. In the context of COVID-19, having a child
with special needs has been identified as one factor causing greater parenting-related
tiredness [
91
]. Youth with SB are a group that is particularly vulnerable to the consequences
of the COVID-19 pandemic. Even under normal circumstances, adolescents, and young
adults with SB (AYA-SB; 15–25 years of age) are in a period of transition that can be
chaotic. They must navigate a complicated medical and self-care regimen, as well as several
serious comorbidities. AYA-SB must also deal with new challenges to adherence and self-
management due to the COVID-19 pandemic, such as disturbed social interactions, more
time at home, and more time accessing technology and social media [
92
,
93
]. Parents of
18-year-olds
with SB face various obstacles, including maintaining the medicine regimen,
being concerned about the health, and being unsure about the independence of their
children [
94
]. The influence of the COVID-19 pandemic on a national level of AYA-SB
(
15–25 years
) and parents of SB youth under the age of 18 was the goal of one study.
The analyses were exploratory, but the goal was to uncover requirements unique to SB
adolescents and their families in vulnerable and frequently underserved communities.
Exposure, Impact and Distress due to the pandemic were studied in detail [
95
]. AYA-SB
(
n = 298
) and parents of children with SB (n = 200) were recruited to participate in this study
by completing an anonymous online survey in English or Spanish. Participants supplied
Viruses 2022,14, 910 18 of 34
information on their demographic and medical conditions, and their access to and use
of technology for mental health care. They also completed the COVID-19 Exposure and
Family Impact Survey (CEFIS), which includes Exposure, Impact, and Distress subscales.
Exploratory correlations and t-tests were used to look into possible links between CEFIS
scores and demographic, medical, and access characteristics [
96
]. The results on the
Exposure, Impact, and Distress subscales varied greatly. Demographic connections with
Exposure differed for those with higher Impact and Distress (for example, White, non-
Hispanic/Latino AYA reported higher rates of exposure [p0.001]; AYA who identified with
a minoritized racial/ethnic identity had a higher impact [p0.03]). The most often appearing
qualitative themes were effects on mental and behavioral health (n = 44), interference with
medical care (n = 28), and interpersonal issues (n = 27) [
96
]. The findings of this study
describe the influence of the pandemic on the lives of AYA-SB and parents of youth with
SB, as well as the various ways in which this impact may affect different groups (e.g., those
with more shunt revisions). Families with children who have SB should practice self-care,
focus on SB self-management, and use digital tools for care and social connection [96].
6.5. COVID-19 and Hypothyroidism
Hypothyroidism is a disorder in which the thyroid produces and releases insufficient
thyroid hormone into the bloodstream, resulting in slowed metabolism. Hypothyroidism,
also known as an underactive thyroid, can induce fatigue, weight gain, and an inability
to tolerate cold. Hormone replacement therapy has been the mainstay of treatment, so far.
Since the start of the COVID-19 pandemic, a growing body of evidence suggests that SARS-
CoV-2 infection affects several organs, with both short- and long-term consequences [
97
].
As thyroid hormones influence the formation and function of nearly every human cell,
viral impacts on thyroid function can result in multisystem involvement (https://www.
hindawi.com/journals/bmri/2016/9583495 accessed on 6 December 2021). SARS-CoV-2
may be directly involved in viral thyroiditis, according to a recent observation [
98
]. Low
fT3 readings were linked to a higher rate of clinical decline, suggesting that SARS-CoV-2
directly influences thyroid function [
98
]. Mild symptoms were discovered in 84.3% of
191 COVID-19 patients (mean age 53.5
±
17.2 years; 51.8% male), 12.6% had moderate
symptoms, and 3.1% had severe symptoms [
98
]. Thyroid function was abnormal in 13.1%
of the population [
98
]. In ten patients, TSH levels were abnormal, indicating subclinical
thyrotoxicosis related to thyroiditis. Autoimmune thyroiditis was a likely factor in some of
the patients’ subclinical hypothyroidism [
98
]. Ten of the patients exhibited low fT3, most
likely due to a non-thyroidal disease condition. Low TSH (p= 0.030) and low fT3 (p= 0.007)
were independently linked with lower SARS-CoV-2 PCR cycle threshold values and higher
C-reactive protein, respectively. With increasing COVID-19 severity, there was a declining
trend in fT3 (p= 0.032). COVID-19-related outcomes were less favorable in patients with
low fT3 [
98
]. According to the study, thyroid dysfunction was seen in 13.2% of individuals
with mild to moderate COVID-19. TSH levels were associated with reduced Ct values
in RT-PCR tests. Systemic inflammation has been linked to low fT3 and fT3/fT4 ratios.
Patients with fever frequently reported low TSH and fT3 values. Finally, a low fT3 level,
associated with poor COVID-19 outcomes, may have a predictive value [98].
6.6. COVID-19 and Fragile X-Syndrome (FXS)
Fragile X-Syndrome (FXS) is a trinucleotide repeat abnormality that is the most com-
mon hereditary form of intellectual disability, with a global prevalence of 1 per 4000 in
males and 1 per 5000–8000 in females. This gender-related illness can manifest as behavioral
issues and delayed language development, akin to ASD [
99
,
100
]. Although it is not widely
recognized as an immunological condition, there is evidence that patients with elevated
trinucleotide repeats, such as those observed in FXS, have immune dysregulation and
reduced cytokine responses [
101
,
102
]. Only one case of COVID-19 in a 46-year-old female
patient with FXS has been documented since the outbreak [
103
]. In the study, the effect of
her genetic condition on the clinical manifestation of COVID-19 was investigated. She had
Viruses 2022,14, 910 19 of 34
a history of a deep venous thrombosis (DVT) in her left lower leg, and other comorbidities
such as hypertension, morbid obesity, type II diabetes, and asthma. FXS not only affects
the central nervous system, but also causes other physiologic dysfunctions, such as alter-
ations in immune-related indicators, according to a recent study. Patients with FXS have
lower serum levels of numerous chemokines, including chemokine (C-X-C motif) ligand 10
(CXCL-10), a pro-inflammatory cytokine [
104
]. As a result, someone with FXS may have
weakened immunity and be more vulnerable to infections. CXCL-10 has also been associ-
ated with a cytokine storm linked to more severe disease in COVID-19 patients [
102
,
105
,
106
].
Cytokine Storm Syndrome (also known as Cytokine Produce Syndrome), is a condition in
which lymphocytes and macrophages release many pro- and anti-inflammatory mediators,
resulting in uncontrolled local and systemic inflammation. Current research has revealed
that the release of pro-inflammatory cytokines by macrophages and monocytes causes
T-lymphocyte activation and, eventually, a cascade of enormous cytokine and chemokine
production in SARS-CoV-2 patients [
106
,
107
]. Interleukin (IL)-1, IL-6, IL-10, tumor necrosis
factor-alpha (TNF-a), interferon-gamma (IFN-
γ
), chemokine (C-C motif) ligand 2 (CCL-2),
CXCL-9, and IL-8 are some of the additional cytokines found to be important in the patho-
physiology of COVID-19 [
102
,
106
,
108
]. It has been hypothesized that a decreased CXCL-10
profile in individuals with FXS would indicate a protective effect against cytokine release
and Cytokine Storm Syndrome in COVID-19 patients [103].
6.7. COVID-19 and Duchenne/Becker Muscular Dystrophy
One of the most frequent neuromuscular illnesses in children is Duchenne muscular
dystrophy (DMD). Approximately 1 in 5000 newborn males worldwide are affected by
this hereditary degenerative condition. Becker muscular dystrophy (BMD) is a milder
type of dystrophinopathy than DMD [
109
]. DMD involves progressive weakening, loss
of motor skills and eventually pulmonary and cardiac failure, with significant respiratory
muscle weakness causing restrictive respiratory illness and a weak cough [
110
–
112
]. Cor-
ticosteroids have been established as the gold standard of therapy for DMD patients, so
far [
113
–
115
]. DMD patients are a high-risk group in the recent global COVID-19 pan-
demic (https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/people-
with-medical-conditions.html accessed on 6 December 2021). During the global outbreak,
one Israeli study intended to evaluate the clinical presentations and outcomes of individ-
uals with severe dystrophinopathies, infected with SARS-CoV-2 [
116
]. From March to
December 2020, the cohort included DMD/BMD patients, who were tested and found to be
infected with SARS-CoV-2 at Schneider Children’s Medical Center (SCMC) in Israel [
116
].
All patients were subjected to standard follow-up visits or phone/virtual contacts over
the trial period. They received a survey about their SARS-CoV-2 infection status during
routine visits or if they were hospitalized. Following their recovery, infected patients
returned to the neuromuscular clinic regularly. Physical examinations, lung function tests,
and chest X-rays were performed during these visits and compared to those acquired
before becoming COVID-19 positive [
116
]. During the study period, seven (6%) of the 116
DMD/BMD patients followed at SCMC tested positive for COVID-19 [
116
]. The median
age of SARS-CoV-2-infected DMD/BMD patients was 14 years (range 8–17), compared
to 11 years (range 4–27) for all DMD/BMD patients monitored at SCMC, who were not
infected (p= 0.26). Five of the COVID-19 positive patients were ambulatory, while the
other two needed to be hospitalized [
116
]. One patient was admitted due to dyspnea and
chest pain, while the others had headache and fever. The chest X-ray of the first patient
revealed low lung volumes and small patch infiltrates. Due to the respiratory exacerbations
in previous years, this patient was suspected of having pseudomonal co-infection and was
treated with ceftazidime and azithromycin. He was also given dexamethasone (6 mg twice
a day) for two days before returning to his regular prednisone medication [
116
]. Before
admission, this patient required daily non-invasive ventilation. The length of time he used
ventilation was increased each day while in hospital until one day before discharge. The
other admitted patient’s chest x-ray indicated low lung volumes without infiltrates, and he
Viruses 2022,14, 910 20 of 34
did not require antibiotics or a dose adjustment of corticosteroids [
116
]. Both patients were
admitted to dedicated negative-pressure air-conditioning rooms to reduce transmission
to the medical team, as one was ventilated using non-invasive ventilation (NIV) and the
other used cough-assist equipment. Both patients were released from the ventilation unit
five days later [
116
]. Five of the seven COVID-19 DMD patients were obese, with the two
symptomatic patients showing extreme obesity, with a BMI of 33 kg/m
2
(>99% for age).
All DMD/BMD COVID-19 patients had a mean and median BMI of 26.7 and 31.2 kg/m
2
,
respectively [
116
]. Finally, all symptomatic individuals recovered without any long-term
consequences. There was no evidence of a severe course of disease in adult individuals
with chronic lung disease and obesity. The hypothesis was that their muscular illness might
have caused more social distancing due to fear of the disease [116].
6.8. COVID-19 and Neuromyelitis Optica Spectrum Disorder
Neuromyelitis optica spectrum disorder (NMOSD) is a rare central nervous system
antibody-mediated illness [
117
]. It was unclear, until as recently as 2004, whether NMOSD
was a distinct illness or simply a more severe variant of ‘optico-spinal’ multiple sclerosis
(MS), when the potential antigenic target, the aquaporin-4 water channel, was discovered,
and the two disorders could be consistently differentiated using aquaporin-4 antibodies
(AQP4-Abs) [
118
,
119
]. NMOSD clustering in families is uncommon but recognized, indi-
cating a complicated genetic predisposition. A recent whole-genome sequencing initiative
discovered genetic variations in the major histocompatibility region that may play a role
in the genesis of NMOSD [
120
,
121
]. One in every four individuals with AQP4-Ab posi-
tive NMOSD has also another autoimmune illness, such as myasthenia gravis, systemic
lupus erythematosus (SLE), Sjogren’s syndrome, or celiac disease [
122
–
124
]. Patients with
NMOSD are sensitive to developing COVID-19 owing to immunosuppressive medica-
tion [
125
]. In individuals with NMOSD, long-term immunosuppression is the basis for
treatment, which might hypothetically raise the risk of infections such as SARS-CoV-2 [
126
].
Paybast et al. reported a case study of a young 25-year-old female with a history of
NMOSD, who had two separate episodes of COVID-19 while receiving rituximab ther-
apy [
125
]. Due to the close contact with a COVID-19 patient, she was recommended for a
COVID-19 screening test in April 2020. The COVID-19 test showed no upper respiratory
tract discomfort symptoms. The neurological examination was significant for a score of
two on the Expanded Disability Status Scale. Due to COVID-19 fear and the proximity of
the next rituximab infusion, the patient had serologic testing, which confirmed positive
SARS-CoV-2 IgM and IgG. Her rituximab treatment was postponed until September 2020.
The patient returned in November 2020 with a five-day history of severe chills, fever, and
shortness of breath. Her chest computed tomography (CT) revealed bilateral ground-glass
infiltrates. The patient was hospitalized and given conventional COVID-19 medication
and non-invasive oxygen supplementation [
125
]. The patient steadily recovered and was
discharged two weeks later. The patient’s symptoms, however, did not totally disappear.
Unfortunately, the patient’s respiratory problems worsened three weeks later, necessitating
readmission. Due to respiratory distress, the patient was brought to the critical care unit
and required breathing assistance. Due to the severity of COVID-19-related respiratory
involvement, the therapy began with therapeutic plasma exchange (TPE). The patient’s
symptoms gradually improved, and she was transferred to the ward five days later. Her
hemodynamics were stable, and her chest CT indicated that the lung infiltration had
cleared significantly. On the 31st day, she was allowed to return home [
125
]. As there
was a long interval between the two episodes, the reported case described both persistent
viral shedding (the second scenario of readmission) and a true reactivation of the infection
(the first scenario of admission). Unlike earlier accounts, this patient was asymptomatic
throughout the first episode, and the second episode was worsened by respiratory distress
due to continuous viral shedding [
125
]. In contrast, there is no evidence that patients taking
immunosuppressive drugs are at a higher risk of COVID-19 complications [
127
]. Although
rituximab appears to decrease the likelihood of severe SARS-CoV-2 infection, a muted
Viruses 2022,14, 910 21 of 34
vaccination response, and a viral reactivation, observational studies on MS and COVID-19
have not found that rituximab plays a role in COVID-19 occurrence [
128
,
129
]. Taking these
factors into account, this case emphasizes the significance of paying extra attention to vul-
nerable groups such as patients with NMOSD during the COVID-19 pandemic, especially
in the event of COVID-19 recurrence [125].
7. Multi-Omics-Based Predicted Congenital Anomalies and Genetic Diseases and
Their Associations with COVID-19
Using a multi-omics approach, Barh and colleagues predicted for the first time the
association between congenital anomalies and genetic disorders and COVID-19 [
5
]. They
predicted various COVID-19 associated symptoms, conditions, and possible long-term
complications with up to 92% accuracy. According to their analysis, 57 various congenital
and genetic diseases could be associated with COVID-19. Based on the cut off values, the
predicted 24 important conditions associated with COVID-19 are congenital hemolytic
anemia, dyserythropoietic anemia, thalassemia, congenital disorders of glycosylation or
congenital porphyria, occipital horn syndrome, gangliosidosis GM1 type 3, Sandhoff dis-
ease, beta-galactosidase-1 deficiency, Aicardi-Goutieres syndrome, DS, Atkin syndrome,
cleft palate or bilateral cleft lip, congenital coagulation defects, genital organ defects, ceroid
storage disease, aspartylglucosaminuria, adrenoleukodystrophy, familial Paget’s disease
of bone, Asperger syndrome, ASD, head morphology, Sotos syndrome, arthrogryposis,
limb defects, CF, rhizomelic chondrodysplasia punctate, fetal hemoglobin quantitative trait
locus, hereditary elliptocytosis, and familial erythrocytosis. As per their prediction, the
33 low
confidence conditions are bare lymphocyte syndrome, hemophagocytic lymphohisti-
ocytosis, pontocerebellar hypoplasia type 1, Canavan disease, Aicardi syndrome, Schwartz
Jampel syndrome type 1, Melnick-Needles syndrome, hereditary connective tissue disorder,
lower limb spasticity/spastic paraplegia, sclerosteosis, Clayton-Smith Donnai syndrome,
alpha-1 anti-trypsin deficiency, type 1 plasminogen deficiency, Polydactyly Zechi Ceide
syndrome, congenital hypoplasia of femur, adducted thumb, sickle cell anemia, congenital
anomalies of the eye, congenital euryblepharon, Kabuki syndrome eyelids, lissencephaly,
Leukomalacia, xeroderma pigmentosum, Rothmund Thomson syndrome, parental lifespan,
CHD, adrenal hypoplasia congenital, tetraploidy, shallow anterior chamber of the eye,
Treacher Collins syndrome, disorders of tooth development, and hereditary spherocytosis.
However, as the prediction accuracy percentage was based on the phenome data and the
congenital/genetic disease associated with COVID-19 data is not available in any struc-
tured form, Barh et al. predicted this association with an accuracy of 40% [
5
]. However,
increasing COVID-19 phenome data indicate that their prediction accuracy on COVID-19
and congenital/genetic disorder association would be higher than calculated and more
focus should be placed on understanding the effect of SARS-CoV-2 infections in persons
with existing congenital/genetic disorders or if congenital/genetic conditions arise as a
long-term consequence of COVID-19.
If we consider that congenital/genetic disorders could have long-term consequences
of COVID-19, they may or may not be expressed in the immediate offspring and may take
generations to manifest themselves. In principle, to develop a congenital/genetic disease,
the genetic material (human genes, chromosomes) must be disrupted to express the disease
phenotype. If the predictions of Barh et al. [
5
] are correct and if we consider their “genetic
remittance” hypothesis, where the SARS-CoV-2 genetic material may integrate in and/or
disrupt the human genome, some human genes or chromosomes may be malfunctional,
which would result in congenital/genetic disorder development in the offspring. Although,
there are Genome-Wide Association Studies (GWAS) to understand the COVID-19 suscep-
tible or resistance loci in humans [
130
–
132
], so far there is not much information available
on whether the SARS-CoV-2 genetic material is integrated in the genome or disrupting it.
However, an
in vitro
analysis suggested that transcribed SARS-CoV-2 RNA may poten-
tially integrate into the genome of cultured human cells [
133
] indicating the possibility of
Barh et al.’s
hypothesis. However, some controversy has been associated with the potential
Viruses 2022,14, 910 22 of 34
genome integration of SARS-CoV-2, which requires more research on the integration process
and its affects and consequences (https://www.science.org/content/article/coronavirus-
may-sometimes-slip-its-genetic-material-human-chromosomes-what-does-mean accessed
on 28 December 2021).
Barh et al. predicted that reproductive system diseases could be long-term con-
sequences of COVID-19 [
5
]. Reports suggest that SARS-CoV-2 is detected in testicular
samples and is associated with impaired testicular function and spermatogenesis [
134
].
Similarly, a declined ovarian reserve and reproductive endocrine disorders are found in
SARS-CoV-2 infected women [
135
]. Therefore, COVID-19 seems to affect the reproductive
health of both males and females, also influencing fertility [
136
], which may also lead to
birth defects and congenital abnormalities in the future. Equally, COVID-19 associated
congenital disorders may arise through alternative mechanisms, like those discovered for
Zika virus (ZIKV). Therefore, it is also necessary to investigate whether transplacental
transmission and placental insufficiency occurring for ZIKV [
137
,
138
] can also be detected
for SARS-CoV-2.
A summary of our discussed congenital anomalies and genetic diseases and their
associations with COVID-19 is presented in Table 1.
Table 1.
A snapshot of reported associations of COVID-19 with congenital anomalies and genetic diseases.
Disease Incidence Association References (DOI)
Sickle-cell anemia Moderate
Increased risk of developing severe COVID-19 symptoms
including acute chest syndrome, vasoocclusive crises,
and death. [139–142]
Thalassemia Low In risk population but does not increase the severity of
COVID-19. However, pulmonary microembolism is
reported and death occurred due to another comorbidity.
[48,143–145]
Aicardi-Goutieres
Syndrome (AGS) Low
Mostly asymptomatic or mild or shows rash on cheeks
and arms. Post-COVID-19 generalized panniculitis is
observed and the SAMDH1 gene could be a potential
link between COVID-19 and AGS
[146,147]
Down Syndrome (DS) Moderate DS exhibits a higher risk of COVID-19 severity and 10
times higher mortality of SARS-CoV-2 infections. [33,148]
Congenital coagulation defect Low May not be a risk factor for increased severity from
COVID-19. Hypercoagulability may have a protective
role against SARS-CoV-2 infection. [149,150]
Genital organ defects Moderate
Although the genetic or congenital condition of genital
organ defects is not reported, testicular spermatogenesis
dysfunction and reduced sperm count are frequent after
SARS-CoV-2 infection.
https://www.europeanreview.
org/article/24682 (accessed on
14 February 2022).
Asperger’s syndrome (AS) Low AS shows mental health and behavioral issues in
COVID-19 patients. [151]
Autism Spectrum Disorder (ASD)
Low
SARS-CoV-2 may impair brain development via cytokine
storm during pregnancy increasing the risk of ASD. ASD
increased vulnerability to COVID-19 in children and
affected their behavior.
[22,152,153]
Sotos syndrome Low Pericardial effusion after infection with SARS-CoV-2
is reported. [154]
Arthrogryposis Low Shows mild or no symptoms of COVID-19. [155]
Cystic fibrosis (CF) Low
CF is not a high-risk, however, CF patients with low lung
function or transplants may show severe symptoms
of COVID-19. [16,156]
Fetal hemoglobin quantitative
trait locus High
Increased level of fetal hemoglobin may prevent hypoxia
and cure respiratory distress syndrome in COVID-19. [157]
Hereditary elliptocytosis Low May show varying severity and risk of hemolysis
in COVID-19. [88]
Familial erythrocytosis Low The presence of erythrocytosis increases the risk of
thrombosis in COVID-19. [158]
Viruses 2022,14, 910 23 of 34
Table 1. Cont.
Disease Incidence Association References (DOI)
Bare lymphocyte syndrome
(BLS)/Congenital immune
deficiencies (CID) Low Convalescent plasma therapy may be effective in CID
patients suffering from COVID-19. [159]
Hemophagocytic
lymphohistiocytosis (HL) Low HL may be a secondary event or a risk factor of
severe COVID-19 [160,161]
Aicardi syndrome/Malformations
in brain Low
Differences in neurodevelopment are observed in infants
of six months infected by SARS-CoV-2 at the fetal stage.
Long-term observation is required. [162–164]
Alpha-1 antitrypsin
deficiency (AAD) High
AAD patients show worse outcome due to TMPRSS2
being activated more easily. They also have an increased
risk of coagulation disorder and severe acute lung injury
from COVID-19.
[165]
Plasminogen deficiency Moderate
Low plasminogen level exhibits 12-fold higher mortality
from COVID-19. [166]
Congenital anomalies of the
eye/congenital euryblepharon Low Eye abnormalities are observed in newborns infected by
SARS-CoV-2 at the fetal stage. [167]
Leukomalacia Low Periventricular leukomalacia is reported in newborns
infected by SARS-CoV-2 at the fetal stage. [164]
Adrenal hypoplasia (AH) Low AH patients undergoing glucocorticoid replacement
therapy for adrenal insufficiency are vulnerable to
developing severe complications from COVID-19. [168]
Disorders of tooth development Low
A fetus may be at high risk for enamel defects due to the
stress of COVID-19 during pregnancy. Tooth loss is
observed in severe COVID-19. [169,170]
Hereditary spherocytosis (HS) Moderate HS patients show an increased risk of hemolysis and
splenomegaly due to COVID-19. [88,171]
Lifespan Not
Known
Available
Genetic polymorphisms that are linked to longer
lifespans are significantly associated with a low risk of
SARS-CoV-2 infection and hospitalization. [172]
Congenital heart disease (CHD) Low CHD are of low or moderate risk, which may develop
hemodynamic abnormalities upon SARS-CoV-2 infection
but has no impact on mortality. [173–175]
Spina Bifida (SB) Low Impact on mental health [90–96]
Fragile X-Syndrome (FXS) Low Decreased CXCL-10 as protection against Cytokine
Storm Syndrome [99–108]
Prader-Willi Syndrome (PWS) Low Youthful age of the cohort had a positive impact, so far [70–81]
Hypothyroidism Low to
Moderate Low fT3 level can lead to poor outcomes [97,98]
Duchenne/Becker Muscular
Dystrophy (DMD/BMD) Low All symptomatic individuals recovered without any
long-term consequences [109–116]
Lysosomal Storage
Disorders (LSD) Low Impact on mental health [82–85]
Autoimmune Hemolytic
Anemia (AIHA) Moderate Hemolysis [23–25]
NMO Spectrum Disorder Low Readmission [117–129]
8. COVID-19 during Early Pregnancy
It is known that miscarriage, congenital anomalies, and fetal growth restriction repre-
sent some of the severe complications of the spectrum of infections by SARS-CoV, MERS-
CoV, and SARS-CoV-2 during pregnancy [
176
]. It was pointed out that pregnant women
tested positive for COVID-19 are more likely to be hospitalized [
177
]. Moreover, SARS-
CoV-2 infections of women at late pregnancy is linked to increased rates of adverse birth
outcomes, with preterm birth being the most common adverse pregnancy outcome (in
addition to preeclampsia, cesarean, and perinatal death) in hospitalized mothers with
coronavirus infections, who also had pneumonia [
2
]. As far as the consequences of SARS-
Viruses 2022,14, 910 24 of 34
CoV-2 infection in early pregnancy are concerned, it was hypothesized that the infection
itself and the utilization of antiviral drugs for COVID-19 containment might be associated
with an increased risk for congenital neurodevelopmental anomalies in newborns [
178
].
The neural tube defects (NTDs) leading to severe malformations of the spinal cord (spina
bifida) or brain (anencephaly, encephalocele, hydrocephalus) [
178
] are among the common
severe congenital malformations developed in early pregnancy complicated by viral in-
fections [
179
,
180
]. Furthermore, a higher incidence of mental illnesses, such as attention
deficit disorders, ASD, and schizophrenia were reported for offspring of women, who
were pregnant during influenza pandemics [
181
–
185
]. It has also been reported that infants
delivered by mothers, who were infected by SARS-CoV-2 during pregnancy might show
decreased motor function, communication, and social development [186].
The capability of SARS-CoV-2 to cross the placental barrier [
186
] and the blood–brain
barrier [187] suggests that this virus can cause some adverse effects and can be associated
with NTD pathogenesis [
178
]. Since the ACE2, the host cell receptor interacting with
the SARS-CoV-2 spike protein (S) and S protein proteases (furin and the transmembrane
serine protease TMPRSS2, which are needed for viral S protein priming) are expressed in
early gametes, zygotes, and four-cell stage embryos [
188
] and since developing human
embryos also possess the machinery necessary for viral internalization and replication,
it is possible that the in utero maternal to fetal transmission of SARS-CoV-2 might occur
during early pregnancy [
188
]. In a recent study of an early miscarriage in a SARS-CoV-
2 maternal infection, prominent damage of the placenta and fetal organs, such as lung
and kidney, was reported, indicating that congenital SARS-CoV-2 infection during the
first trimester of pregnancy is possible and that coronaviruses target fetal organs [
189
].
Although it was suggested that congenital SARS-CoV-2 infection during early pregnancy
could potentially trigger neurodevelopmental complications [
178
], no supporting evidence
has been reported, so far. Furthermore, it was established that pregnant women are less
likely to contract SARS-CoV-2 than the general public [
189
], and that the likelihood of SARS-
CoV-2 vertical transmission is low [
190
–
195
]. For example, only 5.7% of 176 neonatal SARS-
CoV-2 infections cases were classified as confirmed congenital infections [
196
]. In addition,
although SARS-CoV-2 infection was shown to cause significant placental pathology, the
actual consequences of COVID-19 for early pregnancy are not clear, and reported data
indicate that in comparison to other respiratory viral outbreaks, the effects of SARS-CoV-2
in early pregnancy are less severe [197].
Published research indicated that viral infection during early pregnancy, along with
various antiviral drugs, was linked to an elevated risk of neonatal neurological congenital
abnormalities [
178
]. SARS-CoV-2 appears to cross both the placental barrier, based on
detection of viral IgM in newborns hours after birth, and the blood–brain barrier (BBB)
by the presence of the virus in the cerebrospinal fluids [
185
]. There are various issues
regarding the use of antiviral medication to confine SARS-CoV-2 and minimize virus-
related consequences, including pneumonia.
Although no effective drugs to combat SARS-CoV-2 have been discovered, sev-
eral antiviral and anti-inflammatory therapies developed for other viral infections and
pathologies have been repurposed for COVID-19. For example, favipiravir, previously
used against influenza virus, remdesivir, developed for Ebola virus disease; and dolute-
gravir/lamivudine/tenofovir against human immunodeficiency viruses (HIV), have been
evaluated for COVID-19. However, as the implications of these drugs on pregnancy, mainly
in the first trimester, have not been investigated, there is serious concern that they might
cause adverse birth outcomes. Favipiravir has been linked to birth abnormalities and
is not recommended for women who are or may be pregnant [
198
]. Despite that, with
the assistance of the Japanese government, this medication was extensively used to treat
COVID-19 in approximately 40 nations by the end of 2020 and in numerous developing
and source-constrained countries due to its wide availability. However, the drug has not
been licensed or approved by either the Japanese government or the FDA for its use to
combat COVID-19 [
2
]. Dolutegravir, an efficient HIV drug, has also been evaluated for
Viruses 2022,14, 910 25 of 34
the treatment of COVID-19 patients in low- and middle-income economies. However, it
was shown that dolutegravir increased the frequency of neural tube defects, and their
prevalence three-fold [
199
]. Additionally, dolutegravir administration during pregnancy
resulted in a significant increase in external physical abnormalities in newborns (9 cases in
1000 births) [199].
A graphical illustration of COVID-19 impacts on congenital anomalies and genetic
diseases discussed in this review is presented in Figure 3.
Viruses 2022, 14, x FOR PEER REVIEW 26 of 35
resulted in a significant increase in external physical abnormalities in newborns (9 cases
in 1000 births) [199].
A graphical illustration of COVID-19 impacts on congenital anomalies and genetic
diseases discussed in this review is presented in Figure 3.
Figure 3. Summary of associations, disease–disease interactions, and impacts of COVID-19 in con-
genital anomalies and genetic disorders.
9. Conclusions
To the best of our knowledge, this is the first comprehensive review describing the
association between COVID-19 and various congenital anomalies and genetic diseases.
The data assembled here provide strong support for the idea that COVID-19 may induce
long-term congenital anomalies among newborns, either through infections or through
therapeutic intervention. Such facts become much more significant in impoverished and
resource-constrained societies whereby prenatal screening, particularly during the early
stages of pregnancy, is essentially non-existent. Assessing the mechanistic connections be-
tween the host genetic profile with COVID-19 is thus critical to ascertain biomarkers for
those at increased risk, which may also reveal potential candidates for intervention. Fur-
thermore, as observed from various studies, some congenital disorders present high-risk
for developing severe COVID-19. CHD, CF, and DS would be those. These disorders al-
ready include some comorbidities related to the structure and function of respiratory and
cardiovascular systems, leading to severe pneumonia. Other congenital disorders like SB
and PWS cannot be considered risk factors for severe COVID-19 but rather cause psycho-
logical burdens to patients. Low fT3 concentration found in patients with hypothyroidism
may have a predictive value for this type of disease, but without the occurrence of any
severe cases of COVID-19.
On the other hand, due to the lack of data on FXS patients with COVID-19 and lack
of understanding of the cytokines involved in the pathophysiology of SARS-CoV-2 infec-
tion, it is difficult to draw any conclusions about the relationship between FXS and its
protective effect against severe clinical outcomes in COVID-19 patients. According to the
Figure 3.
Summary of associations, disease–disease interactions, and impacts of COVID-19 in
congenital anomalies and genetic disorders.
9. Conclusions
To the best of our knowledge, this is the first comprehensive review describing the
association between COVID-19 and various congenital anomalies and genetic diseases.
The data assembled here provide strong support for the idea that COVID-19 may induce
long-term congenital anomalies among newborns, either through infections or through
therapeutic intervention. Such facts become much more significant in impoverished and
resource-constrained societies whereby prenatal screening, particularly during the early
stages of pregnancy, is essentially non-existent. Assessing the mechanistic connections
between the host genetic profile with COVID-19 is thus critical to ascertain biomarkers
for those at increased risk, which may also reveal potential candidates for intervention.
Furthermore, as observed from various studies, some congenital disorders present high-
risk for developing severe COVID-19. CHD, CF, and DS would be those. These disorders
already include some comorbidities related to the structure and function of respiratory and
cardiovascular systems, leading to severe pneumonia. Other congenital disorders like SB
and PWS cannot be considered risk factors for severe COVID-19 but rather cause psycho-
logical burdens to patients. Low fT3 concentration found in patients with hypothyroidism
may have a predictive value for this type of disease, but without the occurrence of any
severe cases of COVID-19.
Viruses 2022,14, 910 26 of 34
On the other hand, due to the lack of data on FXS patients with COVID-19 and lack of
understanding of the cytokines involved in the pathophysiology of SARS-CoV-2 infection,
it is difficult to draw any conclusions about the relationship between FXS and its protective
effect against severe clinical outcomes in COVID-19 patients. According to the literature,
individuals suffering from DMD, and BMD recovered without any long-term consequences,
excluding muscular dystrophy as a high-risk for developing a severe form of COVID-19.
The severity of SARS-CoV-2 infections in patients with thalassemia, LSD and ASD is low,
however, there was an impact on mental health. On the other hand, the incidence in
patients with CF, AIHA, and HS can be considered moderate to high due to hemolysis
in the case of HS and AIHA or due to transplants in the case of CF. Immunosuppressive
medication in patients with NMOSD might hypothetically increase the risk of infections
such as SARS-CoV-2. However, it was shown that this kind of therapy was not found
to play a role in COVID-19 occurrence. Concerning SARS-CoV-2 infections during early
pregnancy, it was suggested that congenital infections during this period could potentially
trigger neurodevelopmental complications; however, no supporting evidence has been
reported so far. It was also established that pregnant women are less likely to contract
COVID-19 compared to others, and that the likelihood of SARS-CoV-2 vertical transmission
is low.
Author Contributions:
D.B., A.H.-J. and K.L.: Conceptualization and design; A.H.-J., D.B., C.H.R.P.,
L.G.R.G., J.L.P.M., O.O.A., S.T., A.A.A.A., M.M.T., Á.S.-A., E.M.R., V.N.U. and K.L.: Data collection
and analysis; A.H.-J. and D.B.: Prepared the draft manuscript; K.L., V.N.U., A.A.A.A., Á.S.-A. and D.B.;
Edited the final article. All authors have read and agreed to the published version of
the manuscript
.
Funding:
The authors declare that no funds, grants, or other support were received during the
preparation of this manuscript.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Data are contained within the article.
Conflicts of Interest: The authors declare no conflict of interest.
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