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Received: 21 August 2020    Revised: 23 September 2020    Accepted: 24 September 2020

DOI: 10.1111/all.14607

REVIEW ARTICLE

Advances and recent developments in asthma in 2020

Lacin Cevhertas1,2,3  | Ismail Ogulur1,4  | Debbie J. Maurer1 | Daniel Burla1 |

Mei Ding1,2,5 | Kirstin Jansen1  | Jana Koch1,6  | Chengyao Liu1,7 | Siyuan Ma1,7 |
Yasutaka Mitamura1  | Yaqi Peng1,8  | Urszula Radzikowska1,2,9  |
Arturo O. Rinaldi1  | Pattraporn Satitsuksanoa1,2 | Anna Globinska1 |
Willem van de Veen1,2  | Milena Sokolowska1  | Katja Baerenfaller1,6 |
Ya-dong Gao5  | Ioana Agache10  | Mübeccel Akdis1  | Cezmi A. Akdis1,2

1
Swiss Institute of Allergy and Asthma
Research (SIAF), University of Zurich, Davos, Abstract
Switzerland In this review, we discuss recent publications on asthma and review the studies that
2
Christine Kühne-Center for Allergy
have reported on the different aspects of the prevalence, risk factors and preven-
Research and Education (CK-CARE), Davos,
Switzerland tion, mechanisms, diagnosis, and treatment of asthma. Many risk and protective fac-
3
Department of Medical Immunology, tors and molecular mechanisms are involved in the development of asthma. Emerging
Institute of Health Sciences, Bursa Uludag
University, Bursa, Turkey
concepts and challenges in implementing the exposome paradigm and its applica-
4
Faculty of Medicine, Division of Pediatric tion in allergic diseases and asthma are reviewed, including genetic and epigenetic
Allergy and Immunology, Marmara factors, microbial dysbiosis, and environmental exposure, particularly to indoor and
University, Istanbul, Turkey
5 outdoor substances. The most relevant experimental studies further advancing the
Department of Allergology, Zhongnan
Hospital of Wuhan University, Wuhan, understanding of molecular and immune mechanisms with potential new targets for
Hubei, China
6
the development of therapeutics are discussed. A reliable diagnosis of asthma, dis-
Swiss Institute for Bioinformatics (SIB),
Davos, Switzerland ease endotyping, and monitoring its severity are of great importance in the man-
7
Department of Otolaryngology Head and agement of asthma. Correct evaluation and management of asthma comorbidity/
Neck Surgery, Beijing TongRen Hospital,
multimorbidity, including interaction with asthma phenotypes and its value for the
Capital Medical University, Beijing, China
8
Otorhinolaryngology Hospital, The First
precision medicine approach and validation of predictive biomarkers, are further de-
Affiliated Hospital, Sun Yat-sen University, tailed. Novel approaches and strategies in asthma treatment linked to mechanisms
Guangzhou, China
9
and endotypes of asthma, particularly biologicals, are critically appraised. Finally, due
Department of Regenerative Medicine and
Immune Regulation, Medical University of to the recent pandemics and its impact on patient management, we discuss the chal-
Bialystok, Bialystok, Poland lenges, relationships, and molecular mechanisms between asthma, allergies, SARS-
10
Faculty of Medicine, Transylvania
CoV-2, and COVID-19.
University, Brasov, Romania

Correspondence KEYWORDS
Cezmi A. Akdis, Swiss Institute of Allergy asthma biomarkers, asthma phenotypes, biological therapeutics, comorbidities, COVID-19
and Asthma Research (SIAF), University of
Zurich, Davos, Switzerland.
Email: [email protected]

© 2020 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.

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1 |  I NTRO D U C TI O N asthma was found compared to children born to mothers with no thy-
roid dysfunction. The risk was even higher if the mothers did not re-
Asthma is a chronic heterogeneous disease of the lower airways ceive thyroid hormone treatment during pregnancy.11
characterized by chronic inflammation and airway hyper-reactivity
leading to cough, wheeze, difficulty in breathing, and chest tight-
ness. The pathophysiology of asthma is complex. In the past three 2.2 | Gender-specific differences in prevalence
decades, a better understanding of distinct asthma visible proper-
ties (phenotypes) and mechanisms (endotypes) shaped better diag- In a study involving 3115 Swiss adolescents, Ödling et al. reported
nostic and therapeutic tools in support of stratified/personalised that asthma tended to be more common among girls compared to
interventions based on recognition of differences in responsive- boys; however, boys with asthma had more often a doctor's diag-
ness to various therapeutic interventions (theratypes).1,2 In addi- nosis.12 Uncontrolled asthma was more common among girls than
tion, environmental factors, genetic polymorphisms, and epigenetic boys, who also were more often dispensed with high daily doses of
factors contribute to the development of asthma, heterogeneity ICS compared to girls. Subjects with persistent early-onset asthma
3-6
in phenotyping, and steroid responsiveness. Environmental in- had more often a doctor's diagnosis compared to adolescent-onset
terventions and exposure control can improve asthma control and asthma. The authors highlighted the clinical relevance of monitor-
exacerbations.7 ing female adolescents with uncontrolled asthma.12 Gender-specific
The incidence and prevalence of asthma are increasing, though prevalence of rhinitis and asthma as single and multimorbid diseases
8,9
regular use of inhaled corticosteroids (ICS) reduces mortality. during puberty was examined in six European population-based
New therapies and therapeutic targets are required for better con- birth cohorts of MeDALL. Male predominance in prevalence before
trol of symptoms and exacerbations in severe asthma patients and puberty and the “gender-shift” toward females after puberty onset
for avoiding adverse reactions caused by the administration of oral were strongest in multimorbid patients who had rhinitis and asthma
corticosteroids (OCS). concurrently.13
This review highlights the recent studies on immunopatholog-
ical pathways, molecular mechanisms, various environmental fac-
tors, and microbial dysbiosis in asthma. Clinical trials, multi-centered 3 | R EC E NT D E V E LO PM E NT S I N A S TH M A-
international studies, and real-world data are reviewed for novel R E L ATE D G E N E S
approaches in asthma diagnosis, candidate biomarkers, and manage-
ment of asthma in adults and children. Genetic factors have a strong impact on the risk of developing
asthma. 2 In particular, childhood asthma is strongly associated with
the 17q21 locus alleles. Analyzing 14 different populations of asth-
2 |  E PI D E M I O LO G Y A N D R I S K FAC TO R S matic patients from 12 different countries, Farzan et al. showed that
I N TH E D E V E LO PM E NT O F A S TH M A 17q21 polymorphism is related to an increased risk of exacerbations
in children with asthma despite ICS use.14 The authors also ob-
2.1 | Asthma prevalence in adults and children served that the SNP rs7216389 frequency was higher in East Asians,
African Americans, and Hispanics, compared to patients of European
Asthma prevalence seems to be still increasing as suggested by ancestry.14 Interestingly, an interaction between 17q21 variants and
Borna et al., who investigated its change between 2008 and 2016 breastfeeding in relation to respiratory symptoms in the first year of
in Sweden. The authors observed a significant rise of reported fre- life was observed by Gorlanova et al suggesting a protective effect
quencies of ever asthma, physician-diagnosed asthma, use of asthma of breastfeeding on asthma inception linked to early-life respiratory
medication, and current asthma, especially in young adults aged infections in babies carrying the risk alleles. Specifically, when in-
16-25 years.9 At the same time, an increase in the prevalence of res- fants were stratified by breastfeeding status, carriers of asthma risk
piratory symptoms during the same period was reported, suggesting alleles showed a protective effect of breastfeeding on respiratory
the possibility that actually, asthma is underdiagnosed. The potential symptoms during the weeks when they were breastfed, while they
risk factors for asthma remained the same during the study period.9 showed an increased risk of respiratory symptoms during the weeks
Recent studies assessed the prevalence of asthma in preschool- when they were not breastfed.15 The ORMDL3 gene, also related to
ers (4.4%) and elementary school children (6.4%) according to Global the 17q21 region, plays an important role as well. There are higher
Initiative for Asthma (GINA) definition.8 While no significant difference levels of human lung ORMDL3 and its SNPs rs8076131 from asth-
between rural and urban children was observed, Branco et al10 found matic patients than the healthy subjects.16
an association with previously identified risk factors for asthma devel- Associations between childhood asthma phenotypes and ge-
opment, including parental asthma and antibiotics in the first year of netic, immunological, and environmental factors have been largely
life. Liu et al investigated the link between maternal hypothyroidism in established, whereas there is a lack of strategies to integrate high-di-
the perinatal period and childhood asthma risk, in a population-based mensional risk factors from multiple distinct datasets and thereby
cohort study using Danish national registers. A higher incidence of increase the statistical power of analyses.17 In many studies, the
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classification of childhood asthma phenotypes is often based on as- of asthma, as shown by Paciencia et al22 The authors assessed the
sessment of singular risk factor measurements only. Krautenbacher association between EDCs exposure and asthma in children from 20
et al evaluated a new strategy combining cytokine, genotype, flow schools and found that increased individual and combined EDC lev-
cytometry, diagnostic, questionnaire, reverse transcription-poly- els were present in classrooms having more children with asthma
merase chain reaction (RT-PCR), and microarray data by using an in- and with an increased prevalence of nasal obstruction symptoms in
tegrative multilevel learning approach. Following this new discovery the previous 3 months. EDCs are associated with changes in the au-
approach, genes such as PKN2 (protein kinase N2), PTK2 (protein tonomic nervous system, thus suggesting that EDCs may increase
tyrosine kinase 2), and ALPP (alkaline phosphatase, placental) seem parasympathetic activity, resulting in a subsequent increase in the
to be the most important asthma risk factors.18 risk of asthma. 22
Interleukin 1 receptor-like 1 (ST2) is known to be related to the Pollutants can induce type 2 over type 1 response in the airways
pathogenesis of allergic diseases by mediating the response to IL-33. of an allergic asthma mouse model upon costimulation with the house
Interleukin 1 receptor-like 1 (ST2) single-nucleotide polymorphisms dust mite (HDM) allergen as shown by Brandt et al (Figure 1). 23,24
(SNPs) rs13431828, rs1420101, rs1921622, and rs10204137 were Increased IL-33 signaling in the airway epithelium upon diesel ex-
19
related to reduced efficacy of ICS in children and adolescents. haust particle (DEP) exposure can exhibit a synergistic effect with
Recently, Olafsdottir et al3 demonstrated 88 asthma risk genome the type 2 cytokines IL-5 and IL-13 leading to severely increased
variants at 56 loci, 19 previously unreported, in a genome-wide as- AHR as well as a resistance to treatment with dexamethasone. IL-5/
sociation meta-analysis. They investigated the effect of asthma-as- IL-13/IL-17A coproducing CD4+ effector T cells in the lungs of DEP
sociated variants and their genetic correlation between asthma and allergen costimulated mice were identified as potential promot-
and allergic phenotypes as well. They suggest a missense variant in ers of asthma exacerbations.
TNFRSF8 and a 3′ untranslated region variant in TGFBR1 to be re- The activation of Aryl hydrocarbon receptor (AhR) exacerbat-
lated to decreased asthma risk. In a study on the Hispanic/Latino ing an allergic response was previously demonstrated. Weng et al25
population in the United States, genetic predisposition to obesity showed that DEP activates AhR and with upregulation of IL-33, IL-
was found as a risk factor for asthma, especially for childhood-onset 25, and thymic stromal lymphopoietin (TSLP) by means of T helper
asthma in females.4 cell (Th) 2 activation. This finding further supports the link between
pollution and allergic severe asthma. Another recent study has re-
ported AhR signaling critical role in the benzo(a)prene and Der f 1
4 |  E N V I RO N M E NTA L R I S K FAC TO R S FO R co-exposure, leading to epithelial cytokine release through regula-
TH E D E V E LO PM E NT O F A S TH M A tion of reactive oxygen species (ROS) generation. 26 Future studies
on the AhR-ROS axis may provide new therapeutic approaches to
Many environmental factors can affect the risk of developing asthma.
asthma. The American Academy of Allergy Asthma and Immunology Artemisia pollen allergy is a major cause of asthma in Northern
(AAAAI) and European Academy of Allergy and Clinical Immunology China. Gao et al observed that the frequency of sensitization and
(EAACI) have discussed emerging concepts and challenges in im- the IgE levels related to the four main allergens (nArt v 1, nArt ar 2,
plementing the exposome paradigm and its application in allergic nArt v 3, and nArt an 7) were significantly lower in subjects from the
diseases and asthma. The complex network of exposome, genome, south of China compared to those from the north, who were more
transcriptome, proteome, epigenome, and metabolome in driving likely to have allergic asthma. The authors also reported that the co-
the disease phenotype and endotype is described. 20 sensitization to at least three of the most frequent allergens (Art v
Air quality has an influence on asthma symptoms and on trigger- 1, Art v 3, and Art an 7) results in a higher risk of allergic asthma. 27
ing asthma attacks. Kim et al. correlated measurements of air pollut- The most common allergen in allergic asthma is group-1 grass
ants around patients’ houses, including particulate matter (PM), with pollen. A wave of exacerbations of allergic asthma can be observed
asthma status and with the frequency of innate immune cells (ILC) in fall, when grass has undergone senescence and turned to straw,
in induced sputum. A significant positive correlation between the where mold lives. Alternaria alternata spores from the surface of
amount of PM with a diameter ≤10 µm and asthma control was re- straw have been shown to carry the same allergens as grass pollen
ported accompanied by an increased frequency of ILC2s in induced and probably inducing allergen-mediated exacerbations in allergic
sputum.6 asthma patients. 28
Recently, Yang et al. showed prenatal exposure to PM with an Besides exposure to allergens, de novo sensitization to Aspergillus
aerodynamic diameter of smaller than 10 μm (PM) has a higher as- fumigatus is also becoming recognized as a risk factor for asthma pa-
sociation with airway hyper-responsiveness (AHR) and the risk of a tients. From baseline to follow-up over a 10-year observation pe-
new diagnosis of asthma at an early school age than current and life- riod, asthmatic patients acquired noticeably increased frequencies
time exposure. Therefore, stricter monitoring and avoidance of ex- for specific IgE levels to rAsp f 1. 29 The presence of A. fumigatus was
posure to PM might considerably reduce the onset of future asthma associated with reduced BAL macrophages, increased BAL levels of
development in schoolchildren. 21 Indoor air contaminants, contain- IL-4, IL-6, IL-10, IL-13, and TNF-α, and increased plasma IL-4, IL-6,
ing endocrine-disrupting chemicals (EDCs), can also increase the risk IL-10, IL-13, IL-17, and TNF-α. However, there was no relationship
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F I G U R E 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 IL-33 directly
or indirectly stimulate tissue-resident ILC2s. 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 and 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 FcεR, upon cross-linking 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+ T-cell recruitment, further augmenting type
2 cytokine production within the lung. Eosinophils crosstalk 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 type 1, type 2, and type 17 response through Breg and Treg cells and
particularly IL-10, IL-35, and TGF-β. In addition, IgG4 has a blocking antibody function for IgE binding to allergens. Several drugs target type
2 cytokines or their receptors signaling: 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-γ, interferon-γ; Ig, immunoglobulin; IL, interleukin;
IL-4Rα, interleukin 4 receptor alpha; ILC2, innate lymphoid cell 2; LT, leukotriene; MBP, major basic protein; MC, mast cell; NEU, neutrophil;
PGD2, prostaglandin D2; PM, particulate matter; TGF-β, tumor growth factor-β; Th2 Trm, T helper 2 tissue-resident memory; TNF, tumor
necrosis factor; Treg, T regulatory cell; TSLP, thymic stromal lymphopoietin

between the presence of A. fumigatus in the asthmatic airways and and release bio-aerosols containing allergenic particles that pene-
disease severity or control.30 trate deeply into the airways with acute severe allergic inflamma-
Epidemic thunderstorm asthma is an emerging public health tion leading to asthma attacks with hospitalizations in people never
threat triggered by a combination of thunderstorms and massive experiencing before an asthma attack and suffering only of allergic
loads of small pollen allergen particles, and people without a prior rhinitis (AR) symptoms. A study from Melbourne investigated risk
history of asthma can also be affected. D’amato et al5 investigated factors to predict severe asthma attacks requiring hospital admis-
why thunderstorms are associated with a rapid increase in asthmatic sion during thunderstorm. Odds for hospital admission were higher
patients that in need of urgent medical care, due to asthma attacks. in Asian patients born locally compared to those born overseas.
Thunderstorms can bring allergen particles down to ground level, Non-Asian patients had the lowest odds for hospital admission.
and rainfall during thunderstorms is able to rupture pollen grains This suggests gene-environment interactions playing a role in the
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3128       CEVHERTAS et al.

susceptibility to severe thunderstorm asthma. 31 Furthermore, Lol vitamin D lowers the risk of the offspring developing asthma by 3 years
p 5, the major allergen of ryegrass pollen was reported to be re- of age; however, these effects were lost by age 6.44
32
sponsible for triggering an epidemic of thunderstorm asthma. A Tomita et al46 suggested a relationship between the use of ac-
systematic review and meta-analysis on the possible link between id-suppressive medications, such as histamine 2 receptor antagonists
pollen exposure and asthma hospital admissions in children and ad- and proton pump inhibitors, and the occurrence of adult-onset asthma.
olescents aged <18 years with emergency department attendance
demonstrated ambient grass pollen as an important trigger for
childhood asthma exacerbations requiring emergency department 5 | M I C RO B I A L DYS B I OS I S A N D A S TH M A
attendance, especially in relation to thunderstorm asthma. 33
Nasal, lung, and gut microbiota play several important roles in the
development, regulation, and maintenance of healthy and asthmatic
4.1 | Smoking and e-cigarettes immune responses. Dysregulation of microbiota-related immunologi-
cal and metabolic processes impacts the onset of asthma, its clinical
The association of asthma development and smoking has been exten- characteristics, and treatment response.47,48 Antibiotic treatment and
34
sively studied for conventional cigarettes. Extensive hazard to res- changes of the microbiome, especially early in life, are an important
piratory system has been recently reported in multiple studies.35-38 A field of study since the microbiome has been associated with the
study evaluated the impact of electronic cigarettes and heated tobacco health status of individuals in numerous diseases, including asthma.49
products on asthma and AR. The survey in Korean middle and high One-year-old children that had an immature microbiome were shown
school students could not determine these tobacco products to be a to have a higher risk to develop asthma later in life if their mother was
risk factor on their own; however, in combination with conventional asthmatic as well.50 A recent prospective study studied the connection
cigarettes, they could worsen asthma and AR status of children.39 between the gut microbiota and the development of asthma in wheez-
ing preschool children. No connection to the richness of microbes nor
species diversity was found, but an increase in bacteria of the genera
4.2 | Supplements, nutrients, and anti-acid Escherichia and Gemminger at ages 2-4 in children that were diagnosed
medications as asthmatics later on was reported.51 Lee et al52 investigated the dif-
ferences in the microbiome between young adults and elderly asth-
In a recent review, Venter et al40 highlighted the potential roles of fatty matic and nonasthmatic individuals. They found an upregulation in
acid metabolism in biological mechanisms, human epidemiology, and genes, such as relative abundances of microbiome genes associated
intervention studies. The impact of genetics and the microbial dysbio- with the pentose phosphate pathway, lipopolysaccharide biosynthesis,
sis on fatty acid metabolism are discussed briefly. The authors suggest flagellar assembly, and bacterial chemotaxis, and nitric oxide produc-
focusing on the choice of the formats (ie, food versus supplement) and tion were higher in asthmatics than in nonasthmatics that could be re-
standardized doses in clinical studies which will make easier to investi- lated to increased inflammation and colonization of bacteria in young
gate their roles in the prevention and treatment of allergies and asthma. adult asthma patients. Furthermore, genes that could be related to
EAACI’s position paper recommends a diverse diet for the infants and the reduction of inflammation and degradation of air pollutants were
consensus-based definitions, which is a benefit for further studies.41 higher in nonasthmatics of both age-groups. In another study, the au-
A study from Korea found that consumption of fast food was related thors showed a reduction in prostaglandin E2 (PGE2) in the asthma
to asthma incidence in adolescents but not in adults, whereas instant group and an upregulation of the molecules that could be associated
noodles had more impact in adults than in adolescents. No relation was with airway inflammation such as arachidonic acid metabolites, lysine
found between asthma and the intake of vegetables and fruits, which residues, and glycosaminoglycans.53 Together, these data suggest that
might be confounded by the generally high intake of healthy food by alterations in the composition and function of the upper airway micro-
Koreans as background nutrition.42 biome could influence asthma pathogenesis and that specific effects
Another supplement, which was evaluated as an early prevention can be distinguished based on the age-groups.
strategy for asthma, is vitamin D. Vitamin D supplementation remains Probiotic bacteria interventions to prevent and to treat airway
as a controversial issue, because of several recently published nega- and allergic diseases are currently being evaluated. In a mouse
tive studies. Vitamin D supplementation of pregnant mothers did not model of asthma, Spacova et al54 used different strains of and in-
reduce the incidence of asthma in children at 6 years of age. However, tranasally administrations of Lactobacillus rhamnosus to observe
it might provide benefits by reducing the preschool wheezing epi- the preventive effects of probiotics. Only L. rhamnosus GG strain
sodes.43,44 A prospective study with maternal-infant cohort showed treatment leads to a reduction in BAL eosinophil counts, lung IL-5
that during the 2 and 5 years of observation, there is no association and IL-13 levels, and airway hyper-reactivity. Thus, preventing the
between vitamin D exposure antenatal or after birth and the progres- development of birch pollen-induced allergic asthma by probiotics
sion of allergic disease.45 In addition, antenatal supplementation with is strain-specific. Ingestion of bacterial lysate has also shown pre-
vitamin D did not prevent the development of asthma or recurrent ventive effects on asthma. However, when extracts of Escherichia
wheeze. Earlier results by the same group suggested that antenatal coli and Enterococcus faecalis were introduced into the diet of
CEVHERTAS et al. |
      3129

newborns, no significant effect on the occurrence of asthma, IgE levels. Asayama et al. showed that it could inhibit allergic asthma
atopic dermatitis, AR, or sensitization to allergens was observed in by upregulating the type 1 cytokines TNF-α and IL-12 while down-
6- to 11-year-old children. 55 regulating IL-5+ Th2 cells.61 A downregulation of Th2 cells is also
56
Recently, the study of Michalovich et al identified additive achieved by intraperitoneal injection of cysteamine, along with IL17+
effects of obesity and asthma in immunological responses and mi- Th17 and IL13+IL17+ Th2/Th17 cells, thus effectively inhibiting AHR
crobiota composition. The authors also showed that reduction in in an allergic mouse model upon retreatment with the allergen.62 Lu
fecal Akkermansia muciniphila levels is associated with asthma sever- et al reported high ILC2 levels in type 2 asthmatics, while non–type 2
ity. Their findings were confirmed in a mouse model in which ad- asthmatics showed higher levels of Th17 cells and an inversed Th1/
ministration of these bacteria reduces airway hyper-reactivity and Th17 ratio.63 The pathways of Th2-high and Th17-high inflammation
56
inflammation. were reciprocally regulated.
Pulmonary microbial dysbiosis can influence the inflammation A neutrophilic inflammatory response or Th17 response is clas-
status of the host. The dysbiosis can be inherited, if the mother was sified as non-type 2 asthma. The potential mechanisms of non-type
treated with antibiotics during the pregnancy resulting in higher 2 asthma have been well-described in a comprehensive review arti-
57
asthma rates in the offspring as shown by Alhasan et al Surprisingly, cle.64 Th17 cells are also shown to play a key role in allergic asthma
instead of the expected upregulation of type 2 cytokines in allergic by the secretion of inflammatory cytokines, including IL-17A, IL-17F,
offspring, a downregulation was found. Causalities are still unclear IL-21, and IL-23. Worth et al successfully demonstrated that genetic
and will require specifically designed future studies to address this variants in IL-17F, IL-17A, and IL-23 signaling genes (IL-23A, IL-23R,
issue. and IL-12B) are associated with asthma. Their results also confirmed
Microbial dysbiosis can also be induced by air pollution such that IgE levels could influence the Th17-related gene expression.65
as tobacco smoke, while other pollutants influence the epithelium Moreover, the IL-17 levels and leukotriene (LT)B4 were shown to
more directly. Eguiluz-Gracia et al58 reviewed the current under- increase with disease severity in serum and sputum. Ro et al investi-
standing of indoor and outdoor air pollutants as well as the effects gated the role of LTB4 receptors, BLT1 and BLT2, in a neutrophil-dom-
of climate change on human pulmonary health, highlighting how im- inant pulmonary inflammation murine model. BLT1 and BLT2 were
portant clean air is for human health. proven as important in asthma development, and IL-17 was identi-
fied as a key cytokine synthesized through the BLT1/2-cascade.66
In humans, neutrophils released from the bone marrow express low
6 |  M O LECU L A R M EC H A N I S M S I N TH E levels of CD16 and high levels of CD62L. This CD16dimCD62Lhigh
D E V E LO PM E NT O F A S TH M A subset is considered representing the immature neutrophil, whereas
the CD16highCD62Ldim subset is thought to be mature and induced
Immune system cells migrate to the lungs and display their func- systemic inflammation.67 Ekstedt et al recently found that this novel
59
tional properties to develop asthma. It was demonstrated that neutrophil subset, CD16highCD62Ldim, is increased in the blood fol-
Th2-resident memory T cells and circulating memory Th2 traffic into lowing an inhaled allergen bronchial challenge bronchoprovocation
the lung parenchyma and initiate a perivascular inflammation to pro- test. They proposed that increasing neutrophil subgroups in allergic
+
mote eosinophil and CD4 T-cell recruitment. Th2-resident memory asthma might offer new opportunities in advancing allergic asthma
cells proliferate near airways and induce mucus metaplasia, AHR, research (Figure 2).67
and airway eosinophil activation. Transcriptional analysis revealed “Eat me” and “Don’t eat me” signals are an integral part of pha-
that Th2-resident memory cells and circulating memory Th2 cells goptosis, and thus, in neutrophils, they are important for the reso-
share a core Th2 gene signature, but also exhibit distinct transcrip- lution of pulmonary inflammation as prolonged survival of airway
tional profiles (Figure 1).59 neutrophils is directly related to asthma severity.68 In allergic do-
nors, neutrophils showed an upregulation of CD47 (“don’t eat me”)
and a simultaneous downregulation of CD36 and CD43 (“eat me”)
6.1 | Molecular mechanisms in compared to healthy controls (Figure 2).69 Additionally, less mRNA
allergic and nonallergic asthma for CCL4 and CCL20 (significant for the resolution of a pulmonary
inflammation) was found in airway neutrophils of allergic asthmatic
Braga et al60 described the cellular landscape of airway lining at the donors than in healthy controls, which causes dampening in mono-
single-cell level. This comprehensive analysis in asthma identified cyte migration to the site of resolution.
dominance of TH2 cells interacting with structural and inflammatory One of the characteristics of asthmatic lung is airway remod-
cells. The presented data open new perspective on lung biology and eling. Whether airway inflammation and remodeling in asthmatics
molecular mechanisms of asthma.60 A Th1/Th2 imbalance is com- can be related to persistent airflow obstruction was evaluated in a
monly seen in allergic asthma, and it is shifted back toward Th1 by recent study that showed in asthmatics with persistent airflow ob-
protein S. Protein S, an anticoagulant, anti-inflammatory, and anti- struction increased airway smooth muscle area, decreased periostin
apoptotic glycoprotein, is associated with a reduction of AHR, lung and transforming growth factor-beta (TGF-β), and chymase-positive
tissue inflammatory cell infiltration, Th2 cytokines in the lung, and cells compared to patient with nonpersistent obstruction.70
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3130       CEVHERTAS et al.

F I G U R E 2   A novel neutrophil
subgroup in asthma. In humans,
neutrophils released from the bone
marrow that express low levels of
CD16 and high levels of CD62L. This
CD16dimCD62Lhigh subset is considered
representing immature neutrophils,
whereas the CD16highCD62Ldim 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

A recent study has introduced an in vivo molecular platform to elu- the development of asthma after neonatal RSV infection, thus being
cidate both disease mechanisms and therapeutic targets of virus-as- a possible therapeutic target.74 A prospective study suggested infants
sociated and non–virus-associated asthma exacerbations. A group of suffering from bronchiolitis at less than 6 months of age have a twice
exacerbation-related modules included SMAD3 signaling, epidermal higher risk of doctor-diagnosed asthma after follow-up for 11-13 years
growth factor receptor signaling, extracellular matrix production, compared to general Finnish population and that the RSV was the
mucus hypersecretion, and eosinophil activation.71 Another study in main reason for bronchiolitis in these infants.75 The EAACI Influenza
infants suffering from rhinovirus bronchiolitis showed that concen- in Asthma Task Force performed a scoping review about the influenza
trations of IL-4, IL-5, IL-13, and TSLP were correlated with a higher burden, prevention, and treatment in asthma. In this review, vaccina-
risk of asthma onset in childhood.72 A study with 5-year-old children tion conferred a degree of protection against influenza illness and asth-
demonstrated that the development of atopic asthma in children with ma-related morbidity to children with asthma, but not to adults with
early rhinovirus-induced wheezing was associated with differentially asthma. Although influenza vaccines appeared to be safe for asthmatic
methylated genomic regions. The strongest methylation changes were patients, there is a lack of data regarding efficacy in adults.76
observed in the SMAD3 gene promoter region at chr 15q22.33 and in Suojalehto et al examined the protein expressions from nasal
introns of the DDO/METTL24 genes at 6q21.73 brush samples from work-related asthma patients and healthy con-
Respiratory syncytial virus (RSV) infection affects a large num- trols using the proteomic approach. Work-related asthma patients
ber of the population in the early years of their life and is associated often are exposed to welding fumes and aerosols composed of haz-
with an increased asthma risk. Schuler et al. show that uric acid and ardous metals and gases. The nasal brush samples are a relatively
IL-1β play a role in the mechanism, and their inhibition can prevent noninvasive specimen containing proteins secreted from epithelial
CEVHERTAS et al. |
      3131

and inflammatory cells. Their results indicated that the nasal epithe- alpha (IL-4Rα) (Figure 3). Withdrawal of IL-4Rα signaling prevents
lial proteome of the work-related asthma patients is highly enriched the development of AHR, eosinophilia, and goblet cell metaplasia in
in processes related to inflammatory and calcium signaling, free rad- allergen-sensitized mice. However, the IL-4Rα-deficient mice does
ical scavenging and oxidative stress response, and metabolism.77 not develop type 17 immunity after allergic sensitization.81
The increased serum IL-33 levels in asthma patients have been
linked to the activation of mast cells. To characterize the mecha-
6.2 | Molecular mechanisms in asthma due nisms of IL-33 contribution to asthma development, Ro et al82 used
to obesity knockdown or pharmacological inhibitors in bone marrow–derived
mast cells and animal model. The study revealed that the “MyD88-
78
Felix and Kuschnir pointed out that arginase inhibitors could act 5-/12-LO-BLT2-NF-κB” cascade contributes to the IL-33 signaling
beneficially for obese asthma patients by upregulating the L-arginine/ to induce IL-13 synthesis in mast cells, which may represent a new
asymmetric dimethylarginine ratio as an addition to a previous ar- therapeutic target for severe asthma.82
ticle by Meurs et al.79 The reply by Meurs et al80 agreed and sug- Lv et al investigated the role and the mechanisms of IL-37 in
gested an even more direct link in pointing to the previously known type 2-mediated allergic lung inflammation in HDM-induced murine
increased arginase expression and activity in obese asthma patients. asthma model. They found IL-37 impairs HDM-induced asthma, most
However, the mechanism behind this is still unknown, opening up likely by preventing IL-4/IL-13-induced chemokine ligand (CCL) 11
avenues for future research. production from fibroblasts and airway smooth muscle cells through
its direct effect on tracheobronchial epithelial cells.83
In a murine allergic asthma model, IL-4 receptor-α blockade de-
6.3 | Novel molecules and pathways creased serum IgE and IL-5 levels and increased the level of IgG1,
IgG2a, IgG2b, and IgG3 prior to/during sensitization. Thus, following
The type 2 immunity is mainly driven by IL-4 and IL-13 signaling the IL-4 receptor-α blockage, an immediate immunoglobulin response
which share the common receptor subunit interleukin-4 receptor is induced accompanying the suppression of type 2 cytokines with

Epithelial shedding
Goblet cell hyperplasia
Mucus production
Basement membrane thickening
Subepithelial fibrosis
Collagen deposition
Smooth muscle proliferation
Epithelial barrier opening

ENVIRONMENTAL
TRIGGER

IL-4
More central
Type 2 cells Epithelial injury and immunologic effects
and mediators

IL-4
IL-13
Inflammation Epithelial repair
IL-13
More peripheral
related to tissue cells
Pro-inflammatory Airway remodeling
mediators

F I G U R E 3   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, and airway
smooth muscle. IL-4 has mainly central effects related to immunological 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 hyper-responsiveness, 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
3132      | CEVHERTAS et al.

a potential long-lasting reduction in Th2-biased T regulatory (Treg) Asaduzzaman et al92 studied cockroach-induced chronic murine
84
cells. asthma models by using a specific inhibitor of proteinase-activated
Chitotriosidase (chitinase 1, Chit1) has been known as regulator receptor-2 (PAR 2) to identify a role of PAR 2 signaling on AHR and air-
and stimulator in Th2 responses. Hong et al studied the possible way inflammation/remodeling. They showed that administration of
mechanisms and its role in the pathogenesis of allergic asthma.85 an anti-PAR 2 antibody significantly inhibited AHR, inflammation, and
Significantly elevated levels of Chit1 in the sputum of patients with collagen accumulation in the lung tissue. The authors suggest that
childhood asthma were reported. Moreover, in the absence of Chit1 PAR 2 blockade may be a successful therapeutic strategy for human
molecule, forkhead box P3 (Foxp3)+ Treg cell frequency decreased in allergic airway diseases.92
the lungs of mice besides TGF-β1 levels, which suggests a protective A few studies have been performed to reveal the effects of med-
role in asthmatic airway responses by regulating TGF-β secretion ical treatments with ILCs in allergic airway diseases so far. The mech-
and Foxp3+ Treg cells. anisms in action of glucocorticoid therapy on ILCs were assessed in a
A study performed by Guan et al 86 has reported that reduced prospective study by Yu et al93 Their data showed the administration
monocytic myeloid-derived suppressor cells (M-MDSC) may result of glucocorticoids regulates ILC2s via MEK/JAK-STAT signalization
in abnormal T responses with the increase in Th2 and Th17 cells pathways in asthma patients.
and decrease in Treg cells in asthma patients. These results sug- To test the role of MUC1 membrane mucin in uncontrolled severe
gest a new immune regulatory mechanism in the pathogenesis of asthma, the recent study analyzed the association of MUC1-CT (cy-
asthma open for further research. 86 To define whether there is toplasmic tail in the C-terminal subunit) with corticosteroid efficacy
87
a deficiency in Breg subsets, Wirz et al compared the percent- in in vitro and in vivo models. The results suggested that MUC1-CT
ages of IL-10-producing Breg subsets in peripheral blood from pa- has an important role in the modulation of the anti-inflammatory ef-
tients with asthma and AR. They demonstrated that there is no fects of corticosteroids and may be a promising new approach for
difference in numbers of Bregs in the patients when compared to the treatment of asthma.94
87
healthy controls. MicroRNAs (miRNAs) are secreted in extracellular vesicles and
Current research suggests that several receptors are involved regulate signaling pathways by being transferred between cells.
in asthma pathophysiology, including PGD2 receptor 2 (DP2 or Recently, Bartel et al characterized the miRNA secretion in extracel-
CRTH2), as well as colony-stimulating factor 1 receptor (CSF1R). lular vesicles from normal bronchial epithelial cells treated with IL-13
The DP2 receptor is an essential regulator in allergic asthma be- to induce an asthma-like epithelium. They observed that miR-34a,
cause it can be activated by both allergic and nonallergic stim- miR-92b, and miR-210 were involved in the early development of a
uli. 88 The activation of the DP2 receptor pathway increases both Th2 response in the airways and asthma.95
the airway smooth muscle mass and vascularization in airway Uwadiae et al96 studied the role of T follicular helper (TFH) cells
walls, resulting in downstream effects on asthma development. of allergen airway disease in a mouse model of allergic asthma. They
Interestingly, airway epithelial cells secrete CSF1 into the alveolar found that TFH cells accumulate beside the germinal center B cells
space in response to aeroallergen. Moon et al. demonstrated that with constant allergen exposure. Furthermore, blocking the induc-
inhibition of the CSF1-CSF1R signaling pathway could suppress ible costimulatory (ICOS) signaling disrupted the TFH cell response;
sensitization to aeroallergens and subsequent allergic lung inflam- however, it did not have an impact on the differentiating of other
mation in mice with chronic asthma. They conclude that inhibition CD4+ T-cell subsets. Based on these observations, the authors sug-
of CSF1R is a potential new target for the medical treatment of gest that TFH cells have critical roles in the regulation and the ICOS/
allergic asthma. 89 ICOS-L pathway can be a novel therapeutic target in allergic airway
90
Kim et al showed that the ceramide/sphingosine-1-phosphate disease.96
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 7 | CO M O R B I D ITI E S O F A S TH M A
+
eosinophilic inflammation. The percentage of CD66 -activated neu-
trophils positively correlates with C16:0 ceramide levels, indicating Most research of treatments for airways diseases has been re-
neutrophilic inflammation. An upregulation of ceramide-mediated stricted to patients who meet standard definitions of either chronic
pro-apoptotic signals was found in patients with higher CD66+ neu- obstructive pulmonary disease (COPD) or asthma, yet to distinguish
trophils. For both eosinophilic and neutrophilic pathways, genetic COPD from asthma in adult patients who have clinical features of
SNPs were found. Increased ceramide levels may also contribute to both can be challenging.97 Asthma-COPD overlap syndrome (ACOS)
91
the development of obese asthma. Choi et al found multiple cer- is a poorly described condition, which shows a clinically different
amides (C16:0, C18:0, and C20:0) to accumulate in obese mice as a approach compared to asthma or COPD alone. Wang et al esti-
result of a high-fat diet, inducing AHR and inflammation. Increased mated that among newly diagnosed adult-onset asthma patients
expression of ceramide synthase (CerS) 1 and CerS6 was found in in Southern Finland, the prevalence of ACOS is 6.6%. Most of the
the lungs, and CerS6 was identified as a potential future therapeutic cases with ACOS were older, with lower education, more often men
target for obese asthma. and current or former smokers, when compared to the asthma-only
CEVHERTAS et al. |
      3133

cases. Interestingly, having additionally other respiratory diseases comorbidities (eg, chronic rhinosinusitis) might profit from the “bio-
or allergic diseases was less common among the ACOS cases than logicals approach” as well.106
among the asthma-only cases, but familial asthma was associated An important, yet often neglected aspect of asthma is the high
with an increased risk of ACOS.98 prevalence of anxiety and depression in this patient group. A recent
Asthma can come together with the local AR, because of united study reported on the mental health of asthma patients and found a
airways. These patients show seasonal or perennial asthma-like positive correlation between the severity of anxiety and depression
symptoms, negative skin prick test, and/or specific IgE, but display with less well-controlled asthma symptoms.107
positive bronchial and/or nasal allergen provocation test responses Generally, the analysis of comorbidities in asthma patients is
triggered by HDM. These features suggest a new phenotype of extremely relevant, as shown by a study by Lemonnier et al. The
asthma by the absence of systemic atopy, namely local allergic authors have identified gene expression patterns in peripheral blood
asthma.99 mononuclear cells that are associated with the combined presence
Sanna et al reported that the incidence of co-existing AR, aller- of asthma, AR, and/or dermatitis in the mechanisms of the devel-
gic dermatitis, and allergic conjunctivitis, was positively correlated opment of allergy and epigenetic variation and childhood asthma in
with the risk of the adult-onset asthma, and this tendency was de- Puerto Ricans cohorts. Eight common genes were overexpressed in
creased with the increasing of age.100 In a recent review, Samitas multi-morbidities, while no genes were observed to be differentially
et al101 discussed the one airway concept which suggests disease expressed specific to the presence of asthma.108
mechanisms that take place in the upper airway might be reflected In another study in adolescents and adults with asthma and
by lower events. Additionally, bronchial fibroblasts also have been rhinitis (A+R+), multimorbidity evaluating the IgE polysensitization
known with their role in airway remodeling by regulating epithelial toward various aeroallergen components showed frequent IgE sen-
cell functions. sitization to pollen and indoor allergens in A+R+ and contrasting
Sharma et al102 reviewed experimental and clinical informa- with pollen allergens in rhinitis alone.109
tion for specific mediators of asthma and obesity alone or co- Comorbidities also impact mortality in asthma. In a 15-year fol-
morbidity, such as adipokines, cytokines, and fatty acids which low-up cohort of adults with asthma, the development of COPD,
involve in polarization of macrophages, particularly. M1 and M2 malignant respiratory tract neoplasms, and cardiovascular diseases
macrophages might co-present in distinct organs and may impact were the main reasons for an increased mortality. AR and/or allergic
asthma and obesity differently. M1 macrophages are suggested conjunctivitis were associated with decreased mortality but with in-
beneficial for asthma, while M2 macrophages contribute to the creased morbidity.110
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 8 | A S TH M A D I AG N OS I S , PR EC I S I O N
et al indicated that early pubertal maturation is related to child- MEDICINE, AND BIOMARKERS
hood-onset asthma in both genders.103 Besides, obesity together
with early pubertal maturation can increase the risk of asthma, Asthma should be correctly diagnosed as early in life as possible ac-
which implies the importance of the body mass index (BMI) control cording to the latest clinical guidelines. Branco et al reported that
to prevent early pubertal maturation and asthma onset. Using 26 1.3% of children were previously undiagnosed asthmatics, providing
BMI-associated SNPs, Skaaby et al. evaluated the causal effect of evidence of underdiagnosed asthma in both pre- and primary school
BMI on asthma, hay fever, allergic sensitization, total serum IgE, children in both urban and rural areas.10
forced expiratory volume in one second (FEV1), and forced vital Postma et al. reported the baseline data from the multi-cen-
capacity. As a result of genetic analysis of 162  124 participants, tered, international study specifically designed to explore the rele-
the authors concluded that increasing BMI is causally related to a vance and extent of small airway dysfunction (SAD) in asthma. In the
higher prevalence of asthma and decreased lung function, but not largest such study to date, the team developed a clinical SAD score
104
with hay fever or biomarkers of allergy. and showed that SAD is present across all asthma severities, but
Future directions in asthma therapy, compromise both the opti- consistently more so in severe asthma. The clinical impact of SAD
mization of known treatments and the implementation of novel ap- in asthma is further explored in the longitudinal study.111 A study
proaches. As an example of the first option, Tay et al highlighted the proposed the addition of oscillometry together with spirometry as it
importance of comorbid “treatable traits” in difficult asthma, where proved useful to assess earlier changes in responders to treatment
they concluded that treatment of most extra-pulmonary comorbid- with benralizumab.112
ities (eg, rhinitis, chronic rhinosinusitis, gastroesophageal reflux, or Dunn et al113 evaluated asthma in the elderly and the late-onset
obesity) improves asthma outcomes. They suggested a targeted asthma in adults. Elderly asthmatics have higher rates of morbidity
assessment of patients suffering from difficult-to-treat asthma, and mortality compared to younger patients. It is more likely that
including questionnaires, specialist assessments, and tailored re- the disease is undiagnosed and undertreated. Elderly patients more
ferrals, preferably before initiating phenotype-driven biological often have a non–type 2 asthma endotype, with a Th17-mediated
treatment.105 However, it is noteworthy that some common asthma pathology, which is also less responsive to traditional therapies such
 |
3134       CEVHERTAS et al.

as ICS. Therefore, it is important that more elderly patients are in- chest tightness, late asthmatic reactions, and increased risk of se-
cluded in clinical trials. vere exacerbations. Beretta et al highlighted that the measurement
Nonsteroidal anti-inflammatory drug (NSAID)-exacerbated re- of nonspecific bronchial hyper-responsiveness alone is often not
spiratory disease (NERD) is a severe eosinophilic asthma pheno- enough to diagnose occupational asthma. Combining it with the as-
type.114 It has been well defined as an inflammatory phenotype sessment of FeNO levels and sputum eosinophil count significantly
responsive to corticosteroids. Although no absolute/consistent increases the sensitivity and accuracy of the method, improving the
cutoff values have been established, subanalyses show an over- identification of subjects, who may have occupational asthma and
all better response in patients with more inflammation, defined therefore require further testing.123
by higher blood eosinophil levels.115 Recently, Celejewska-Wójcik Multiple omics, big data, and systems biology have demon-
et al demonstrated that three distinct NERD subphenotypes re- strated a profound complexity and dynamic variability in asthma be-
flect differences in inflammatory response measured by airway tween individuals, as well as between regions. Reliable diagnosis of
eosinophils and the ratio of logLTE4/logPGE 2 in induced spu- asthma and the monitoring of its severity are challenging particularly
tum.116 Mastalerz et al117 studied airways PGE2 in induced spu- in daily clinics. Asthma is an umbrella term, including several distinct
tum and reported that NERD subjects had higher levels of PGE2 phenotypes and endotypes, which are characterized by specific cel-
before aspirin challenge compared to controls. After exposure to lular and molecular immune response patterns.47,115,124,125 The main
aspirin, PGE2 levels significantly dropped, which was not the case asthma endotypes, type 2 and non–type 2 inflammation, are broader
for aspirin-tolerant asthmatic individuals. The inhibition of bron- described in the section below. Type 2 allergic asthma is defined by
chial PGE2 biosynthesis can trigger bronchoconstriction in NERD. IgE, IL-13, IL-4, IL-5, and eosinophil responses and covers more than
Chen et al118 showed that the levels of exhaled PGE2, LTB4, LXA4, 50% of asthma endotypes.115
and LTE4 may efficiently differentiate asthmatic children from Boudier et al. highlighted the value of unsupervised asthma
healthy controls. Especially, the measurement of LTB4 and lipoxin phenotypes research, including multiple asthma characteristics, for
A4 together with FeNO and FEV1 might help for the better diag- understanding the long-term evolution of asthma patients. Using a
nosis of asthma. cluster-based model developed for longitudinal data, asthma phe-
A nationwide Japanese prospective study has investigated 190 notypes were identified in a large population of adults with asthma
patients with near-fatal asthma exacerbation. By analyzing asthma 20 years after recruitment.126 This model was developed by taking
symptoms over the 2-week period before their admission, the au- into account two time points and nine variables combining clini-
thors could define three different clusters of symptoms. Analysis of cal and functional characteristics, such as respiratory symptoms,
clusters indicated the most relevant factors to be assigned to three asthma treatment, allergic characteristics, lung function, and bron-
different clusters, such as a degree of ICS or ICS/LABA compliance, chial hyper-responsiveness. These cluster-based asthma phenotypes
low or high perception of dyspnea, and hypersensitivity to environ- showed a stronger long-term clinical prognosis compared to pheno-
mental stimuli.119 types classically used in epidemiological studies, allowing a strong
Additional to clinical trials, the analysis of real-world data is tracking of lung function over the life course to better tailor asthma
very important to confirm effectiveness also in larger, more diverse management strategies.126
patient groups. Jutel et al analyzed changes in AR progression and Ivanova et al reviewed the role of “omics” technologies in
asthma status after HDM allergen immunotherapy (AIT) based on asthma.127 Although omics data studies have several limitations,
data on prescription medicine consumption. They found that treat- usually due to limited sample size and the complexity of the data
ment of AR patients with HDM allergoid can ameliorate asthma and all its interactions, different insights were acquired. Another
symptoms, slow down asthma progression, and reduce the general review also highlighted the importance of omics data for molecu-
incidence of asthma as compared to untreated control groups.120 lar phenotyping, defining the endotypes, and identifying pathways
Asthma-inducing agents are also present at many workplaces. and mechanisms, such as type 2-high and type 2-low.1 In regard to
Occupational asthma is often hard to diagnose since the reference this purpose, the transcriptome and protein levels in three differ-
test (specific inhalation challenge) can only be conducted in a few ent mouse models for eosinophilic, mixed, and neutrophilic asthma
centers worldwide. Recently, a model to improve diagnosis of occu- were analyzed. The authors found that differential expression of
pational asthma without specific inhalation challenge was published tight junctions, mucin, and inflammasome-related molecules in
on the basis of a Canadian dataset and was successfully validated in distinct inflammatory phenotypes of asthma may be linked to the
121
a European population. Clinicians could use this model with de- pathophysiology and might reflect the differences observed in the
cision making on referral to a specialized center in the future. Van clinic.125 Eosinophil and neutrophil dominant phenotypes were de-
122
der Plas et al studied the differences between sensitization to scribed in children with asthma as well. The neutrophil dominant
high-molecular-weight proteins and low-molecular-weight chemicals phenotype was associated with the biggest differences compared
in occupational asthma. Asthma caused by high-molecular-weight to the other asthma phenotypes. The vast majority of the differen-
chemicals showed a stronger association with rhinitis, conjunctivitis, tially expressed genes was associated with corticosteroid response,
atopy, and early asthmatic reactions and had a higher risk of airflow and the neutrophilic phenotype was associated with corticosteroid
limitation, while low-molecular-weight agents were associated with nonresponsiveness.128
CEVHERTAS et al. |
      3135

Severe asthma is a heterogeneous disorder, including different evaluated eosinophils during Mycobacterium tuberculosis infection in
clinical characteristics (phenotypes) and immunopathological path- an experimental model. They observed that eosinophil production in
ways (endotypes). The identification of noninvasive biomarkers that the bone marrow is weakened in Mycobacterium tuberculosis infec-
are able to predict treatment response and assist in designing per- tion and protects against asthma.135
sonalized therapies for severe asthma patients is demanding. The role of eosinophils in personalized asthma treatment remains
Eguiluz-Gracia et al broadly reviewed recent developments in controversial. In a real-life study, Bagnasco et al showed no correla-
biomarkers in allergic diseases, highlighting the importance of eosin- tion between peripheral blood eosinophils count with the clinical,
ophils in allergic asthma diagnosis and management.124 functional, and biological outcome changes in asthma patients.136,137
According to an EAACI position paper in 2019, biomarkers for Not only frequencies of eosinophils can serve as a biomarker
124
the clinical and inflammatory phenotype of asthma were summa- of asthma severity and response to the treatment.138 Rodrigo-
139
rized as follows (1) type 2 asthma: (a) serum IgE, (b) blood and sputum Muñoz et al recently reported a set of 14 miRNAs stratifying
eosinophils, and (c) FeNO; (2) non-type 2 asthma: (a) sputum neutro- eosinophils from asthmatic patients and controls. Interestingly, 3
phils and (b) blood and sputum eosinophils.115 However, the etiology of those miRNAs (miR-144-5p, miR-185-5p, and miR-320a) were val-
of asthma with non-type 2 inflammation is less clear. idated as asthma biomarkers in the serum, distinguishing not only
Eosinophils as biomarkers: Sputum eosinophilia is the most useful asthma status but also the severity.139
biomarker in asthma. In general, sputum eosinophilia is associated Other immune cells as biomarkers: The level of human circulating
with steroid responsiveness. Although there is no standardized cut- neutrophil extracellular trap but not eosinophil extracellular trap can
off, a blood eosinophil count of 300 cells/μL and the normal range for act as a potential marker for asthma severity and poor control.140
sputum eosinophilia defined as 1–2% have commonly been used as Another candidate marker for asthma severity could be the frequen-
a threshold to indicate eosinophilic asthma.115 Higher blood or spu- cies of circulating chemokine receptor (CCR) 10+ ILC2s and plasma
tum eosinophil count has been assessed to be a sensitive and prac- CCL27 level. Conversely, CCR10+ ILC2s resemble the characteristics
tical predictive biomarker for biological therapies targeting allergic of ILC1s and display higher levels of T-bet expression and increased
and/or eosinophilic pathways in patients with severe asthma.129-131 production of interferon (IFN)-γ compare to the CCR10 -ILC2 coun-
Systematic reviews showed the efficacy and safety of benralizumab, terpart, which favors the controlling of allergic inflammation in
dupilumab, mepolizumab, omalizumab, and reslizumab for severe eo- asthma.141
129,130
sinophilic asthma and allergic asthma. A high blood eosinophil IgE as a biomarker: IgE exerts several biological functions as an Fc
count (>300 cells/μL) has been reported as a potential biomarker receptor–bound antigen sensor for mast cells, basophils, dendritic
to predict successful treatment effects of omalizumab in children cells (DCs), T and B cells, and other cells in the allergic inflammation.
with severe allergic asthma.115 Sputum eosinophilia also adequately Total serum IgE and allergen-specific IgE have been strongly associ-
predicts response to biologics. Patients with refractory asthma are ated with asthma.115 Omalizumab is the recombinant humanized mAb
more likely to respond to anti-IL-5 or anti-IL-4/IL-13-targeted treat- that binds to the Fc region of IgE. Correlations between treatment
ment if they have sputum eosinophils of >3% or ≥ 300 cells/μL blood response and baseline total serum IgE or antigen-specific IgE levels
eosinophils.115,129-131 are not clear, but serum IgE is used to dose omalizumab.115,129,130
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 8.1 | Proteins as biomarkers:
the use of peripheral blood eosinophil counts and eosinophil-derived
neurotoxin as predictive biomarkers.132 Hoang et al showed that seed storage proteins (Ara h 1, 2, 3, 6), uter-
The transcriptomic data from bronchial biopsies of European oglobin from cat (Fel d 1), and lipocalin from dog (Can f 1) demon-
U-BIOPRED cohort patients showed that MMP-10 and MET genes strated the strongest linkage to clinical markers of asthma severity.
were significantly overexpressed in severe asthma. These results These results suggest their potential contribution as biomarkers in
demonstrated that MMP-10 and MET play an important role in path- preschool asthma.142
ways of airway remodeling and cellular inflammation that are associ- A study in the Spanish population identified serum biomarkers
ated with submucosal eosinophilia.133 for allergic or nonallergic asthma by using isobaric tags for relative
Recent studies have shown that eosinophils can also display pro- and absolute quantitation (iTRAQ)-based proteomics. It indicates
tective regulatory properties in asthma. In a recent study, Pineros that increasing levels of plasma insulin-like growth factor-binding
et al134 provided ex vivo and in vivo evidence that mouse and human protein acid-labile subunit, which has a role in the regulation of in-
eosinophils are capable of rapid capture and inactivation of respira- sulin-like growth factor pathway, could act as a potential biomarker
tory viruses. They also showed that eosinophils from asthma patients for defining severity of allergic asthma, whereas the proteins of the
displayed a reduced capacity to bind virus, which may lead to a less complement ficolin-2 and mannan-binding lectin serine peptidase 1
effective virus inactivation.134 These results underlie the in vivo an- levels seem increased in nonallergic individuals.143
tiviral activity of eosinophils and the pathogenesis of virus-induced Exhaled Biomarkers: Measurement of biomarkers in exhaled
asthma exacerbations. Another study conducted by Tarancon et al. breath (ie, FeNO) and exhaled breath condensate (ie, volatile organic
 |
3136       CEVHERTAS et al.

compounds) are noninvasive and safe. FeNO is a widely accepted the healthcare providers and can increase self-medication and share
biomarker for type 2-driven airway inflammation. Recently, a new decision making in rhinitis and asthma multimorbidity.150 Using the
subgroup of patients with high FeNO levels (>25 ppb) and low blood MASK-air app, 14 189 users and 205 904 days, a visual analog scale
eosinophils (<300 cells/μL) was described. These patients showed (VAS) days, have been recorded. VAS work correlates with other out-
a significantly higher number of sensitizations against aeroaller- comes (VAS global, nose, eye, and asthma) but less well with a symp-
115
gens compared to patients with low FeNO subgroups. FeNO is tom-medication score. VAS profile has potential for prevention, for
also associated with increased risk of asthma exacerbations and a the assessment of AR severity and progression, and for monitoring
beneficial effect of ICS. Pavord et al investigated whether these the drug effects in patients.151 Another study has determined the
biomarkers have prognostic value or predict the effects of regular importance of mobile technologies in rhinitis control by using AR
144
or as-needed ICS on exacerbations in patients with mild asthma. and its impact on asthma (ARIA) score.152 Subsequent to this study,
The open-label, randomized controlled trial showed that the effects Bousquet et al examined the use of mobile technology to get in-
of as-needed budesonide-formoterol are independent of biomarker formation in the change management of AR and asthma multimor-
profile.144 Dupilumab improves asthma control, quality of life, and bidity, with the aim of providing an active and healthy lifestyle for
FEV1. The use of rescue medication is reduced above the minimally these patients.150 The European Innovation Partnership on Active
important clinical difference threshold only in patients with high and Healthy Ageing transferred innovation from the “Allergy Diary”
blood eosinophils and high FeNO (blood eosinophils >300/μL and/ to 22 reference sites or regions across Europe, aiming to compare
or FeNO >50 ppb).131 the phenotypic characteristics of rhinitis and asthma multimorbidity
The non-T2 endotype covers both patients with a neutrophilic in adults and the elderly, to assess the percentage of accepting the
and a pauci-granulocytic airway inflammatory pattern. Childhood Allergy Diary in adults and elderly, and to understand the pheno-
asthma comprises more different phenotypes with complex patho- typic characteristics and follow-up treatment over 1 year of rhinitis
physiology. Su et al. showed that neutrophil-predominant asthma is and asthma multimorbidity.153
the most severe asthma phenotype in children with a poor cortico-
steroid response.128 Less is known about biomarkers for pauci-gran-
ulocytic asthma. The role of biomarkers in the non-type 2 endotype 9 | N OV E L TR E ATM E NT S D R I V E N BY
has yet to be fully elucidated. A S TH M A E N D OT Y PE S
AIT is an allergen tolerance-inducing treatment for allergic dis-
eases. There are no biomarkers that sufficiently predict response Precision medicine, which is fitting very well asthma’s heterogeneity
to AIT. The Allergen Immunotherapy User's Guide summarized the and complex pathogenesis, is becoming an overarching medical disci-
potential biomarkers for monitorization of the clinical efficacy of pline that requires a good understanding of biomarkers, phenotypes,
AIT as follows: (a) IgE (total IgE, specific IgE (sIgE)/total IgE ratio), endotypes, genotypes, regiotypes, and theratypes of diseases. 2 ICS
(b) subclasses of IgG (allergen-specific IgG, IgG1 and sIgG4, sIgE/ have been the foundation for asthma treatment; however, inhaled
IgG4 ratio), (c) IgE serum inhibitory activity for IgE (IgEFAB), (d) ba- or systemic corticosteroids can be ineffective in many patients with
sophil activation, (e) chemokines and cytokines, (f) cell markers such asthma. Few treatment options exist for patients with steroid-re-
as Tregs, Bregs, and DCs, and (g) in vivo biomarkers including provo- sistant asthma. The recent development of a new class of biological
cation tests.145,146 agents that target airway type 2 inflammation has provided an op-
Digital asthma biomarkers: Exhaled breath analysis using an elec- portunity for treating patients with corticosteroid refractory asthma
tronic nose (eNose) is a new technique. This tool has the potential (Figure 1).154
147,148
to assess asthma control and tailoring asthma treatment. In a A significant amount of research supports the separation into
study including participants between 6 and 18 years of age, Cavaleiro type 2 and non–type 2 asthma endotypes.8,155,156 Type 2 asthma
Rufo et al showed that the exhaled breath condensate volatilome usually has high sputum and blood eosinophil counts and high FeNO
analysis by an eNose has good accuracy for asthma identification levels. The diagnosis of non–type 2 patients, who are usually unre-
being able to distinguish individuals with diagnosed pediatric asthma sponsive to the ICS treatment, remains a challenge. Some studies
from those without the disease.149 Farraia et al demonstrated that have suggested that elevated levels of circulating interleukin (IL)-17,
the analysis of the exhaled volatile organic compounds profiles IL-6, IL-23, or other factors, such as bacterial infection and obesity
using an eNose could be used as a fast and noninvasive complemen- are all involved in the pathogenesis of the non-type 2 asthma.157
147
tary assessment tool for the detection of uncontrolled asthma. Neutrophilia observed in these non-type 2 patients was related to
Moreover, the eNose was able to identify individuals with persistent recurrent respiratory tract infection facilitated probably by a defi-
asthma under prescribed corticosteroid therapy, supporting the di- ciency of local airway immunoglobulins. Asthma patients who re-
agnostic ability of this method to identify individuals in need of cor- ceived intravenous immunoglobulin exhibited higher levels of serum
149
ticosteroid therapy. IgA and fewer infection exacerbations 12 months afterward.158
Mobile Airways Sentinel Network [MASK] is an information Several earlier studies have highlighted the impact of high-alti-
technology-based tool that developed through ARIA studies, which tude treatment in atopic dermatitis and asthma.159,160 A recent study
can inform patient decisions based on a self-care plan proposed by by Boonpiyathad et al161 described the clinical and immunological
CEVHERTAS et al. |
      3137

changes after high-altitude treatment in asthma patient subgroups (XPORT) trial assessing omalizumab discontinuation effects in an
and showed that clinical improvement is dependent on the asthma adult population.169
phenotype. Furthermore, high-altitude treatment reduced the type The identification of treatment responders is of great signif-
2 immune response and corrected the elevated CRTH2 expression icance for patient selection; however, validated biomarkers are
and its dysregulated functions.161 currently scarce. For benralizumab, Mathur et al found several in-
Severe asthma is defined by the ERS/ATS criteria as either dicators of enhanced response of the drug in two phase III trials
asthma requiring escalation to step 5 medical therapy (=high-dose in patients with elevated blood eosinophil counts, decreased lung
ICS in combination with a second controller and/or additional sys- function, long-term oral corticosteroid use, and nasal polyposis.170
temic corticosteroid therapy) to maintain asthma control or asthma In a small prospective study, Antonicelli et al. showed that forced
162,163
that remains uncontrolled despite step 5 therapy. Only 5%- oscillation technique (a noninvasive method that provides informa-
10% of asthma patients fulfill these criteria, but they are responsi- tion of the degree of obstruction of the respiratory system) could
ble for >80% of the total asthma healthcare costs. Adverse effects detect specific mepolizumab-induced changes in peripheral airway
due to an overload of corticosteroid therapy (resulting from an often function in patients undergoing treatment for severe eosinophilic
combined nasal, cutaneous, and/or inhaled therapy) are recognized asthma.171
162
as a major contributor to the immense healthcare costs. Voorham EAACI recently launched its guidelines for the use of biologicals
et al showed in a matched, historical cohort study that patients un- in severe asthma. Recommendations follow the GRADE approach
dergoing long-term systemic corticosteroid treatment suffered an- for each biological and each outcome. In addition, a management
nually increasing healthcare costs compared to patients who do not algorithm for the use of biologicals in the clinic is proposed, together
receive systemic.164 with future approaches and research priorities.172
Targeted therapies play a critical role in severe and diffi- Fokkens et al stated that it is likely that biologics will become an
cult-to-treat asthma in adults, including monoclonal antibodies alternative for sinus surgery in chronic rhinosinusitis with nasal pol-
against IgE, blockage of IL-4 and IL-13 signaling, and anti-IL-5 yposis, which is a frequent comorbidity of severe asthma.106
165,166
and anti-IL-5 receptor therapies. This is partly why optimi- Optimizing patient empowerment and satisfaction by allowing
zation of severe asthma therapy (ie, by reducing steroid use) re- self-injection of currently approved biologicals administered subcu-
ceived considerable attention in the past decades, with targeted taneously is another approach.173 Another key future development
162
approaches (eg, biologicals) (Figure 1). Currently, there are five could be optimization of airway delivery of biological agents by using
biologicals approved for difficult-to-control asthma, targeting IgE nebulized monoclonal antibodies.163
(omalizumab), IL-5 (mepolizumab and reslizumab), IL-5Rα (benrali- Another promising new approach is the use of arginase inhib-
zumab), and IL-4Rα (dupilumab). These drugs were shown to have itors which lead to an increase in nitric oxide levels, thus promot-
steroid-sparing effects and reduce asthma exacerbations, as well ing bronchodilation and inhibiting airway inflammation. Currently,
as hospital admissions, in randomized control trials.106 Biological drugs based on arginase inhibition are under development.79 Other
treatment of severe asthma also comes with a high cost for the possible future targets in personalized asthma therapy include the
healthcare system (it exceeds the recommended maximal cost per epithelial cell–derived cytokines (eg, IL-33 or TSLP), kinases (eg,
quality-adjusted life-year by far); thus, the selection of the patient JAK and Pi3K), and the PGD2 (acts as a pro-inflammatory mediator)
is required to be rigorous.106,162 One difficulty in patient selection (Figure 1).162,163 A comprehensive review by an EAACI task force174
is due to the overlapping severe asthma phenotypes, such as se- highlighted the complex roles of eicosanoids in asthma and allergy.
vere allergic asthma and severe eosinophilic asthma. A multi-cen- Type 2 inflammation-independent asthma represents a critical
ter, open-label, single-arm study conducted by Chapman et al. unmet medical need in the search for potential drug targets, as such
showed that a direct switch from omalizumab to mepolizumab patients show a decreased response to asthma therapies targeting
(within 2-4 weeks of the last biologic dose) is possible without any type 2 cytokines. By generating a noncompetitive inhibitory anti-
tolerability issues and can be highly beneficial for patients with tryptase antibody in humanized mouse and cynomolgus monkey
severe eosinophilic asthma not optimally controlled by omali- models, Maun et al. provided the scientific rationale for clinical test-
zumab.167,168 As crucial as the patient selection is for the initiation ing of such antibodies.175
of biological treatment, the decision in which patients to discon- Kere et al examined the association between biologicals, cor-
tinue it after long-term usage is equally important. In a real-life ticosteroids, and DNA methylation in peripheral blood cells from
study involving children with severe allergic asthma, Deschildre asthmatic children and found no evidence that ICS or other asthma
et al demonstrated that omalizumab discontinuation could be medications affect peripheral blood cell DNA methylation levels.176
safely proposed after at least 24 months of treatment in children However, the usage of biologicals provides therapeutic options
with prolonged controlled asthma and no severe exacerbations when conventional approaches fail.
for at least one year. They also showed that some phenotypic Allergen-specific immunotherapy. The only causal treatment in
markers (female gender, allergic multimorbidity, and decreased allergic asthma is AIT, the role of which has been largely explored
lung function) should be taken into account, consistent with the in recent clinical and experimental research. In a large cohort
findings from the persistency of response after long-term therapy study involving 39 167 asthmatic subjects, a remarkable reduction
 |
3138       CEVHERTAS et al.

of symptomatic medication was observed among 4111 patients regarding asthma prevalence among COVID-19 patients are incon-
treated by AIT during a 8-year follow-up. This outcome, which was sistent, varying from 0.9% in Wuhan to 17% in the United States.186
mainly observed in young subjects, suggests that AIT might play a Wang et al exclude asthma as a factor influencing COVID-19. Their
role in preventing progression from mild to more severe asthma.177 statement is supported by the data from Avdeev et al and Zhang
Moreover, AIT was shown to decrease serum IgE levels, while in- et al187,188 Both groups did not observe the increase in the preva-
creasing serum levels of Der p 2-specific IgG4 and Der p 2-specific lence of bronchial asthma or COPD among patients with COVID-
IgD in HDM-sensitized asthmatic patients. The longitudinal change 19.187,188 Likewise, in a cohort of 1504 severe asthmatics, Heffler
in Der p 2-specific IgE/IgD ratio was similar to that in Der p 2-spe- et al. demonstrated that asthma patients are not at high risk of SARS-
cific IgE/IgG4 ratio. Asthma symptoms were improving during the CoV-2 infection.189 Several more clinical studies ruled out asthma
AIT process, which also correlated with allergen-specific B-cell as COVID-19-predisposing factor.188,190,191 In the line with available
178
responses. reports, experts from 43 countries around the world in ARIA-EAACI
186
Many retrospective AIT studies investigated the risk of new-on- statement do not consider asthma as a factor predisposing for
set asthma, the relative risk of medication dispensing for asthma SARS-CoV-2-related disease. In contrast, another study advocates
and its potential progression among multimorbid allergic subjects. asthma as a COVID-19 risk factor based on the impaired antiviral
It was found that use of sublingual allergen immunotherapy tablets responses (interferon (IFN)-α, IFN-β, and IFN-λ) that may predis-
for pollen allergy for the treatment of AR could reduce the preva- pose asthmatic patients to severe COVID-19 manifestations.192 The
lence of asthma, decrease asthma medication usage, and also slow US Center for Disease Control and Prevention also proposed that
down progression of asthma in comparison with a group receiving moderate-to-severe asthma should be considered a risk for severe
only symptomatic AR medication.179-181 Moreover, AIT with grass COVID-19 manifestations.186 Additionally, a recent study from Zhu
allergen peptide over 3 weeks before the beginning of grass pollen et al (n =  492  768) demonstrated inflammatory phenotype of un-
season was considered as an efficient and safe modality to pro- derlying asthma as a crucial factor for COVID-19 risk assessment.
tect patients with rhinoconjunctivitis and asthma from symptom They showed that nonallergic, but not allergic asthma predisposes
onset.182 Additionally, it was suggested that in patients with both al- patients to COVID-19. Due to the reported discrepancies, available
lergic asthma and AR, compared to standard care, sublingual allergen data should be interpreted with caution.193
immunotherapy may have a cost-effective benefit with an incremen- Data are still unclear as the COVID-19 population included in
tal cost-effectiveness ratio of £10,726 per quality-adjusted life-year the studies is skewed toward older and hospitalized patients with
which is nearly half of the (English) National Institute for Health and predisposing comorbidities (such as hypertension, obesity, or diabe-
Clinical Excellence threshold.183 tes) which are strong confounders.186,187 Additionally, early clinical
Studies have been continued to develop novel vaccines for al- reports regarding asthma prevalence among COVID-19 cases often
lergen-specific immunotherapy. In a HDM-driven allergic asthma vary in terms of patients’ severity including those undergoing home
mouse model, purified Der p1 and 2, similar to crude HDM extract, quarantine,194 hospitalized,191,195 or referred to intensive care units
demonstrated a suppressive effect on AHR, eosinophilic inflam- and requiring mechanical ventilation.187 As gender, smoking status,
mation, type 2 cytokines, and activation of lung structural cells.184 ethnicity, lifestyle, genetic background, and asthma phenotype can
These optimal results based on purified natural allergens from ani- influence COVID-19 outcomes, these factors should be carefully in-
mal studies suggest further research focusing on novel vaccines due vestigated.186,195 Age seems especially significant, as childhood and
to high demands in the field of allergic asthma. adolescent asthma do not seem to be a hazard for COVID-19.195 This
A systematic review summarized recent updates about nonphar- may be related to reduced prevalence of comorbidities, lack of smok-
macological asthma management. This review epitomized the meth- ing, or boosted immune system due to recent vaccinations.195
ods used in studies, highlighted the importance of education and Allergic responses accompanying asthma are hypothesized to
self-management, and called for a thorough description of methods play a protective role in the course of COVID-19. Eosinopenia (de-
in future studies.185 creased numbers of eosinophils in the blood) is a biomarker of se-
verity and poor prognosis for COVID-19 patients.195 Eosinophils
respond to viral infections by releasing cytotoxic proteins, reac-
10 | C H A LLE N G E S I N A S TH M A tive oxygen species, and type 1 cytokines.195 Therefore, they play
M A N AG E M E NT D U R I N G COV I D -19 a supportive role in fighting the infection. Allergic patients present
PA N D E M I C S eosinophilia (increased numbers of eosinophils in the blood) and
could have an advantage for the eosinophil-dependent antiviral re-
The recent outbreak of severe acute respiratory syndrome corona- sponses.195 Notably, Licari et al. compared COVID-19 children only
virus 2 (SARS-CoV-2) causing coronavirus disease 2019 (COVID-19) with a large cohort (n = 120) of allergic children and concluded that
pandemics led to the worldwide emergency affecting the life of allergic children had significantly higher frequencies of eosinophils
more than 21 million people (status for 14.08.2020). It also raised in the blood.195
a vigorous discussion in the research community, whether or not Receptor ACE2 and serine protease TMPRSS2 mediates SARS-
asthma should be classified as a COVID-19 risk factor. Reports CoV-2 entry into host cells.196-198 CD147, CD26, ANPEP, ENPEP,
CEVHERTAS et al. |
      3139

or DC-SIGN are other receptors, proven or potentially involved in response and the type 2 immunity signature in asthmatic patients
196
COVID-19 pathogenesis. Radzikowska, Ding et al demonstrated downregulated the late-phase hyperinflammation and consequently
that ACE2 and TMPRSS2 are expressed only in the epithelial tissues, decreased tissue damage in the lungs, which might be beneficial in
whereas CD147 and its interaction partners are present in both epi- allergic asthma during COVID-19.191 In contrast, the inhibition of
thelial tissues and immune cells.199 The expression of several SARS- type I IFNs is believed to play a crucial role in SARS-CoV-2 patho-
CoV-2 receptors seems to be different in asthma patients (increased: genesis. Delayed IFN response and exaggerated inflammation might
TMPRSS2, CD44, ITGA6, NFATC2, NME1, and APOD; decreased: be related to increased virus replication, tissue damage, and se-
ACE2, ACE, MCT4, APH1A, S100A9, and NOD2). These findings were vere COVID-19 complications. 201 Apparently, IFN response and its
partially confirmed by others.186,200 There is growing evidence that mechanisms during COVID-19 represent a double-edged sword and
allergic type 2 inflammation (mainly IL-13) decreases ACE2 and in- should be carefully investigated.
creases TMPRSS2 expression.186,200 Additionally, ACE2 is an IFN- Asthma management in the times of COVID-19 pandemics pre-
induced gene. 200 Intriguingly, the suppressed production of type I sented a challenge due to the overlap of the respiratory symptoms
and III IFNs (IFN-α/β and IFN-λ) has been defined in severe atopic induced by asthma or by SARS-CoV-2 and by reduced face-to-face
191
patients. During viral defense, initial activation of innate immu- appointments and risky pulmonary function testing generating aero-
nity and IFN-α/β and IFN-λ are crucial to eliminate the virus. One sols (Figure 4).186,202-207 If possible, a video examination and atten-
can hypothesize that impaired/delayed type I and III IFN response tive observation of the patient may help in proper diagnosis. 202,208
observed in asthma patients, usually a foe, may play a protective role Fever, persistent dry cough, flu-like symptoms, and lack of wheeze
during SARS-CoV-2 infection and resulted in a subsequent decrease can indicate COVID-19 over asthma exacerbation. 202 Severe asthma
200
in an ACE2. Carli et al. suggested that the altered type I IFN exacerbation leads to the hospitalization, which exposes asthmatics

Asthma control
Social Triggers
distancing avoidance
Personal Steroid
protection continuation

F I G U R E 4   Management of asthma
patients during COVID-19 pandemic.
Assuring patients’ safety can be provided
by prevention of infection with SARS-
CoV-2 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.
EAACI Position Papers on COVID-19 Several EAACI position papers have
been published on patient management
• ARIA-EAACI statement on asthma and COVID-19 READ ALSO during the COVID-19 pandemics that
• Intranasal corticosteroids in allergic rhinitis • Management should be referred in specific conditions,
of ocular allergy such as biological usage, allergen
• Handling of allergen immunotherapy
• Measurement immunotherapy, drug hypersensitivity,
• Immunology of COVID-19 of olfactory venom immunotherapy, ophthalmology,
dysfunction and asthma. EAACI, European Academy of
• Practical considerations on the organization of an allergy clinic
• Treatment Allergy and Clinical Immunology; COVID,
• Considerations on biologicals for patients with allergic disease of venom allergy coronavirus disease 2019; ICS, inhaled
corticosteroids
 |
3140       CEVHERTAS et al.

to unnecessary risk of being infected with SARS-CoV-2.195 Steroid and should receive the SARS-CoV-2 vaccine with priority, as rec-
therapy in asthmatic patients in times of COVID-19 pandemics should ommended for the influenza and the pneumococcal vaccine. In the
be continued as clinically indicated.187,192,200,202,205 Additionally, ICS present situation, prevention and proper asthma control, including
use can be beneficial during COVID-19 as it restores the impaired continuation of the background controller treatment, are the most
antiviral responses in asthma, subsequently leading to less severe efficacious way to assure the safety of asthma patients. 210
192
manifestations. ICS suppresses coronavirus replication and de-
creases the ACE2/TMPRSS2 expression. 200 However, ICS treatment
can cause SARS-CoV-2 nebulization and its spread to the lower air- 11 | CO N C LU S I O N
ways and surrounding surfaces.195 Therefore, the use of a spacer is
encouraged.195 On the opposite, NICE guideline speaks against this Asthma research produces up to 9000 publications per year and
perception stating that nebulizer-generated aerosols do not carry represents one of the most rapidly developing areas. Most of the
SARS-CoV-2 virus (www.nice.org.uk/guida​nce/ng168). On the other novel developments of the last year focus in the areas of precision
hand, the use of OCS was linked with a risk of severe COVID-19 man- medicine, endotypes and phenotypes, biomarkers, novel treatments
186
ifestations (including death). If good asthma control in patients such as biologicals, and real-life studies. The stratified/personalized
cannot be maintained, the introduction of azithromycin prophylaxis approach to patients and targeted treatments represents the future
can be considered.192 Azithromycin reduces asthma exacerbations in many chronic diseases. A better understanding of the molecular
in patients, probably by augmenting IFN-β and IFN-λ responses, a mechanisms and discovering novel biomarkers represents the main
subsequent decrease in viral replication, and reduced inflammatory target areas for further improving patient care.
response.192,200 Azithromycin interferes with the CD147 receptor
and decreases its downstream signals after viral (rhinovirus) infec- C O N FL I C T O F I N T E R E S T
tions. 200 COVID-19 in high endemic HDM environment may affect Lacin Cevhertas, Ismail Ogulur, Debbie J. Maurer, Daniel Burla,
antiviral immune responses. In a study by Akbarshahi et al., the Mei Ding, Kirstin Jansen, Jana Koch, Chengyao Liu, Siyuan Ma,
authors hypothesized that HDM may adversely affect viral stimu- Yasutaka Mitamura, Yaqi Peng, Urszula Radzikowska, Arturo O.
lus-induced antiviral IFN (types I and III) responses. To test the hy- Rinaldi, Pattraporn Satitsuksanoa, Anna Globinska Willem van de
pothesis, the authors investigated the effects of HDM exposure in Veen, Milena Sokolowska, Katja Baerenfaller, Ya-dong Gao, and
both human bronchial epithelial cells and a mouse model of asthma Mübeccel Akdis declare no conflict of interest. Ioana Agache reports
exacerbation. They observed that Toll-like receptor-3 is the main tar- and Allergy journal Associate Editor Cezmi Akdis reports grants
get involved in reducing the IFN-β and IFN-λ responses by HDM. 209 from Allergopharma, Idorsia, Swiss National Science Foundation,
Lommatzsch et al reported the safety of omalizumab in an 52-year- Christine Kühne-Center for Allergy Research and Education,
194
old severe allergic asthmatic patient with SARS-CoV-2 infection. European Commission’s Horison's 2020 Framework Programme,
During the SARS-CoV-2 infection, the patient did not report any Cure, Novartis Research Institutes, AstraZeneca, Scibase,
asthma exacerbation and maintained proper asthma control. A mild GlaxoSmithKline, and other from Sanofi & Regeneron.
manifestation of COVID-19 observed in this study might have been
related to either (a) allergic endotype of underlying asthma, (b) ongoing ORCID
omalizumab treatment, or (c) both.194 However, this observation needs Lacin Cevhertas  https://orcid.org/0000-0003-2287-3569
further confirmation in the bigger patients’ population. Furthermore, Ismail Ogulur  https://orcid.org/0000-0001-8282-7762
omalizumab decreases the duration of rhinovirus infections and vi- Kirstin Jansen  https://orcid.org/0000-0002-9176-8562
192,200
rus-related exacerbations. It can be hypothesized that anti-IgE Jana Koch  https://orcid.org/0000-0002-7552-6088
therapy protects also during SARS-CoV-2 infection. Experts sug- Yasutaka Mitamura  https://orcid.org/0000-0001-6389-9285
gest that immunomodulatory biological treatment strategies should Yaqi Peng  https://orcid.org/0000-0003-0084-9541
continue in SARS-CoV-2-negative asthmatic individuals in times of Urszula Radzikowska  https://orcid.org/0000-0002-7341-9764
186,195,200
pandemics. However, due to possible immunosuppres- Arturo O. Rinaldi  https://orcid.org/0000-0001-8967-3866
sive effects, they should be suspended in patients which developed Willem van de Veen  https://orcid.org/0000-0001-9951-6688
COVID-19, until disease resolution.186,195 Milena Sokolowska  https://orcid.org/0000-0001-9710-6685
In summary, available data suggest asthma is not a risk factor Ya-dong Gao  https://orcid.org/0000-0003-1251-7608
for the development of severe forms of COVID-19. Yet, COVID-19 Ioana Agache  https://orcid.org/0000-0001-7994-364X
can be a severe disease in already damaged lungs of chronic asthma, Mübeccel Akdis  https://orcid.org/0000-0003-0554-9943
particularly, ACOS and COPD patients. More evidence is needed Cezmi A. Akdis  https://orcid.org/0000-0001-8020-019X
to fully understand the impact of asthma and asthma therapies on
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