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\begin{document}

\title{Advances and Recent Developments in Asthma in 2020}



\author[1]{Lacin Cevhertas}%
\author[2]{Ismail Ogulur}%
\author[3]{debbie maurer}%
\author[1]{daniel burla}%
\author[4]{Mei Ding}%
\author[5]{Kirstin Jansen}%
\author[1]{Jana Koch}%
\author[1]{Chengyao Liu}%
\author[1]{Siyuan Ma}%
\author[1]{yasutaka mitamura}%
\author[4]{Yaqi Peng}%
\author[4]{Urszula Radzikowska}%
\author[6]{Arturo Rinaldi}%
\author[7]{Pattraporn Satitsuksanoa}%
\author[1]{anna globinska}%
\author[5]{Willem van de Veen}%
\author[3]{Milena Sokolowska}%
\author[4]{Katja Baerenfaller}%
\author[8]{Ya-dong Gao}%
\author[9]{Ioana Agache}%
\author[10]{Mubeccel Akdis}%
\author[5]{Cezmi Akdis}%
\affil[1]{University of Zurich Swiss Institute of Allergy \& Asthma Research}%
\affil[2]{Marmara Universitesi}%
\affil[3]{Swiss Institute of Allergy and Asthma Research, University of Zurich}%
\affil[4]{Swiss Institute of Allergy and Asthma Research}%
\affil[5]{University of Zurich}%
\affil[6]{Swiss Institute for Allergy and Asthma Research (SIAF)}%
\affil[7]{SIAF}%
\affil[8]{Zhongnan Hospital of Wuhan University}%
\affil[9]{Transylvania University of Brasov}%
\affil[10]{University of Zürich}%


\vspace{-1em}



  
  \date{May 08, 2024}


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\selectlanguage{english}
\begin{abstract}
In this review, we discuss recent publications on asthma and review the
studies that have reported on the different aspects of the prevalence,
risk factors and prevention, mechanisms, diagnosis and treatment of
asthma. Many risk and protective factors and molecular mechanisms are
involved in the development of asthma. Emerging concepts and challenges
in implementing the exposome paradigm and its application in allergic
diseases and asthma are reviewed, including genetic and epigenetic
factors, microbial dysbiosis and environmental exposure, particularly to
indoor and outdoor substances. The most relevant experimental studies
further advancing the understanding of molecular and immune mechanisms
with potential new targets for the development of therapeutics are
discussed. A reliable diagnosis of asthma, disease endotyping and
monitoring its severity are of great importance in the management of
asthma. Correct evaluation and management of asthma
comorbidity/multimorbidity, including interaction with asthma phenotypes
and its value for the precision medicine approach and validation of
predictive biomarkers are further detailed. Novel approaches and
strategies in asthma treatment linked to mechanisms and endotypes of
asthma, particularly biologicals, are critically appraised. Finally, due
to the recent pandemics and its impact on patient management, we discuss
the challenges, relationships, and molecular mechanisms between asthma,
allergies, SARS-CoV-2 and Covid-19.%
\end{abstract}%



\sloppy


\textbf{Introduction}

Asthma is a chronic heterogeneous disease of the lower airways
characterized by chronic inflammation and airway hyperreactivity leading
to cough, wheeze, difficulty in breathing and chest tightness. The
pathophysiology of asthma is complex. In the past three decades a better
understanding of distinct asthma visible properties (phenotypes) and
mechanisms (endotypes) shaped better diagnostic and therapeutic tools in
support of stratified/personalised interventions based on recognition of
differences in responsiveness to various therapeutic interventions
(theratypes).\textsuperscript{1,2} In addition, environmental factors,
genetic polymorphisms and epigenetic factors contribute to the
development of asthma, heterogeneity in phenotyping and steroid
responsiveness.\textsuperscript{3-6} Environmental interventions and
exposure control can improve asthma control and
exacerbations.\textsuperscript{7}

The incidence and prevalence of asthma are increasing, though regular
use of inhaled corticosteroids (ICS) reduces
mortality\textbf{.\textsuperscript{8,9}} New therapies and therapeutic
targets are required for better control of symptoms and exacerbations in
severe asthma patients and for avoiding adverse reactions caused by the
administration of oral corticosteroids (OCS).

This review highlights the recent studies on immunopathological
pathways, molecular mechanisms, various environmental factors and
microbial dysbiosis in asthma. Clinical trials, multi-centered
international studies and real-world data are reviewed for novel
approaches in asthma diagnosis, candidate biomarkers and management of
asthma in adults and children.

\textbf{Epidemiology and risk factors in the development of asthma}

\emph{Asthma prevalence in adults and children}

Asthma prevalence seems to be still increasing as suggested by Borna et
al., who investigated its change between 2008 and 2016 in Sweden. The
authors observed a significant rise of reported frequencies of ever
asthma, physician-diagnosed asthma, use of asthma medication and current
asthma, especially in young adults aged
16-25~years.\textsuperscript{9}At the same time, an increase in the
prevalence of respiratory symptoms during the same period was reported,
suggesting the possibility that actually, asthma is underdiagnosed. The
potential risk factors for asthma remained the same during the study
period.\textsuperscript{9}

Recent studies assessed the prevalence of asthma in preschoolers (4.4
\%) and elementary school children (6.4\%) according to Global
Initiative for Asthma (GINA) definition.\textsuperscript{8} While no
significant difference between rural and urban children was observed,
Branco et al. found an association with previously identified risk
factors for asthma development, including parental asthma and
antibiotics treatment in the first year of life.\textsuperscript{10} Liu
et al. investigated the link between maternal hypothyroidism in the
perinatal period and childhood asthma risk, in a population-based cohort
study using Danish national registers. A higher incidence of asthma was
found compared to children born to mothers with no thyroid dysfunction.
The risk was even higher if the mothers did not receive thyroid hormone
treatment during pregnancy.\textsuperscript{11}

\emph{Gender-Specific Differences in Prevalence}

In a study involving 3115 Swiss adolescents, \selectlanguage{ngerman}Ödling et al. reported that
asthma tended to be more common among girls compared to boys, however
boys with asthma had more often a doctor's
diagnosis.\textsuperscript{12} Uncontrolled asthma was more common among
girls than boys, who also were more often dispensed with high daily
doses ICS compared to girls. Subjects with persistent early onset asthma
had more often a doctor's diagnosis compared to adolescent\selectlanguage{english}-onset asthma.
The authors highlighted the clinical relevance of monitoring female
adolescents with uncontrolled asthma.\textsuperscript{12}Gender-specific
prevalence of rhinitis and asthma as single and multimorbid diseases
during puberty was examined in six European population-based birth
cohorts of MeDALL. Male predominance in prevalence before puberty and
the ``gender-shift'' towards females after puberty onset were strongest
in multimorbid patients who had rhinitis and asthma
concurrently.\textsuperscript{13}

\textbf{Recent developments in asthma-related genes}

Genetic factors have a strong impact on the risk of developing
asthma.\textsuperscript{2} In particular, childhood asthma is strongly
associated with the 17q21 locus alleles. Analyzing 14 different
populations of asthmatic patients from 12 different countries, Farzan et
al. showed that 17q21 polymorphism is related to an increased risk of
exacerbations in children with asthma despite ICS
use.\textsuperscript{14} The authors also observed that the SNP
rs7216389 frequency was higher in East Asians, African Americans and
Hispanics, compared to patients of European
ancestry.\textsuperscript{14} Interestingly, an interaction between
17q21 variants and breastfeeding in relation to respiratory symptoms in
the first year of life was observed by Gorlanova et al., suggesting a
protective effect of breastfeeding on asthma inception linked to
early\selectlanguage{english}-life respiratory infections in babies carrying the risk alleles.
Specifically, when infants were stratified by breastfeeding status,
carriers of asthma risk alleles showed a protective effect of
breastfeeding on respiratory symptoms during the weeks when they were
breastfed, while they showed an increased risk of respiratory symptoms
during the weeks when they were not breastfed.\textsuperscript{15}
The\emph{ORMDL3} gene, also related to the 17q21 region, plays an
important role as well. There are higher levels of human lung
\emph{ORMDL3} and its SNPs rs8076131 from asthmatic patients than the
healthy subjects.\textsuperscript{16}

Associations between childhood asthma phenotypes and genetic,
immunological, and environmental factors have been largely established
whereas there is a lack of strategies to integrate high\selectlanguage{english}-dimensional risk
factors from multiple distinct data sets and thereby increase the
statistical power of analyses.\textsuperscript{17} In many studies the
classification of childhood asthma phenotypes is often based on
assessment of singular risk factors measurements only. Krautenbacher et
al. evaluated a new strategy combining cytokine, genotype, flow
cytometry, diagnostic, questionnaire, Reverse transcription polymerase
chain reaction (RT\selectlanguage{english}-PCR), and microarray data by using an integrative
multilevel learning approach. Following this new discovery approach
genes such as PKN2 (protein kinase N2), PTK2 (protein tyrosine kinase
2), and ALPP (alkaline phosphatase, placental) seem to be the most
important asthma risk factors.\textsuperscript{18}

Interleukin 1 receptor-like 1 (ST2) is known to be related to the
pathogenesis of allergic diseases by mediating the response to
IL-33.\emph{Interleukin 1 receptor-like 1 (ST2)} single\selectlanguage{english}-nucleotide
polymorphisms (SNPs) rs13431828, rs1420101, rs1921622, and rs10204137
were related to reduced efficacy of ICS in children and
adolescents.\textsuperscript{19}

Recently, Olafsdottir et al.\textsuperscript{3} demonstrated 88 asthma
risk genome variants at 56 loci, 19 previously unreported, in a
genome-wide association meta-analysis. They investigated the effect of
asthma-associated variants and their genetic correlation between asthma
and allergic phenotypes as well. They suggest a missense variant
in\emph{TNFRSF8} and a 3' untranslated region variant in \emph{TGFBR1}
to be related to decreased asthma risk. In a study on the
Hispanic/Latino population in the US genetic predisposition to obesity
was found as a risk factor for asthma, especially for childhood-onset
asthma in females\textsuperscript{4}.

\textbf{Environmental risk factors for the development of asthma}

Many environmental factors can affect the risk of developing asthma. The
American Academy of Allergy Asthma and Immunology (AAAAI) and European
Academy of Allergy and Clinical Immunology (EAACI) have discussed
emerging concepts and challenges in implementing the exposome paradigm
and its application in allergic diseases and asthma. The complex network
of exposome, genome, transcriptome, proteome, epigenome and metabolome
in driving the disease phenotype and endotype is
described.\textsuperscript{20}

Air quality has an influence on asthma symptoms and on triggering asthma
attacks. Kim et al. correlated measurements of air pollutants around
patients' houses, including particulate matter (PM), with asthma status
and with the frequency of innate immune cells (ILC) in induced sputum. A
significant positive correlation between the amount of PM with a
diameter \selectlanguage{english}[?]10 \selectlanguage{greek}µ\selectlanguage{english}m and asthma control was reported accompanied by an
increased frequency of ILC2s in induced sputum.\textsuperscript{6}

Recently Yang et al. showed prenatal exposure to PM with an aerodynamic
diameter of smaller than 10~\selectlanguage{greek}μ\selectlanguage{english}m (PM) has a higher association with airway
hyperresponsiveness (AHR) and the risk of a new diagnosis of asthma at
an early school age than current and lifetime exposure. Therefore,
stricter monitoring and avoidance of exposure to PM might considerably
reduce the onset of future asthma development in
schoolchildren.\textsuperscript{21} Indoor air contaminants, containing
endocrine-disrupting chemicals (EDCs), can also increase the risk of
asthma, as shown by Paciencia et al.\textsuperscript{22} The authors
assessed the association between EDCs exposure and asthma in children
from 20 schools and found that increased individual and combined EDCs
levels were present in classrooms having more children with asthma and
with an increased prevalence of nasal obstruction symptoms in the
previous 3~months. EDCs are associated with changes in the autonomic
nervous system, thus suggesting that EDCs may increase parasympathetic
activity, resulting in a subsequent increase in the risk of
asthma.\textsuperscript{22}

Pollutants can induce type 2 over type 1 response in the airways of an
allergic asthma mouse model upon co-stimulation with the house dust mite
(HDM) allergen as shown by Brandt et al (Figure
1).\textsuperscript{23,24} Increased IL-33 signaling in the airway
epithelium upon diesel exhaust particles (DEP) exposure can exhibit a
synergistic effect with the type 2 cytokines IL-5 and IL-13 leading to
severely increased AHR as well as a resistance to treatment with
dexamethasone. IL-5/IL-13/IL-17A coproducing
CD4\textsuperscript{+}effector T-cells in the lungs of DEP and allergen
co-stimulated mice were identified, potential promoters of asthma
exacerbations.

The activation of Aryl hydrocarbon receptor (AhR) exacerbating an
allergic response was previously demonstrated. Weng CM et
al.\textsuperscript{25} showed that DEP activates AhR and with
upregulation of IL-33, IL-25, and thymic stromal lymphopoietin (TSLP) by
means of T helper cell (Th) 2 activation. This finding further supports
the link between pollution and allergic severe asthma. Another recent
study has reported AhR signaling critical role in the benzo(a)prene and
Der f 1 co-exposure, leading to epithelial cytokine release through
regulation of reactive oxygen species (ROS)
generation.\textsuperscript{26} Future studies on the AhR-ROS axis may
provide new therapeutic approaches to asthma.

\emph{Artemisia} ~pollen allergy is a major cause of asthma in Northern
China.~Gao et al. observed that the frequency of sensitization and the
IgE levels related to the four main allergens (nArt v 1, nArt ar 2, nArt
v 3, nArt an 7) were significantly lower in subjects from the South of
China compared to those from the North, who were more likely to have
allergic asthma. The authors also reported that the co-sensitization to
at least three of the most frequent allergens (Art v 1, Art v 3, and Art
an 7) results in a higher risk of allergic asthma.\textsuperscript{27}

The most common allergen in allergic asthma is group-1 grass pollen. A
wave of exacerbations of allergic asthma can be observed in fall, when
grass has undergone senescence and turned to straw, where mold
lives.\emph{Alternaria alternata} spores from the surface of straw have
been shown to carry the same allergens as grass pollen and probably
inducing allergen-mediated exacerbations in allergic asthma
patients.\textsuperscript{28}

Besides exposure to allergens, \emph{de novo} sensitization
to\emph{Aspergillus fumigatus} is also becoming recognized as a risk
factor for asthma patients. From baseline to follow-up over a 10-year
observation period, asthmatic patients acquired noticeably increased
frequencies for specific IgE levels to rAsp f 1.\textsuperscript{29} The
presence of \emph{A. fumigatus} was associated with reduced BAL
macrophages, increased BAL levels of IL-4, IL-6, IL-10, IL-13 and TNF-\selectlanguage{greek}α,
\selectlanguage{english}and increased plasma IL-4, IL-6, IL-10, IL-13, IL-17, and TNF-\selectlanguage{greek}α.
\selectlanguage{english}However, there was no relationship between the presence of \emph{A.
fumigatus} in the asthmatic airways and disease severity or
control.\textsuperscript{30}

\emph{Epidemic thunderstorm asthma} is an emerging public health threat
triggered by a combination of thunderstorms and massive loads of small
pollen allergen particles, and people without a prior history of asthma
can also be affected. D'amato \emph{et al.}
\textsuperscript{5}investigated why thunderstorms are associated with a
rapid increase of asthmatic patients that in need of urgent medical
care, due to asthma attacks. Thunderstorms can bring allergen particles
down to ground level and rainfall during thunderstorms is able to
rupture pollen grains and release bio-aerosols containing allergenic
particles that penetrate deeply into the airways with acute severe
allergic inflammation leading to asthma attacks with hospitalizations in
people never experiencing before an asthma attack and suffering only of
allergic rhinitis symptoms. A study from Melbourne investigated risk
factors to predict severe asthma attacks requiring hospital admission
during thunderstorm. Odds for hospital admission were higher in Asian
patients born locally compared to those born overseas. Non-Asian
patients had the lowest odds for hospital admission. This suggests
gene-environment interactions playing a role in the susceptibility to
severe thunderstorm asthma.\textsuperscript{31} Furthermore, Lol p 5,
the major allergen of ryegrass pollen was reported to be responsible for
triggering an epidemic of thunderstorm asthma.\textsuperscript{32} A
systematic review and meta-analysis on the possible link between pollen
exposure and asthma hospital admissions in children and adolescents aged
\textless{}18 years with emergency department attendance demonstrated
ambient grass pollen as an important trigger for childhood asthma
exacerbations requiring emergency department attendance, especially in
relation to thunderstorm asthma.\textsuperscript{33}

\emph{Smoking and e-cigarettes}

The association of asthma development and smoking has been extensively
studied for conventional cigarettes.\textsuperscript{34} Extensive
hazard to respiratory system have been recently reported in multiple
studies.\textsuperscript{35-38} A study evaluated the impact of
electronic cigarettes and heated tobacco products on asthma and allergic
rhinitis (AR). The survey in Korean middle and high school students
could not determine these tobacco products to be a risk factor on their
own, however, in combination with conventional cigarettes they could
worsen asthma and AR status of children.\textsuperscript{39}

\emph{Supplements, nutrients and anti-acid medications}

In a recent review, Venter et al.\textsuperscript{40} highlighted the
potential roles of fatty acid metabolism in biological mechanisms, human
epidemiology, and intervention studies. The impact of genetics and the
microbial dysbiosis on fatty acid metabolism are discussed briefly. The
authors suggest focusing on to the choice of the formats (i.e., food
versus supplement) and standardized doses in clinical studies which will
make easier to investigate their roles in the prevention and treatment
of allergies and asthma. EAACI`s position paper recommending a diverse
diet for the infants and consensus-based definitions, which is a benefit
for further studies.\textsuperscript{41} A study from Korea found that
consumption of fast food was related to asthma incidence in adolescents
but not in adults, whereas instant noodles had more impact in adults
than in adolescents. No relation was found between asthma and the intake
of vegetables and fruits, which might be confounded by the generally
high intake of healthy food by Koreans as background
nutrition.\textsuperscript{42}

Another supplement, which was evaluated as an early prevention strategy
for asthma is vitamin D. Vitamin D supplementation remains as a
controversial issue, because of several recently published negative
studies. Vitamin D supplementation of pregnant mothers did not reduce
the incidence of asthma in children at 6 years of age. However, it might
provide benefits by reducing the preschool wheezing
episodes.\textsuperscript{43,44} A prospective study with
maternal-infant cohort showed that during the 2 and 5 years of
observation, there is no association between vitamin D exposure
antenatal or after birth and the progression of allergic
disease.\textsuperscript{45} In addition, antenatal supplementation with
vitamin D did not prevent the development of asthma or recurrent wheeze.
Earlier results by the same group suggested that antenatal vitamin D
lowers the risk of the offspring developing asthma by 3 years of age,
however, these effects were lost by age 6.\textsuperscript{44}

Tomita et al\textsuperscript{46} suggested a relationship between the
use of acid-suppressive medications, such as histamine 2 receptor
antagonists and proton pump inhibitors, and the occurrence of
adult-onset asthma.

\textbf{Microbial dysbiosis and asthma}

Nasal, lung and gut microbiota play several important roles in the
development, regulation, and maintenance of healthy and asthmatic immune
responses. Dysregulation of microbiota-related immunological and
metabolic processes impacts the onset of asthma, its clinical
characteristics and treatment response.\textsuperscript{47,48}Antibiotic
treatment and changes of the microbiome, especially early in life, are
an important field of study since the microbiome has been associated
with the health status of individuals in numerous diseases, including
asthma.\textsuperscript{49} 1-year old children that had an immature
microbiome were shown to have a higher risk to develop asthma later in
life if their mother was asthmatic as well.\textsuperscript{50}A recent
prospective study studied the connection between the gut microbiota and
the development of asthma in wheezing preschool children. No connection
to the richness of microbes nor species diversity was found, but an
increase in bacteria of the genera \emph{Escherichia}
and\emph{Gemminger} at ages 2-4 in children that were diagnosed as
asthmatics later on was reported.\textsuperscript{51} Lee \emph{et al.}
\textsuperscript{52}investigated the differences in the microbiome
between young adults and elderly asthmatic and non-asthmatic
individuals. They found an upregulation in genes, such as relative
abundances of microbiome genes associated with the pentose phosphate
pathway, lipopolisaccaride biosynthesis, flagellar assembly, and
bacterial chemotaxis, and nitric oxide production were higher in
asthmatics than in non-asthmatics. that could be related to increased
inflammation and colonization of bacteria in young adult asthma
patients. Furthermore, genes that could be related to the reduction of
inflammation and degradation of air pollutants were higher in
non-asthmatics of both age groups. In another study the authors showed a
reduction in prostaglandin E2 (PGE2) in the asthma group, and an
upregulation of the molecules that could be associated to airway
inflammation such has arachidonic acid metabolites, lysine residues, and
glycosaminoglycans.\textsuperscript{53} Together these data suggest that
alterations in the composition and function of the upper airway
microbiome could influence asthma pathogenesis and that specific effects
can distinguished based on the age groups.

Probiotic bacteria interventions to prevent and to treat airway and
allergic diseases are currently being evaluated. In a mouse model of
asthma, Spacova et al.\textsuperscript{54} used different strains of and
intranasally administrations of \emph{Lactobacillus} \emph{rhamnosus} to
observe the preventive effects of probiotics. Only \emph{L. rhamnosus}GG
strain treatment lead to a reduction in BAL eosinophil counts, lung IL-5
and IL-13 levels, and in airway hyperreactivity. Thus, preventing the
development of birch pollen-induced allergic asthma by probiotics is
strain-specific. Ingestion of bacterial lysate has also been proposed to
asthma. However, when extracts of \emph{Escherichia coli}
and\emph{Enterococcus faecalis} were introduced into the diet of
newborns, no significant effect on the occurrence of asthma, atopic
dermatitis, AR or sensitization to allergens was observed in
6-11-year-old children.\textsuperscript{55}

Pulmonary microbial dysbiosis can influence the inflammation status of
the host. The dysbiosis can be inherited, if the mother was treated with
antibiotics during the pregnancy resulting in higher asthma rates in the
offspring as shown by Alhasan et al.\textsuperscript{56} Surprisingly,
instead of the expected upregulation of type 2 cytokines in allergic
offspring, a downregulation was found. Causalities are still unclear and
will require specifically designed future studies to address this issue.

Microbial dysbiosis can also be induced by air pollution like tobacco
smoke, while other pollutants influence the epithelium more directly.
Eguiluz-Gracia et al\textsuperscript{57} reviewed the current
understanding of indoor and outdoor air pollutants as well as the
effects of climate change on human pulmonary health, highlighting how
important clean air is for human health.

\textbf{Molecular mechanisms in the development of asthma}

Immune system cells migrate to the lungs and display their functional
properties to develop asthma.\textsuperscript{58} It was demonstrated
that Th2 resident memory T cells and circulating memory Th2 traffic into
the lung parenchyma and initiate a perivascular inflammation to promote
eosinophil and CD4\textsuperscript{+} T cell recruitment. Th2 resident
memory cells proliferate near airways and induce mucus metaplasia, AHR
and airway eosinophil activation. Transcriptional analysis revealed that
Th2 resident memory cells and circulating memory Th2 cells share a core
Th2 gene signature, but also exhibit distinct transcriptional profiles
(Figure 1).\textsuperscript{58}

Braga et al.\textsuperscript{59} described the cellular landscape of
airway lining at the single-cell level. This comprehensive analysis in
asthma identified dominance of T\textsubscript{H}2 cells interacting
with structural and inflammatory cells. The presented data open new
perspective on lung biology and molecular mechanisms of
asthma.\textsuperscript{59} A Th1/Th2 imbalance is commonly seen in
allergic asthma and it is shifted back towards Th1 by Protein S. Protein
S, an anticoagulant, anti-inflammatory and anti-apoptotic glycoprotein
is associated with a reduction of AHR, lung tissue inflammatory cell
infiltration, Th2 cytokines in the lung and IgE levels. Asayama et al.
showed that it could inhibit allergic asthma by upregulating the type 1
cytokines TNF-\selectlanguage{greek}α \selectlanguage{english}and IL-12 while downregulating
IL-5\textsuperscript{+}Th2 cells.\textsuperscript{60} A downregulation
of Th2 cells is also achieved by intraperitoneal injection of
cysteamine, along with IL17\textsuperscript{+} Th17 and
IL13\textsuperscript{+}IL17\textsuperscript{+} Th2/Th17 cells, thus
effectively inhibiting AHR in an allergic mouse model upon retreatment
with the allergen.\textsuperscript{61} Lu et al. reported high ILC2
levels in type 2 asthmatics, while non-type 2 asthmatics showed higher
levels of Th17 cells and an inversed Th1/Th17
ratio.\textsuperscript{62}The pathways of Th2-high and Th17-high
inflammation were reciprocally regulated.

The type 2 immunity is mainly driven by IL-4 and IL-13 signaling which
share the common receptor subunit interleukin-4 receptor alpha (IL-4R\selectlanguage{greek}α\selectlanguage{english})
(Figure 2). Withdrawal of IL-4R\selectlanguage{greek}α \selectlanguage{english}signaling prevents the development of
AHR, eosinophilia, and goblet cell metaplasia in allergen-sensitized
mice. However, the IL-4R\selectlanguage{greek}α-\selectlanguage{english}deficient mice does not develop type 17
immunity after allergic sensitization.\textsuperscript{\textbf{63}}
\textbf{}

The increased serum IL-33 levels in asthma patients has been linked to
the activation of mast cells. To characterise the mechanisms of IL-33
contribution to asthma development, Ro et al.\textsuperscript{64} used
knockdown or pharmacological inhibitors in bone marrow-derived mast
cells and animal model. The study revealed that the
`MyD88-5-/12-LO-BLT2-NF-\selectlanguage{greek}κ\selectlanguage{english}B' cascade contributes to the IL-33 signaling
to induce IL-13 synthesis in mast cells, which may represent a new
therapeutic target for severe asthma.\textsuperscript{64}

Lv et al. investigated the role and the mechanisms of IL-37 in type
2-mediated allergic lung inflammation in HDM-induced murine asthma
model. They found IL-37 impairs HDM-induced asthma, most likely by
preventing IL4/IL13-induced chemokine ligand (CCL)11 production from
fibroblasts and airway smooth muscle cells through its direct effect on
tracheobronchial epithelial cells.\textsuperscript{65}

In a murine allergic asthma model, IL-4 receptor \selectlanguage{greek}α \selectlanguage{english}blockade decreased
serum IgE and IL-5 levels and increased the level of IgG1, IgG2a, IgG2b
and IgG3 prior/during sensitization. Thus following the IL-4 receptor \selectlanguage{greek}α
\selectlanguage{english}blockage, an immediate immunoglobulin response is induced accompanying
the suppression of type 2 cytokines with a potential long-lasting
reduction in Th2-biased T-regulatory (Treg) cells.\textsuperscript{66}

Chitotriosidase (chitinase 1, Chit1) has been known as regulator and
stimulator in Th2 responses. Hong et. al. studied the possible
mechanisms and its role in the pathogenesis of allergic
asthma.\textsuperscript{67} Significantly elevated levels of Chit1 in
the sputum of patients with childhood asthma were reported. Moreover, in
the absence of Chit1 molecule, forkhead box P3
(Foxp3)\textsuperscript{+} Treg cell frequency decreased in the lungs of
mice besides TGF-\selectlanguage{greek}β\selectlanguage{english}1 levels, which suggests a protective role in
asthmatic airway responses by regulating TGF-\selectlanguage{greek}β \selectlanguage{english}secretion and
Foxp3\textsuperscript{+} Treg cells.

A neutrophilic inflammatory response or Th17 response is classified as
non-type 2 asthma. The potential mechanisms of non-type 2 asthma have
been well-described in a comprehensive review
article.\textsuperscript{\textbf{68}} Th17 cells are shown to play a key
role in allergic asthma by the secretion of inflammatory cytokines,
including IL-17A, IL-17F, IL-21, and IL-23. Worth \emph{et
al.}successfully demonstrated that genetic variants in IL17F, L17A, and
IL-23 signaling genes (IL23A, IL23R, IL12B) are associated with asthma.
Their results also confirmed that IgE levels could influence the
Th17-related gene expression.\textsuperscript{\textbf{69}} Moreover, the
IL-17 levels and leukotriene (LT)B4 were shown to increase with disease
severity in serum and sputum. Ro \emph{et al.} investigated the role of
LTB4 receptors, BLT1 and BLT2, in a neutrophil-dominant pulmonary
inflammation murine model. BLT1 and BLT2 were proven as important in
asthma development, and IL-17 was identified as a key cytokine
synthesized through the BLT1/2-cascade.\textsuperscript{\textbf{70}} In
humans\textbf{,} neutrophils released from the bone marrow express low
levels of CD16 and high levels of CD62L. This
CD16\textsuperscript{dim}CD62L\textsuperscript{high} subset is
considered representing the immature neutrophil, whereas the
CD16\textsuperscript{high}CD62L\textsuperscript{dim} subset is thought
to be mature and induced systemic
inflammation.\textsuperscript{\textbf{71}} Ekstedt \emph{et al.}recently
found that this novel neutrophil subset,
CD16\textsuperscript{high}CD62L\textsuperscript{dim}, is increased in
the blood following an inhaled allergen bronchial challenge
bronchoprovocation test. They proposed that increasing neutrophil
subgroups in allergic asthma might offer new opportunities in advancing
allergic asthma research (Figure 3).\textsuperscript{\textbf{71}}
\textbf{}

`Eat me' and `Don't eat me' signals are an integral part of phagoptosis
and thus, in neutrophils, they are important for the resolution of
pulmonary inflammation as prolonged survival of airway neutrophils is
directly related to asthma severity.\textsuperscript{72} In allergic
donors, neutrophils showed an upregulation of CD47 (`don't eat me') and
a simultaneous downregulation of CD36 and CD43 (`eat me') compared to
healthy controls (Figure 3).\textsuperscript{73} Additionally, less mRNA
for CCL4 and CCL20 (homing cytokines for macrophages) was found in
airway neutrophils of asthmatic donors than in healthy controls.

A study performed by Guan et al.\textsuperscript{74} has reported that
reduced monocytic myeloid-derived suppressor cells (M-MDSC) may result
in abnormal T responses with the increase in Th2 and Th17 cells and
decrease in Treg cells in asthma patients. These results suggest a new
immune regulatory mechanism in the pathogenesis of asthma open for
further research.\textsuperscript{74} To define whether there is a
deficiency in Breg subsets, Wirz et al.\textsuperscript{75} compared the
percentages of IL-10-producing Breg subsets in peripheral blood from
patients with asthma and AR. They demonstrated that there is no
difference in numbers of Bregs in the patients when compared to healthy
controls.\textsuperscript{75}

Current research suggests that several receptors involving in asthma
pathophysiology, including PGD\textsubscript{2} receptor 2 (DP2 or
CRTH2), as well as, colony-stimulating factor 1 receptor (CSF1R). The
DP2 receptor is an essential regulator in allergic asthma because it can
be activated by both allergic and nonallergic
stimuli.\textsuperscript{76} The activation of the DP2 receptor pathway
increases both the airway smooth muscle mass and vascularization in
airway walls, resulting in downstream effects on asthma development.
Interestingly, airway epithelial cells secrete CSF1 into the alveolar
space in response to aeroallergen. Moon \emph{et al.} demonstrated that
inhibition of the CSF1-CSF1R signaling pathway could suppress
sensitization to aeroallergens and subsequent allergic lung inflammation
in mice with chronic asthma. They conclude that inhibition of CSF1R is a
potential new target for the medical treatment of allergic
asthma.\textsuperscript{77}

Kim et al\textsuperscript{78} showed that the
ceramide/sphingosine-1-phosphate ratio can discriminate between two
different asthma endotypes. Sphingosine-1-phosphate (S1P) was found to
positively correlate with the percentage of platelet adherent
eosinophils, indicating eosinophilic inflammation. The percentage of
CD66\textsuperscript{+} activated neutrophils positively correlates with
C16:0 ceramide levels, indicating neutrophilic inflammation. An
upregulation of ceramide-mediated pro-apoptotic signals were found in
patients with higher CD66\textsuperscript{+} neutrophils. For both
eosinophilic and neutrophilic pathways, genetic SNPs were found.
Increased ceramide levels may also contribute to the development of
obese asthma. Choi et al.\textsuperscript{79} found multiple ceramides
(C16:0, C18:0 and C20:0) to accumulate in obese mice as a result of a
high fat diet, inducing AHR and inflammation. Increased expression of
ceramide synthase (CerS)1 and CerS6 were found in the lungs, and CerS6
was identified as a potential future therapeutic target for obese
asthma.

Felix and Kuschnir\textsuperscript{80} pointed out that Arginase
inhibitors could act beneficial for obese asthma patients by
upregulating the L-Arginine/asymmetric dimethylarginine ratio as an
addition to a previous article by Meurs et al.\textsuperscript{81} The
reply by Meurs et al.\textsuperscript{82} agreed and suggested an even
more direct link in pointing to the previously known increased arginase
expression and activity in obese asthma patients. However, the mechanism
behind this is still unknown, opening up avenues for future research.
One of the characteristics of asthmatic lung is airway remodeling.
Whether airway inflammation and remodeling in asthmatics can be related
to persistent airflow obstruction was evaluated in a recent study that
showed in asthmatics with persistent airflow obstruction increased
airway smooth muscle area, decreased periostin and transforming growth
factor beta (TGF-\selectlanguage{greek}β\selectlanguage{english}) and chymase positive cells compared to patient with
non-persistent obstruction.\textsuperscript{83} Asaduzzaman et
al.\textsuperscript{84} studied cockroach-induced chronic murine asthma
models by using a specific inhibitor of proteinase-activated receptor-2
(PAR\textsubscript{2}) to identify a role of
PAR\textsubscript{2}signalling on AHR and airway
inflammation/remodelling. They showed that administration of an
anti-PAR\textsubscript{2} antibody significantly inhibited AHR,
inflammation and collagen accumulation in the lung tissue. The authors
suggest that PAR\textsubscript{2} blockade may be a successful
therapeutic strategy for human allergic airway
diseases.\textsuperscript{84}

A recent study has introduced an \emph{in vivo} molecular platform to
elucidate both disease mechanisms and therapeutic targets of virus
associated and non-virus-associated asthma exacerbations. A group of
exacerbation-related modules included SMAD3 signaling, epidermal growth
factor receptor signaling, extracellular matrix production, mucus
hypersecretion, and eosinophil activation.\textsuperscript{85}~ Another
study in infants suffering from rhinovirus bronchiolitis showed that
concentrations of IL-4, IL-5, IL-13, and TSLP, were correlated with a
higher risk of asthma onset in childhood.\textsuperscript{86} In a study
with 5-year-old children demonstrated that the development of atopic
asthma in children with early rhinovirus-induced wheezing was associated
with differentially methylated genomic regions. The strongest
methylation changes were observed in the \emph{SMAD3} gene promoter
region at chr 15q22.33 and in introns of~the \emph{DDO/METTL24} ~genes
at 6q21.\textsuperscript{87}

Respiratory syncytial virus (RSV) infection affects a large number of
the population in the early years of their life and is associated with
an increased asthma risk. Schuler et al. show that uric acid and IL-1\selectlanguage{greek}β
\selectlanguage{english}play a role in the mechanism, and their inhibition can prevent the
development of asthma after neonatal RSV infection, thus being a
possible therapeutic target.\textsuperscript{88} A prospective study
suggested infants suffering from bronchiolitis at less than 6 months of
age, have a twice higher risk of doctor-diagnosed asthma after follow-up
for 11-13 years compared to general Finnish population, and that the RSV
was the main reason for bronchiolitis in these
infants.\textsuperscript{89} The EAACI Influenza in Asthma Task Force
performed a scoping review about the influenza burden, prevention, and
treatment in asthma. In this review, vaccination conferred a degree of
protection against influenza illness and asthma-related morbidity to
children with asthma, but not to adults with asthma. Although influenza
vaccines appeared to be safe for asthmatic patients, there is a lack of
data regarding efficacy in adults.\textsuperscript{90}

A few studies have been performed to reveal the effects of medical
treatments with ILCs in allergic airway diseases so far. The mechanisms
in action of glucocorticoid therapy on ILCs were assessed in a
prospective study by Yu et al.\textsuperscript{91} Their data showed the
administration of glucocorticoids regulates ILC2s via MEK/JAK-STAT
signalization pathways in asthma patients.

To test the role of MUC1 membrane mucin in uncontrolled severe asthma,
the recent study analysed the association of MUC1-CT (cytoplasmic tail
in the C-terminal subunit) with corticosteroid efficacy in \emph{in
vitro} and \emph{in vivo} models. The results suggested that MUC1-CT has
an important role in the modulation of the anti-inflammatory effects of
corticosteroids and may be a promising new approach for the treatment of
asthma.\textsuperscript{92}

MicroRNAs (miRNA) are secreted in extracellular vesicles and regulate
signaling pathways by being transferred between cells. Recently, Bartel
et al. characterized the miRNA secretion in extracellular vesicles from
normal bronchial epithelial cells treated with IL-13 to induce an
asthma-like epithelium. They observed that miR-34a, miR-92b, and miR-210
were involved in the early development of a Th2 response in the airways
and asthma\textsuperscript{93}.

Suojalehto et al. examined the protein expressions from nasal brush
samples from work-related asthma patients and healthy controls using the
proteomic approach. Work-related asthma patients often are exposed to
welding fumes, aerosols composed of hazardous metals and gases. The
nasal brush samples are a relatively non-invasive specimen containing
proteins secreted from epithelial and inflammatory cells. Their results
indicated that the nasal epithelial proteome of the work-related asthma
patients is highly enriched in processes related to inflammatory and
calcium signalling, free radical scavenging and oxidative stress
response, and metabolism.\textsuperscript{\textbf{94}}

Uwadiae et al.\textsuperscript{95} studied the role of T follicular
helper (TFH) cells of allergen airway disease in a mouse model of
allergic asthma. They found that TFH cells accumulate beside the
germinal center B cells with constant allergen exposure. Furthermore,
blocking the inducible costimulatory (ICOS) signaling disrupted the TFH
cell response; however, it did not have an impact on the differentiating
of other CD4+ T-cell subsets. Based on these observations, the authors
suggest that TFH cells have critical roles in the regulation and the
ICOS/ICOS-L pathway can be a novel therapeutic target in allergic airway
disease.\textsuperscript{95}

\textbf{Comorbidities of asthma}

Most research of treatments for airways diseases has been restricted to
patients who meet standard definitions of either chronic obstructive
pulmonary disease (COPD) or asthma, yet to distinguish COPD from asthma
in adult patients who have clinical features of both can be
challenging.\textsuperscript{96} Asthma-COPD overlap syndrome (ACOS) is
a poorly described condition, which shows a clinically different
approach compared to asthma or COPD alone. Wang et al. estimated that
among newly diagnosed adult-onset asthma patients in Southern Finland,
the prevalence of ACOS is of 6.6\%. Most of the cases with ACOS were
older, with lower education, more often men and current or former
smokers, when compared to the asthma-only cases. Interestingly, having
additionally other respiratory diseases or allergic diseases were less
common among the ACOS cases than among the asthma-only cases, but
familial asthma was associated to an increased risk of
ACOS.\textsuperscript{97}

Asthma can come together with the local AR, because of united airways.
These patients show seasonal or perennial asthma-like symptoms, negative
skin prick test and/or specific IgE, but display positive bronchial
and/or nasal allergen provocation test responses triggered by HDM. These
features suggests a new phenotype of asthma by the absence of systemic
atopy, namely local allergic asthma.\textsuperscript{98}

Sanna et al reported that the incidence of co-existing AR, allergic
dermatitis, and allergic conjunctivitis, was positively correlated with
the risk of the adult-onset asthma, and this tendency was decreased with
the increasing of age.\textsuperscript{99} In a recent review, Samitas
et al.\textsuperscript{100} discussed the one airway concept which
suggests disease mechanisms take place in the upper airway might be
reflected by lower events. Additionally, bronchial fibroblasts also have
been known with their role in airway remodeling by regulating epithelial
cell functions.

Sharma et al.\textsuperscript{101} reviewed experimental and clinical
information for specific mediators of asthma and obesity alone or
comorbidity, such as adipokines, cytokines, fatty acids which involve in
polarization of macrophages, particularly. M1 and M2 macrophages might
co-present in distinct organs and may impact asthma and obesity
differently. M1 macrophages are suggested beneficial for asthma, while
M2 macrophages contribute to the pathology of both asthma and obesity.
Potential therapeutics for obese asthmatics by breaking the
macrophage-mediated cycle between obesity and asthma were suggested.
Recently, Chen et al. indicated that early pubertal maturation is
related to childhood-onset asthma in both
genders.\textsuperscript{102}Besides, obesity together with early
pubertal maturation can increase the risk of asthma, which implies the
importance of the body mass index (BMI) control to prevent early
pubertal maturation and asthma onset. Using 26 BMI-associated SNPs,
Skaaby et al. evaluated the causal effect of BMI on asthma, hay fever,
allergic sensitization, total serum IgE, forced expiratory volume in
one-second (FEV1) and forced vital capacity. As a result of genetic
analysis of 162124 participants, the authors concluded that increasing
BMI is causally related to a higher prevalence of asthma and decreased
lung function, but not with hay fever or biomarkers of
allergy.\textsuperscript{103}

Future directions in asthma therapy, compromise both the optimization of
known treatments and the implementation of novel approaches. As an
example of the first option, Tay et al. highlighted the importance of
comorbid ``treatable traits'' in difficult asthma, where they concluded
that treatment of most extra-pulmonary comorbidities (e.g. rhinitis,
chronic rhinosinusitis, gastroesophageal reflux or obesity) improves
asthma outcomes. They suggested a targeted assessment of patients
suffering from difficult-to-treat asthma, including questionnaires,
specialist assessments and tailored referrals; preferably before
initiating phenotype-driven biological
treatment.\textsuperscript{104}However, it is noteworthy that some
common asthma comorbidities (e.g. chronic rhinosinusitis) might profit
from the ``biologicals approach'' as well.\textsuperscript{105}

An important, yet often neglected aspect of asthma is the high
prevalence of anxiety and depression in this patient group. A recent
study reported on the mental health of asthma patients and found a
positive correlation between the severity of anxiety and depression with
less well controlled asthma symptoms.\textsuperscript{106}

Generally, the analysis of comorbidities in asthma patients is extremely
relevant, as shown by a study by Lemonnier et al. The authors have
identified gene expression patterns in peripheral blood mononuclear
cells that are associated with the combined presence of asthma, allergic
rhinitis and/or dermatitis in the mechanisms of the Development of
Allergy and epigenetic variation and Childhood Asthma in Puerto Ricans
cohorts. 8 common genes were overexpressed in multi-morbidities, while
no genes were observed to be differentially expressed specific to the
presence of asthma.\textsuperscript{107}

In another study in adolescents and adults with asthma and rhinitis
(A+R+) multimorbidity evaluating the IgE polysensitization towards
various aeroallergen components showed frequent IgE sensitization to
pollen and indoor allergens in A+R+ and contrasting with pollen
allergens in rhinitis alone.\textsuperscript{108}

Comorbidities also impact mortality in asthma. In a 15-year follow-up
cohort of adults with asthma, the development of COPD, malignant
respiratory tract neoplasms and cardiovascular diseases were the main
reasons for an increased mortality. Allergic rhinitis and/or allergic
conjunctivitis were associated with decreased mortality but with
increased morbidity.\textsuperscript{109}

\textbf{Asthma diagnosis, precision medicine and biomarkers}

Asthma should be correctly diagnosed as early in life as possible
according to the latest clinical guidelines. Branco et al. reported that
1.3\% of children were previously undiagnosed asthmatics, providing
evidence of under-diagnosed asthma in both pre- and primary school
children in both urban and rural areas.\textsuperscript{10}

Postma et al. reported the baseline data from the multi-centred,
international study specifically designed to explore the relevance and
extent of small airway dysfunction (SAD) in asthma. In the largest such
study to date, the team developed a clinical SAD score and showed that
SAD is present across all asthma severities, but consistently more so in
severe asthma. The clinical impact of SAD in asthma is further explored
in the longitudinal study.\textsuperscript{110} A study proposed the
addition of oscillometry together with spirometry as it proved useful to
assess earlier changes in responders to treatment with
benralizumab.\textsuperscript{111}

Dunn et al.\textsuperscript{112} evaluated asthma in the elderly and the
late onset asthma in adults. Elderly asthmatics have higher rates of
morbidity and mortality compared to younger patients. It is more likely
that the disease is undiagnosed and undertreated. Elderly patients more
often have a non-type 2 asthma endotype, with a Th17 mediated pathology,
which is also less responsive to traditional therapies such as ICS.
Therefore, it is important that more elderly patients are included in
clinical trials.

Non-steroidal anti-inflammatory drug (NSAID) -exacerbated respiratory
disease (NERD) is a severe eosinophilic asthma
phenotype.\textsuperscript{113} It has been well defined as an
inflammatory phenotype responsive to corticosteroids. Although no
absolute/consistent cut-off values have been established, sub-analyses
show an overall better response in patients with more inflammation,
defined by higher blood eosinophil levels.\textsuperscript{114}Recently,
Celejewska-W\selectlanguage{ngerman}ójcik et al. demonstrated that three distinct NERD sub
phenotypes reflect differences in inflammatory response measured by
airway eosinophils and the ratio of
logLTE\textsubscript{4}/logPGE\textsubscript{2} in induced
sputum.\textsuperscript{115} Mastalerz et
al.\textsuperscript{116}studied airways PGE2 in induced sputum and
reported that NERD subjects had higher levels of PGE2 before aspirin
challenge compared to controls. After exposure to aspirin, PGE2 levels
significantly dropped, which was not the case for aspirin tolerant
asthmatic individuals. The inhibition of bronchial PGE2 biosynthesis can
trigger bronchoconstriction in NERD. Chen et al.\textsuperscript{117}
showed that the levels of exhaled PGE2, LTB4, LXA4, and LTE4 may
efficiently differentiate asthmatic children from healthy controls.
Especially the measurement of LTB4 and lipoxin A4 together with FeNO and
FEV\textsubscript{1}, might help for the better diagnosis of asthma.

A nationwide Japanese prospective study has investigated 190 patients
with near-fatal asthma exacerbation. By analysing asthma symptoms over
the 2-week period before their admission, the authors could define 3
different clusters of symptoms. Analysis of clusters indicated the most
relevant factors to be assigned to 3 different clusters, such as a
degree of ICS or ICS/LABA compliance, low or high perception of dyspnea
and hypersensitivity to environmental stimuli.\textsuperscript{118}

Additional to clinical trials, the analysis of real-world data is very
important to confirm effectiveness also in larger, more diverse patient
groups. Jutel et al. analysed changes in AR progression and asthma
status after HDM allergen immunotherapy (AIT) based on data on
prescription medicine consumption. They found that treatment of AR
patients with HDM allergoid can ameliorate asthma symptoms, slow asthma
progression and reduce the general incidence of asthma as compared to
untreated control groups.\textsuperscript{119}

Asthma inducing agents are also present at many workplaces. Occupational
asthma is often hard to diagnose since the reference test (specific
inhalation challenge) can only be conducted in a few centres worldwide.
Recently, a model to improve diagnosis of occupational asthma without
specific inhalation challenge was published on basis of a Canadian
dataset and was successfully validated in a European
population.\textsuperscript{120} Clinicians could use this model with
decision making on referral to a specialized centre in the future. Van
der plas et al. \textsuperscript{121} studied the differences between
sensitization to high molecular-weight proteins and low-molecular-weight
chemicals in occupational asthma. Asthma caused by high molecular-weight
chemicals showed a stronger association to rhinitis, conjunctivitis,
atopy, early asthmatic reactions and had a higher risk of airflow
limitation, while low-molecular-weight agents were associated with chest
tightness, late asthmatic reactions, and increased risk of severe
exacerbations. Beretta et al. highlighted that the measurement of
nonspecific bronchial hyperresponsiveness alone is often not enough to
diagnose occupational asthma. Combining it with the assessment of FeNO
levels and sputum eosinophils count significantly increases the
sensitivity and accuracy of the method, improving the identification of
subjects, who may have occupational asthma and therefore require further
testing.\textsuperscript{122}

Multiple omics, big data, and systems biology have demonstrated a
profound complexity and dynamic variability in asthma between
individuals, as well as between regions. Reliable diagnosis of asthma
and the monitoring of its severity are challenging particularly in daily
clinics. Asthma is an umbrella term, including several distinct
phenotypes and endotypes, which are characterized by specific cellular
and molecular immune response
patterns.\textsuperscript{47,114,123,124}The main asthma endotypes: type
2 and non-type 2 inflammation, are broader described in the section
below. Type 2 allergic asthma is defined by IgE, IL-13, IL-4, IL-5, and
eosinophil responses and covers more than 50\% of asthma
endotypes.\textsuperscript{114}

Boudier et al. highlighted the value of unsupervised asthma phenotypes
research, including multiple asthma characteristics, for understanding
the long\selectlanguage{english}-term evolution of asthma patients. Using a cluster\selectlanguage{english}-based model
developed for longitudinal data, asthma phenotypes were identified in a
large population of adults with asthma 20~years after
recruitment.\textsuperscript{125} This model was developed by taking
into account two time points and nine variables combining clinical and
functional characteristics, such as respiratory symptoms, asthma
treatment, allergic characteristics, lung function and bronchial
hyper\selectlanguage{english}-responsiveness. These cluster\selectlanguage{english}-based asthma phenotypes showed a
stronger long\selectlanguage{english}-term clinical prognosis compared to phenotypes classically
used in epidemiological studies, allowing a strong tracking of lung
function over the life course to better tailor asthma management
strategies.\textsuperscript{125}

Ivanova \emph{et al.} reviewed the role of `omics' technologies in
asthma.\textsuperscript{126} Although omics data studies have several
limitations, usually due to limited sample size and the complexity of
the data and all its interactions, different insights were acquired.
Another review also highlighted the importance of omics data for
molecular phenotyping, defining the endotypes and identifying pathways
and mechanisms, such as type 2-high and type 2-low.\textsuperscript{1}In
regard to this purpose, the transcriptome and protein levels in three
different mouse models for eosinophilic, mixed, and neutrophilic asthma
were analyzed. The authors found that differential expression of tight
junctions, mucin and inflammasome-related molecules in distinct
inflammatory phenotypes of asthma may be linked to the pathophysiology
and might reflect the differences observed in the
clinic.\textsuperscript{124} Eosinophil and neutrophil dominant
phenotypes were described in children with asthma as well. The
neutrophil dominant phenotype was associated with the biggest
differences compared to the other asthma phenotypes. The vast majority
of the differentially expressed genes was associated with corticosteroid
response, and the neutrophilic phenotype with corticosteroid
non-responsiveness.\textsuperscript{127}

Severe asthma is a heterogeneous disorder, including different clinical
characteristics (phenotypes) and immunopathological pathways
(endotypes). The identification of non-invasive biomarkers is able to
predict treatment response and assist in designing personalized
therapies for severe asthma patients is demanding.

Eguiluz-Gracia et al. broadly reviewed recent developments in biomarkers
in allergic diseases, highlighting the importance of eosinophils in
allergic asthma diagnosis and management.\textsuperscript{123}

According to an EAACI position paper in 2019, biomarkers for the
clinical and inflammatory phenotype of asthma were summarized as follows
1) type 2 asthma: a) serum IgE, b) blood and sputum eosinophils, and c)
FeNO; 2) Non-type 2 asthma: a) sputum neutrophils and b) blood and
sputum eosinophils.\textsuperscript{114} However, the etiology of asthma
with non-type 2 inflammation is less clear.

\emph{Eosinophils as biomarkers:} Sputum eosinophilia is the most useful
biomarker in asthma. In general, sputum eosinophilia is associated with
steroid responsiveness. Although there is no standardized cut-off, a
blood eosinophil count of 300 cells/\selectlanguage{greek}μ\selectlanguage{english}L and the normal range for sputum
eosinophilia defined as 1--2\% have commonly been used as a threshold to
indicate eosinophilic asthma.\textsuperscript{114} Higher blood or
sputum eosinophil count has been assessed to be a sensitive and
practical predictive biomarker for biological therapies targeting
allergic and/or eosinophilic pathways in patients with severe
asthma.\textsuperscript{128-130} Systematic reviews showed the efficacy
and safety of benralizumab, dupilumab, mepolizumab, omalizumab, and
reslizumab for severe eosinophilic asthma and allergic
asthma.\textsuperscript{128,129} A high blood eosinophil count
(\textgreater{}300 cells/\selectlanguage{greek}μ\selectlanguage{english}L) has been reported as a potential biomarker
to predict successful treatment effects of omalizumab in children with
severe allergic asthma.\textsuperscript{114} Sputum eosinophilia also
adequately predicts response to biologics. Patients with refractory
asthma are more likely to respond to anti--IL-5 or anti--IL-4/IL-13
targeted treatment if they have sputum eosinophils of \textgreater{}3\%,
or [?] 300 cells/\selectlanguage{greek}μ\selectlanguage{english}L blood eosinophils.\textsuperscript{114,128-130}

For evaluating treatment success with mepolizumab and patient
stratification, possible biomarkers were investigated in a post-hoc
study of Phase III clinical trial data. The results of this study
reinforce the use of peripheral blood eosinophil counts and
eosinophil-derived neurotoxin as predictive
biomarkers.\textsuperscript{131}

The transcriptomic data from bronchial biopsies of European U-BIOPRED
cohort patients showed that \emph{MMP-10} and \emph{MET} genes were
significantly overexpressed in severe asthma. These results demonstrated
that \emph{MMP-10} and \emph{MET} play an important role in pathways of
airway remodeling and cellular inflammation that are associated with
submucosal eosinophilia.\textsuperscript{132}

Recent studies have shown that eosinophils can also display protective
regulatory properties in asthma. In a recent study Pineros et
al.\textsuperscript{133} provided \emph{ex vivo} and \emph{in
vivo}evidence that mouse and human eosinophils are capable of rapid
capture and inactivation of respiratory viruses. They also showed that
eosinophils from asthma patients displayed a reduced capacity to bind
virus, which may lead to a less effective virus
inactivation.\textsuperscript{133} These results underlie the \emph{in
vivo} antiviral activity of eosinophils, and the pathogenesis of
virus-induced asthma exacerbations. Another study conducted by Tarancon
et al., evaluated eosinophils during \emph{Mycobacterium
tuberculosis}infection in an experimental model. They observed that
eosinophil production in the bone marrow is weakened in
\emph{Mycobacterium tuberculosis} infection and protects against
asthma.\textsuperscript{\textbf{134}}

The role of eosinophils in personalized asthma treatment remains
controversial. In a real-life study Bagnasco et al. showed no
correlation between peripheral blood eosinophils count with the
clinical, functional, biological outcome changes in asthma
patients.\textsuperscript{\textbf{135,136}} \textbf{}

Not only frequencies of eosinophils can serve as a biomarker of asthma
severity \textsuperscript{123} and response to the
treatment.\textsuperscript{137} Rodrigo-Mu\selectlanguage{ngerman}ñoz et
al.\textsuperscript{138} recently reported a set of 14 miRNAs
stratifying eosinophils from asthmatic patients and controls.
Interestingly, 3 of those miRNAs (miR-144-5p, miR-185-5p, and miR-320a)
were validated as asthma biomarkers in the serum, distinguishing not
only asthma status but also the severity. \textsuperscript{138}

\emph{Other immune cells as biomarkers:} The level of human circulating
neutrophil extracellular trap but not eosinophil extracellular trap can
act as a potential marker for asthma severity and poor
control.\textsuperscript{139} Another candidate marker for asthma
severity could be the frequencies of circulating chemokine receptor
(CCR)10\textsuperscript{+} ILC2s and plasma CCL27 level. Conversely,
CCR10\textsuperscript{+} ILC2s resemble the characteristics of ILC1s and
display higher levels of T-bet expression and increased production of
interferon (IFN)-\selectlanguage{greek}γ \selectlanguage{english}compare to the CCR10\textsuperscript{-}ILC2
counterpart, which favours the controlling of allergic inflammation in
asthma.\textsuperscript{140}

\emph{IgE as a biomarker:} IgE exerts several biological functions as an
Fc-receptor-bound antigen sensor for mast cells, basophils, dendritic
cells (DCs), T and B cells and other cells in the allergic inflammation.
Total serum IgE and allergen-specific IgE have been strongly associated
with asthma.\textsuperscript{114} Omalizumab is the recombinant
humanized mAb that binds to the Fc region of IgE. Correlations between
treatment response and baseline total serum IgE or antigen specific IgE
levels are not clear, but serum IgE is used to dose
omalizumab.\textsuperscript{114,128,129}

\emph{Proteins as biomarkers:}

Hoang et al. showed that seed storage proteins (Ara h 1, 2, 3, 6),
uteroglobin from cat (Fel d 1), and lipocalin from dog (Can f 1)
demonstrated the strongest linkage to clinical markers of asthma
severity. These results suggest their potential contribution as
biomarkers in preschool asthma.\textsuperscript{141}

A study in the Spanish population was identified serum biomarkers for
allergic or non-allergic asthma by using isobaric tags for relative and
absolute quantitation (iTRAQ)-based proteomics. It indicates that
increasing levels of plasma insulin-like growth factor-binding protein
acid labile subunit, which has a role in the regulation of insulin-like
growth factor pathway, could act as a potential biomarker for defining
severity of allergic asthma, whereas the proteins of the complement
ficolin-2 and mannan-binding lectin serine peptidase 1 levels seems
increased in non-allergic individuals.\textsuperscript{142}

\emph{Exhaled Biomarkers:} Measurement of biomarkers in exhaled breath
(i.e. FeNO) and exhaled breath condensate (i.e. volatile organic
compounds) are non-invasive and safe. FeNO is a widely accepted
biomarker for type 2 driven airway inflammation. Recently, a new
subgroup of patients with high FeNO levels (\textgreater{}25 ppb) and
low blood eosinophils (\textless{}300 cells/\selectlanguage{greek}μ\selectlanguage{english}L) was described. These
patients showed a significantly higher number of sensitizations against
aeroallergens compared to patients with low FeNO
subgroups.\textsuperscript{114} FeNO is also associated with increased
risk of asthma exacerbations and a beneficial effect of ICS. Pavord et
al. investigated whether these biomarkers have prognostic value or
predict the effects of regular or as-needed ICS on exacerbations in
patients with mild asthma.\textsuperscript{143} The open label,
randomized controlled trial showed that the effects of as-needed
budesonide-formoterol are independent of biomarker
profile.\textsuperscript{143} Dupilumab improves asthma control, quality
of life, and FEV1 are improved and use of rescue medication is reduced
above the minimally important clinical difference threshold only in
patients with high blood eosinophils and high FeNO (blood eosinophils
\textgreater{} 300/\selectlanguage{greek}μ\selectlanguage{english}L and/or FeNO \textgreater{} 50
ppb).\textsuperscript{130}

The non-T2 endotype covers both patients with a neutrophilic and a
pauci-granulocytic airway inflammatory pattern. Childhood asthma
comprises more different phenotypes with complex pathophysiology. Su et
al. showed that neutrophil-predominant asthma is the most severe asthma
phenotype in children with a poor corticosteroid
response.\textsuperscript{127} Less is known about biomarkers for
pauci-granulocytic asthma. The role of biomarkers in the non-type 2
endotype has yet to be fully elucidated.

AIT is an allergen tolerance-inducing treatment for allergic diseases.
There are no biomarkers that sufficiently predict response to AIT. The
Allergen Immunotherapy User's Guide summarized the potential biomarkers
for monitorization of the clinical efficacy of AIT as follows: a) IgE
(total IgE, specific IgE (sIgE) /total IgE ratio), b) subclasses of IgG
(allergen-specific IgG, IgG1 and sIgG4, sIgE/IgG4 ratio), c) IgE serum
inhibitory activity for IgE (IgEFAB), d) basophil activation, e)
chemokines and cytokines, f) cell markers such as Tregs, Bregs, and DCs,
and g) \emph{in vivo} biomarkers including provocation
tests.\textsuperscript{144,145}

\emph{Digital asthma biomarkers:} Exhaled breath analysis using an
electronic nose (eNose) is a new technique. This tool has the potential
to assess asthma control and tailoring asthma
treatment.\textsuperscript{146,147} In a study including participants
between 6 and 18~years of age, Cavaleiro Rufo et al. showed that the
exhaled breath condensate volatilome analysis by an eNose has good
accuracy for asthma identification being able to distinguish individuals
with diagnosed pediatric asthma from those without the
disease.\textsuperscript{148} Farraia et al. demonstrated that the
analysis of the exhaled volatile organic compounds profiles using an
eNose could be used as a fast and non-invasive complementary assessment
tool for the detection of uncontrolled
asthma.\textsuperscript{146}Moreover, the eNose was able to identify
individuals with persistent asthma under prescribed corticosteroid
therapy, supporting the diagnostic ability of this method to identify
individuals in need of corticosteroid therapy.\textsuperscript{148}

Mobile Airways Sentinel Network {[}MASK{]} is an information
technology-based tool that developed through ARIA studies, which can
inform patient decisions based on a self-care plan proposed by the
health care providers, and can increase self-medication and share
decision making in rhinitis and asthma
multimorbidity.\textsuperscript{149}. Using the MASK-air app, 14,189
users and 205,904 days, a visual analogue scale (VAS) days, have been
recorded. VAS work correlates with other outcomes (VAS global, nose, eye
and asthma) but less well with a symptom-medication score. VAS profile
has potential for prevention, for the assessment of allergic rhinitis
severity and progression, and for monitoring the drug effects in
patients.\textsuperscript{150} Another study has determined the
importance of mobile technologies in rhinitis control by using allergic
rhinitis and its impact on asthma (ARIA)
score.\textsuperscript{151}Subsequent to this study, Bousquet et al.
examined the use of mobile technology to get information in the change
management of allergic rhinitis and asthma multimorbidity, with the aim
of providing an active and healthy lifestyle for these
patients.\textsuperscript{149} The European Innovation Partnership on
Active and Healthy Ageing transferred innovation from the ``Allergy
Diary'' to 22 Reference Sites or regions across Europe, aiming to
compare the phenotypic characteristics of rhinitis and asthma
multimorbidity in adults and the elderly, to assess the percentage of
accepting the Allergy Diary in adults and elderly, understand the
phenotypic characteristics and follow-up treatment over 1-year of
rhinitis and asthma multimorbiditiy.\textsuperscript{152}

\textbf{Novel treatments driven by asthma endotypes}

Precision medicine, which is fitting very well asthma's heterogeneity
and complex pathogenesis, is becoming an overarching medical discipline
that requires a good understanding of biomarkers, phenotypes, endotypes,
genotypes, regiotypes, and theratypes of
diseases.\textsuperscript{2}~ICS have been the foundation for asthma
treatment, however, inhaled or systemic corticosteroids can be
ineffective in many patients with asthma. Few treatment options exist
for patients with steroid resistant asthma. The recent development of a
new class of biological agents that target airway type 2 inflammation
has provided an opportunity for treating patients with corticosteroid
refractory asthma (Figure 1).\textsuperscript{153}

A significant amount of research supports the separation into type 2 and
non-type 2 asthma endotypes.\textsuperscript{8,154,155} Type 2 asthma
usually has high sputum and blood eosinophil counts, high FeNO. The
diagnosis of non-type 2 patients, who are usually unresponsive to the
inhaled corticosteroids treatment, remains a challenge. Some studies
have suggested that elevated levels of circulating interleukin(IL)-17,
IL-6, IL-23 or other factors, such as, bacterial infection, obesity are
all involved in the pathogenesis of the non-type 2
asthma.\textsuperscript{156} Neutrophilia observed in these non-type 2
patients was related to recurrent respiratory tract infection
facilitated probably by a deficiency of local airway immunoglobulins.
Asthma patients who received intravenous immunoglobulin exhibited higher
levels of serum IgA and fewer infection exacerbations 12 months
afterwards.\textsuperscript{157}

Several earlier studies have highlighted the impact of high altitude
treatment in atopic dermatitis and asthma.\textsuperscript{158,159} A
recent study by Boonpiyathad et al.\textsuperscript{160} described the
clinical and immunological changes after high altitude treatment in
asthma patient subgroups and showed that clinical improvement is
dependent on the asthma phenotype. Furthermore, high altitude treatment
reduced the type 2 immune response and corrected the elevated CRTH2
expression and its dysregulated functions.\textsuperscript{160}

Severe asthma is defined by the ERS/ATS criteria as either asthma
requiring escalation to step 5 medical therapy (= high-dose ICS in
combination with a second controller and/or additional systemic
corticosteroid therapy) to maintain asthma control or asthma that
remains uncontrolled despite step 5
therapy.\textsuperscript{161,162}Only 5-10\% of asthma patients fulfil
these criteria, but they are responsible for \textgreater{}80\% of the
total asthma healthcare costs. Adverse effects due to an overload of
corticosteroid therapy (resulting from an often combined nasal,
cutaneous and/or inhaled therapy) are recognized as a major contributor
to the immense healthcare costs.\textsuperscript{161} Voorham et al.
showed in a matched, historical cohort study that patients undergoing
long-term systemic corticosteroid treatment suffered annually increasing
healthcare costs compared to patients who do not receive
systemic.\textsuperscript{163}

Targeted therapies play a critical role in severe and difficult-to-treat
asthma in adults, including monoclonal antibodies against IgE, blockage
of IL-4 and IL-13 signaling, anti-IL5 and anti-IL-5 receptor
therapies.\textsuperscript{164,165} This is partly why optimization of
severe asthma therapy (i.e. by reducing steroid use) received
considerable attention in the past decades, with targeted approaches
(e.g. biologicals) (Figure 1).\textsuperscript{161} Currently, there are
five biologicals approved for difficult-to-control asthma, targeting IgE
(omalizumab), IL-5 (mepolizumab and resilizumab), IL-5R\selectlanguage{greek}α \selectlanguage{english}(benralizumab)
and IL-4R\selectlanguage{greek}α \selectlanguage{english}(dupilumab). These drugs were shown to have steroid sparing
effects and reduce asthma exacerbations, as well as hospital admissions,
in randomized control trials.\textsuperscript{105} Biological treatment
of severe asthma also comes with a high cost for the healthcare system
(it exceeds the recommended maximal cost per quality-adjusted life-year
by far); thus, the selection of the patient is required to be
rigurous.\textsuperscript{105,161} One difficulty in patient selection
is due to the overlapping severe asthma phenotypes, such as severe
allergic asthma and severe eosinophilic asthma. A multi-center,
open-label, single-arm study conducted by Chapman et al. showed that a
direct switch from omalizumab to mepolizumab (within 2-4 weeks of the
last biologic dose) is possible without any tolerability issues and can
be highly beneficial for patients with severe eosinophilic asthma not
optimally controlled by omalizumab.\textsuperscript{166,167} As crucial
as the patient selection is for the initiation of biological treatment,
the decision in which patients to discontinue it after long-term usage
is equally important. In a real-life study involving children with
severe allergic asthma, Deschildre et al. demonstrated that omalizumab
discontinuation could be safely proposed after at least 24 months of
treatment in children with prolonged controlled asthma and no severe
exacerbations for at least one year. They also showed that some
phenotypic markers (female gender, allergic multimorbidity, and
decreased lung function) should be taken into account, consistent with
the findings from the persistency of response after long-term therapy
(XPORT) trial assessing omalizumab discontinuation effects in an adult
population.\textsuperscript{168}

The identification of treatment responders is of great significance for
patient selection; however, validated biomarkers are currently scarce.
For benralizumab Mathur et al. found several indicators of enhanced
response of the drug in two phase III trials in patients with elevated
blood eosinophil counts, decreased lung function, long-term oral
corticosteroid use and nasal polyposis.\textsuperscript{169} In a small
prospective study Antonicelli et al. showed that forced oscillation
technique (a non-invasive method that provides information of the degree
of obstruction of the respiratory system) could detect specific
mepolizumab-induced changes in peripheral airway function in patients
undergoing treatment for severe eosinophilic
asthma.\textsuperscript{170}

EAACI recently launched its guidelines for the use of biologicals in
severe asthma. Recommendations follow the GRADE approach for each
biological and each outcome. In addition, a management algorithm for the
use of biologicals in the clinic is proposed, together with future
approaches and research priorities.\textsuperscript{171}

Fokkens et al. stated that it is likely that biologics will become an
alternative for sinus surgery in chronic rhinosinusitis with nasal
polyposis, which is a frequent co-morbidity of severe
asthma.\textsuperscript{105}

Optimizing patient empowerment and satisfaction by allowing
self-injection of currently approved biologicals administered
subcutaneously is another approach.\textsuperscript{172} Another key
future development could be optimization of airway delivery of
biological agents by using nebulized monoclonal
antibodies.\textsuperscript{162}

Another promising new approach is the use of arginase inhibitors which
lead to an increase in nitric oxide levels, thus promoting
bronchodilatation and inhibiting airway inflammation. Currently, drugs
based on arginase inhibition are under
development.\textsuperscript{81}Other possible future targets in
personalized asthma therapy include the epithelial-cell-derived
cytokines, (e.g. IL-33 or TSLP), kinases (e.g. JAK, Pi3K) and the PGD2
(acts as a pro-inflammatory mediator) (Figure
1).\textsuperscript{161,162} A comprehensive review by an EAACI task
force\textsuperscript{173} highlighted the complex roles of eicosanoids
in asthma and allergy.

Type 2 inflammation-independent asthma represents a critical unmet
medical need in the search for potential drug targets, as such patients
show a decreased response to asthma therapies targeting type 2
cytokines. By generating a noncompetitive inhibitory anti-tryptase
antibody in humanized mouse and cynomolgus monkey models, Maun et al.
provided the scientific rationale for clinical testing of such
antibodies.\textsuperscript{174}

Kere et al. examined the association between biologicals,
corticosteroids and DNA methylation in peripheral blood cells from
asthmatic children and found no evidence that ICS or other asthma
medications affect peripheral blood cell DNA methylation
levels.\textsuperscript{\textbf{175}} However, the usage of biologicals
provides therapeutic options when conventional approaches fail.

\emph{Allergen-specific immunotherapy.} The only causal treatment in
allergic asthma is AIT, the role of which has been largely explored in
recent clinical and experimental research. In a large cohort study
involving 39,167 asthmatic subjects, a remarkable reduction of
symptomatic medication was observed among 4,111 patients treated by AIT
during a 8-year follow-up. This outcome, which was mainly observed in
young subjects, suggests that AIT might play a role in preventing
progression from mild to more severe
asthma.\textsuperscript{176}Moreover, AIT was shown to decrease serum
IgE levels, while increasing serum levels of Der p 2-specific IgG4 and
Der p 2-specific IgD in HDM-sensitized asthmatic patients. The
longitudinal change in Der p 2-specific IgE/IgD ratio was similar to
that in Der p 2-specific IgE/IgG4 ratio. Asthma symptoms were improving
during the AIT process, which also correlated with allergen-specific B
cell responses.\textsuperscript{177}

Many retrospective AIT studies investigated the risk of new-onset
asthma, the relative risk of medication dispensing for asthma and its
potential progression among multimorbid allergic subjects. It was found
that use of sublingual allergen immunotherapy tablets for pollen allergy
for the treatment of allergic rhinitis could reduce the prevalence of
asthma, decrease asthma medication usage and also slow progression of
asthma in comparison to a group receiving only symptomatic allergic
rhinitis medication.\textsuperscript{178-180} Moreover, AIT with grass
allergen peptide over 3 weeks before the beginning of grass pollen
season was considered as an efficient and safe modality to protect
patients with rhino conjunctivitis and asthma from symptom
onset.\textsuperscript{181} Additionally, it was suggested that in
patients with both allergic asthma and allergic rhinitis, compared to
standard care, sublingual allergen immunotherapy may have a
cost-effective benefit with an incremental cost-effectiveness ratio of
\selectlanguage{ngerman}£10,726 per quality-adjusted life year which is nearly half of the
(English) National Institute for Health and Clinical Excellence
threshold.\textsuperscript{182}

Studies have been continued to develop novel vaccines for
allergen-speci\selectlanguage{english}fic immunotherapy. In a HDM-driven allergic asthma mouse
model purified Der p1 and 2, similar to crude HDM extract, demonstrated
a suppressive effect on AHR, eosinophilic inflammation, type 2 cytokines
and activation of lung structural cells.\textsuperscript{183} These
optimal results based on purified natural allergens from animal studies
suggest further research focusing on novel vaccines due to high demands
in the field of allergic asthma.

A systematic review summarized recent updates about nonpharmacological
asthma management. This review epitomised the methods used in studies,
highlight the importance of education and self-management and called for
a through description of methods in future studies.\textsuperscript{184}

\textbf{Challenges in asthma management during COVID-19 pandemics}

The recent outbreak of severe acute respiratory syndrome coronavirus 2
(SARS-CoV-2) causing Coronavirus Disease 2019 (COVID-19) pandemics led
to the worldwide emergency affecting the life of more than 21 million
people (status for 14.08.2020). It also raised a vigorous discussion in
the research community, whether or not asthma should be classified as a
COVID-19 risk factor. Reports regarding asthma prevalence among COVID-19
patients are inconsistent, varying from 0.9\% in Wuhan to 17\% in the
US. \textsuperscript{185} Wang et al. exclude asthma as a factor
influencing COVID-19. Their statement is supported by the data from
Avdeev et al. and Zhang et al. \textsuperscript{186,187} Both groups did
not observe the increase in the prevalence of bronchial asthma or COPD
among patients with COVID-19. \textsuperscript{186,187} Additionally,
experts from 43 countries around the world in ARIA-EAACI
statement\textsuperscript{185}, as well as a recent publication from
Carli et al.\textsuperscript{188} rule out asthma as a risk factor for
COVID-19, while another group advocates asthma as a COVID-19 risk factor
based on the impaired antiviral responses that may predispose asthmatic
patients to severe COVID-19 manifestations. \textsuperscript{189}
Indeed, the United Kingdom reported increased asthma-related deaths in
non-COVID-19 patients.\textsuperscript{190} The US Center for Disease
Control and Prevention proposed that moderate to severe asthma should be
considered a risk for severe COVID-19
manifestations.\textsuperscript{185}Additionally, a recent study from
Zhu et al. (n=492 768) demonstrated inflammatory phenotype of underlying
asthma as a crucial factor for COVID-19 risk assessment. They showed,
that nonallergic, but not allergic asthma predisposes patients to
COVID-19. Due to the reported discrepancies, available data should be
interpreted with caution.\textsuperscript{191}

Data are still unclear as the COVID-19 population included in the
studies is skewed towards older and hospitalized patients with
predisposing comorbidities (such as hypertension, obesity, or diabetes)
which are strong confounders.\textsuperscript{185,186} As gender,
smoking status, ethnicity, lifestyle and genetic background can
influence COVID-19 outcomes, these factors should be carefully
investigated. \textsuperscript{185,192} Age seems especially
significant, as childhood and adolescent asthma does not seem to be a
hazard for COVID-19. \textsuperscript{192} This may be related to
reduced prevalence of comorbidities, lack of smoking, or boosted immune
system due to recent vaccinations.\textsuperscript{192}

Allergic responses accompanying asthma are hypothesized to play a
protective role in the course of COVID-19. Eosinopenia (decreased
frequencies of eosinophils in the blood) is a biomarker of severity and
poor prognosis for COVID-19 patients.\textsuperscript{192} Eosinophils
respond to viral infections by releasing cytotoxic proteins, reactive
oxygen species, and type 1 cytokines.\textsuperscript{192} Therefore,
they play a supportive role in fighting the infection. Allergic patients
present eosinophilia (increased frequencies of eosinophils in the blood)
and could have an advantage for the eosinophil-dependent antiviral
responses.\textsuperscript{192} Notably, in the cohort from Licari et
al. allergic children had significantly higher frequencies of
eosinophils in the blood, when compared to COVID-19 pediatric
patients.\textsuperscript{192}

Receptor ACE2 and serine protease TMPRSS2 mediates SARS-CoV-2 entry into
host cells.\textsuperscript{193-195} CD147, CD26, ANPEP, ENPEP, or
DC-SIGN are other receptors, proven or potentially involved in COVID-19
pathogenesis.\textsuperscript{193} Radzikowska, Ding et al. demonstrated
that ACE2 and TMPRSS2 are expressed only in the epithelial tissues,
whereas CD147 and its interaction partners are present in both --
epithelial tissues and immune cells. \textsuperscript{196} The
expression of several SARS-CoV-2 receptors seems to be different in
asthma patients (increased: \emph{TMPRSS2} , \emph{CD44} , \emph{ITGA6}
,\emph{NFATC2} , \emph{NME1} , \emph{APOD} ; decreased: \emph{ACE2}
,\emph{ACE} , \emph{MCT4} , \emph{APH1A} , \emph{S100A9} , \emph{NOD2}
). These finding were partially confirmed by
others.\textsuperscript{185,197} There is growing evidence that allergic
type 2 inflammation (mainly IL-13) decreases ACE2 and increase TMPRSS2
expression.\textsuperscript{185,197} Additionally, ACE2 is an
interferon-induced gene.\textsuperscript{197} Impaired/delayed
interferon responses observed in asthma patients, usually a foe, may
play a protective role during SARS-CoV-2 infection and result in a
subsequent decrease of an ACE2. \textsuperscript{197} Carli et al.
suggested that the altered interferon responses and the type 2 immunity
signature in asthmatic patients downregulates the late phase hyper
inflammation and consequently decrease tissue damage in the lungs which
might be beneficial in allergic asthma during
COVID-19.\textsuperscript{188}

Asthma management in the times of COVID-19 pandemics presented a
challenge due to the overlap of the respiratory symptoms induced by
asthma or by SARS-CoV-2 and by reduced face-to-face appointments and
risky pulmonary function testing generating aerosols (Figure
4).\textsuperscript{185,190,198-202} If possible, a video examination
and attentive observation of the patient may help in proper
diagnosis.\textsuperscript{190,203} Fever, persistent dry cough,
flu-like symptoms, and lack of wheeze can indicate COVID-19 over asthma
exacerbation.\textsuperscript{190} Severe asthma exacerbation leads to
the hospitalization, which exposes asthmatics to unnecessary risk of
being infected with SARS-CoV-2. \textsuperscript{192} Steroid therapy in
asthmatic patients in times of COVID-19 pandemics should be continued as
clinically indicated.\textsuperscript{186,189,190,197,200} Additionally,
ICS use can be beneficial during COVID-19 as it restores the impaired
antiviral responses in asthma, subsequently leading to less severe
manifestations.\textsuperscript{189} ICS suppresses coronavirus
replication and decreases the ACE2/TMPRSS2
expression.\textsuperscript{197} However, ICS treatment can cause
SARS-CoV-2 nebulization and its spread to the lower airways and
surrounding surfaces.\textsuperscript{192} Therefore the use of a spacer
is encouraged.\textsuperscript{192} On the other hand, the use of OCS
was linked with a risk of severe COVID-19 manifestations (including
death).\textsuperscript{185} If good asthma control in patients cannot
be maintained, the introduction of azithromycin prophylaxis can be
considered. \textsuperscript{189} Azithromycin reduces asthma
exacerbations in patients, probably by augmenting IFN-\selectlanguage{greek}β \selectlanguage{english}and IFN-\selectlanguage{greek}λ
\selectlanguage{english}responses, a subsequent decrease in viral replication, and reduced
inflammatory response. \textsuperscript{189,197} Azithromycin interferes
with the CD147 receptor and decrease its downstream signals after viral
(rhinovirus) infections.\textsuperscript{197} COVID-19 in high endemic
HDM environment may affect antiviral immune responses. In a study by
Akbarshahi et al. the authors hypothesized that HDM may adversely affect
viral stimulus-induced antiviral interferon response. To test the
hypothesis, they investigated the effects of HDM exposure in both human
bronchial epithelial cells and a mouse model of asthma exacerbation.
They observed that toll-like receptor-3 is the main target involved in
reducing the antiviral response by HDM.\textsuperscript{204}

Lommatzsch et al. reported the safety of Omalizumab in an 52-year-old
severe allergic asthmatic patient with SARS-CoV-2
infection.\textsuperscript{205} During the SARS-CoV-2 infection, the
patient did not report any asthma exacerbation and maintained proper
asthma control. A mild manifestation of COVID-19 observed in this study,
was related to either i) allergic endotype of underlying asthma, ii)
ongoing omalizumab treatment, or iii) both.\textsuperscript{205}However,
this observation needs further confirmation in the bigger patients'
population. Furthermore, Omalizumab decreases the duration of rhinovirus
infections and virus-related exacerbations.\textsuperscript{189,197} It
can be hypothesized that anti-IgE therapy protects also during
SARS-CoV-2 infection. Experts suggest that immunomodulatory biological
treatment strategies should continue in SARS-CoV-2-negative asthmatic
individuals in times of pandemics.\textsuperscript{185,192,197} However,
due to possible immunosuppressive effects, they should be suspended in
patients which developed COVID-19, until disease
resolution.\textsuperscript{185,192}

In summary, available data suggest, asthma is not a risk factor for the
development of severe forms of COVID-19. Yet, COVID-19 can be a severe
disease in already damaged lungs of chronic asthma, particularly, ACOS
and COPD patients. More evidence is needed to fully understand the
impact of asthma and asthma therapies on the prevalence and the course
of COVID-19. More data are required from controlled clinical trials.
Meanwhile, considering the current emergency, asthmatic patients should
avoid SARS-CoV-2 infection and should receive the SARS-CoV-2 vaccine
with priority, as recommended for the influenza and the pneumococcal
vaccine. In the present situation, prevention and proper asthma control,
including continuation of the background controller treatment, is the
most efficacious way to assure the safety of asthma
patients.\textsuperscript{206}

\textbf{Conclusion}

Asthma research produces up to 9000 publications per year and represents
one of the most rapidly developing area. Most of the novel developments
of the last year focus in the areas of precision medicine, endotypes and
phenotypes, biomarkers, novel treatments such as biologicals and
real-life studies. The stratified/ personalized approach to patients and
targeted treatments represent the future in many chronic diseases. A
Better understanding of the molecular mechanisms and discovering novel
biomarkers represents the main target areas for further improving
patient care.

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\textbf{Figure Legends}

\textbf{Figure 1: Immune responses and mechanisms of asthma.} The
external environment can impair the epithelial barrier. The disrupted
barrier allows the penetration of the substances through the tissues
where they encounter the antigen presenting cells. Additionally,
submucosal DCs can gain access to outside the epithelium by screening
with their dendrites. Activated or damaged epithelial cells stimulate
DCs through their secreted cytokines: TSLP, IL-25, IL-33. After
capturing the antigen DCs migrate through the lymphatics to regional
lymph nodes and prime the naïve T cells. The differentiation into Th2
cells is driven mainly by IL-4. Mature DCs and TSLP, IL-25 and IL33
directly or indirectly stimulate tissue-resident ILC2`s. Th2 cells and
ILC2 secrete mainly IL-5, IL-9 and IL-13 but also small amounts of IL-4.
While IL-5 stimulates eosinophils, IL-9 and IL-13 induce mucus
production and activation of epithelium and mast cells. IL-4, IL-13 are
involved in the opening the epithelial barrier, activation of the
endothelium and migration of Th2 cells, ILC2 and eosinophils and IgE
class switching in B cells. After the sensitization of mast cells due to
the binding of specific IgE to Fc\selectlanguage{greek}ε\selectlanguage{english}R, upon crosslinking of IgE, they get
activated and release histamine, tryptase, prostaglandins, leukotrienes
and cytokines, which leads to smooth muscle contraction, mucus
production and increased vascular permeability. While Th2 resident
memory cells proliferate close to airways, circulating memory Th2 cells
traffic into the lung parenchyma and initiate a perivascular
inflammation with eosinophil and CD4\textsuperscript{+} T cell
recruitment, further augmenting type 2 cytokine production within the
lung. Eosinophils cross talk with the resident tissue cells through
their secreted leukotrienes and specific proteins such as MBP and EPO.
Furthermore, several substances, such as bacteria and mold-derived
molecules in allergens can induce Th17 and neutrophil recruitment.
Immune regulation mechanisms prevent type1, type 2 and type 17 response
through Breg and Treg cells and particularly IL-10, IL-35 and TGF- \selectlanguage{greek}β. \selectlanguage{english}In
addition, IgG4 has a blocking antibody function for IgE binding to
allergens. Several drugs target type 2 cytokines or their receptors
signalling: the IL-5 pathway (benralizumab, mepolizumab, reslizumab),
the IL-4 and IL-13 pathway (dupilumab) and IgE pathway (omalizumab).
Breg, B regulatory cell; Circ, circulating; DC, dendritic cell; EOS,
eosinophil; EPO, eosinophil peroxidase; GM-CSF, granulocyte-macrophage
colony-stimulating factor; HDM, house dust mite; IFN-\selectlanguage{greek}γ, \selectlanguage{english}interferon-\selectlanguage{greek}γ;
\selectlanguage{english}Ig, immunoglobulin; IL, interleukin; IL-4R\selectlanguage{greek}α, \selectlanguage{english}interleukin 4 receptor
alfa; ILC2, innate lymphoid cell 2; LT, leukotriene; MBP, major basic
protein; MC, mast cell; NEU, neutrophil; PGD2, Prostaglandin D2; PM,
particulate matter; TGF-\selectlanguage{greek}β, \selectlanguage{english}tumor growth factor- \selectlanguage{greek}β; \selectlanguage{english}Th2 Trm, T helper 2
tissue resident memory; TNF, tumor necrosis factor;Treg, t regulatory
cell; TSLP, thymic stromal lymphopoietin.

\textbf{Figure 2 - The roles of IL-4 and IL-13 in asthma pathogenesis}

Two main drivers of type 2 asthma are IL-4 and IL-13. These cytokines
indirectly and directly lead to airway remodeling by inducing many cell
types and factors, such as DC, epithelial cells, fibroblasts, airway
smooth muscle. IL-4 has mainly central effects related to immunologic
effects in the lymph nodes, while IL-13 mainly acts on tissue cells and
mucus production. Environment factors can trigger the inflammation by
damaging the epithelial barrier. Cycles of inflammation cause repetitive
injury of and repair of the airway wall. IL-4 and IL-13 contribute to
alterations in the epithelium (epithelial shedding, subepithelial
fibrosis). Activated smooth muscle cells contribute airway
hyperresponsiveness, basement membrane thickening and collagen
deposition. Repetitive stimulation of airway epithelium by IL-13 causes
goblet cell hyperplasia and mucus hypersecretion in airway epithelial
cells. Airway remodeling supports the production of pro-inflammatory
mediators.

\textbf{Figure 3 - A novel neutrophil subgroup in asthma}

In humans\textbf{,} neutrophils released from the bone marrow that
express low levels of CD16 and high levels of CD62L. This
CD16\textsuperscript{dim}CD62L\textsuperscript{high} subset is
considered representing immature neutrophils whereas the
CD16\textsuperscript{high}CD62L\textsuperscript{dim} subset is thought
to be mature and induces systemic inflammation. Also, their frequency
increases in the blood after the bronchoprovocation test. In allergic
asthmatics, neutrophils upregulate surface CD47 and simultaneously
downregulate surface CD36 and CD43. The phagoptosis signals may play a
role in prolonging neutrophil survival and asthma severity. CD62L;
cluster of differentiation 62 Ligand.

\textbf{Figure 4 - Management of asthma patients during COVID-19
pandemic}

Assuring patients safety can be provided by prevention of infection with
SARS-CoV2 and appropriate control of asthma. In addition to personal
protection by using a mask, hand sanitizer, washing hands and socially
distancing, the control of asthma symptoms is essential. The decision of
sustaining or postponing the therapy of asthma (severe) patients must be
taken multidisciplinary and based on individual circumstances. The usage
of ICS and other asthma controllers should be continued. Several EAACI
position papers have been published on patient management during the
COVID-19 pandemics that should be referred in specific conditions, such
as biological usage, allergen immunotherapy, drug hypersensitivity,
venom immunotherapy, ophtalmology and asthma. EAACI, European Academy of
Allergy and Clinical Immunology; COVID, Coronavirus Disease 2019; Inhale
corticosteroids, ICS.\selectlanguage{english}
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