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Immunopathological changes, complications, sequelae and immunological memory in COVID-19 patients

April 2022
Heliyon 8(4):e09302

April 2022
8(4):e09302

DOI:10.1016/j.heliyon.2022.e09302

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CC BY-NC-ND 4.0

Authors:

Wenxue Ma

University of California, San Diego

Confirmed SARS-CoV-2-caused disease (COVID-19) cases have reached 275.65 million worldwide. Although the majority of COVID-19 patients present mild to moderate symptoms, some have severe complications including death. We first reviewed the pathogenesis on ACE2, a binding receptor of SARS-CoV-2 expressed in multiple organs, and prevalent multinucleate syncytia in the lung tissues of COVID-19 patients. Then, we evaluated the pathological, immunological changes and sequelae in the major organs. Finally, we reviewed the immunological memory after SARS-CoV-2 infection and vaccination. The binding of SARS-Cov-2 to ACE2 receptor results in reduced ACE2 protein levels, which may lead to elevated susceptibility to inflammation, cell death, organ failure, and potentially severe illness. These damages increase the risk of health problems over a long period, which result in many complications. The complications in multiple organs lead to the increased risk of long-term health problems that require additional attention. A multidisciplinary care team is necessary for further management and recovery of the COVID-19 survivors. Many COVID-19 patients will probably make antibodies against SARS-CoV-2 virus for most of their lives, and the immunity against reinfection would last for 3–61 months.

Status of COVID-19 vaccines within WHO EUA.

…

SARS-CoV-2 variants of concern (VOC).

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Review article

Immunopathological changes, complications, sequelae and immunological

memory in COVID-19 patients

Liqin Yao

, Lingeng Lu

, Wenxue Ma

Department of Thyroid and Breast Surgery, The First Afﬁliated Hospital, Huzhou University School of Medicine, Huzhou, Zhejiang, 313000, China

Department of Chronic Disease Epidemiology, Yale School of Public Health, School of Medicine, New Haven, CT, 06520, USA

Center for Biomedical Data Science and Yale Cancer Center, Yale University, 60 College Street, New Haven, CT, 06520, USA

Department of Medicine, Moores Cancer Center and Sanford Stem Cell Clinical Center, University of California San Diego, La Jolla, CA, 92093, USA

ARTICLE INFO

Keywords:

SARS-CoV-2

COVID-19

Immunopathology

Complication

Sequelae

ABSTRACT

Conﬁrmed SARS-CoV-2-caused disease (COVID-19) cases have reached 275.65 million worldwide. Although the

majority of COVID-19 patients present mild to moderate symptoms, some have severe complications including

death. We ﬁrst reviewed the pathogenesis on ACE2, a binding receptor of SARS-CoV-2 expressed in multiple

organs, and prevalent multinucleate syncytia in the lung tissues of COVID-19 patients. Then, we evaluated the

pathological, immunological changes and sequelae in the major organs. Finally, we reviewed the immunological

memory after SARS-CoV-2 infection and vaccination. The binding of SARS-Cov-2 to ACE2 receptor results in

reduced ACE2 protein levels, which may lead to elevated susceptibility to inﬂammation, cell death, organ failure,

and potentially severe illness. These damages increase the risk of health problems over a long period, which result

in many complications. The complications in multiple organs lead to the increased risk of long-term health

problems that require additional attention. A multidisciplinary care team is necessary for further management and

recovery of the COVID-19 survivors. Many COVID-19 patients will probably make antibodies against SARS-CoV-2

virus for most of their lives, and the immunity against reinfection would last for 3–61 months.

1. Introduction

Highly contagious severe acute respiratory syndrome coronavirus 2

(SARS-CoV-2) is a novel coronavirus, which has spread worldwide and

caused over 275.65 million infections (Figure 1) since its outbreak in

Wuhan, China in Dec. 2019 [1]. The SARS-Cov-2-caused infection is

named as COVID-19. Although different measurements, such as lock-

down, social distance, masking, and recent roll-out of vaccines, have

been executed and decreased the initial spread of infection, low vacci-

nation rates, the emergence of COVID-19 virus variants, and the release

of control measurements such as re-opening and unmasking has led to the

resurgence of COVID-19, which was driven predominantly by the Omi-

cron (B.1.1.529) variant of SARS-CoV-2 [2].

By binding to angiotensin-converting enzyme 2 (ACE2), SARS-CoV-2

virus particles are fused with membrane of human epithelial cells mainly

in lung and then enter the cells for ﬂu-like systemic replication [3]. ACE2

is ubiquitously expressed in different tissues and organs (e.g., lung, heart,

kidney), which catalyzes hepatocytes-generated angiotensin, playing an

important role in regulating blood pressure. Approximately one third of

patients with COVID-19 are asymptomatic [4]. COVID-19 typically pre-

sents with ﬂu-like systemic and/or respiratory symptoms, which include

cough, fever higher than 38 C (100.4 F), myalgia, headache, dyspnea,

sore throat, diarrhea, nausea/vomiting, anosmia, ageusia, dysgeusia,

abdominal pain, runny nose, loss of smell and taste. Severe cases

demonstrate acute respiratory distress syndrome (ARDS) complications

with multiple organ injury and failure, and even death [5,6]. Isolation of

symptomatic and asymptomatic cases and tracing of contacts have been

used in many countries, with additional physical distancing measures

[7]. Speciﬁc and effective treatments have not been developed before

COVID-19 vaccines are available, and the standard of care for COVID-19

is focused on the alleviation of symptoms (e.g., oxygen supply, preven-

tion of dehydration, etc.). Although monoclonal antibodies (e.g., Tocili-

zumab, a monoclonal antibody binding to human interleukin-6

receptors) have been used to the patients who are at the high risk of

progressing to severe COVID-19 or being hospitalized [8]. According to

The Centers for Disease Control and Prevention (CDC) and Mayo Clinic,

most of patients with mild symptoms recover from COVID-19 with a

minimal standard of care at home and are back to normal life. Some,

* Corresponding author.

E-mail address: wma@ucsd.edu (W. Ma).

Contents lists available at ScienceDirect

Heliyon

journal homepage: www.cell.com/heliyon

https://doi.org/10.1016/j.heliyon.2022.e09302

Received 6 September 2021; Received in revised form 25 November 2021; Accepted 14 April 2022

2405-8440/Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Heliyon 8 (2022) e09302

however, have post-viral symptoms (termed as sequelae), such as fatigue,

loss of sense of smell or taste, and brain fog, after recovery [9]. These

sequelae can sometimes last for months or longer and are becoming other

critical health issues of post COVID-19 [10]. These symptoms are the

barriers preventing individuals from returning to work [11].

Over the past 2 years, accumulating knowledge in COVID-19 is very

helpful in beating COVID-19 and containing the pandemic. But we still

need to be on alert for this virus to come back at any time. This review

aims to comprehensively summarize the complications and sequelae of

COVID-19 from the perspectives of its pathogenesis, pathological and

immunological characteristics.

2. Pathogenesis

COVID-19 is a systemic disease with the major involvement of the

lungs, showing diffuse alveolar damage (DAD) and pulmonary throm-

botic microangiopathy [12,13]. Inﬂammation and vascular damage were

also observed in other organs such as heart, liver, kidney, and brain [4,

14]. Multi-organ failure is the major cause of COVID-19-related death

[15]. However, the exact pathogenesis of COVID-19 related deaths re-

mains poorly understood [16,17].

ACE2 is a pivotal cell membrane receptor for the entry of SARS-CoV-

2. Under normal circumstances, ACE2 protein plays an important role in

regulating physiological and biological processes including wound

healing, blood pressure, and inﬂammation, via the renin-angiotensin

system (RAS) pathway [18]. ACE2 enzyme converts angiotensin I into

angiotensin II (ANG II) [19]. ANG II, causing vasoconstriction and an

increase in blood pressure, inﬂammation, increasing damage to the lining

of blood vessels and various types of tissue injury [20]. ANG II can be

broken down by ACE2 into the molecules that counteract the harmful

effects of ANG II, whereas its role is blunted if the virus occupies the

ACE2 receptor on the surface of cells [21]. ACE2 is found in a variety of

human organs [3,6,7], which is highly abundant on type 2 pneumocytes

in the respiratory system [22]. Once SARS-CoV-2 spike protein binds to

ACE2 receptor, the complex is cleaved by transmembrane serine protease

2 (TMPRSS2), leading to membrane fusion, and the virus consequently

enters the cells [23]. Because patients with hypertension, diabetes and

coronary heart disease have higher levels of ACE2 protein, it is not sur-

prising that these health conditions are at risk for COVID-19 [9]. A study

has shown that COVID-19 patients with these conditions have higher

viral load and relatively more loss of epithelial cells with ACE2 expres-

sion [10]. On the other hand, the binding of SARS-CoV-2 spike proteins

to ACE2 receptor can block the breakdown of ANG II proteins by ACE2,

consequently leading to cell damage and inﬂammation [21]. Kuba et al.

demonstrated that reduction of ACE2 expression by the injection of

SARS-CoV spike protein into mice worsened acute lung failure in vivo,

which could be attenuated by interrupting the renin-angiotensin

pathway [24]. However, it is unclear whether the prevalent phenome-

non exists in SARS-CoV-2 infection, although both SARS-CoV and

SARS-CoV-2 are the members of coronavirus family.

In addition to ACE2, another potential molecular mechanism was

recently reported. Zhang et al. demonstrated that generation of multi-

nucleate syncytia was prevalently in the lung tissues of COVID-19 pa-

tients [25]. The authors further demonstrated that a few of human

CD45

cells were enclosed in the special structure of multinucleate

syncytia. They also found a negative correlation between the number of

both syncytia and syncytia containing CD45

cells and the number of

peripheral blood lymphocytes. Their ﬁndings conﬁrmed that the multi-

nucleate syncytia internalize human CD45

cells [25]. Consequently,

internalization of human CD45

cells in the multinucleate syncytia in

COVID-19 patients may be responsible for lymphocytopenia [25].

Microthrombosis is an exclusive clinical feature of COVID-19, and it

was found in 91.3% of dead patients [26]. Microthrombi formation oc-

curs mainly in the pulmonary vasculature but can also occur in other

organs [27]. The disruption of the local reninangiotensin system, endo-

thelial injury (mostly DAD), the complement cascade activation and

powerful thromboinﬂammatory reactions can profoundly result from

entry of the SARS-CoV-2 into microvessels [28]. Particularly, microvas-

cular plugging, ischemia and ultimately organ failure might be led by the

induction of von Willebrand factor [28]. The production of membrane

attack complex (MAC) and culminating in acquired ARDS attribute to the

activation of three complement pathways [29]. Through either direct

Figure 1. Reported COVID-19 cases and death daily worldwide and in the US in the past two weeks. These data are from the Center for Systems Science and En-

gineering (CSSE) at Johns Hopkins University. A. New reported COVID-19 cases globally by day, this number is decreased by 10%. B. New reported death globally by

day, this number is decreased by 8%. C. Cumulative conﬁrmed COVID- 19 death worldwide. D. The conﬁrmed new cases increased by 20% daily in USA. E. New

hospitalized cases daily increased by 14% in USA. F. New death increased by 3% daily in USA.

L. Yao et al. Heliyon 8 (2022) e09302

action on platelets and the endothelium or indirect effects of inﬂamma-

tion and coagulopathy, COVID-19 can lead to increased thrombus for-

mation, emboli and hemorrhage [11]. Zhang et al. demonstrated that

platelets can be directly activated by the binding of SARS-CoV-2 spike

protein to ACE2 receptor [30]. Thus, thrombus formation and inﬂam-

matory responses can be further promoted in COVID-19 patients [30]. In

addition, neutrophil extracellular traps trigger thromboinﬂammation in

patients with COVID-19 [12], which leads to vascular thrombosis and

then death.

Aggressive inﬂammatory response and its related hypercoagulability

was found in association with disease severity in patients with COVID-19

and poor outcomes [31]. The exact relationship between the levels of

ACE2, infectivity of SARS-CoV-2, and severity of infection, however, are

not well illustrated [12]. Burki et al. also pointed out that when

COVID-19 cases progress to severe disease and death, men are at a sub-

stantial disadvantage [32]. Evidence from a large study shows that men

have higher concentrations of ACE2 in the blood than women [33,34].

Other factors may include gender behavior (i.e., higher rates of drinking

and smoking among males compared to females), and attitude (i.e., more

females are responsible and more cautious regarding the pandemic than

males) [35]. In addition, sex chromosome genes and hormones (i.e., es-

trogens, progesterone and androgens) contribute to the differential

regulation of immune responses between the sexes [36]. Females have 2

copies of X chromosomes that contain genes related to immune response

and gene silencing, while males only have 1 copy [37]. These genes can

inﬂuence the immune system through regulating many other proteins

(e.g., TLR8, CD40L and CXCR3) that are overexpressed in females, as well

as inﬂuence the response to viral infections and vaccinations [37].

In summary, the characteristics of COVID-19 pathogenesis include

damage of endothelial cells, activation of platelet, thrombogenesis, blood

coagulation disorder, and failure of multiple organs [38,39]. Besides the

respiratory system, cardiovascular, gastrointestinal and renal abnormal-

ities have also been injured [40]. These changes are summarized in

Figure 2.

3. Immunological features of COVID-19

The role of innate and adaptive immunities has not been fully

explored in COVID-19. To date, scientists have mainly focused on

adaptive immunity that are carried out by lymphocytes [41]. Among

patients who died of COVID-19-related respiratory failure, it was found

that DAD with perivascular T-cell inﬁltration was the typical histological

pattern in the peripheral lung [42]. T cell inﬁltration is characterized by

CD4

and CD8

T lymphocytes, which are predominantly distributed in

interstitial spaces, larger bronchioles, and perivascular areas [14]. In

addition to these T cells, CD61

megakaryocytes were also notably

found, which were located within alveolar capillaries, actively producing

platelets [43].

A common feature in severe COVID-19 patients is lymphopenia, but

not in mild cases, which are characterized by drastic reduction of im-

mune cells including CD4

T cells, CD8

T cells, B cells, natural killer

(NK) cells, and a decreased proportion of monocytes, eosinophils, and

basophils [44,45]. In contrast, a gain in neutrophil cell count and the

ratio of neutrophil to lymphocyte are found in association with more

severe disease and poorer clinical outcome [46]. These abnormal

changes are restored in the recovered patients [47].

Cytokine release syndrome (CRS) is an acute systemic inﬂammatory

syndrome caused by a sudden and acute increase of different pro-

inﬂammatory cytokines including IL-6, IL-1, TNF

, and interferon in

circulation [48]. The increased levels of cytokines result in converging of

immune cells from circulation to the infection sites, lead to destructive

effects on human tissues, which include instability of the interactions

among endothelial cells, damages of diffuse alveoli, vascular barrier,

capillaries, and multi-organ failure [49]. Lung injury is one of the con-

sequences of cytokine storm, which can progress to acute lung injury or

more severe ARDS [50]. In general, severely CRS is life threatening,

while mild patients with CRS have the symptoms of fever, nausea,

headache, rash, rapid heartbeat, low blood pressure, and difﬁculty in

breathing [51]. Cytokine storm induced-vascular endothelial injury

mediates hypercoagulability in blood vessels and disseminated intra-

vascular coagulation (DIC) [52].

ARDS is a major complication of severe COVID-19 patients [53].

Some studies have showed that the overall mortality rate from ARDS in

COVID-19 patients was 39% (95% CI: 23–56%) [54], it was 69% (95%

CI: 67–72%) in China, 73% in Poland (95% CI: 58–86%), while it was

13% (95% CI: 2–29%) in Germany [6,54]. Risk factors such as older age,

increased neutrophils, elevated lactate dehydrogenase and D-dimer

levels increase the risk of ARDS and death in those patients hospitalized

with COVID-19 [6,55].

ARDS is the prominent immunopathological feature [6,46]. Among

the patients with SARS-CoV-2 infection, severe inﬂammation in lung may

lead to dysregulation of the renin-angiotensin pathway, which then

progressed to ARDS [56]. Cytokine storm is an essential mechanism of

ARDS along with unregulated systemic inﬂammatory stimulus [57].

Nearly 20% of COVID-19 patients experiencing acute kidney injury (AKI)

and ARDS are related to the cytokine storm [52].

A distinct difference of cytokines, chemokines, and additional im-

mune markers has been found between healthy adults and COVID-19

patients at levels from moderate to severe [58]. Several studies have

indicated that the increased levels of serum proinﬂammatory cytokines

were associated with pulmonary inﬂammation, and lung and organ

failure in COVID-19 disease. It was reported that serum levels of IL-1Ra,

IL-1β, IL-7, IL-8, IL-9, IL-10, FGFβ, G-CSF, GM-CSF, IFNγ, IP10, MCP1,

MIP1A, MIP1B, PDGF, TNF

, and VEGF concentration were higher in the

COVID-19 patients at both intensive care unit (ICU) and non-ICU than it

in healthy adults [59,60,61]. In contrast, the serum levels of IL-5,

IL-12p70, IL15, Eotaxin, and RANTES (a chemokine, also known as

CCL5) are similar between COVID-19 patients and healthy adults [59,

62]. Further study showed that plasma concentrations of IL-2, IL-7, IL-10,

G-CSF, IP10, MCP1, MIP1A, and TNF

in the ICU patients with COVID-19

are higher than those in non-ICU COVID-19 patients [57]. To investigate

the difference in cytokines, chemokines, and other immune markers

between the COVID-19 patients with moderate and severe disease, Lucas

et al. conducted a longitudinal study to determine the correlation of these

soluble proteins in the patients [63]. The results showed that patients in

the groups of both moderate and severe COVID-19 shared a “core

COVID-19 signature”deﬁned by the inﬂammatory cytokines, which

positively correlated with each other, including IL-1

, IL-1β, IL-17A,

IL-12 p70, and IFN

. In the severe patients with COVID-19, other in-

ﬂammatory factors were observed and deﬁned, which are thrombo-

poietin (TPO), IL-33, IL-16, IL-21, IL-23, IFNλ, eotaxin and eotaxin 3.

These CRS-associated cytokines (e.g., IL-1

, IL-1β, IL-6, IL-10, IL-18, and

TNF) are positively correlated with severe disease in patients [63].

Overall, cytokine storm contributes to a poor prognosis [64].

4. Pathological changes and damages

Although COVID-19 mainly affects the respiratory systems, other

systems are also affected, which include cardiovascular, urinary, nervous

system and gastrointestinal tract, etc. [65]. Pathological analyses play a

crucial role in elucidating the pathogenesis of COVID-19, and autopsies

have provided many valuable direct insights of pathological changes

[66].

4.1. Lung

The lung is the main site of injury for SARS-CoV-2 infection [67].

Bilaterally infected lungs show edema and maroon in color, weighing 2–3

times as much as normal lungs (1939 vs. 685–1050 g [68,69,70]. All the

severely infected lungs showed varying degrees of consolidation, pre-

dominantly located at the borders of lobes [70,71]. Many viscous se-

cretions are seen in the section of lung in response to SARS-CoV-2 [43].

L. Yao et al. Heliyon 8 (2022) e09302

Pulmonary pathological examination revealed thrombus and micro-

angiopathy in pulmonary small vessels and capillaries, accompanied by

hemorrhage [72]. Other studies also showed severe endothelial injury,

disrupted cell membranes and microthrombi, as well as lymphocytic

interstitial inﬂammation and reactive pneumocyte hyperplasia in the

lung [73]. Thrombosis in pulmonary arteries is associated with hemor-

rhagic lung infarction, and it is found in 20–30% of lethal courses [74].

However, venous thromboembolism is more common than arterial

thromboembolism in hospitalized COVID-19 patients [75].

Acute pulmonary infection caused by COVID-19 has distinct char-

acteristics of acute interstitial pneumonia with DAD components,

microvascular involvement of ﬁbrin deposition and intravascular cap-

ture of neutrophils, as well as microthrombus formation in arterioles

[4,13]. Severe patients presented with ventilation/perfusion imbalance

and respiratory failure emerge [76]. Some patients with respiratory

insufﬁciency present with exudative DAD, accompanied by hyaline

membrane formation [13] and pneumocyte type 2 hyperplasia, which

can progress to DAD at the stage of organization/ﬁbrosis [72,77]. Firm

thrombi in the peripheral pulmonary vessels along with DAD, have

been the most consistent feature of COVID-19-related lung pathology

[78].

Pulmonary ﬁbrosis, a symptom of ARDS, is the most severe change in

the lung [79]. Some patients develop ﬁbrosis [74], which is usually

associated with severe lung injury, permanent pulmonary structural

distortion, and irreversible pulmonary dysfunction [80]. The potential

mechanism underlying SARS-CoV-2-induced pulmonary ﬁbrosis include

(i) pulmonary ﬁbrosis is a known sequela to ARDS, 40% of COVID-19

patients develop ARDS, 20% of ARDS cases are severe, (ii) the levels of

TGF-β, TNF-

, IL-6, etc. in peripheral blood of severe patients were

increased [81].

Figure 2. Organs affected by COVID-19. When SARS-COV-2 particles enter human body through the respiratory tract, they bind to the ACE2 receptors that are

expressed in multiple organs. With the activation of the immune system, inﬂammation occurs leading to endothelial cell injury, especially the damage of DAD,

resulting in the formation of microthrombosis, ARDS and multiple organ failure via virus, cytokine storm, hypoxia and microthrombosis. IL-6 causes subacute

thyroiditis. SARS-CoV-2 can also cause brain lesions and eye conjunctivitis. In addition to ACE2, individual factors including genetics, immune response, healthy

status, and age also need to be considered in the disparity of COVID-19, and the heterogeneity of COVID-19 manifestations.

L. Yao et al. Heliyon 8 (2022) e09302

4.2. Kidney damage

Acute kidney injury (AKI) is one of the most common and most severe

organ complications of COVID-19, which seriously affects the mortality

of patients [82]. Approximately 30% of COVID-19-related deaths had

AKI [83]. Another study showed that 27% of the COVID-19 patients

exhibited AKI [84]. COVID-19 patients with AKI had a three-fold higher

death risk than those without AKI [85]. The ICU/severe patients had

about 30 times higher risk of AKI compared to the non-ICU/severe cases

[86]. Chronic diseases, including hypertension and diabetes, are another

risk factors for kidney damage associated with COVID-19 [87].

SARS-CoV-2 particles has been identiﬁed in renal tissue [88,89,90], this

discovery suggested that human kidneys were directly infected by

SARS-CoV-2, leading to pathogenesis of renal tubules and AKI [84].

Nearly 20% of patients experiencing AKI are caused by cytokine storm

[52]. In most cases, the kidneys display acute tubular injury, with the

characteristics of lymphocyte depletion in the lymph nodes spleen, and

hyperplastic adrenal glands [74], while CD68

macrophages inﬁltration

into the tubule-interstitium are observed [84]. The patients present

abnormal renal functions such as increased serum creatinine (sCr), blood

urea nitrogen (BUN), D-dimer, proteinuria, and hematuria [86].

Renal changes include ﬁne granular kidneys and focal cortical scars

[91]. These changes were caused by arteriolosclerosis, mesangial scle-

rosis, hypercellularity, and focal global glomerulosclerosis [91]. How-

ever, no inﬂammatory or ischemic changes were found in the medulla

section [91]. An occasional adrenal cortical nodule and a papillary thy-

roid adenocarcinoma were also detected [91]. COVID-19 patients

develop extensive glomerular and tubular diseases [92]. Acute renal

tubular injury is the most common type of injury in both live kidney

biopsies and autopsy [93].

In summary, current evidences suggest that the causes of renal injury

in patients with COVID-19 include hypovolemia, ARDS associated

cytokine storm, and direct viral invasion as seen on renal autopsy

ﬁndings [94]. COVID-19 may leave people with lasting damage to their

kidneys, among many other organs. The possibilities are the most likely

due to: (1) presence of ACE2 receptors in kidney cells allowing

SARS-CoV-2 to bind them, invade, potentially damaging kidney tissues;

(2) too little oxygen in blood causes kidneys to malfunction, (3) cyto-

kine storms destroy kidney tissue; and (4) tiny clots form in the

bloodstream, blocking the smallest blood vessels in the kidney and

impairing renal function.

4.3. Neurologic disorder

Some COVID-19 patients may develop cerebral edema, neuronal

degeneration, encephalitis, meningoencephalitis, acute disseminated

encephalomyelitis, Guillain-Barr

e Syndrome, Bickerstaff's brainstem en-

cephalitis, Miller Fisher syndrome, polyneuritis, myositis/rhabdomyol-

ysis, toxic encephalopathy, and stroke [95].

An autopsy report revealed the presence of SARS-CoV2 particles in

the brain tissues of a COVID-19 patient [96]. SARS-CoV-2 has been

detected in both the cerebrospinal ﬂuid (CSF) and brain parenchyma of

many patients [97]. Brain tissue oedema and partial neurodegeneration

have also been observed [98], showing increased weight (~1221 g) and

hydrocephalus ex vacuo [91]. The pathological changes in brain prob-

ably show the consequence of both direct cytopathic effects due to

SARS-CoV-2 replication and indirect effects such as respiratory failure,

injurious cytokine reaction, reduced immune response and cerebrovas-

cular accidents caused by viral infection [99].

The brainstem is another part infected by SARS-CoV2 in CNS. Au-

topsy studies provide evidence for the presence of SARS-CoV-2 RNA and

proteins in the brainstem [100]. ACE2 receptor expression is relatively

higher in the brainstem than in other brain regions [100]. In addition,

another receptor of SARS-CoV-2 named neuropilin-1 is also expressed in

the brainstem [101]. Moreover, the brainstem is susceptible to damages

derived from either pathological immune or vascular activation [100].

Therefore, patients with encephalitis, encephalomyelitis, and brainstem

encephalitis recover slowly and have a high mortality rate [102].

4.4. Heart damage

The heart is one of the most common organs affected by COVID-19;

however, the nature and scope of cardiac pathology has been contro-

versial [103]. A study reported that cardiac histopathological ﬁndings

associated with COVID-19 are very common, but myocarditis is rare

(<2%) [104]. Another study reported that the existence of SARS-CoV-2

in the myocardium was found in 47% of 316 deceased with COVID-19

[105], while cardiac pathological changes contributed to the death of

4.7% (15/316) cases [105]. Furthermore, postmortem examination

demonstrated other pathological changes including cardiac dilatation

(20%), acute ischemia (8%), intracardiac thrombi (2.5%), pericardial

effusion (2.5%), and myocarditis (1.5%) [105]. Myocardial pathological

examination revealed hypertrophy of myocardial cells with interstitial,

and perivascular ﬁbrous tissue, but no acute ischemic changes or in-

ﬂammatory inﬁltration were observed [106]. Moreover, Zhou et al. re-

ported that 48 % of the patients (91/191) with COVID-19 had

comorbidities. Hypertension is the most common comorbidity (58/191,

30%), followed by diabetes (36/191, 19%) and coronary artery disease

(15/191, 8%) [107].

Troponin is a marker of cardiomyocyte damage or injury. The ma-

jority of patients with an acute myocardial infarction have an elevated

troponins within 2–3h[108]. In the case of COVID-19, myocardial injury

can occur, which is deﬁned as elevated troponin level [109]. Among the

patients in ICU, the levels of cardiac troponin are signiﬁcantly higher in

those with more severe infections [110]. Overall, the potential mecha-

nisms of myocardial tissue damage include direct myocardial injury

caused by SARS-CoV2 (i.e., viral myocarditis), systemic hyper-

inﬂammatory response (i.e., CRS), hypoxemia, downregulation of ACE2,

endothelialitis induced by systemic virus, and myocardial infarction

[111].

4.5. Liver damage

More than 1/3 patients with COVID-19 develop liver damage that is

manifested by increased liver enzymes [112]. SARS-CoV-2 is mostly

considered unlikely to cause liver infection because ACE2 expression is

very low in liver cells. In the individuals with increased aminotransfer-

ases, autopsy liver biopsies were randomly obtained. Surprisingly, typical

coronavirus particles with spike structures were found in the cytoplasm

of liver cells in the patients with COVID-19 [113].

The distribution of ACE2 receptors is generally considered to be

consistent with the distribution of infected organs [114]. However, the

presence of ACE2 expression was signiﬁcantly inconsistent with multiple

organs targeted by SARS-CoV-2. Therefore, it is speculated that another

Extra-ACE2 receptor or co-receptor may exists. Another possibility is that

ACE2 expression in hepatocytes may be upregulated in response to viral

invasion [115]. Analysis of ACE2 expression in

post-SARS-CoV-2-infection hepatocytes will be interesting and helpful to

untangle this inconsistence.

A meta-analysis of 18 studies from 7 countries showed that the

combined prevalence of liver histopathological ﬁndings was: hepatic

steatosis 55.1%, hepatic sinus congestion 34.7%, vascular thrombosis

29.4%, ﬁbrosis 20.5%, Kupffer cell hyperplasia 13.5%, portal vein

inﬂammation 13.2%, and lobular inﬂammation 11.6% [116]. In addi-

tion, venous outﬂow obstruction, portal vein sclerosis, portal vein her-

niation, abnormal periportal vessels, hemophagocytosis, and necrosis

were also found [116]. In summary, the high prevalence of hepatic

steatosis and vascular thrombosis are the major histological features of

the liver in COVID-19 patients [116]. The liver steatosis, liver cell ne-

crosis, portal inﬂammation, and proliferation of Kupffer cells are also

very common [74].

L. Yao et al. Heliyon 8 (2022) e09302

During the clinic evaluation of COVID-19, liver injury has been

observed in a large number of patients, especially in those who are in

severe or critical conditions. The pathologic changes reported were a

slight increase in sinusoidal lymphocytic inﬁltration, sinusoidal dilata-

tion, steatosis and multifocal hepatic necrosis [117].

4.6. Thyroid damage

SARS-CoV-2 infects host cells with ACE2-binding TMPRSS2 as the key

molecular complex. Interestingly, ACE2 and TMPRSS2 were expressed at

higher levels in the thyroid glands than in the lungs [118]. Subacute

thyroiditis is a thyroid disease of viral or post-viral origin. A study re-

ported that about two-thirds (66.7%) of COVID-19 patients developed

subacute thyroiditis among 27 cases, including 11.1% of the COVID-19

patients required hospitalization, and 83.3% of the cases had subacute

thyroiditis after COVID-19 [119]. Accordingly, patients who develop

thyroid inﬂammation during acute COVID-19 may develop subacute

thyroiditis months later, even after thyroid function has returned to

normal.

COVID-19 may be associated with a high risk of hyperthyroidism

associated with systemic immune activation caused by the SARS-CoV-2

infection, and thus plays a pivotal role in inducing hyperthyroidism of

Graves’disease [120]. On this point, Lania et al. demonstrated that hy-

perthyroidism was signiﬁcantly associated with higher IL-6 levels [121].

Similarly, another study showed that 75% of COVID-19 patients devel-

oped thyroid abnormalities and higher IL-6 levels (P<0.01) [122]. Thus,

there are several potential thyroid outcomes in patients with COVID-19,

such as thyrotoxicosis, low-T3 syndrome and subacute thyroiditis [123].

Taken together, COVID-19 are negatively impacting the thyroid. How-

ever, further investigations are required to validate the causal relation-

ship between subacute thyroiditis and COVID-19.

4.7. Gastrointestinal tract

Considering that gastrointestinal epithelial cells express ACE2, SARS-

CoV-2 may also affect gastrointestinal tract. Mao and colleagues reported

that 15% of the patients with COVID-19 had gastrointestinal symptoms,

and the typical gastrointestinal symptoms were nausea, vomiting, diar-

rhea, and anorexia [124]. In addition, intestinal involvement of

COVID-19 can be associated with intestinal ischemia, caused by shock or

local thrombosis [74].

4.8. Eyes

Conjunctivitis is the most common type of eye infection among

COVID-19 patients [125]. SARS-CoV-2 particles were found from

conjunctival swabs and tears of COVID-19 patients, additionally,

SARS-CoV-2 RNA was detected in conjunctival, anterior corneal, poste-

rior corneal, and vitreous from the deceased with COVID-19 [126]. In a

case series report from the patients with COVID-19, some of them had

ocular manifestations, including epiphora, conjunctival congestion, or

chemosis [127]. This positive SARS-CoV-2 ﬁnding is common in severe

COVID-19 patients. RT-PCR results of nasopharyngeal swabs and

conjunctival swabs were positive for SARS-CoV-2, blood test results

showed signiﬁcant value changes among the COVID-19 patients with

ocular abnormalities [128]. In addition, the presence of SARS-CoV-2

RNA on ocular surface suggests that the eye may be a site of viral repli-

cation [129]. SARS-CoV-2 proteins (e.g., spike and envelope proteins)

were identiﬁed in the corneal epithelium undisinfected with

povidone-iodine (PVP–I) [126].

5. Complications

Most COVID-19 patients can recover within 2–6 weeks. But some of

them still have symptoms after recovery. COVID-19 patients can expe-

rience multiple complications during infection. About 1 in 6 people with

COVID-19 will develop complications, which can be life-threatening. The

result of a cohort demonstrated that COVID-19 survivors mainly had

fatigue, muscle weakness, sleep difﬁculties, anxiety, depression, adjust-

ment disorders, and tic disorders. During hospitalization, patients with

severe COVID-19 had severely impaired pulmonary dispersion and

abnormal chest imaging ﬁndings [130]. Another report indicated that

80% of the COVID-19 patients developed one or more long-term symp-

toms. The top ﬁve most common symptoms were fatigue (58%), head-

ache (44%), attention disorder (27%), hair loss (25%), and dyspnea

(24%) [131].

According to the pathogenesis, pathological and immunological

changes, these complications may include acute respiratory failure,

pneumonia, ARDS, acute liver injury, acute myocardial injury, acute

kidney injury, secondary infection, septic shock, DIC, blood clots, multi-

system inﬂammatory syndrome in children, chronic fatigue, and rhab-

domyolysis may adversely affect the prognosis. Some complications may

be unanticipated. In severe cases of COVID-19, cytokine storm-induced

thrombotic complications including DIC are a prominent feature [78].

5.1. Pulmonary complications

Reported complications of COVID-19 include long period damage to

tiny air alveoli in the lungs and the resulting scar tissue, which can lead to

long-term breathing problems. About 30–40% of COVID-19 hospitaliza-

tion and nearly 70% of fatal cases develop ARDS [132]. ARDS occurs in

42% of COVID-19 patients, and 61–81% of the patients required inten-

sive care [55].

5.2. Cardiac concerns

Imaging tests taken months after recovery from COVID-19 showed

that even people with only mild symptoms of COVID-19 suffered lasting

damage to the heart muscle. This damage can be caused by the formation

of blood clots in both large and tiny vessels. This could increase the risk of

heart failure or other cardiac complications in the future. Data on long-

term cardiovascular complications of COVID-19 are scarce. However, it

can be learned from the experience of dealing with other types of

myocardial injury. In a follow-up study of patients with acute myocarditis

(mean age 40.2 years), the authors noted that the rate of hospitalization

associated with heart failure ranged from 6% to 8% [133]. Patients with

viral myocarditis may be associated with COVID-19 related myocarditis

and/or ﬁbrosis due to inﬂammation (regional or local) associated with

acute disease.

5.3. Brain

While SARS-CoV-2 virus mainly targets the respiratory system, pa-

tients and survivors of COVID-19 can also experience neurological

changes and develop neurological and psychiatric symptoms. SARS-CoV-

2 bind directly to the cells in neural tissue [95]. 73% of hospitalized

COVID-19 patients had neurological symptoms, mainly headache, my-

algias and impaired consciousness [134]. These symptoms including

anosmia, hypogeusia, headache, nausea and altered consciousness are

very common, but more severe and speciﬁc conditions have also been

clinically reported, such as acute cerebrovascular accident, encephalitis,

and demyelinating disease. Even in young people, COVID-19 can also

cause strokes, seizures, and Guillain-Barre syndrome according to Mayo

Clinic. Additionally, COVID-19 may also raise the risk of suffering Par-

kinson's disease and Alzheimer's disease.

The manifestation in central nervous system (CNS) is caused by direct

viral invasion of CNS or by indirect mechanisms [99]. Studies have

shown that SARS-CoV-2 can get access into CNS through olfactory nerves

and even stretch to the medulla. The virus impairs CNS through either

direct viral damage or immunopathological damage to nerve cells.

Neurological symptoms involving the CNS can lead to acute or longer

period consequences [135]. Wyss-Coray and colleagues compared

L. Yao et al. Heliyon 8 (2022) e09302

samples of the frontal cortex and choroid plexus from control and

COVID-19 patients, they observed extensive cellular perturbations, with

T cell inﬁltrating into the parenchyma. They identiﬁed subpopulations of

microglia and astrocyte associated with COVID-19 disease that share

genetic signatures with pathological cell states in human neurodegen-

erative disease, such as cognitive disorders, schizophrenia, and depres-

sion [136]. These ﬁndings may help to interpret the symptoms of brain

fog, fatigue, and other neurological and psychiatric symptoms.

5.4. Kidney

Kidney complications are relatively common. As above mentioned,

AKI is a lethal complication in COVID-19 patients [137]. In addition,

rhabdomyolysis is also a fatal syndrome caused by the breakdown of

skeletal muscle ﬁbers and leakage of muscle contents into the systemic

circulation. However, this can lead to serious complications of renal

failure. A study has reported rhabdomyolysis in 10 COVID-19 patients

[138].

6. Sequelae or long-standing effects of COVID-19

Much remain unknown about the long period effects of COVID-19 on

human health. Sequelae of SARS-CoV-2 infection include fatigue, dys-

pnea, chest pain, cognitive impairment, joint pain, and reduced quality of

life [139]. Daugherty et al. reported that 14% of the adult patients (65

years) with COVID-19 had at least one clinical sequelae. These sequelae

including chronic respiratory failure, cardiac arrythmia, hypercoagula-

bility, encephalopathy, peripheral neuropathy, amnesia, diabetes,

abnormal liver function tests, myocarditis, anxiety, and fatigue need

medical care after passing through the acute phase of COVID-19 [140].

SARS-CoV-2 infection-induced cellular damage, a strong innate immune

response that produces inﬂammatory cytokines, and a pro-coagulant

state may contribute to these sequelae [141,142]. COVID-19 infection

can cause lasting damage to kidneys.

Close monitoring of the COVID-19 patients is recommended to un-

derstand the function of their organs after recovery. Many medical cen-

ters are going to set up and open specialist clinics to provide better cares

for the individuals who have persistent symptoms or related illnesses

after recovering from COVID-19. In general, most COVID-19 patients

recover quickly; however, the potential long standing problems make it

more important in addition to reduce the spread of COVID-19. Extreme

fatigue with sleep changes, post-exercise nerve failure, multiregional

cognitive dysfunction, persistent headache, demyelinating syndromes,

peripheral neuropathy, and autonomic nervous instability are notable

features of post-viral syndromes; similar concerns exist for people with

persistent symptoms of COVID-19 [9]. Currently, there is no curative

treatment for post-viral syndromes. The aim of treatment is symptomatic

treatment to relieve symptoms.

6.1. Problems with mood, fatigue, and chronic brain disorders

Patients with severe COVID-19 who are admitted to an ICU might

experience mechanical assistance for breathing. The patients who had

ventilator-aid experience are more likely to experience post-traumatic

stress syndrome, depression, and anxiety. Early intervention should

begin to reduce the risk for posttraumatic stress syndrome (PTSS) after

hospitalization [143]. In addition, an extensive cellular perturbation was

discovered in the brains of COVID-19 patients, may be due to inﬂam-

mation caused by the infection. T cell inﬁltration was observed in the

parenchyma, and these disturbances overlap with chronic cognitive

impairment, schizophrenia, and depression [87].

6.2. Clots in blood vessel

SARS-CoV-2 infection makes blood cells at high risk of clotting and

forming blood clots in many organs (e.g., lungs, heart, legs, liver, and

kidneys, etc.). While large clots can cause heart attacks and strokes,

smaller clots can damage heart by blocking capillaries in cardiac muscle.

COVID-19 can also damage the lining of blood vessels, resulting in vessel

leaking, and potentially long-term issues with both the liver and kidneys.

A previous study reported that blood clots in the veins occurred in 20% of

the COVID-19 patients, and in 31% patients in the ICU. Clots in vein or

thrombosis in deep vein can circulate to the lungs and form pulmonary

embolism, which consequently result in higher risk of death. An ampu-

tation may be needed if the clots are not treated timely with either a

surgical or interventional treatment [144].

7. Prevention and immunological memory

Isolation and quarantine of infected individuals are effective ap-

proaches in controlling respiratory infectious diseases aside from vacci-

nation of susceptible persons. Nevertheless, a key blind spot in the

pandemic is asymptomatic infection in the community and pre-

symptomatic viral transmission, which posed a major barrier in halting

the spread of the virus. Although large-scale screening with RNA detec-

tion or rapid antibody detection are helpful in identifying these potential

infection sources; however, society and economic costs are huge.

The publication of SARS-CoV-2's genome sequence has accelerated

the development of vaccines, particularly novel RNA vaccines [145]. As

of Aug. 31, 2021, WHO has authorized the following COVID-19 vaccines

for emergency use (EUA). All the vaccines under EUA (1–7) together with

2 more with rolling data submission (8–9) were summarized in Table 1.

As of Nov. 23, 2021, 132 vaccines are still in clinical development and

194 vaccines are in pre-clinical development according to WHO (https://

www.who.int/publications/m/item/draft-landscape-of-covid-19-candi

date-vaccines). Novel delivery systems are under developing, for

example, exosomes-mediated mRNA delivery [146], and exosomes car-

rying immunogenic viral peptides from COVID-19 patients (www

.covidx.eu/exocovac).

mRNA vaccine (e.g., BNT162b/Pﬁzer, or mRNA-1273/Moderna) uses

genetically engineered mRNA derived from S-protein of SARS-CoV-2 and

it is delivered through lipid nanoparticles. Once the mRNA vaccine is

administered, the lipid nanoparticles encapsulated mRNA are taken up

by cells. The mRNA is then translated into the S-protein within the

recipient cell cytoplasm. S-protein are next transported to the cytoplasm

and cell membrane of the host cells. The S-protein can be recognized by

the innate immune cells including NK cells, eosinophils, etc. and

phagocytic cells (macrophages, neutrophils, and dendritic cells) for an-

tigen presentation; adaptive immune cells (T- and B cells) are then trig-

gered to recognize and memorize how to attack the virus that causes

COVID-19 if infected again in the future.

Protein vaccines (e.g., inactivated cronavac/Sinovac and Sinopharm)

include harmless protein pieces, which are derived from SARS-CoV-2.

After vaccination, the immune system recognizes the proteins. B cells

produce antibodies and T-lymphocytes recognizes and memorize the

proteins, and therefore attack the virus once invaded in the future.

Vector-based vaccines (e.g., Ad26.COV2. S/Johnson &Johnson) use a

modiﬁed version of a different virus as a vector to deliver the nucleic acid

coding S-protein to the recipient's host cells. Once administrated, the host

will build immune responses including T- and B-lymphocytes.

Duration of immunological memory (memory B cells, memory T cells

including CD4þT cells, and/or memory CD8þT cells, as well as anti-

bodies) after SARS-CoV-2 infection is unclear. Many COVID-19 patients

will probably make life time antibodies against SARS-CoV-2 [147].

Because Turner et al. recently reported that long-lived anti-

body-producing cells (plasma cells) were identiﬁed in the bone marrow

from the patients who recovered from COVID-19 [148,149]. These

people infected with SARS-CoV-2 induce robust antigen-speciﬁc, long--

lived humoral immune memory [148]. Another study investigated

immunological memory by measuring the titer of antibodies against

SARS-CoV-2 speciﬁc antigens, and immune cells in the blood. The results

demonstrated that 95% of subjects remained immunological memory for

L. Yao et al. Heliyon 8 (2022) e09302

8 months since infection [150]. Another similar study showed speciﬁc

immunological memory for 5 months after recovery [151]. In addition, a

very recent study reported that unvaccinated people should have im-

munity against reinfection for 3–61 months after getting infected with

COVID-19 [152]. A further study has demonstrated that SARS-CoV-2

antibodies remain stable for at least 7 months after an infection with

the virus [153]. The relatively short immunological memory suggests

that COVID-19 infection-induced immune memory will not last too long.

Similarly, COVID-19 vaccine-induced immune memory may have a

similar situation, suggesting that people may need the fourth dose as a

booster. Before the rollout of a large-scale of booster vaccination, it is a

priority to understand who need the booster vaccination, how the

booster vaccination affects long period health, and how long the

immunological memory lasts for the booster vaccination.

Breakthrough and second infection of COVID-19 indicate that it is

unknown what antibody levels are able to prevent reinfection and how

Table 1. Status of COVID-19 vaccines within WHO EUA.

Vaccine Brand Vaccine Name Vaccine Types/Platform EOI

Accepted

EUA Date Age to get

vaccines

Doses Interval

1Pﬁzer-BioNTech BNT162b2 Nucleoside modiﬁed

mRNA

Yes Dec. 31, 2020 12 years 3 shots 3 weeks for

the ﬁrst 2 doses,

6 months for

the booster

2 Moderna mRNA-1273 mRNA encapsulated in

lipid nanoparticle (LNP)

Yes Apr. 30, 2021 18 years 3 shots 4 weeks for

the ﬁrst 2 doses,

6 months for

the booster

3 Janssen Ad26.COV2. S Vectored vaccine

encoding the (SARS-CoV-

2) Spike (S) protein

Yes Mar. 12, 2021 18 years 2 shot 2 months after

completing the

primary

vaccination

4 Astrazeneca-Oxford

University

AZD1222 Adenoviral vector

encoding the Spike

protein antigen of the

SARS-CoV-2

Yes Apr. 16, 2021 18 years 2 shots 4 weeks

5 Serum Institute

of India

Covishield

(ChAdOx1_nCoV- 19)

Adenoviral vector

encoding the Spike

protein antigen of the

SARS-CoV-2

Yes Feb. 15, 2021 18 years 2 shots 8–12 weeks

6 Sinopharm SARS-CoV-2 Vaccine

(Vero Cell), Inactivated

(lnCoV)

Inactivated, produced in

Vero cells

Yes May 7, 2021 18 years 2 shots 2–4 weeks

7 Sinovac COVID-19 Vaccine (Vero

Cell), Inactivated/

Coronavac

Inactivated, produced in

Vero cells

Yes Jun. 1, 2021 18 years 2 shots 2–4 weeks

8 The Gamaleya

National Center

Sputnik V

Russian MRNA, Human

Adenovirus Vector- based

Covid-19 vaccine

Additional

information

submitted

Rolling submission

of clinical and CMC

data has started.

Anticipated date will be

set once all data is submitted,

and follow-up of inspection

observations completed.

18 years 2 shots 3 weeks

9 Bharat Biotech,

India

SARS-CoV-2 Vaccine,

Inactivated (Vero Cell)/

COVAXIN

DCGI, Whole-Virion

Inactivated Vero Cell

Yes Rolling data started

06 July 2021. Decision

date: To be conﬁrmed.

12 years 2 shots 4–8 weeks

Abbreviation: WHO: The World Health Organization; EUA: Emergency Use Authorization; EOI: Expression of Interest; DCGI: the Drugs Controller General of India.

Table 2. SARS-CoV-2 variants of concern (VOC).

Bango Lineage Name WHO Label First Identiﬁed Spike Protein Substitutions

B.1.1.7 Alpha United Kingdom 69del, 70del, 144del, (E484K*), (S494P*), N501Y,

A570D, D614G, P681H, T716I, S982A, D1118H (K1191N*)

B.1.351

B.1.351.2, B.1.351.3

Beta South Africa D80A, D215G, 241del, 242del, 243del, K417N, E484K,

N501Y, D614G, A701V

B.1.617.2

AY.1, AY.2, AY.3, AY.4,

AY.5, AY.6, AY.7, AY.8,

AY.9, AY.10, AY.11, AY.12

Delta India T19R, (V70F*), T95I, G142D, E156-, F157-, R158G, (A222V*),

(W258L*), (K417N*), L452R, T478K, D614G, P681R, D950N

P.1

P.1.1,

P.1.2

Gamma Japan/Brazil L18F, T20N, P26S, D138Y, R190S, K417T, E484K, N501Y,

D614G, H655Y, T1027I

B.1.1.529 Omicron South Africa and

Botswana

A67V, Δ69–70, T95I, G142D, Δ143–145, N211I, Δ212, ins215EPE,

G339D, S371L, S373P, S375F, K417N, N440K, G446S, S477N, T478K,

E484A, Q493R, G496S, Q498R, N501Y, Y505H, T547K, D614G, H655Y,

N679K, P681H, N764K, D796Y, N856K, Q954H, N969K, L981F

L. Yao et al. Heliyon 8 (2022) e09302

long it can last against the virus, even if the neutralizing antibodies

produced by the COVID-19 vaccines are protective, protecting vulnerable

populations from severe disease, and limiting the spread of the virus.

8. Conclusions

COVID-19 is a systemic disease that mainly affects the lungs, but often

other organs as well. COVID-19 is a new virus infection disease, and

nobody has adaptive immunity against it. Infected individuals were re-

ported to have a broad range of symptoms ranging from mild to severe

sicknesses. Minor symptoms include fever or chills, cough, shortness of

breath, fatigue muscle or body aches, headache, loss of taste or smell,

sore throat, congestion or runny nose, nausea or vomiting, diarrhea, joint

pain, and chest pain. Other concerns include cognitive disorders, difﬁ-

culty in focusing, depression, myalgia, headache, fast heartbeat, and

sporadic fever. Severe illness include difﬁculty in breathing, constant

pain or compression in the chest, and cyanosis caused by hypoxemia, etc.

Organ damage caused by SARS-CoV-2 increase the risk of long period

health problems, leading to complications and sequelae that require

special attention to pay. 95% of the COVID-19 patients retained immu-

nological memory for up to 8 months, a booster of COVID-19 vaccine may

need eight months after being fully vaccinated.

9. Outlook

The complete eradication of SARS-CoV-2 remains challenging at least

in a short term for a variety of reasons. SARS-CoV-2 is going to be present

for a while, especially the emergence of the mutant viruses such as Delta

and Omicron variants, etc. Even if we eventually eliminate SARS-CoV-2,

there might be other novel coronavirus strains in nature waiting their

turn. Given the large number of incident cases are diagnosed and a

certain considerable number of COVID-19-related death occurring every

day globally, the intellectual collaboration on SARS-CoV-2 and the var-

iants must continue, requiring multidisciplinary knowledge collabora-

tion not only between academia but also between industry.

Generally, herd immunity can be reached if over 80% of individuals

are vaccinated. Vaccination coverage is still far below this level, partic-

ularly in undeveloped countries. Severe inequality exists in vaccine re-

sources and supplies around the world. Even in the developed countries,

although they have enriched vaccine resources with strong economic and

treasure support, the goal of herd immunity has not been all reached. One

of the potential reasons for those who are reluctant to get vaccinated is

the concern for long-term effects of vaccines since all vaccines are EUA

except recently FDA-approved Pﬁzer/BNT and Moderna vaccines. It is

still debatable whether mRNA from the VOVID-19 vaccines can be in-

tegrated into human genome DNA or not [154,155]. A study demon-

strated that chimeric transcription of SARS-CoV-2 and infected host cell

RNA were observed, suggesting the ability of SARS-CoV-2 RNA to be

reverse-transcribed and integrated into the genome of the infected host

cells [156]. Another study showed no evidence that SARS-CoV-2 mRNA

was able to be reverse transcribed and integrated into host cells [157].

Additional possibility is that some individuals doubt the transparency of

vaccines. Injected lipid nanoparticles encapsulated mRNA vaccines

invoke immune response when they are engulfed by antigen-presenting

cells (e.g., macrophage and dendritic cells). However, lipid nano-

particles are non-speciﬁc vesicles, which can be engulfed by other types

of cells (e.g., cardiocytes, endothelial cells, etc.) even after the release of

packaged mRNAs from macrophages and dendritic cells. Spike-protein

expressed on cardiocytes and endothelial cells may lead to myocarditis

and thrombosis. Thus, it is necessary to develop a relatively more speciﬁc

vaccine. For example, by modifying proteins in lipid membrane, which

can be engulfed by a certain type of cells through ligand-receptor

mechanisms or targeting with certain antibodies. In addition, adjuvants

are usually used in vaccine manufacture. Whereas AS03 (Adjuvant Sys-

tem 03), and MF59 (an oil-in-water emulsion of squalene oil) are

squalene-based immunologic adjuvants that have been used in licensed

vaccine products by GSK (GlaxoSmithKline) and Novartis, respectively

[158], it is unknown what adjuvants are used in mRNA vaccines or other

types of vaccines. Breakthroughs and the emergence of new variants

remind the scientiﬁc communities that we still have much uncover and

improve regarding future vaccines.

Lockdown is an effective measurement to suppress the spreading.

However, lengthy period lockdown brings a heavy society and economic

burden. Re-opening is necessary and on the way around the world. With

new variants of SARS-CoV-2 emerging, e.g., Omicron (B.1.1.529) and

Delta (B.1.617.2) variants, which can double hospitalization risk

compared to the Alpha variant (B.1.1.7), however, new strategies are

needed to re-open.

As a major target in controlling SARS-CoV-2, mutations in the re-

ceptor binding domain (RBD) are being of particular concern, which may

substantially weaken RBD-binding antibodies. It is a gap to ﬁll how much

cross-protection exists against variant strains following the original

vaccination or infection [159]. The Delta variant has 3 RBD mutations,

417, 452 and 478, respectively, which change the conformation of S

protein, and may aid immune escape. Novel vaccines may be necessary,

and mRNA vaccines may have some advantages by including the muta-

tion containing ORFs. The SARS-CoV-2 variants of concern have been

listed in Table 2.

SARS-CoV-2 may also infect other species besides human. Certain

strains of wild type (i.e., non-hACE2 bearing) mice are vulnerable to the

SARS-CoV-2 variants, e.g., B.1.1.7, B.1.351, and P.1 can infect mice via

the endogenous mouse ACE2 receptor (https://www.jax.org/jax-mice

-and-services/sarscov2-test-kit).

We still have some key unknown questions to be addressed: how soon

after infection do T cells become activated to stop the spread of the virus?

How long do T cells retain SARS-CoV-2 memory? These would be of

concern to us because traditional vaccines focus on producing neutral-

izing antibodies. As our understanding of the interaction between the

immune system and SARS-CoV-2 continues to grow, it is important to go

beyond neutralizing antibodies to pursue T cell immunity.

Each newly emerging variant raises concerns: Will the disease course

be changed? How will the immune system respond to new variants? Can

the variant evade a pre-existing immune response from previous infec-

tion or vaccination, or pre-existing vaccines are still valid or not?

Apart from the above SARS-CoV-2 variants of concern, the variants of

interest (VOI) have also caught the attention of scientists (Table 3).

Among the VOI, Mu was just designated by the WHO on August 30, 2021.

Outbreaks of the Mu variant has been reported in South America and

Table 3. SARS-CoV-2 variants of interest (VOI).

Pango Lineage Name WHO Label First Identiﬁed Spike Protein Substitution

B.1.525 Eta UK/Nigeria A67V, 69del, 70del, 144del, E484K, D614G, Q677H, F888L

B.1.526 Iota USA/New York L5F, (D80G*), T95I, (Y144-*), (F157S*), D253G, (L452R*), (S477N*),

E484K, D614G, A701V, (T859N*), (D950H*), (Q957R*)

B.1.617.1 Kappa India (T95I), G142D, E154K, L452R, E484Q, D614G, P681R, Q1071H

B.1.617.3 None India T19R, G142D, L452R, E484Q, D614G, P681R, D950N

B.1.621

B.1.621.1

Mu Columbia N/A

L. Yao et al. Heliyon 8 (2022) e09302

Europe, a descendent (B.1.621.1) of Mu has already been detected in 43

countries. Although this Mu belongs to VOI, but it has mutations that

indicate a risk of resistance to the current COVID-19 vaccines. Table 3

summarized the VOI according to the previous information from the

CDC. Currently, no SARS-CoV-2 variants are designated as VOI.

Scientiﬁc source-tracking of SARS-CoV-2 is another important issue in

prevention and control of SARS-CoV-2 infection. With accumulating

knowledges in this novel emerging virus, in addition to the ﬁrst wave of

COVID-19 cases reported in Wuhan, China in Dec. 2019 [57], COVID-19

was also spreading in other countries. Alteri, etc. described that the

highest numbers of SARS-CoV-2 cases was found in Lombardy, Italy from

February to April 2020. Over 16,000 deaths were reported in Lombardy

in a couple of weeks during the time frame [160]. After analyzing 346

whole SARS-CoV-2 genomes, seven viral lineages were found; at least

two were likely originated in Lombardy, Italy [160].

Declarations

Author contribution statement

All authors listed have signiﬁcantly contributed to the development

and the writing of this article.

Funding statement

This research did not receive any speciﬁc grant from funding agencies

in the public, commercial, or not-for-proﬁt sectors.

Data availability statement

No data was used for the research described in the article.

Declaration of interests statement

The authors declare no conﬂict of interest.

Additional information

No additional information is available for this paper.

Acknowledgements

The authors would like to thank Ms. Amy Yiming Ma for her critical

reading and editing.

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Psychological Capital and Self-Acceptance Modified the Association of Depressive Tendency with Self-Rated Health of College Students in China during the COVID-19 Pandemic

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Jul 2023

Background: To explore the association between the self-reported health status, depressive tendency, psychological capital, and self-acceptance of college students in China during the COVID-19 pandemic. Methods: Using the online survey platform "questionnaire star", a two-phase cross-sectional study was conducted on a total number of 1438 undergraduates with informed consents. The questionnaires of Self-Rated Health Measurement Scale (SRHMS), the Center for Epidemiological Studies-Depression Scale (CES-D), Psychological Capital Questionnaire (PCQ-24), and self-acceptance questionnaire were administered to each participant. Results: Male college students had significantly higher depressive tendency scores than female (17.59 vs. 15.82) (p < 0.01). College students having no siblings had significantly higher psychological capital scores than those having siblings (108.63 vs. 105.60) (p < 0.05). Exercise had significantly positive associations with self-rated health, psychological capital, and self-acceptance scores, while online time per day had significantly negative associations. Multivariate analysis showed that the interaction between depressive tendency, psychological capital, and self-acceptance was statistically significant (β = 0.004, p = 0.013 for phase 1 and β = 0.002, p = 0.025 for phase 2) in health status with depressive tendency ranking the top (β = -0.54 for phase 1 and -0.41 for phase 2, p < 0.001). Mediation analysis showed that psychological capital and self-acceptance modified the association of depressive tendency with health status. Conclusion: Physical exercise is beneficial to both physical and psychological health. Depressive tendency is the main risk factor that associates with self-rated health. Regardless of depressive tendency level, high psychological capital and self-acceptance could improve college students' health.

COVID-19 and the Nervous System from a Cuban Experience

Article

Full-text available

Sep 2023

Neuropsychiatric manifestations of viral infections (both per se and secondary to the neuroinflammatory reaction of the host) are mainly attributed to immunological reactions, so many aspects of their pathogenesis are still nuclear. Some novel therapeutic strategies are progressively emerging in which a vaccination may be having a particular impact on recovery and reduction of death. In this context, it is accepted that the SARS-CoV-2 virus is profoundly neurotropic and neuroinvasive, with various effects on the nervous system, although there is no complete understanding of the mechanism of neuroinvasion, brain injury, or short- or long-term neuropsychiatric sequelae. Therefore, it is necessary to understand the post-infectious manifestations of COVID-19 to guide the management of neuropsychiatric diseases. Thus, based on different research groups focused on this field, in this manuscript we summarize papers on COVID-19 and the nervous system (NS) published in a series of articles by Cuban authors. This review focuses on cognitive and affective emotional states, pathogenesis, biomarkers, clinical manifestations, and intervention strategies.

Portal Vein and Mesenteric Artery Thrombosis Following the Administration of an Ad26.COV2-S Vaccine—First Case from Romania: A Case Report

Article

Full-text available

Nov 2022

COVID-19 has significantly affected public health, social life, and economies worldwide. The only effective way to combat the pandemic is through vaccines. Although the vaccines have been in use for some time, safety concerns have still been raised. The most typical adverse effects of receiving a COVID-19 vaccine are localized reactions near the injection site, followed by general physical symptoms such as headaches, fatigue, muscle pain, and fever. Additionally, some people may experience VITT (vaccine-induced immune thrombotic thrombocytopenia), a rare side effect after vaccination. We present the case of a 60-year-old female patient that developed VITT-like symptoms with spleno-portal thrombosis and intestinal ischemia two weeks after the administration of the Ad26.COV2-S vaccine. Surgical treatment consisted of extensive bowel resection with end jejunostomy and feeding ileostomy. Two weeks after the first operation, a duodenal-ileal anastomosis was performed. The patient was discharged five weeks after the onset of the symptoms. Although some rare adverse effects are associated with the SARS-CoV-2 vaccines, the risk of hospitalization from these harmful effects is lower than the risk of hospitalization from COVID-19. Therefore, recognizing VITT is significant for ensuring the early treatment of clots and proper follow-up.

Virus-mediated cell fusion of SARS-CoV-2 variants

Article

Jan 2024

SARS-CoV-2 has the ability to form large multi-nucleated cells known as syncytia. Little is known about how syncytia affect the dynamics of the infection or severity of the disease. In this manuscript, we extend a mathematical model of cell–cell fusion assays to estimate both the syncytia formation rate and the average duration of the fusion phase for five strains of SARS-CoV-2. We find that the original Wuhan strain has the slowest rate of syncytia formation (6.4 × 10−4 ∕h), but takes only 4.0 h to complete the fusion process, while the Alpha strain has the fastest rate of syncytia formation (0.36 /h), but takes 7.6 h to complete the fusion process. The Beta strain also has a fairly fast syncytia formation rate (9.7 × 10−2 ∕h), and takes the longest to complete fusion (8.4 h). The D614G strain has a fairly slow syncytia formation rate (2.8 × 10−3 ∕h), but completes fusion in 4.0 h. Finally, the Delta strain is in the middle with a syncytia formation rate of 3.2 × 10−2 ∕h and a fusing time of 6.1 h. We note that for these SARS-CoV-2 strains, there appears to be a tradeoff between the ease of forming syncytia and the speed at which they complete the fusion process.

Association between echocardiographic features and inflammatory biomarkers with clinical outcomes in COVID-19 patients in Saudi Arabia

Article

Full-text available

May 2023

Background: Respiratory infections are one of the most common comorbidities identified in hospitalized patients. The coronavirus disease 2019 (COVID-19) pandemic greatly impacted healthcare systems, including acute cardiac services. Aim: This study aimed to describe the echocardiographic findings of patients with COVID-19 infections and their correlations with inflammatory biomarkers, disease severity, and clinical outcomes. Methods: This observational study was conducted between June 2021 and July 2022. The analysis included all patients diagnosed with COVID-19 who had transthoracic echocardiographic (TTE) scans within 72 h of admission. Results: The enrolled patients had a mean age of 55.6 ± 14.7 years, and 66.1% were male. Of the 490 enrolled patients, 203 (41.4%) were admitted to the intensive care unit (ICU). Pre-ICU TTE findings showed significantly higher incidence right ventricular dysfunction (28 [13.8%] vs. 23 [8.0%]; P = 0.04) and left ventricular (LV) regional wall motion abnormalities (55 [27.1%] vs. 29 [10.1%]; p < 0.001) in ICU patients compared to non-ICU patients. In-hospital mortality was 11 (2.2%), all deaths of ICU patients. The most sensitive predictors of ICU admission (p < 0.05): cardiac troponin I level (area under the curve [AUC] = 0.733), followed by hs-CRP (AUC = 0.620), creatine kinase-MB (AUC = 0.617), D-dimer (AUC = 0.599), and lactate dehydrogenase (AUC = 0.567). Binary logistic regression showed that reduced LV ejection fraction (LVEF), elevated pulmonary artery systolic pressure, and dilated right ventricle were echocardiographic predictors of poor outcomes (p < 0.05). Conclusion: Echocardiography is a valuable tool in assessing admitted patients with COVID-19. Lower LVEF, pulmonary hypertension, higher D-dimer, C-reactive protein, and B-type natriuretic peptide levels were predictors of poor outcomes.

Analysis of 52 240 source plasma donors of convalescent COVID ‐19 plasma: Sex, ethnicity, and age association with initial antibody levels and rate of dissipation

Article

Jul 2022

Background: COVID-19 convalescent plasma (CCP) was approved under emergency authorization to treat critically ill patients with COVID-19 in the United States in 2020. We explored the demographics of donors contributing plasma for a hyperimmune, plasma-derived therapy to evaluate factors that may be associated with anti-SARS-CoV-2 antibody response variability and, subsequently, antibody titers. Study design: An electronic search of CCP donors was performed across 282 US plasma donation centers. Donations were screened for nucleocapsid protein-binding-IgG using the Abbott SARS-CoV-2 IgG assay. Results: Overall, 52 240 donors donated 418 046 units of CCP. Donors were of various ethnicities: 43% Caucasian, 34% Hispanic, 17% African American, 2% Native American, 1% Asian, and 3% other. Females had higher initial mean anti-SARS-CoV-2 antibody titers but an overall faster rate of decline (P < .0001). Initial antibody titers increased with age: individuals aged 55 to 66 years had elevated anti-SARS-CoV-2 titers for longer periods compared with other ages (P = .0004). African American donors had the lowest initial antibody titers but a slower rate of decline (P < .0001), while Caucasian (P = .0088) and Hispanic (P = .0193) groups had the fastest rates of decline. Most donor antibody levels decreased below the inclusion criteria (≥1.50) within 30 to 100 days of first donation, but donation frequency did not appear to be associated with rate of decline. Conclusion: Several factors may be associated with anti-SARS-CoV-2 antibody response including donor age and sex. Evaluating these factors during development of future hyperimmune globulin products may help generation of therapies with optimal efficacy.

Will SARS-CoV-2 impact the incidence and nature of other respiratory infections?

Article

Sep 2023

Ahmad Z. Al Meslamani

The durability of immunity against reinfection by SARS-CoV-2: a comparative evolutionary study

Article

Full-text available

Oct 2021

Background Among the most consequential unknowns of the devastating COVID-19 pandemic are the durability of immunity and time to likely reinfection. There are limited direct data on SARS-CoV-2 long-term immune responses and reinfection. The aim of this study is to use data on the durability of immunity among evolutionarily close coronavirus relatives of SARS-CoV-2 to estimate times to reinfection by a comparative evolutionary analysis of related viruses SARS-CoV, MERS-CoV, human coronavirus (HCoV)-229E, HCoV-OC43, and HCoV-NL63. Methods We conducted phylogenetic analyses of the S, M, and ORF1b genes to reconstruct a maximum-likelihood molecular phylogeny of human-infecting coronaviruses. This phylogeny enabled comparative analyses of peak-normalised nucleocapsid protein, spike protein, and whole-virus lysate IgG antibody optical density levels, in conjunction with reinfection data on endemic human-infecting coronaviruses. We performed ancestral and descendent states analyses to estimate the expected declines in antibody levels over time, the probabilities of reinfection based on antibody level, and the anticipated times to reinfection after recovery under conditions of endemic transmission for SARS-CoV-2, as well as the other human-infecting coronaviruses. Findings We obtained antibody optical density data for six human-infecting coronaviruses, extending from 128 days to 28 years after infection between 1984 and 2020. These data provided a means to estimate profiles of the typical antibody decline and probabilities of reinfection over time under endemic conditions. Reinfection by SARS-CoV-2 under endemic conditions would likely occur between 3 months and 5·1 years after peak antibody response, with a median of 16 months. This protection is less than half the duration revealed for the endemic coronaviruses circulating among humans (5–95% quantiles 15 months to 10 years for HCoV-OC43, 31 months to 12 years for HCoV-NL63, and 16 months to 12 years for HCoV-229E). For SARS-CoV, the 5–95% quantiles were 4 months to 6 years, whereas the 95% quantiles for MERS-CoV were inconsistent by dataset. Interpretation The timeframe for reinfection is fundamental to numerous aspects of public health decision making. As the COVID-19 pandemic continues, reinfection is likely to become increasingly common. Maintaining public health measures that curb transmission—including among individuals who were previously infected with SARS-CoV-2—coupled with persistent efforts to accelerate vaccination worldwide is critical to the prevention of COVID-19 morbidity and mortality. Funding US National Science Foundation.

COVID-19-Associated Subacute Thyroiditis: Evidence-Based Data From a Systematic Review

Article

Full-text available

Sep 2021

Subacute thyroiditis (SAT) is a thyroid disease of viral or post-viral origin. Whether SAT represents a complication of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is still unclear. Our aim was to systematically review the literature to 1) explore the size of the literature about SAT in COVID-19 and 2) evaluate the clinical characteristics of SAT. PubMed/MEDLINE, Embase, and Scopus were searched until April 20, 2021. Original papers, case reports, and case series reporting SAT in COVID-19 patients were included. Authors and their country, journal, year of publication, COVID-19 and SAT clinical presentation, thyroid function, therapy, and follow-up data were extracted. Nineteen papers (17 case reports and 2 case series) were included, describing 27 patients, 74.1% females, aged 18 to 69 years. COVID-19 was diagnosed by nasopharyngeal swab in 66.7% cases and required hospitalization in 11.1%. In 83.3% cases, SAT occurred after COVID-19. Neck pain was present in 92.6% cases and fever in 74.1%. Median TSH, fT3, and fT4 were 0.01 mU/l, 10.79 pmol/l, and 27.2 pmol/l, respectively. C-reactive-protein and erythrocyte sedimentation rate were elevated in 96% of cases. Typical ultrasonographic characteristics of SAT were observed in 83.3% of cases. Steroids were the most frequent SAT therapy. Complete remission of SAT was recorded in most cases. In conclusion, the size and quality of published data of SAT in COVID-19 patients are poor, with only case reports and case series being available. SAT clinical presentation in COVID-19 patients seems to be similar to what is generally expected.

Insights into Pathology and Pathogenesis of Coronavirus Disease 2019 from a Histopathological and Immunological Perspective

Article

Full-text available

Jul 2021

Since the first case of COVID-19 was reported in Wuhan, China, in December 2019, the SARS-CoV-2 epidemic has spread all over the world and has become a significant public health issue. The development of treatments for COVID-19 is currently in progress; however, their effects remain limited, and the development of more effective therapeutics is desired. Thus, sufficient understanding of the pathophysiology of COVID-19 is essential to develop effective therapeutics for this disease. Pathological analyses in particular play an important role to demonstrate the causal link between an infectious disease and the pathogen and elucidate the mechanism of pathogenesis. As per pathological analyses to date, respiratory organs are identified as the major affected organs in most COVID-19 cases; also, various lesions were noted in other organs. Further, there have been increasing reports that show that the immune responses of the host contribute to the deterioration of the pathological condition of COVID-19, and a novel concept of MIS-C/MIS-A is also being established. Thus, in this article, we have provided an overview of the pathology of COVID-19 from a histopathological and immunological perspective focusing on the mechanisms of COVID-19 pathogenesis.

More than 50 long-term effects of COVID-19: a systematic review and meta-analysis

Article

Full-text available

Aug 2021

COVID-19 can involve persistence, sequelae, and other medical complications that last weeks to months after initial recovery. This systematic review and meta-analysis aims to identify studies assessing the long-term effects of COVID-19. LitCOVID and Embase were searched to identify articles with original data published before the 1st of January 2021, with a minimum of 100 patients. For effects reported in two or more studies, meta-analyses using a random-effects model were performed using the MetaXL software to estimate the pooled prevalence with 95% CI. PRISMA guidelines were followed. A total of 18,251 publications were identified, of which 15 met the inclusion criteria. The prevalence of 55 long-term effects was estimated, 21 meta-analyses were performed, and 47,910 patients were included (age 17–87 years). The included studies defined long-COVID as ranging from 14 to 110 days post-viral infection. It was estimated that 80% of the infected patients with SARS-CoV-2 developed one or more long-term symptoms. The five most common symptoms were fatigue (58%), headache (44%), attention disorder (27%), hair loss (25%), and dyspnea (24%). Multi-disciplinary teams are crucial to developing preventive measures, rehabilitation techniques, and clinical management strategies with whole-patient perspectives designed to address long COVID-19 care.

Seven-month kinetics of SARS-CoV-2 antibodies and role of pre-existing antibodies to human coronaviruses

Article

Full-text available

Aug 2021

Unraveling the long-term kinetics of antibodies to SARS-CoV-2 and the individual characteristics influencing it, including the impact of pre-existing antibodies to human coronaviruses causing common cold (HCoVs), is essential to understand protective immunity to COVID-19 and devise effective surveillance strategies. IgM, IgA and IgG levels against six SARS-CoV-2 antigens and the nucleocapsid antigen of the four HCoV (229E, NL63, OC43 and HKU1) were quantified by Luminex, and antibody neutralization capacity was assessed by flow cytometry, in a cohort of health care workers followed up to 7 months ( N = 578). Seroprevalence increases over time from 13.5% (month 0) and 15.6% (month 1) to 16.4% (month 6). Levels of antibodies, including those with neutralizing capacity, are stable over time, except IgG to nucleocapsid antigen and IgM levels that wane. After the peak response, anti-spike antibody levels increase from ~150 days post-symptom onset in all individuals (73% for IgG), in the absence of any evidence of re-exposure. IgG and IgA to HCoV are significantly higher in asymptomatic than symptomatic seropositive individuals. Thus, pre-existing cross-reactive HCoVs antibodies could have a protective effect against SARS-CoV-2 infection and COVID-19 disease.

No evidence of SARS-CoV-2 reverse transcription and integration as the origin of chimeric transcripts in patient tissues

Article

Full-text available

Aug 2021

There is interest in understanding the mechanisms that underlie reports that patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remain PCR positive many weeks after initial infection. The recent paper by Zhang et al. (1) suggests a potential explanation of this phenomenon by claiming that SARS-CoV-2 RNA can integrate into the genome of infected human cells. The authors also reanalyze RNA se-quencing (RNA-seq) data and report that SARS-CoV-2− host chimeric reads are present in cells and patient tissues. Given the potential implications of this research on the long-term impacts of COVID-19, we feel that it's necessary to scrutinize the evidence presented. To determine whether SARS-CoV-2 RNA might be retrotranscribed and integrated into the genome, the authors conducted a proof-of-principle experiment where human lung cells (Calu3) and kidney cells overexpress-ing class I transposable elements and wild type (HEK293T-L1/HEK293T) were infected with SARS-CoV-2 and subjected to high-throughput DNA sequencing (1). The very low frequency of identified chimeric events (Table 1) suggests that SARS-CoV-2 integration into the host genome is unlikely. Given that the HEK293T-L1 model increases detection of "rare integration events" and L1 can retrotranspose any poly-adenylated cellular RNA (2) and "insertions" are found preferentially in protein-coding exons, a bias unknown to L1 endonuclease insertions (3), these findings are likely spurious. Additionally, 2 of the identified 61 chime-ric nanopore genomic DNA (gDNA) reads contain human DNA from separate chromosomes (chr1,chr22 and chr18,chrX, respectively), suggesting a portion of chime-ric gDNA nanopore reads have arisen due to infrequent technical artifacts, such as base-calling software not recognizing an open-pore state between distinct molecules. Further to this, the authors reanalyzed published sequencing data and identified SARS-CoV-2 and human host chimeric reads in vitro and in patient RNA-seq (1). They show that the fraction of human-viral chimeric reads derived from negative-sense SARS-CoV-2 RNAs is higher in patients than that observed in vitro. These data are presented as evidence of SARS-CoV-2 integration and transcription. We question the presented data as evidence for this phenomenon for several key reasons. Firstly, chimeric virus−host reads are often reported in RNA-seq (4), including SARS-CoV-2 (5). This is partly due to complementary DNA fusions introduced during the reverse transcription step of library preparation (6). Secondly, larger pools of negative-sense SARS-CoV-2 chimeric reads may be due to differences in RNA extraction, library preparation, and sequencing platform. Given that negative-sense RNA is formed during the replication of SARS-CoV-2 and a template for messenger RNA production, significant variation of negative-sense reads is expected in patient RNA samples. Finally, there is no evidence of coronaviruses ever having integrated into the germ-line of host species, as might be expected if retro-transcription and integration occurs in nature, as systematic screening of >750 animal species failed to identify any coronavirus-derived endogenous viral elements (7).

Long COVID or Post-acute Sequelae of COVID-19 (PASC): An Overview of Biological Factors That May Contribute to Persistent Symptoms

Article

Full-text available

Jun 2021

The novel virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a pandemic of coronavirus disease 2019 (COVID-19). Across the globe, a subset of patients who sustain an acute SARS-CoV-2 infection are developing a wide range of persistent symptoms that do not resolve over the course of many months. These patients are being given the diagnosis Long COVID or Post-acute sequelae of COVID-19 (PASC). It is likely that individual patients with a PASC diagnosis have different underlying biological factors driving their symptoms, none of which are mutually exclusive. This paper details mechanisms by which RNA viruses beyond just SARS-CoV-2 have be connected to long-term health consequences. It also reviews literature on acute COVID-19 and other virus-initiated chronic syndromes such as post-Ebola syndrome or myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) to discuss different scenarios for PASC symptom development. Potential contributors to PASC symptoms include consequences from acute SARS-CoV-2 injury to one or multiple organs, persistent reservoirs of SARS-CoV-2 in certain tissues, re-activation of neurotrophic pathogens such as herpesviruses under conditions of COVID-19 immune dysregulation, SARS-CoV-2 interactions with host microbiome/virome communities, clotting/coagulation issues, dysfunctional brainstem/vagus nerve signaling, ongoing activity of primed immune cells, and autoimmunity due to molecular mimicry between pathogen and host proteins. The individualized nature of PASC symptoms suggests that different therapeutic approaches may be required to best manage care for specific patients with the diagnosis.

Dysregulation of brain and choroid plexus cell types in severe COVID-19

Article

Full-text available

Jul 2021
NATURE

Though SARS-CoV-2 primarily targets the respiratory system, patients and survivors can suffer neurological symptoms1–3. Yet, an unbiased understanding of the cellular and molecular processes affected in the brains of COVID-19 patients is still missing. Here, we profile 65,309 single-nucleus transcriptomes from 30 frontal cortex and choroid plexus samples across 14 control (including 1 terminal influenza) and 8 COVID-19 patients. While a systematic analysis yields no molecular traces of SARS-CoV-2 in the brain, we observe broad cellular perturbations which predict that choroid plexus barrier cells sense and relay peripheral inflammation into the brain and show that peripheral T cells infiltrate the parenchyma. We discover COVID-19 disease-associated microglia and astrocyte subpopulations that share features with pathological cell states reported in human neurodegenerative disease4–6. Synaptic signaling of upper-layer excitatory neurons—evolutionarily expanded in humans7 and linked to cognitive function8—are preferentially affected in COVID-19. Across cell types, COVID-19 perturbations overlap with those in chronic brain disorders and reside in genetic variants associated with cognition, schizophrenia, and depression. Our findings and public dataset provide a molecular framework to understand COVID-19 related neurological disease observed now and which may emerge later.

The Impact of the Renin-Angiotensin-Aldosterone System on Inflammation, Coagulation, and Atherothrombotic Complications, and to Aggravated COVID-19

Article

Full-text available

Jun 2021

Atherosclerosis is considered a disease caused by a chronic inflammation, associated with endothelial dysfunction, and several mediators of inflammation are up-regulated in subjects with atherosclerotic disease. Healthy, intact endothelium exhibits an antithrombotic, protective surface between the vascular lumen and vascular smooth muscle cells in the vessel wall. Oxidative stress is an imbalance between anti- and prooxidants, with a subsequent increase of reactive oxygen species, leading to tissue damage. The renin-angiotensin-aldosterone system is of vital importance in the pathobiology of vascular disease. Convincing data indicate that angiotensin II accelerates hypertension and augments the production of reactive oxygen species. This leads to the generation of a proinflammatory phenotype in human endothelial and vascular smooth muscle cells by the up-regulation of adhesion molecules, chemokines and cytokines. In addition, angiotensin II also seems to increase thrombin generation, possibly via a direct impact on tissue factor. However, the mechanism of cross-talk between inflammation and haemostasis can also contribute to prothrombotic states in inflammatory environments. Thus, blocking of the renin-angiotensin-aldosterone system might be an approach to reduce both inflammatory and thrombotic complications in high-risk patients. During COVID-19, the renin-angiotensin-aldosterone system may be activated. The levels of angiotensin II could contribute to the ongoing inflammation, which might result in a cytokine storm, a complication that significantly impairs prognosis. At the outbreak of COVID-19 concerns were raised about the use of angiotensin converting enzyme inhibitors and angiotensin receptor blocker drugs in patients with COVID-19 and hypertension or other cardiovascular comorbidities. However, the present evidence is in favor of continuing to use of these drugs. Based on experimental evidence, blocking the renin-angiotensin-aldosterone system might even exert a potentially protective influence in the setting of COVID-19.

Omicron blindspots: why it’s hard to track coronavirus variants

Article

Dec 2021

Amy Maxmen

Researchers are rapidly sequencing the genomes of virus samples worldwide, but shortcomings in the global surveillance system make the task a challenge. Researchers are rapidly sequencing the genomes of virus samples worldwide, but shortcomings in the global surveillance system make the task a challenge.

Immunopathological changes, complications, sequelae and immunological memory in COVID-19 patients

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