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\begin{document}

\title{Recent developments in the immunopathology of COVID-19}



\author[1]{Ya-dong Gao}%
\author[2]{Huan-ping Zhang}%
\author[1]{Yuan-li Sun}%
\author[2]{Yan-fen Wang}%
\author[3]{Duygu Yazici}%
\author[4]{Dilek Azkur}%
\author[5]{Ismail Ogulur}%
\author[4]{Ahmet Kursat AZKUR}%
\author[6]{Zhaowei  Yang}%
\author[2]{Xiao-xue Chen}%
\author[1]{Jia-qian Hu}%
\author[1]{Guanghui Liu}%
\author[5]{Mübeccel Akdis}%
\author[5]{Cezmi Akdis}%
\author[7]{Ai-zhi Zhang}%
\affil[1]{Zhongnan Hospital of Wuhan University}%
\affil[2]{Shanxi Medical University}%
\affil[3]{Marmara Universitesi}%
\affil[4]{Kirikkale Universitesi}%
\affil[5]{Universitat Zurich Schweizerisches Institut fur Allergie- und Asthmaforschung}%
\affil[6]{First Affiliated Hospital of Guangzhou Medical University}%
\affil[7]{Second Hospital of Shanxi Medical University}%


\vspace{-1em}



  
  \date{May 18, 2024}


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\selectlanguage{english}
\begin{abstract}
There has been an important change in the clinical characteristics and
immune profile of COVID-19 patients during the pandemic thanks to the
extensive vaccination programs. Here, we highlight recent studies on
COVID-19, from the clinical and immunological characteristics to the
protective and risk factors for severity and mortality of COVID-19. The
efficacy COVID-19 vaccines and potential allergic reactions after
administration are also discussed. The occurrence of new variants of
concerns such as Omicron BA.2, BA.4 and BA.5 and the global
administration of COVID-19 vaccines have changed the clinical scenario
of COVID-19. Multisystem inflammatory syndrome in children (MIS-C) has
been identified as an important cause of death of children with
COVID-19. Perturbations in immunity of T cells, B cells, and mast cells,
as well as autoantibodies and metabolic reprogramming may contribute to
the long-term symptoms of COVID-19. Atopic diseases, such as allergic
asthma and rhinitis, have been shown to be associated with a lower
susceptibility and better outcomes of COVID-19. At the beginning of
pandemic, EAACI developed guidelines that provided timely information
for the management of allergic diseases and preventive measures to
reduce transmission in the allergic clinics. The global distribution of
COVID-19 vaccines and emerging SARS-CoV-2 variants with reduced
pathogenic potential dramatically decreased the morbidity, severity, and
mortality of COVID-19. Nevertheless, breakthrough infection remains a
challenge for disease control. Hypersensitivity reactions (HSR) to
COVID-19 vaccines are low compared to other vaccines, and these were
addressed in EAACI statements that provided indications for the
management of allergic reactions, including anaphylaxis to COVID-19
vaccines. We have gained a depth knowledge and experience in the over 2
years since the start of the pandemic, and yet a full eradication of
SARS-CoV-2 is not on the horizon. Novel strategies are warranted to
prevent severe disease in high-risk groups, the development of MIS-C and
long COVID.%
\end{abstract}%



\sloppy


\textbf{1. INTRODUCTION}

The coronavirus disease 2019 (COVID-19) pandemic, caused by infection
with the severe acute respiratory syndrome-related coronavirus 2
(SARS-CoV-2), has led to alarming numbers of infections and deaths
worldwide since it was firstly reported in December
2019\textsuperscript{1}. SARS-CoV-2 belongs to the beta-coronavirus
genus and is closely related to SARS-CoV\textsuperscript{2}. SARS-CoV-2
binds to angiotensin-converting enzyme 2 (ACE2) via its spike protein to
enter cells\textsuperscript{3}. The host serine protease transmembrane
protease serine 2 (TMPRSS2) cleaves the spike protein and thus enable
cellular membrane fusion\textsuperscript{4,5}. The host protease furin
cleaves the full-length spike precursor to S1 and S2
peptides\textsuperscript{6}. S1 directly binds to neuropilin-1 on the
cell surface and may facilitate cell invasion and infectivity of
SARS-CoV-2\textsuperscript{6,7}. ACE2 and TMPRSS2 are expressed at the
epithelial sites of the lung and skin, whereas other host molecules that
may be involved in SARS-CoV-2 invasion such as CD147, cyclophilins, CD26
and related molecules are expressed in both epithelium and immune
cells\textsuperscript{8}. The global administration of COVID-19 vaccines
has dramatically decreased the infection rate, severity and mortality of
this disease\textsuperscript{9,10}. However, new SARS-CoV-2 variants of
concern (VOC) of have emerged that will dampen the protective immunity
induced by natural infection and current vaccines and lead to
breakthrough infection\textsuperscript{11,12}.

In this review, we highlight recent studies on the clinical and
immunological characteristics of COVID-19 in the context of allergy and
asthma. The impact of asthma on the susceptibility and severity of
COVID-19 is not fully understood and it is discussed here in further
detail. Moreover, recent studies on the immune responses and protective
effects of COVID-19 vaccines are summarized. The possible culprit
components of the vaccines that can induce an allergic reaction are
elaborated, along with appropriate vaccination measures for reducing the
risk of anaphylaxis.

\textbf{clinical AND LABoratory characteristics of COVID-19}

\textbf{Clinical characteristics of COVID-19}

The clinical scenarios of COVID-19 are diverse and range from
asymptomatic to critical illness and even fatal
outcomes\textsuperscript{5}. The symptoms of COVID-19 include dry cough,
fatigue, fever, myalgia, headache, diarrhea, and even respiratory
failure\textsuperscript{1}. Olfactory and gustatory dysfunctions have
been also identified as distinct symptoms of SARS-CoV-2 infection,
especially in the western countries\textsuperscript{13}. Thus, the
respiratory symptoms of COVID-19 may be confused with those of allergic
rhinitis (AR) and the common cold\textsuperscript{14}. Skin
manifestations of COVID-19 include vesicular, urticarial, and
maculopapular eruptions and livedo, necrosis, and other vasculitis
forms\textsuperscript{15} and are more common among European and North
Americans than among Asians\textsuperscript{16}. The heterogeneity of
COVID-19 warrants the elucidation of the phenotypes and endotypes of
COVID-19 that will benefit from precision
medicine\textsuperscript{17,18}. In addition, persistent symptoms such
as fatigue, brain fog, body aches, and loss of smell may persist for
months following acute infection and are referred as post-acute COVID-19
syndrome or long-COVID\textsuperscript{19,20}. After a 1-year follow-up,
most COVID-19 recovered patients regain their physical and functional
status, although it remains lower than individuals without
infection\textsuperscript{21}.

Children at all ages appear to be susceptible to SARS-CoV-2 infection,
although most of them are asymptomatic or develop mild
symptoms\textsuperscript{22}. Multisystem inflammatory syndrome in
children (MIS-C) has been described in COVID-19 patients with an overall
2\% mortality\textsuperscript{23}. MIS-C predominantly affects children
between 6 and 12 years. Most MIS-C children were critically ill, mostly
from shock and/or left ventricular dysfunction, with less severe or no
respiratory involvement\textsuperscript{24}. Regarding the treatment of
MIS-C, intravenous immune globulin (IVIG) plus glucocorticoids was
associated with a lower risk of cardiovascular dysfunctions but not the
recovery from disease when compared to IVIG treatment
alone\textsuperscript{25,26}.

\textbf{Laboratory findings of SARS-COV-2 infection}

The nucleic acid amplification test using RT-qPCR has become the gold
standard for detection of SARS-CoV-2. Novel methods have been reported
to enhance its efficacy and sensitivity\textsuperscript{27}. IgG
antibody assays against the receptor binding domain (RBD) and S1 domain
were developed as an alternative diagnostic test, albeit with varying
accuracies depending on the assay used\textsuperscript{28}. Overall,
antibody tests for SARS-COV-2 have high specificity but relatively lower
sensitivity, which varied with different immunoassays and
epitopes\textsuperscript{29}. Antigen testing is inexpensive, can
provide results in a few minutes and be performed at home.
Population-wide antigen testing was demonstrated to reduce the
transmission of SARS-CoV-2\textsuperscript{30}. Asymptomatic SARS-CoV-2
infection is associated with a longer duration of viral shedding and
needs to be promptly detected to stop viral
transmission\textsuperscript{31,32}. The concentrations of neutrophil
extracellular traps increase in the plasma, trachea aspirate and lung
autopsies and contribute to the pathophysiology of
COVID-19\textsuperscript{33,34}. Thus, blood neutrophil extracellular
traps can be a potential biomarker for SASR-CoV-2 infection. In
addition, asymptomatic patients have lower levels of SARS-COV-2 specific
IgG antibodies, which decay during the early convalescent
phase\textsuperscript{31}. Laboratory changes during COVID-19 have been
reviewed and are summarized in our previous
studies\textsuperscript{35,36}.

\textbf{Risk and protective factors for susceptibility, severity and
mortality of COVID-19}

\textbf{Protective factors}

Health systems resilience is critical for the control of the COVID-19
pandemic\textsuperscript{37}. A healthy diet and sufficient nutrition
have been identified as protective factors against SARS-CoV-2
infection\textsuperscript{35}. Both the incidence rate and mortality of
COVID-19 were lower in Bacillus Calmette-Guerin (BCG)-vaccinated
countries than in those without vaccination
program\textsuperscript{38,39}. Moreover, BCG vaccination during early
childhood seems to selectively protect against infection in the
elderly\textsuperscript{40}. BCG was suggested to enhance innate immune
responses, leading to ``trained immunity'' and confer protection against
viral infections\textsuperscript{41}. Similarly, recent administration
of the mumps-measles-rubella vaccine was observed to be associated with
a reduction in SARS-CoV-2 infection in males\textsuperscript{42} and
severity of COVID-19\textsuperscript{43}, although the real correlation
between this vaccine and COVID-19 is still unclear\textsuperscript{44}.

Lower levels of nasal ACE2\textsuperscript{45} and airway cathepsin
L/CTSL1\textsuperscript{46}, a protease that cleaves and primes the
SARS-CoV-2 spike protein, may contribute to the mild disease of COVID-19
in children. Atopy and type 2 inflammation have been associated with a
decreased expression of ACE2 in airway epithelial cells and thus lower
susceptibility to SARS-CoV-2\textsuperscript{47}. More importantly, the
type 2 cytokine IL-13 reduced ACE2 expression\textsuperscript{47},
intracellular viral load and cell-to-cell transmission, whilst
increasing the cilial keratan sulfate coating in airway epithelial
cells, suggesting a role of IL-13 in attenuating viral shedding and thus
reducing the entry, replication, and spread of
SARS-CoV-2\textsuperscript{48}. Genetic variation of allergic disease
was associated with a lower risk of COVID-19\textsuperscript{49}.

Most studies suggested that AR and chronic rhinosinusitis (CRS) are not
associated with a higher risk of susceptibility and severity of
COVID-19\textsuperscript{35,50,51}. Reduced ACE2 expression was observed
in bronchial epithelial cells from patients with concomitant AR and
allergic asthma\textsuperscript{47}, suggesting a potential protective
effect of atopy against susceptibility and severity of COVID-19. The
expression of ACE2 in nasal polyp tissues of patients with CRS was lower
than that of healthy controls\textsuperscript{52}. The expression of
ACE2 and TMPRSS2 was also lower in the olfactory mucosa of patients with
chronic rhinosinusitis with nasal polys (CRSwNP) compared to healthy
controls, and the protein expression of ACE2 was negatively correlated
with eosinophils numbers in olfactory mucosa\textsuperscript{53}.
Moreover, the expression of ACE2 was upregulated by interferon (IFN)-\selectlanguage{greek}γ
\selectlanguage{english}and downregulated by type 2 cytokines in nasal epithelial
cells\textsuperscript{47,54,55}. All these data support a protective
role of type 2 inflammation against SARS-CoV-2 infection and severe
disease.

The corticosteroid dexamethasone can increase ventilator-free
days\textsuperscript{56} and reduce the death rate\textsuperscript{57}in
severe and critically ill COVID-19 patients. Mechanistically,
dexamethasone treatment restrains neutrophil pathogenicity by reducing
IFN\textsuperscript{active}-neutrophils and expanding immunosuppressive
immature neutrophils\textsuperscript{58}. Treatment with inhaled
corticosteroids (ICS) reduced the expression of ACE2 in induced
sputum\textsuperscript{59} from asthma patients and in bronchial
epithelia from patients with chronic obstructive pulmonary
diseases\textsuperscript{60}. Clinical studies reported that inhaled
budesonide in COVID-19 patients reduced time to recovery and resulted in
less severe outcome\textsuperscript{61,62}. Mechanistically, early Th2
inflammation and attenuated IFN-\selectlanguage{greek}γ \selectlanguage{english}production in the nose may indicate
worse clinical outcomes, and ICS budesonide treatment inhibited Th2
inflammation in the nose\textsuperscript{63}. Inhalable
SARS-CoV-2-specific siRNA and human ACE2-containing nanocatchers were
shown to reduce SARS-CoV-2 infection\textsuperscript{64,65} and lung
inflammation\textsuperscript{64}, as shown in SARS-CoV-2 infected mice.

\textbf{Risk factors}

The emergence of new variants of SARS-CoV-2, such as Omicron and its
subvariants, present a challenge for the eradication of COVID-19 as they
have evolved immune escape from the neutralizing antibodies developed in
previous infections and vaccinations\textsuperscript{66,67}. COVID-19
breakthrough infection has become a major concern associated with the
new variants\textsuperscript{68}. Whole genome sequencing revealed two
distinct mechanisms that can predispose an individual to
life-threatening COVID-19, namely failure to control viral replication
or an enhanced tendency towards pulmonary inflammation and intravascular
coagulation\textsuperscript{69}. Older age, male sex, cardiovascular and
metabolic comorbidities, racial/ethnic disparities, chronic kidney
diseases and cancer have been identified as risk factors for SARS-CoV-2
infection and worse outcomes of COVID-19\textsuperscript{35,36}.
Healthcare workers are at higher risk of SARS-CoV-2 infection compared
to non-healthcare workers\textsuperscript{36,70}. Blood levels of
neutrophil elastase\textsuperscript{71} and
histone-DNA\textsuperscript{72} were associated with severe and systemic
and multi-organ manifestations of COVID-19. Higher levels of bacteria
DNA in the system circulation were associated with severe and fatal
COVID-19\textsuperscript{73}. COVID-19 patients with inborn errors of
immunity, except type I IFN immunity errors, exhibit an almost similar
natural COVID-19 course compared to the general
population\textsuperscript{74}. Interestingly, individuals with blood
group A are at higher risk of SARS-CoV-2 infection and severe disease,
whereas blood group O may be protective against
COVID-19\textsuperscript{75}.

The higher expression of entry receptors ACE2 and TMPRSS2 increase the
susceptibility to SARS-CoV-2 infection\textsuperscript{35}. Smoking was
associated with higher expression of ACE2, TMPRSS2, FURIN, and BSG in
bronchial brushes\textsuperscript{8} and represents a risk factor for
COVID-19 mortality when not adjusted for chronic respiratory
diseases\textsuperscript{76}.

Air pollution has been shown to be associated with SARS-CoV-2 infection
and COVID-19 mortality\textsuperscript{77}. Mechanistically, air
pollutants such as nitrogen dioxide, ozone, and particulate matters (PM)
may disrupt the airway epithelial barrier and impair the defense against
respiratory viruses\textsuperscript{77,78}. The airway epithelial
barrier interacts with the respiratory microbiome to shape the immune
response in the lungs\textsuperscript{79}. In addition, air pollution
may contribute to chronic systemic inflammation and a higher prevalence
of comorbidities such as cardiovascular and respiratory diseases which
have been demonstrated to be risk factors for severe
COVID-19\textsuperscript{78,80,81}. Air pollution is also correlated
with a higher expression of ACE2 receptor in the
lung\textsuperscript{82}. Furthermore, fine particulate matters such as
PM\textsubscript{2.5} and PM\textsubscript{10} may act as carriers of
SARS-CoV-2 and promote the transmission of this
virus\textsuperscript{80}. Lockdown during COVID-19 was associated with
a reduction in PM\textsubscript{2.5} concentrations due to reduced
traffic emission\textsuperscript{83}. Interestingly, the concentrations
of airborne pollen correlated with the infection rates of SARAS-CoV-2 in
thirty-one countries across both hemispheres\textsuperscript{84}. This
may be attributed to the impairment of innate antiviral immunity of
airway epithelia upon pollen exposure\textsuperscript{84}.

As an interesting risk factor, exposure to pollution and gut barrier
leakiness have been proposed to play a role on COVID-19 severity.
Although further studies are needed, severity and excess death rate in
northern Italy were suggested to have a link with increased air
pollution\textsuperscript{78}, in accordance with several other
studies\textsuperscript{85-87}.

\textbf{New variants of concerns}

New variants of SARS-CoV-2 emerged sequentially, becoming the
predominant strains during the pandemic. These variants have distinct
ACE2 binding affinity, virulence, transmissibility and host immune
responses\textsuperscript{88-100} (Figure 1). Currently, the most
pronounced risk factor for SARS-CoV-2 infection is the emergence of new
variants or subvariants that are resistant to neutralizing antibodies
and with higher transmissibility\textsuperscript{101}. The subvariants
BA.4 and BA.5, most likely stem from Omicron lineage
BA.2\textsuperscript{101}, were firstly detected in South
Africa\textsuperscript{99} and are now spreading in Europe and the
United States\textsuperscript{102}. BA.4 and BA.5 have become the
dominant VOC in many European countries. The hospitalization and death
rate of BA.4 and BA.5 were significantly lower compared to previous
waves of infection in South Africa\textsuperscript{99}, which may be due
to the high population immunity. However, in Portugal, the
hospitalization and mortality caused by BA.4/5 were similar to that in
the first wave of Omicron infection, which may be due to the higher
proportion of elderly individuals in this country\textsuperscript{101}.
BA.4 and BA.5 carry additional mutations in the spike proteins assisting
the immune escape induced by 3-dose vaccinations and by post-vaccination
infection of BA.1\textsuperscript{103,104}. The Omicron variant is
continuously evolving escape antibody neutralization resulting in
breakthrough infection of SARS-CoV-2 in both vaccinated and in
previously infected individuals\textsuperscript{105}. The biological and
clinical characteristics of rhinovirus, influenza A, SARS-CoV-2 variants
delta, Omicron BA.1 and BA.5 are compared in Table 1.

\textbf{Table 1. Biological and clinical characteristics and comparison
of SAR-CoV2 variants, rhinovirus and influenza.}\selectlanguage{english}
\begin{longtable}[]{@{}llllll@{}}
\toprule
\begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
\textbf{Rhinovirus}\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
\textbf{Influenza A}\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
\textbf{SARS-CoV-2 Delta B.1.617.2}\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
\textbf{SARS-CoV-2 Omicron B.1.1.529}\strut
\end{minipage} & \begin{minipage}[b]{0.14\columnwidth}\raggedright\strut
\textbf{SARS-CoV-2 Omicron BA.5}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
\textbf{Classification}\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Picornaviridae {\guilsinglright} Enterovirus {\guilsinglright} Rhinovirus A/80 subtypes Rhinovirus B/32
subtypes Rhinovirus C/57 subtypes\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Orthomyxoviridae {\guilsinglright} Alphainfluenzavirus {\guilsinglright} Influenza A virus\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Coronaviridae {\guilsinglright} Orthocoronavirinae {\guilsinglright} Betacoronavirus {\guilsinglright} Sarbecovirus {\guilsinglright}
SARS-CoV-2\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Coronaviridae {\guilsinglright} Orthocoronavirinae {\guilsinglright} Betacoronavirus {\guilsinglright} Sarbecovirus {\guilsinglright}
SARS-CoV-2\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Coronaviridae {\guilsinglright} Orthocoronavirinae {\guilsinglright} Betacoronavirus {\guilsinglright} Sarbecovirus {\guilsinglright}
SARS-CoV-2\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{Genome}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
ssRNA positive strand linear\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
ssRNA negative strand segments\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
ssRNA positive strand linear\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
ssRNA positive strand linear\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
ssRNA positive strand linear\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
\textbf{Size}\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Rhinovirus A 6.5-7.2 kb Rhinovirus B 6.9-7.3 kb Rhinovirus C 6.7-7.2
kb\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
13.1-13.6 kb\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
29.8 kb\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
29.6 kb\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
29.6 kb\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
\textbf{Receptor}\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Rhinovirus A: Immunoglobulin-type cell adhesion molecule (ICAM-1) B:
low-density lipoprotein receptor (LDLR) C: Cadherin-related family and
member-3 (CDHR3)\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Sialic acid (NeuAc alpha 2,3Gal and NeuAc alpha 2,6Gal) DC-SIGN,
L-SIGN\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Angiotensin converting enzyme 2 (ACE2)\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Angiotensin converting enzyme 2 (ACE2)\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Angiotensin converting enzyme 2 (ACE2)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{Incubation period}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
2-3 days\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
2-5 days\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
4-7 days\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
2-4 days\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
2-4 days\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
\textbf{Local diseases}\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Rhinovirus A/B: Common cold, acute otitis media, rhinosinusitis.
Rhinovirus C: Lower respiratory tract infections, bronchiolitis and
pneumonia, wheezing and asthma exacerbations, croup\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Pneumonia, headache, chills, dry cough, fever, myalgia, fatigue,
anorexia, nasal congestion, rhinorrhea, sneezing, conjunctivitis\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Fever and chills, cough, shortness of breath/dyspnea, burnout, myalgia,
headache, loss of taste or smell, sore throat, nasal congestion, runny
nose, nausea, vomiting, diarrhea\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Runny nose, headache, fatigue, hoarseness, sneezing, sore throat, fever,
cough, loss of smell or taste\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Runny nose, headache, fatigue, hoarseness, sneezing, sore throat, fever,
cough, loss of smell or taste\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{System diseases}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Viremia, myocarditis, myositis, central nervous system symptoms
(irritability, lethargy, noise, confusion, encephalopathy, encephalitis,
etc.), toxic shock syndrome, cytokine storm, kidney failure, liver
failure\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Viremia, myocarditis, myositis, central nervous system symptoms
(irritability, lethargy, noise, confusion, encephalopathy, encephalitis,
etc.), toxic shock syndrome, cytokine storm, kidney failure, liver
failure\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
More focused to elderly and risk groups, same type of diseases as in
delta. Relatively low prevalence compared to delta\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
More focused to elderly and risk groups, same type of diseases as in
delta. Relatively low prevalence compared to delta\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
\textbf{Risk groups}\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Babies and toddlers, chronic disease Primary and secondary
immunodeficiencies\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Older age, chronic diseases (asthma, coronary artery disease, diabetes,
cirrhosis, chronic kidney failure, Parkinson's disease, etc.)\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Adults 70 years and older, chronic heart disease, diabetes, obesity,
immunodeficiency transplantation, cancer chemotherapy, chronic kidney
disease, pregnancy\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Adults 70 years and older, chronic heart disease, diabetes, obesity,
immunodeficiency transplantation, cancer chemotherapy, chronic kidney
disease, pregnancy\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
Adults 70 years and older, chronic heart disease, diabetes, obesity,
immunodeficiency transplantation, cancer chemotherapy, chronic kidney
disease, pregnancy\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{Mortality}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
0.001\%\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
0.1\%\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
2-4\%\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
0.01\%\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Similar to the Omicron BA.1 wave\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\textbf{COVID-19 and asthma}

Observational studies indicated a potential protective factor of asthma
for the morbidity and mortality of COVID-19\textsuperscript{1,50},
although conflicting data from the United States and United Kingdom (UK)
suggested a higher prevalence of asthma in COVID-19
patients\textsuperscript{106}. A UK study found that asthmatic patients
were associated with a higher risk of COVID-19\textsuperscript{107}. For
allergic asthma, the protective effects have been partly attributed to
the antiviral effect of eosinophils\textsuperscript{35}, whose
beneficial effects on COVID-19 outcomes depend on
ICS\textsuperscript{108}. However, whether COVID-19 patients with asthma
are at higher risk of long-COVID symptoms is still unclear as there are
contradictory research studies\textsuperscript{109,110}.

It remains unclear whether asthma is a risk factor for the severe and
worse outcome of COVID-19. However, it appears to be related to the
asthma phenotype, treatment and severity\textsuperscript{111,112}.
Asthma was shown to be associated with an increased hospitalization risk
of COVID-19 both in adults\textsuperscript{50} and in
children\textsuperscript{113}. Another study observed an increased
hospitalization rate only in asthmatic patients needing regular ICS or
regular/intermittent ICS with add-on therapy\textsuperscript{107}. The
hospitalization rate of allergic asthmatics was 50\% lower compared to
non-allergic asthmatics\textsuperscript{110}. A recent meta-analysis
identified preexisting asthma as a risk factor for intensive care unit
(ICU) admission among COVID-19 patients\textsuperscript{114}. The
heterogeneity of asthma endotypes (allergic vs. nonallergic asthma) may
underly the different disease course in these
studies\textsuperscript{35,110}. Eosinopenia was associated with worse
outcomes of COVID-19, including longer duration of hospitalization,
higher severity and mortality\textsuperscript{1,36,110}. Dynamic
monitoring of eosinophils counts in addition toother laboratory indices,
such as neutrophil-to-lymphocytes ratio lymphocytopenia and D-dimer, may
be used as predictive biomarkers of the outcomes of
COVID-19\textsuperscript{35,36}. Biologicals were associated with lower
susceptibility in asthmatic patients\textsuperscript{115}. Omalizumab
augmented IFN-\selectlanguage{greek}α \selectlanguage{english}production from plasmacytoid dendritic
cells\textsuperscript{116}, which may also contribute to the protecting
effects of asthma against COVID-19.

A lower expression of ACE2 in bronchial epithelial or lung tissue was
observed in allergic asthmatic patients\textsuperscript{106,117,118}. In
addition, ICS may decrease the expression of ACE2 and TMPRSS2 in
bronchial epithelia of asthmatic patients\textsuperscript{59} and thus
contribute to lower susceptibility to infection. The current evidence
does not indicate an increased risk of long COVID-19 in asthmatic
patients, although studies with more patients are
warranted\textsuperscript{118}. The symptoms of long COVID-19 are
summarized in Table 2.

\textbf{Table 2.Reported symptoms of post-acute COVID-19 syndrome or
long COVID-19.}\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
\textbf{Organs and systems} & \textbf{Symptoms}\tabularnewline
\midrule
\endhead
General status & Fatigue, general asthenia, low fever, dizziness,
sweating\textsuperscript{119,120}\tabularnewline
Neuro-psychiatric system & Headache, insomnia, depression, distress,
anxiety, dysphoria, post traumatic stress disorder, memory loss, loss of
attention, anorexia, other mental health
conditions\textsuperscript{120-122}\tabularnewline
Cardiovascular systems & Chest pain, palpitation, elevated HR, diastolic
dysfunction, stress cardiomyopathy, changes in cardiac MRI, ongoing
elevation in high-sensitivity troponin
T\textsuperscript{19,120-123}\tabularnewline
Upper respiratory tract & Runny nose, anosmia, sore throat, blocked
nose\textsuperscript{120,121}\tabularnewline
Pulmonary system & Cough, phlegm, hemoptysis, chest tightness, chest
pain, shortness of breath, ventilator and oxygen dependence, chest
imaging abnormality, fibrotic lung disease, impaired pulmonary
function\textsuperscript{120-122}\tabularnewline
Gastrointestinal system & Abdominal discomfort, diarrhea, constipation,
vomiting, loss of appetite\textsuperscript{121}\tabularnewline
Hepato-biliary system & Nausea, jaundice, transaminase
increase\textsuperscript{121}\tabularnewline
Endocrine and metabolic system & New- onset hyperglycemia and diabetes,
diabetic ketoacidosis, subacute
thyroiditis\textsuperscript{120,122}\tabularnewline
Genito-urinary system & Proteinuria, haematuria, development of kidney
injury, uncontrolled bladder,
pollakiuria\textsuperscript{19,121,124}\tabularnewline
Vascular complications & Thromboembolism, bleeding, disseminated
intravascular coagulation\textsuperscript{19,125}\tabularnewline
Reproduction & Male infertility\textsuperscript{122}\tabularnewline
Musculoskeletal system & Arthralgia, myalgia, muscle
weakness\textsuperscript{121,122}\tabularnewline
Dermatological complications & Maculopapular exanthem, papulovesicular
rash, urticaria, painful red acral purple papules, hair
loss\textsuperscript{121,122}\tabularnewline
Others & Conjunctivitis, neck pain\textsuperscript{125}\tabularnewline
\bottomrule
\end{longtable}

\textbf{Immune responses and pathogenesis of COVID-19}

The immunological pathogenicity of COVID-19 is complex and may be
associated with the virulence of SARS-CoV-2 and the lack of the temporal
coordination between innate and adaptive immune
responsces\textsuperscript{126-128}. Other mechanisms such as
pre-existing immunity to SARS-CoV-2, super-antigens and autoimmunity
have been also suggested to participate in the immune responses to this
virus\textsuperscript{129}. Adaptive responses to SARS-CoV-2 develop
mainly to the spike protein. It is postulated that SARS-CoV-2 RNA is
sensed by toll-like receptor (TLR)-3/7/8 and activates innate immune
pathways\textsuperscript{130,131}. SARS-CoV-2 replication induced a
delayed type I IFN response in lung epithelial cells, which is regulated
by melanoma differentiation-associated gene 5
(MDA5)\textsuperscript{132}. Activation of NLRP3 inflammasomes
participates in the pathophysiology of COVID-19 and is associated with
the severity of this disease\textsuperscript{133}. Type I IFN-mediated
antiviral responses and activation of both CD4\textsuperscript{+}Th1 and
CD8\textsuperscript{+} cytotoxic T lymphocytes result in viral clearance
in SARS-CoV-2-infected subjects with mild symptoms\textsuperscript{134}.
Impairment in the number and function of dendritic cells may also lead
to dysregulation in innate and adaptive immunity including antiviral
response\textsuperscript{129,135}. The insufficient antiviral
response\textsuperscript{136}, or autoantibodies against type I
IFNs\textsuperscript{137,138}, combined with the system inflammation
induced by a large number of immune cells and resident tissue cells, may
contribute to the cytokine storm in severe disease\textsuperscript{131}.

Virus-specific IgM and IgA can be detected in the acute phase followed
by an increase in virus-specific IgG at a later stage of
COVID-19\textsuperscript{129}. More severe COVID-19 patients were
associated with higher anti-RBD IgA and IgG antibody responses when
compared to those not hospitalized or asymptomatic. No deaths were
reported in patients with higher a IgG antibody index
(NT50/IgG\textgreater{} 100)\textsuperscript{139}. Dupilumab
(anti-IL-4/13 R\selectlanguage{greek}α\selectlanguage{english}) used in atopic dermatitis (AD) patients with COVID-19
was associated with a lower IgG antibodies
response\textsuperscript{140}. Poor and delayed anti-SARS-CoV-2 IgM and
IgG antibodies responses correlated with poor outcomes of COVID-19 in
children\textsuperscript{141}. A visible antibody cross-reactivity was
reported to infectious bronchitis virus, a non-SARS-CoV infection and
chicken aerosol vaccines particularly in highly exposed veterinarians
who administered the vaccines. However, this immune cross-reactivity did
not show a viral neutralizing activity and focused on non-RBD
antibodies, which substantially differ between SARS-CoV-2 and
non-SARS-CoVs\textsuperscript{142}. Activated inflammatory caspases can
induce pyroptosis which may partly contribute to lymphopenia in
COVID-19, and the caspases inhibitors have been suggested to be
potential therapeutics for severe and long
COVID-19\textsuperscript{143}.

Mild COVID-19 patients exhibited SARS-CoV-2-specific memory B and T
cells responses that display hallmarks of antiviral
immunity\textsuperscript{144}. The antigen-driven activation of
anti-SARS-CoV-2 memory B cells persisted and matured up to 6 months
after SARS-CoV-2 infection and may provide long-term
protection\textsuperscript{145}. Long COVID-19 patients were
characterized with over-activated innate immune cells, lacked naive T
and B cells and showed persistent elevated expression of IFN-\selectlanguage{greek}β \selectlanguage{english}and
IFN-\selectlanguage{greek}λ\selectlanguage{english}1 at 8 months after infection\textsuperscript{146}. Mast cell
activation may also contribute to long-term COVID-19 as evidenced by
persistent mediators release\textsuperscript{147}. Diverse autoantibody
responses were identified in COVID-19 patients and were correlated with
disease severity and duration of hospitalization \textsuperscript{138}.
Preexisting and de novo autoantibodies were more frequently detected in
hospitalized or severe COVID-19 patients and may play a role in
post-acute sequelae of COVID-19\textsuperscript{148}. Dysregulated
respiratory CD8\textsuperscript{+} T cell responses were associated with
impaired lung function after acute COVID-19\textsuperscript{149}. In
summary, poor viral clearance, persistent inflammation and autoimmunity
were proposed as the major mechanisms contributing to long
COVID-19\textsuperscript{125,131,150,151} (Figure 2).

\textbf{MANAGEMENT of allergic diseases during THE COVID-19 pandemic}

The COVID-19 pandemic has SHAPED the ways medical services are conducted
in order to accommodate for the imposed lockdown and social distancing
measures. Accordingly, telemedicine was adopted by many physicians to
guide the treatment and follow-up of allergic
patients\textsuperscript{152}.

Continuation of intranasal corticosteroids (INCS) was suggested for AR
patients with COVID-19 at the recommended doses\textsuperscript{153}.
Treatment with INCS before SARS-CoV-2 infection was associated with a
lower risk of COVID-19-related hospitalization, ICU admission or
death\textsuperscript{154}. A systematic review assessed the use of INCS
on the olfactory dysfunction of COVID-19 patients, but only identified a
single study to include in the review\textsuperscript{155}. The impact
of INCS on the susceptibility and outcomes of COVID-19 is still
inconclusive\textsuperscript{51}. Oral corticosteroids, biologicals and
surgical treatment should be avoided or suspended in CRS patients with
SARS-CoV-2 infection\textsuperscript{51}. Telemedicine was advocated to
replace in-person visits for the care of CRS patients during the
COVID-19 pandemic with high patient satisfaction\textsuperscript{156}.

Inhaled or oral corticosteroids should be continued to for asthmatic
patients without SARS-CoV-2 infection to maintain asthma control, and
oral corticosteroids and biologicals should be continued to treat severe
asthma exacerbations\textsuperscript{157}. In the case of asthmatic
patients with confirmed SARS-CoV-2 infection, the use of inhalers should
be indicated over nebulizers for the delivery of aerosolized medications
to avoid viral transmission via aerosol\textsuperscript{158}. Current
evidence suggests that treatment with biologicals targeting type 2
inflammation does not increase the risk of SARS-CoV-2 infection and
COVID-19 severity\textsuperscript{159} and may have beneficial
effects\textsuperscript{115}. Therefore, biologicals may be continued
during COVID-19 for asthmatic patients without SARS-CoV-2 infection.

AIT should be temporarily discontinued until recovery for SARS-CoV-2
positive asthmatic patients or in contact with confirmed cases of
COVID-19\textsuperscript{160}. AIT can be continued in SARS-CoV-2
negative confirmed patients but with a prolonged injection
interval\textsuperscript{160}. Switching from subcutaneous to sublingual
immunotherapy may be considered for AIT during
COVID-19\textsuperscript{161}. Skin manifestations of COVID-19 may be
similar to other viral infections and drug hypersensitivity reactions
(DHRs)\textsuperscript{162,163}. The diagnosis and management of DHRs
induced by medications repurposed and off-label for the treatment of
COVID-19 have been discussed in a few review
papers\textsuperscript{162-164}.

Pulmonary function tests such as spirometry should be restricted to
those patients with high clinical priority and using a high-efficiency
inline filter. The patients should be encouraged to perform peak
expiratory flow measurement at home to reduce the possible transmission
via small droplets and aerosol generated during the pulmonary function
test\textsuperscript{165,166}.

Many studies have focused on the impact of the COVID-19 pandemic on the
status and control of allergic diseases. In asthmatic children,
environmental changes, altered medical practice and medication use,
changes in transportation and travel patterns, school attendance and
physical activity impacted asthma control during the
pandemic\textsuperscript{167}. A survey revealed that the majority of
the AD patients experienced AD flares with mild worsening of the disease
during the COVID-19 pandemic\textsuperscript{168}. Dupilumab seems to be
safe and crucial for a better outcome of COVID-19 and should be
continued in AD patients during the COVID-19
pandemic\textsuperscript{169}. During COVID-19, AIT was initiated and
continued by most physicians in patients without indications of
SARS-CoV-2 infection\textsuperscript{170}. In contrast, lockdown during
COVID-19 resulted in decreased numbers of patients initiating AIT but
without significant impact on sublingual
immunotherapy\textsuperscript{171}.

COVID-19 was reported to increase the incidence of acute
urticaria\textsuperscript{172} and disease activity of chronic urticaria
in males but not females, which may be associated with loss of
omalizumab efficacy\textsuperscript{173}. Single-cell sequencing and
proteomic analysis revealed that the cytokine storm associated with
severe COVID-19 may promote the activation of monocytes/macrophages and
cytotoxic CD8\textsuperscript{+} T cells, which may be involved in the
development of maculopapular drug rash associated with
COVID-19\textsuperscript{174}.

\textbf{COVID-19 vaccines}

Natural SARS-CoV-2 infection does not establish a strong antibody
response that can prevent reinfection\textsuperscript{175}. COVID-19
vaccines offer promising protective immunity against SARS-CoV-2
infection. Two groups of vaccines are available for the global
vaccination strategy of COVID-19. The classic group includes subunit,
inactivated, live-attenuated and virus-like particle vaccines; novel
approaches include RNA-based vaccines which deliver RNA coding target
viral proteins into human cells\textsuperscript{176}. Two mRNA -based
vaccines, BNT162b2 and Moderna mRNA vaccines were approved with
emergency use or conditioned marked authorization by the USA, European
Union and other countries' governmental agencies. Phase III clinical
trials and real-world data suggested that COVID-19 vaccines have
dramatically reduced severe COVID-19 cases\textsuperscript{177} and
excess mortality due to COVID-19 (Figure 3), although breakthrough
infection in fully vaccinated individuals is not
uncommon\textsuperscript{178}.

\textbf{Efficacy and immune responses of COVID-19 vaccines}

The RBD of the SARS-CoV-2 spike protein is the primary target for
neutralizing antibodies induced by COVID-19 vaccines. Specific IgG
antibodies against conformational but not sequential RBD epitopes have
the potential to block the binding of SARS-CoV-2 with ACE2 and confer
protective immunity\textsuperscript{179}. Mutations in RBD, as
identified in several VOC, display increased binding affinity to
ACE2\textsuperscript{180} and/or reduced neutralization ability of sera
from convalescent and BNT162B2 vaccinated
individuals\textsuperscript{181-184}. Noticeably, BNT162b2-induced IgG
antibodies had higher avidity to mutated RBD than those induced by
natural infection\textsuperscript{66}. The variant Omicron exhibited
approximately fourfold greater immune escape relative to the Beta
variant\textsuperscript{183}. Prior COVID-19 was associated with higher
neutralization capacity for the ancestral virus after BNT162b2
vaccination\textsuperscript{183}. More importantly, two doses of mRNA
COVID-19 vaccines provided almost non-existent, whereas a booster dose
yielded almost 75\% protection against symptomatic infection of
Omicron\textsuperscript{184}. It is predicted that BNT162b2 boosted, or
vaccination (two doses) combined with previous infection can prevent
73\% symptomatic infection by Omicron, which is significantly higher
than in individuals with BNT162b2 vaccination only\textsuperscript{183}.

Other types of vaccines have also been administered around the world.
CVnCoV is a vaccine based on unmodified RNA and induced only a 48\%
reduction in the incidence of symptomatic disease\textsuperscript{185}.
CV2CoV is the second-generation unmodified mRNA vaccine but with
optimized non-coding regions and enhanced antigen expression. Compared
to CVnCoV, CV2CoV induced higher titers of binding and neutralizing
antibodies against SARS-COV-2 variants, and memory B and T cell
responses non-human primates\textsuperscript{186}. The inactivated
Sinopharm/BBIBP COVID-19 vaccine is widely used in developing countries
including China due to its low storage requirements. Seroconversion
rates in unexposed individuals after first and second dose reached 40\%
and 100\% respectively, and younger individuals and women had the
highest antibody concentrations. Previous SARS-CoV-2 infection was
associated with a strong antibody response after a single dose of the
BBIBP vaccine. A sharp increase in antibody concentrations was observed
following SARS-CoV-2 infection after the first and second
doses\textsuperscript{187}. Virus-like particle-based COVID-19 vaccines
induced high levels of neutralizing antibodies and protection against
infection with SARS-CoV-2 and its variants in mice and rhesus
macaques\textsuperscript{188,189}. PreS-RBD vaccine was developed based
on a recombinant fusion protein consisting of the human hepatitis B
virus-derived PreS antigen and two SARS-CoV-2 RBD domains. It induced a
robust anti-RBD IgG response in rabbits consisting of an early IgG1 and
sustained IgG4 which can be detected in serum and mucosa secretions.
Moreover, the vaccine-induced antibodies potently inhibited the
interaction of RBD with ACE2 and possessed the neutralizing ability of
the omicron VOC\textsuperscript{190}. The efficacy and immune responses
elicited by different types of COVID-19 vaccines are listed in Table 3.

\textbf{Table 3. Efficacy and immune response of different SARS-CoV-2
vaccines}\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
\begin{minipage}[b]{0.30\columnwidth}\raggedright\strut
\textbf{Vaccine name}\strut
\end{minipage} & \begin{minipage}[b]{0.30\columnwidth}\raggedright\strut
\textbf{Types of vaccines}\strut
\end{minipage} & \begin{minipage}[b]{0.30\columnwidth}\raggedright\strut
\textbf{Efficacy and immune responses}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
BNT162b2\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
mRNA vaccines\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
95\% effective in preventing COVID-19 Induced IgG antibodies had higher
avidity to mutated RBD than those induced by natural
infection\textsuperscript{66,183,191}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Moderna\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
mRNA vaccines\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
94.1\% efficacy at preventing COVID-19 Preclinical testing in advanced
clinical evaluation has shown a Th1-skewed vaccine response and no
pathologic lung infiltrates\textsuperscript{192-194}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
AZD1222\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Viral vector\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
After the second dose, efficacy was higher in those with a longer
prime-boost interval (vaccine efficacy 81.3\% at [?]12 weeks) than in
those with a short interval (vaccine efficacy 55.1\% at \textless{}6
weeks) Higher binding and neutralizing antibody titers in sera with a
longer prime-boost interval\textsuperscript{195}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Sputnik V\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Viral vector\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
91.6\% efficacious against COVID-19 (from day 21 after the first dose,
to the day of receiving the second dose) RBD-specific IgG was detected
in 98\% of samples, with a geometric mean titer (GMT) of 8996, and a
seroconversion rate of 98.25\% Increased SARS-CoV-2 neutralizing
antibody titers By day 28 after the first vaccination, all vaccinated
participants had significantly higher levels of IFN-\selectlanguage{greek}γ \selectlanguage{english}secretion upon
antigen restimulation compared with the day of administration of the
first dose\textsuperscript{196}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Ad26.COV2.S\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Viral vector\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
The level of protection for the combined endpoints of moderate and
severe disease varied: 72\%~in the United States; 66\%~in Latin American
countries; and 57\%~in South Africa, 28 days post-vaccination. The
investigated vaccine was reportedly 85\%~effective in preventing
severe/critical COVID-19 across all geographical regions. Induced
durable protection at low doses in preclinical SARS-CoV-2 challenge
studies; initial clinical data showed that a single dose at
5\selectlanguage{ngerman}×10\textsuperscript{10} viral particles was safe and induced excellent
humoral and cellular immune responses\textsuperscript{197-200}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
BBIBP COVID-19 vaccine\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Inactivated vaccines\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Sinopharm has announced an efficacy of 79\% A sharp increase in antibody
concentrations was observed following SARS-CoV-2 infection after the
first and second doses\textsuperscript{177,187,201}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Covaxin (BBV152)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Viral vector\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
81\% interim efficacy in preventing COVID-19 in those without prior
infection after the 2nd dose In the phase 1 trial, BBV152 induced high
neutralizing antibody responses that remained elevated at 3 months after
the 2nd vaccination In the phase 2 trial, BBV152 enhanced humoral and
cell-mediated immune responses compared with the phase 1
trial\textsuperscript{202}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
CoronaVac\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Inactivated virus\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Multiple studies in different countries: 50.7\% (Brazil), 56.5\%
(Chile), 65\% (Indonesia), 78\% (Brazil) and 91\% (Turkey) Immune
responses in phase 2 were much better than those recorded in phase 1;
seroconversion rates over 90\% in both the 3 \selectlanguage{greek}μ\selectlanguage{english}g and 6 \selectlanguage{greek}μ\selectlanguage{english}g groups Well
tolerated and induced humoral responses against SARS-CoV-2 In an
exploratory analysis by age, seroconversion rates at day 28 after the
second dose were higher than 94\% in the 3 \selectlanguage{greek}μ\selectlanguage{english}g and 6 \selectlanguage{greek}μ\selectlanguage{english}g groups for
participants aged 60-64 years, 65-69 years, and 70 years or older, with
GMTs ranging from 36.4 to 55.2\textsuperscript{201,203,204}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
AD5-nCOV\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Viral vector\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Tolerable and immunogenic in healthy adults. Specific humoral responses
against SARS-CoV-2 peaked at day 28 post-vaccination, and rapid,
specific T-cell responses were noted from day 14 after one shot of the
vaccine Aerosolized Ad5-nCoV is well tolerated, and two doses of
aerosolised Ad5-nCoV elicited neutralizing antibody responses, similar
to one dose of intramuscular injection.~An aerosolized booster
vaccination at 28 days after first intramuscular injection induced
strong IgG and neutralizing antibody
responses\textsuperscript{205,206}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
CV2CoV\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Unmodified RNA vaccines\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Induced higher titers of binding and neutralizing antibodies against
SARS-COV-2 variants, and memory B and T cell responses non-human
primates\textsuperscript{186}.\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
PreS-RBD vaccine\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Recombinant fusion protein\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Median inhibitions of RBD to ACE2 (100 ng RBD: 8.6\% to 98.3\%
inhibition, median inhibition: 16.0\%; 50 ng RBD: 14.4\% to 99.4\%
inhibition, median inhibition: 52.8\%) Robust anti-RBD IgG response in
rabbits consisting of an early IgG1 and sustained IgG4 which can be
detected in serum and mucosa secretions The vaccine-induced antibodies
potently inhibited the interaction of RBD with ACE2 and possessed the
neutralizing ability to the omicron VOC\textsuperscript{190}.\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
NVX-CoV2373\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Protein subunit\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
A two-dose regimen of the NVX-CoV2373 vaccine administered to adult
participants conferred 89.7\% protection against SARS-CoV-2 infection
and showed high efficacy against the B.1.1.7 variant Elicited immune
responses that exceeded levels in COVID-19 convalescent
serum\textsuperscript{207,208}\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\textbf{Allergic reactions to COVID-19 vaccines}

Local and systemic reactions were reported in phase III clinical trial
of the ChAdOx1 nCoV-19 vaccine, which were mostly mild and moderate in
intensity\textsuperscript{209}. Cutaneous adverse effects of the
available COVID-19 vaccines include injection site reactions, urticaria,
angioedema, exacerbation of atopic eczema and systemic allergic
reactions including anaphylaxis\textsuperscript{210}. Anaphylaxis to the
BNT162b2 vaccine was reported several days after the initiation of
public vaccinations\textsuperscript{211}. Overall, the incidence of
COVID-19 mRNA vaccine-associated anaphylaxis is very
low\textsuperscript{212}, with only was 4.8 per million doses for
BNT162b2 and 5.1 per million doses for mRNA-1273 according to data from
Vaccine Safety Datalink\textsuperscript{213}. Moreover, the second dose
of the BNT162b2 vaccine elicited a higher rate of systemic
events\textsuperscript{191}. Nevertheless, the incidence of anaphylaxis-
associated with COVID-19 vaccines is comparable to that of other
vaccines\textsuperscript{214} and the benefits may outweigh the
potential risks of COVID-19 vaccinations\textsuperscript{215,216}.
Unfortunately, the fear of an allergic reaction has caused vaccine
hesitancy in the general public, haltering global vaccination
efforts\textsuperscript{217}.

Polyethylene glycol (PEG) is an additive present in the Pfizer-BioNtech
and Moderna mRNA vaccines used to prevent premature degradation of the
nanoparticless\textsuperscript{218}, and it has been suggested to be the
major culprit for anaphylaxis to COVID-19 vaccines\textsuperscript{219}.
PEG and its derivatives are also widely used in household products
including toothpaste, cosmetics, pharmaceuticals, and
foods\textsuperscript{220}. Many types of vaccines, therapeutic
medications and diagnostic media contain PEG with different molecular
weights and their risks of anaphylaxis has been previously
reported\textsuperscript{220,221}. Exposure to products containing PEG
via intravenous and intramuscular injection is the major route causing
HSR to PEG. There is evidence showing that lipid-conjugated PEG or
PEGylated liposomes have a stronger immunogenicity than PEG alone and
may contribute to the anaphylaxis elicited by COVID-19 mRNA
vaccines\textsuperscript{222,223}. Anti-PEG IgE-mediated HSR, complement
activation-related pseudoallergy induced by anti-PEG IgM and IgG
antibodies and potential interaction of PEG with mast cells and viral
RNA have been suggested to underly COVID-19 vaccine
anaphylaxis\textsuperscript{222,224}. IgG and IgM antibodies against PEG
were found in up to 25\% of the population without known prior exposure
to PEGylated products and in up to 89\% of patients with known prior
exposure to PEGylated products\textsuperscript{225}. Other excipients
than PEG present in authorized COVID-19 vaccines might also cause severe
allergic reactions to COVID-19 vaccines and need appropriate
allergological assessment\textsuperscript{226}.

EAACI has reported recommendations to perform in vivo tests (skin prick
test and intradermal test) and in vitro tests (basophil activation test,
BAT) to the vaccines or their components in individuals with severe
reactions to the first dose of COVID-19 vaccines\textsuperscript{227}.
The positive rate of skin test with PEG or mRNA vaccine in patients with
reactions to COVID-19 mRNA vaccine or with previous PEG or polysorbate
allergies was very low\textsuperscript{228,229}. Thus, the clinical
significance of skin testing with mRNA vaccine in those with negative
skin testing results with PEG is still unknown. BAT performed in
patients with PEG allergy demonstrated that BNT162b2 and AZD1222
vaccines and PEGylated lipids, but not unmodified PEG, can activate mast
cells\textsuperscript{223}. Thus, positive BAT results to mRNA vaccines
may be a potential diagnostic tool for confirming HSR to PEG excipient.

Studies have shown that most individuals with allergic reactions to the
first dose tolerated well the second dose irrespective of the skin test
results\textsuperscript{230,231}. Thus, the second dose vaccine may be
administered after careful evaluation and under careful monitoring in an
allergy clinic. In a position paper by EAACI, allergic patients without
prior allergic reaction to any of the vaccine components and patients
with mild and moderate allergies were recommended that they should not
be excluded from COVID-19 vaccinations\textsuperscript{227}. On the
contrary, it would put population immunity with vaccination at risk due
to the high prevalence of allergic diseases\textsuperscript{227} .
However, anaphylaxis may occur after vaccination in the absence of a
history of allergic disease. Therefore, strategies for the prevention,
diagnosis and treatment of severe allergic reactions and a list of
recommended medications and equipment for vaccine centers were provided
in the EAACI statement to minimize the risk of allergic reactions to
COVID-19 vaccines\textsuperscript{227}. Anaphylaxis induced by COVID-19
vaccines is rare but may be more severe in older people due to
comorbidities and polypharmacy\textsuperscript{232}. Intramuscular
injection of adrenaline remains the first-line therapy for anaphylaxis
in older people\textsuperscript{232}. Modified dosing or alternative
vaccines were recommended by EAACI for those with confirmed reactions to
COVID-19 vaccines\textsuperscript{227}. Herein, we provide a flow chart
for the treatment of allergic reactions to COVID-19 vaccines (Figure 4).

\textbf{Perspectives and conclusions}

Anthropogenic activities, climate change and global population movement
set a perfect environment for new outbreaks of zoonotic pathogens. Using
the knowledge and experience gained from the COVID-19 pandemic, there is
an urgent need to develop novel strategies to predict and prevent the
emergence and transmission of novel pathogens \textsuperscript{233}.
Effective surveillance of new SARS-CoV-2 variants and reporting their
transmissibility and rate of breakthrough infection is warranted to
assist international policymaking\textsuperscript{234}. The trajectory
of COVID-19 needs to be closely monitored to further our understanding
of the immunity waning, antigen drifting and re-entries from zoonotic
reservoirs \textsuperscript{235}. As we deepen our knowledge on
COVID-19, vaccination strategies should be updated and revised, such as
frequent administration of booster doses. The continuously mutating
virus warrants the development of novel vaccines targeting current
variant sequences\textsuperscript{236}. The impacts of COVID-19 on
allergen sensitization and the incidence of allergic disease are still
unknown and need to be investigated by the society of allergy and
clinical immunology.

In conclusion, similarly to other respiratory viruses, full eradication
of COVID-19 is not on the horizon. Novel strategies should be developed
for the prevention and management of this disease, particularly for
patients at high risk of severe disease and to prevent MIS-C and long
COVID. The emergence of new variants of concerns and global vaccinations
efforts have substantially changed the clinical and immunological
profiles of COVID-19.

\textbf{FUNDING INFORMATION:}

This work was supported by the Scientific Research Initiative Funds of
Shanxi Bethune Hospital (Number: 2020RC004).

\textbf{AUTHOR CONTRIBUTION:}

YG and CA initiated the idea and designed the study. HZ, YS, YW, DY, DA,
IO, AKA, ZY, XC, AZ, JH, GL contributed to the data collection and
writing. HZ and YG finalized the manuscript. MA and CA revised the
manuscript. All authors contributed to the final review.

\textbf{FIGURE LEGENDS}

\textbf{Figure 1. Daily new cases and deaths, and the characteristics of
different mutations in the COVID-19 coronavirus pandemic.} The data were
obtained from\emph{https://www.worldometers.info/coronavirus/}

\textbf{Figure 2. Proposed mechanisms of long COVID-19.} Persistent
tissue damage and inflammation are suggested to be the major mechanisms
of persistent symptoms of COVID-19. Persistent dendritic cell (DC)
deficiency, autoimmunity and dysbiosis may also contribute to the
long-term symptoms. Severe disease, aging and female are risk factors
for long COVID-19.

\textbf{Figure 3. Time-series visualization of global daily reported
COVID-19 deaths, excess mortality estimates and vaccinations.} Source
data were downloaded from Our World in Data on August 19, 2022. Excess
mortality estimates and the 95\% confidence interval (CI) were modeled
by the Economist. The lines indicate 7-day rolling averages of daily
reported deaths and excess mortality estimates per million people as
well as all daily vaccination doses per billion people, including
boosters that are counted individually.

\textbf{Figure 4. Flow chart for the management of individuals with
allergic reactions to COVID-19 vaccines.} Premedication can be used for
those with local reactions before the next dose of vaccine. For those
with systemic symptoms, assessment with skin test or basophil activation
test (BAT) in an allergy clinic is recommended and then treated with
premedication or alternative vaccines.

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