Clinical Commentary Review
Rhinovirus Infections and Their Roles in Asthma:
Etiology and Exacerbations
David J. Jackson, MRCP, MSc, PhDa,b, and James E. Gern, MDc
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Target Audience: Physicians and researchers within the field of
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Rhinovirus infections can cause wheezing illnesses in all age groups.
In preschool children, rhinovirus infections frequently initiate acute
wheezing illnesses. Children who wheeze with rhinoviruses are at
increased risk to go on to develop asthma. Once asthma is
established, rhinovirus infections are potent triggers for acute
a
Guy’s Severe Asthma Centre, Guy’s & St Thomas’ NHS Trust, London, United
Kingdom
b
School of Immunology & Microbial Sciences, King’s College London, London,
United Kingdom
c
Departments of Pediatrics and Medicine, University of Wisconsin School of
Medicine and Public Health, Madison, Wis
This work was funded by the National Institutes of Health (grant nos. UM1
AI160040-01, U19 AI104317, and UH3 OD023282).
Conflicts of interest: D. J. Jackson has received speaker fees and consultancy fees
from AstraZeneca, GlaxoSmithKline, Sanofi, Teva, and Chiesi. J. E. Gern is a paid
consultant to AstraZeneca, Gossamer Bio, and Meissa Vaccines, has stock options
in Meissa Vaccines, and has patents on methods for producing rhinoviruses.
Received for publication November 17, 2021; revised manuscript received and
accepted for publication January 6, 2022.
Available online January 22, 2022.
Corresponding author: David J. Jackson, MRCP, MSc, PhD, Guy’s Severe Asthma
Centre, School of Immunology & Microbial Sciences, King’s College London,
London SE1 9RT, UK. E-mail: David.Jackson@gstt.nhs.uk.
2213-2198
Ó 2022 The Authors. Published by Elsevier Inc. on behalf of the American Academy
of Allergy, Asthma & Immunology. This is an open access article under the CC
BY license (http://creativecommons.org/licenses/by/4.0/).
https://doi.org/10.1016/j.jaip.2022.01.006
London, United Kingdom; and Madison, Wis
AMA PRA Category 1 CreditÔ. Physicians should claim only the credit
commensurate with the extent of their participation in the activity.
List of Design Committee Members: David J. Jackson, MRCP, MSc,
PhD, and James E. Gern, MD (authors); Robert S. Zeiger, MD, PhD
(editor)
Learning objectives:
1. To predict the subsequent asthma risk for preschool children who
wheeze with rhinoviruses (RVs).
2. To recognize that respiratory viruses and in particular RVs are the
dominant drivers of exacerbations in asthma.
3. To explain the relationship between deficiencies in antiviral immune
responses and RV-induced morbidity in asthma.
4. To discuss how controlling underlying allergic and type 2 (T2)
immune pathways could reduce RV-induced morbidity in asthma.
Recognition of Commercial Support: This CME has not received
external commercial support.
Disclosure of Relevant Financial Relationships with Commercial
Interests: All authors and reviewers reported no relevant financial
relationships.
airway obstruction and exacerbations in children and adults.
Paradoxically, for most individuals, rhinovirus infections
commonly cause cold symptoms with little or no involvement of the
lower airways. This paradox has led investigators to identify specific
risk factors and mechanisms for rhinovirus wheezing, and this
review will outline progress in 3 main areas. First, the 3 species of
rhinoviruses have different patterns of infection and virulence.
Second, personal factors such as lung function and immunity
influence lower respiratory outcomes of rhinovirus infection. The
mucosal immune response is critical, and the quality of the
interferon response and allergic inflammation interacts to
determine the risk for rhinovirus wheezing. Finally, rhinovirus
infections can promote pathogen-dominated airway microbiota
that increase the risk for wheezing. Although specific antivirals for
rhinovirus are still not available, identifying risk factors for
wheezing illnesses has provided several other potential targets and
strategies for reducing the risk of rhinovirus-induced wheezing and
exacerbations of asthma. Ó 2022 The Authors. Published by
Elsevier Inc. on behalf of the American Academy of Allergy, Asthma
& Immunology. This is an open access article under the CC BY
license (http://creativecommons.org/licenses/by/4.0/). (J Allergy
Clin Immunol Pract 2022;10:673-81)
Key words: Rhinovirus; Infection; Asthma; Exacerbation; Type 2
inflammation
673
674 JACKSON AND GERN
Abbreviations used
COVID-19- coronavirus disease 2019
ICS- inhaled corticosteroid
IFN- interferon
ILC2- type 2 innate lymphoid cell
RV- rhinovirus
type 2- T2
INTRODUCTION
Rhinovirus (RV)-induced wheezing illnesses are a prominent
feature of asthma in children and adults. Although several res-
piratory viruses can cause wheezing illnesses and exacerbations of
asthma, RV infections are the most common cause of wheezing
in children older than 2 years. Children who experience RV-
induced wheezing and develop respiratory allergies at an early
age are quite likely to develop persistent childhood asthma. Once
asthma is established, RV infections continue to be a major cause
of acute wheezing illnesses. The contrast between RV infections
causing severe wheezing in asthma compared with mild upper
respiratory illnesses in the general population has led to extensive
studies to identify risk factors for more severe RV illnesses in
asthma. This review will summarize current concepts to explain
how RV infections and illnesses in early childhood relate to the
subsequent onset of asthma. We will also discuss mechanisms
linking RV infections to acute exacerbations of asthma. Finally,
we will explore opportunities for the prevention and treatment of
more severe RV wheezing illnesses.
RV INFECTIONS AND IMMUNE RESPONSES
RV infections are the most common illness of childhood.
During the first few years of life, nearly all children are infected
multiple times. The multitude of RV infections in children is due
to the large number of viral serotypes (w170) that induce
antibody responses with little or no cross-neutralization among
known serotypes.1 Epidemiologic studies demonstrate that
approximately 20 RV types can circulate in a given geographic
area during the spring or fall season.2 This broad circulation of
viruses, which are spread most efficiently by young children,
likely contributes to infection rates that peak when children re-
turn to school following summer or spring vacations.3 RV in-
fections are widespread and typically produce mild illnesses in
most children. Although only a subset of RV infections cause
lower respiratory infections and wheezing, RV-induced
morbidity and health care costs are immense due to the sheer
number of infections.
RV types are classified into 3 species on the basis of sequence
similarity.4 The A and B species were first identified decades ago,
whereas the RV-C species was first recognized in 2006.5 The
delay in finding RV-C was because it binds to a unique receptor
(cadherin-related family member 3), which is not expressed in
cell lines commonly used for viral culture.6 These viruses grow in
ciliated airway epithelial cells in the upper airways and the large
and medium-size lower airways.7 Infections are generally limited
to the airway, although the virus can sometimes be detected in
the bloodstream of young children infected with RV-C.8
The immune response to the virus begins in the airway
epithelial cell. Sensors for viral capsid and RNA initiate innate
J ALLERGY CLIN IMMUNOL PRACT
MARCH 2022
immune antiviral responses and stimulate the secretion of che-
mokines and growth factors that recruit and activate leuko-
cytes.9,10 Notably, interferon (IFN) responses are lower in young
infants, which may partially explain the greater severity of RV
illnesses in this age group. Infections cause increases in airway
neutrophils and mononuclear cells during the acute phase, along
with smaller numbers of eosinophils during the recovery period.
IFNs produced by epithelial cells and mononuclear cells have
potent anti-RV activity.11 A brisk IFN response at the beginning
of infection likely limits viral replication and prevents significant
illnesses.12 If antiviral defenses do not control viral replication
and spread during the early stages of infection, high-level viral
replication can induce pronounced IFN and neutrophilic re-
sponses that likely add to the severity of illness.13,14 Analysis of
nasal epithelial cell transcriptional responses suggests that some
illnesses are accompanied by marked activation of IFN pathways,
whereas others are IFN-low and instead increase expression of
proinflammatory cytokines and growth factors.15
RV infections of the upper and lower airway can induce
cellular inflammation, proinflammatory mediators, shedding of
dead cells, and mucus production, which can contribute to res-
piratory symptoms. In addition, lower airway infection can in-
crease airway responsiveness, which correlates with the induction
of proinflammatory cytokines such as IL-6.16 These pathophys-
iologic responses to the virus can lead to airway obstruction in
preschool children and both children and adults with asthma.
RV INFECTIONS AND THE ONSET OF ASTHMA
Several factors related to the virus, host, and environment are
associated with the risk of developing more severe RV illnesses.
Children who wheeze with RV infections are more likely to
develop asthma, and risk factors for this transition have also been
identified (Figure 1).
Viral factors
RV-A and RV-C species viruses are more commonly associ-
ated with significant illnesses and wheezing compared with RV-B
species viruses.17 RV-B infections generally cause either mild
symptoms or are asymptomatic but can contribute to exacerba-
tions in patients with more severe or unstable asthma.17,18 The
increased virulence of the A and C species may be related to
faster rates of viral replication and eliciting greater inflammatory
responses compared with the RV-B spcies.19 A pooled analysis of
RV epidemiology from multiple studies suggests that there may
be certain RV types that are consistently more common and that
virulence may vary by type even within species.17
Host factors
Several host factors are related to a greater risk for severe RV
illnesses and wheezing. First, young age predisposes to wheezing
or febrile illnesses, especially with RV-C infection.17 Second,
genetic factors can increase the risk for RV wheezing. For
example, single nucleotide polymorphisms in the 17q12-21 re-
gion are associated with acute RV wheezing and asthma devel-
opment in children who experience RV wheezing episodes.20
The polymorphisms most closely linked to asthma risk also
regulate expression of gasdermin-B,21 a protein that regulates a
cell death and inflammatory process known as pyroptosis. When
a cell senses an intracellular pathogen, pyroptosis and other cell
death pathways may help to limit the spread of viruses to other
cells.22 For RV-C, a single nucleotide polymorphism in the
J ALLERGY CLIN IMMUNOL PRACT
VOLUME 10, NUMBER 3
FIGURE 1. Risk factors for RV wheezing illnesses and for pro-
gression from RV wheezing to childhood asthma. sIgE, Specific
IgE.
cadherin-related family member 3 (RV-C receptor) gene regu-
lates how much protein is expressed on the surface of airway
epithelial cells,23 and increases RV-C binding and replica-
tion.24,25 The single nucleotide polymorphism (rs6967330)
associated with greater cell surface expression also increases the
risk of RV-C infections during childhood,26 wheezing illnesses
during infancy and childhood,17,23 and early-onset childhood
asthma.23 The association of genetic risk factors for RV wheezing
with childhood asthma suggests that injury due to repeated RV
lower respiratory infections in early life could promote the
development of asthma.
There may be bidirectional relationships between lung func-
tion and RV lower respiratory illnesses. Low lung function in-
creases the risk of wheezing during infections with RV and other
respiratory viruses. For example, van der Zalm et al27 reported
that airway resistance in the first 2 months of life was related to
the risk of RV wheezing illness in the first year of life. In addi-
tion, RV wheezing illnesses in early childhood are associated with
reduced FEV1 and FEV1/forced vital capacity measured by
spirometry at age 5 to 8 years.28 Given that RV infections can
induce factors involved in airway remodeling,29 repeated RV
lower respiratory infections could promote progressive airway
obstruction.
Allergy and evidence of type 2 inflammation are important
risk factors for RV wheeze. Preschoolers sensitized to aero-
allergens or who have other atopic features such as eczema or
eosinophilia are at increased risk for RV wheeze.30 Family history
of allergies or asthma in first-degree relatives also increases the
risk for RV wheeze. Furthermore, the combination of atopy and
RV wheeze in the first few years of life strongly predicts pro-
gression to asthma.31,32
Environmental factors
Birth cohort studies have identified the airway microbiome as
an important factor in determining the risk for viral wheeze and
asthma. In the Copenhagen Prospective Study on Asthma in
Childhood birth cohort, pharyngeal aspirates that tested positive
for bacterial pathogens were associated with recurrent wheezing
and early childhood asthma.33 In the Childhood Asthma Study
conducted in Perth, Australia, acute illnesses were related to
detecting respiratory viruses and transient pathogen-dominated
airway microbiomes.34 These studies suggest that viral respira-
tory infections can cause a temporary increase in pathogenic
JACKSON AND GERN 675
bacteria that contribute to the severity of illness, as has been
demonstrated in school-age children.2
Conversely, airway microbiomes dominated by commensals
were associated with reduced risk for viral wheezing episodes.
RV-C wheezing episodes, febrile illnesses, and colonization with
Streptococcus were all associated with subsequent risk for
asthma.34 In addition, the combination of a pathogen-dominated
microbiome during acute illnesses and allergic sensitization was
associated with persistent wheeze in early childhood.35 The
Childhood Origins of Asthma birth cohort study compared the
etiology of wheezing illnesses and changes in the airway micro-
biota through the age of 2 years to subsequent asthma diagnoses
through age 18 years. This analysis identified 2 risk factors for
persistent asthma: (1) an airway microbiome dominated by
Staphylococcus aureus in the first 6 months of life, and (2)
detection of RV and Moraxella-dominated microbiome during
wheezing illnesses.36 An analysis of upper airway secretions
during RV bronchiolitis using an integrated “omics” approach
identified 4 different phenotypes. The phenotype associated with
RV-C infection, Moraxella-dominated microbiome, and
increased type 2 (T2) cytokine response had the highest inci-
dence of childhood asthma by age 5 years.37
These studies suggest that in early life, the balance between airway
commensals and pathogens in airway secretions influences the risk
for wheezing illnesses. Underlying mechanisms may be related to the
ability of pathogens to induce inflammation or disturb epithelial cell
function. Defining mechanisms for bacterial pathogens to interact
with viruses, allergic inflammation, and epithelial cell function may
lead to new strategies for asthma prevention.
Do RV wheezing illnesses cause asthma?
Longitudinal studies have established that children with RV
wheezing illnesses are at increased risk for developing asthma,
leading to speculation that this relationship is causal. Consider-
able data from experimental models support this theory. As
discussed above, RV lower respiratory infection can damage the
airway epithelium and induce secretion of factors that influence
repair and promote pathologic remodeling of the airways. In
mouse models, RV infection at an earlier age produces long-
lasting effects on airway physiology.38 However, proving cau-
sality would require a clinical trial with an effective antiviral
intervention. For example, treatment with palivizumab effec-
tively prevents wheezing episodes due to respiratory syncytial
virus and has enabled studies to test for effects on incident
asthma. Although palivizumab treatment reduces the risk of
recurrent wheeze through the preschool years, it has not
consistently reduced subsequent asthma.39,40 Similar studies are
needed to determine whether inhibiting RV-induced preschool
wheezing can reduce the risk of asthma.
RV INFECTIONS AND EXACERBATIONS OF
ASTHMA
It is now almost 50 years since Minor et al41 from Madison,
Wisconsin, first described a clear association between RV infec-
tion and exacerbations of asthma. In this early report, an exac-
erbation was observed in 21 of 23 patients with severe viral
respiratory tract infections, of which 14 of 21 (66.7%) were
identified as having infections caused by RV. The significance
and seriousness of this link was further underscored a few years
later with the first case report of a fatal outcome of a young child
with an RV infection exacerbating their asthma.42
676 JACKSON AND GERN J ALLERGY CLIN IMMUNOL PRACT
MARCH 2022

FIGURE 2. The pathogenesis of an RV-induced asthma exacerbation. RV infects the respiratory epithelium, leading to release of the
epithelial-derived cytokines IL-25, IL-33, and TSLP, which drives downstream release of IL-4, IL-5, and IL-13 from TH2 cells and ILC2s. IL-5
plays a key role in driving airway eosinophilia and is itself released by eosinophils; IL-13 is central for mucus hypersecretion and airway
hyperresponsiveness and is additionally eosinophil-derived. pDCs are important sources of antiviral type 1 IFN, and their responsiveness
to RV infection is impaired in the presence of allergic inflammation. ILC2 production of T2 cytokines is partly inhibited by type 1 IFN. pDC,
Plasmocytoid dendritic cell; TSLP, thymic stromal lymphopoietin.

Since then, several larger analyses have been conducted
including the Origins of Asthma study, which recorded respira-
tory viruses in more than two-thirds of 217 exacerbations in
children, with RV again identified as the most common
precipitant.43
As described earlier, a clear seasonal pattern of pediatric
asthma exacerbations is well established, with asthma hospitali-
zation rates in children peaking each year in autumn and early
winter, hypothesized to be mediated by viral transmission.3
Although this pattern is slightly more variable in adults, a
strong link between asthma exacerbations and respiratory virus
infections remains, with RV and influenza A standing out as the
main culprits.44,45 This is true even in the most severe cases, as
evidenced by a recent analysis of adults with near-fatal asthma
exacerbations requiring extracorporeal membrane oxygenation in
which respiratory viruses were the trigger in more than 50% of
patients, with RV again the most common pathogen.46
A significant step forward in understanding the mechanisms of
RV-induced exacerbations of asthma followed the development
of human models of experimental infection with RV. Clinically,
experimental infection with RV-16 results in significant declines
in lung function and increased lower respiratory symptoms in
subjects with asthma compared with healthy subjects.47 More-
over, the level of asthma control at the time of experimental
infection directly relates to the severity of the lower respiratory
symptoms,48 a finding that accurately reflects the increased risk
for exacerbations in patients with poor asthma control in the real
world.49-51
In combination with a substantial body of work using both
experimental mouse models and human in vitro studies, the
human in vivo data to emerge from experimental RV infection of
subjects with asthma have highlighted 2 critical interconnected
areas of dysregulated immunity underpinning the relationship
between RV infection and asthma exacerbations.47,52-55 The first
relates to an exaggerated activation of T2 immune pathways in
individuals with asthma following infection with RV; the second
relates to a deficiency and/or delay in the antiviral immune
response to RV infection (Figure 2). These mechanisms will each
be discussed in the following sections.
RV-INDUCED T2 INFLAMMATION IN ASTHMA
Upregulated T2 immune pathways represent the dominant
inflammatory phenotype seen in asthma, with levels directly
relating to both disease severity and disease control.50,56,57 RV
has been shown to induce a wide range of factors relevant to this
pathway, including activation of the key transcription factor
signal transducer and activator of transcription 6, and induction
of the T-cell and eosinophil chemokines CCL11, CCL17,
CCL22, and CCL26, the epithelial-derived IL-25 and IL-33, as
well as the cytokines IL-4, IL-5, IL-13, and prostaglandin
D2.47,54,58-61
J ALLERGY CLIN IMMUNOL PRACT
VOLUME 10, NUMBER 3
FIGURE 3. Potentially modifiable risk factors for RV-induced
wheezing and exacerbations of asthma.
Early in the T2 cascade, IL-33 (synthesized in response to
bronchial epithelial infection) appears to be a particularly critical
mediator in both TH2 cell and T2 innate lymphoid cell (ILC2)-
driven responses to RV.47 Levels of IL-33 during infection
correlate with asthma symptom severity, with IL-5 and IL-13
induction as well as with viral load. Blocking the IL-33 recep-
tor ST2 completely inhibits RV-induced TH2 polarization,
making the prospect of IL-33 inhibition an exciting one.47
ILC2s are important sources of T2 cytokines including IL-5,
IL-9, and IL-13, leading to the recruitment and activation of
eosinophils and mast cells, and goblet cellemediated mucus
production, respectively. In subjects with asthma, experimental
RV infection leads to an increase in airway eosinophilia47 as well
as ILC2 numbers, with the ILC2:ILC1 ratio correlating with
exacerbation severity and duration of RV infection.62
Somewhat counterintuitively, airway neutrophilia is also
increased during virus-induced exacerbations and may have an
important role in exacerbation pathogenesis by activating
neutrophil extracellular traps (NETosis). However, rather than
this process being independent of T2 pathways, NETosis boosts
T2 responses, further driving exacerbation severity.63
EVIDENCE FOR A DEFICIENT ANTIVIRAL
RESPONSE IN ASTHMA
IFNs represent the first-line defense against respiratory viruses
such as RV and are a critical component of the innate immune
response. Three classes of IFNs have been described: types 1
(IFN-a and IFN-b), 2 (IFN-g), and 3 (IFN-l). To date, a
substantial number of studies using various cell types including
human bronchial epithelial cells, bronchoalveolar lavage cells,
PBMCs, and dendritic cells have demonstrated a delay and/or
deficiency in IFN induction following RV infection in patients
with asthma.52,53,64 During experimental infection with RV, this
antiviral deficiency manifests in vivo as increased virus load in
subjects with asthma compared with healthy subjects.47,62
JACKSON AND GERN 677
However, others have not seen a difference in viral titers be-
tween subjects with asthma and healthy controls,65 which may
reflect differences in the baseline level of asthma control and
severity between studies.
Although much of the data to date relate to bronchial
epithelial cells as the primary site of infection, the range of cells
involved in the dysregulated antiviral immune response in
asthma continues to expand. Wirz et al66 recently investigated a
potential new function of B cells comparing the response of
circulating B cells upon experimental RV infection in healthy
versus asthmatic subjects. Costimulation of B cells with RV and
IFN-a upregulated proinflammatory cytokine expression;
notably, subjects with asthma showed dysregulation of antiviral
gene expression. Jansen et al67 recently investigated the effects of
RV infection on regulatory T cells by isolating regulatory T cells
from subjects with asthma and controls after experimental
infection with the RV. The authors demonstrated that RV
induced a strong antiviral response in regulatory T cells; however,
in subjects with asthma, the inflammatory response was dysre-
gulated compared with that observed in the controls. In addition,
subjects with asthma failed to upregulate several immunosup-
pressive molecules such as CTLA4 and CD69.67
RELATIONSHIP BETWEEN IMPAIRED ANTIVIRAL
RESPONSES AND T2 INFLAMMATION
Although first considered an independent finding and distinct
from the exaggerated T2 inflammation triggered by RV in asthma,
the deficient antiviral immune response is increasingly considered
tightly connected. Altman et al12 reported that the ratio of T2 to
T1 IFN gene expression was predictive in determining the risk for
a future exacerbation; individuals in the highest quartile for this
expression ratio were associated with a significantly shorter time to
exacerbation than were individuals in the lower 3 quartiles. This
finding very much supports the clinical association between the
routinely used T2 biomarkers (blood eosinophil count and frac-
tional exhaled nitric oxide) and exacerbation risk.68,69
Using mouse models of infection, Duerr et al70 elegantly
demonstrated that deficiency in type 1 IFN signaling led to
dysregulated activation of ILC2s and infection-associated T2
immunopathology. They showed that IFN-b acted directly on
ILC2s in vivo and that cytokine secretion by human ILC2s was
significantly decreased by the addition of IFN-b. The authors
also observed that IFN-b inhibited the IL-33emediated increase
in pulmonary eosinophilia, and that IL-33einduced airway
hyperresponsiveness was significantly suppressed by IFN-b.70
The reverse has also been demonstrated, with IL-33 shown to
have a role in dampening innate and adaptive TH1-like responses
including suppressing IFN-b.71
A fascinating piece of evidence corroborating the relationship
between allergic inflammation and antiviral responses has been
the observation that impaired IFN responses to RV in children
with asthma correlate with increased FcεRI expression on plas-
macytoid dendritic cells (a key cellular source of type 1 IFN) as
well as reduced IFN responses in the presence of FcεRI cross-
linking.72 Subsequently, a landmark study using the anti-IgE
therapy omalizumab reduced the infection-related seasonal
peaks in exacerbations.73 In the controlled setting of an experi-
mental RV challenge, Heymann et al74 administered omalizu-
mab or matched placebo in a blinded fashion to 20 subjects with
mild asthma, demonstrating both subjective symptom benefit
678 JACKSON AND GERN
and a blunting of the RV-induced blood eosinophilia. Another
mechanism that could contribute to the effectiveness of anti-IgE
may relate to a potential role of RV-specific IgE in mediating
RV-triggered asthma exacerbations.75 However, data supporting
this possibility are limited at present.
THERAPEUTIC APPROACHES TO LIMIT VIRUS-
INDUCED MORBIDITY
Identifying risk factors for more severe RV wheezing illnesses
and exacerbations of asthma suggest several potential approaches
to reducing RV-related illnesses and respiratory morbidity. Risk
factors that are potentially modifiable include T2 inflammation,
impaired antiviral responses, and pathogen-dominated micro-
biome (Figure 3). Apart from preventing the immediate harm
from an exacerbation, these measures are important because
repeated RV-induced exacerbations may drive an irreversible loss
of lung function through induction of airway remodeling factors
including TGF-b, and vascular endothelial growth factor.29
Targeting T2 inflammation
The remarkable success of the current generation of biologic
agents targeting mediators and cells of the T2 cascade in pre-
venting asthma exacerbations has provided overwhelming evi-
dence of the central role of this pathway in virus-induced asthma
exacerbations. How much of this relates to the direct inhibition
of these mediators or the indirect augmentation and normaliza-
tion of antiviral pathways remains unclear. However, it most
likely is a combination of the 2. In addition to the results of the
anti-IgE therapy omalizumab described earlier, some of the most
impressive results have been seen in the controlled and real-world
studies of the eosinophil targeting antieIL-5/5R mAbs mepoli-
zumab and benralizumab, in which most patients become
completely exacerbation-free, despite a high probability that
most encounter at least 1 seasonal respiratory virus during the
autumn or winter months.76-81 Interestingly, the reductions in
exacerbation rates also seen in the placebo arms of the biologic
trials are likely to reflect the impact of improved adherence to the
T2-inhibiting inhaled corticosteroids (ICSs)76,81,82 these patients
are also prescribed and is in keeping with the general effectiveness
of even short-term ICSs in preventing exacerbations.83
Following the identification of the annual September
epidemic of asthma exacerbations in children returning to school,
Johnston et al84 performed a randomized, placebo-controlled
trial of the addition of the antileukotriene montelukast to
usual asthma therapy between September and mid-October with
the aim of curtailing this trend. Although a less potent anti-T2
therapy compared with ICSs, of the 194 children with asthma
who participated in the study, 22 (4 montelukast vs 18 placebo)
required an unscheduled physician visit, representing a 78%
reduction in those receiving montelukast.84
Augmenting antiviral pathways
Unfortunately, there are currently no approved antiviral agents
for the treatment of RV infection. Several approaches have been
evaluated in clinical trials, including the small-molecule capsid-
binding inhibitor pleconaril, the 3C protease inhibitor rupin-
trivir, as well as soluble intercellular adhesion molecule 1.85 All
have failed to progress either because of safety concerns, limited
efficacy, or potential drug interactions. The hope of a vaccine has
been additionally hampered by the large number of antigenically
distinct RV serotypes.
J ALLERGY CLIN IMMUNOL PRACT
MARCH 2022
As a natural progression to the in vitro studies of human
primary bronchial epithelial cells highlighting that exogenous
IFNs reduce virus shedding of RV, Djukanovic et al86 conducted
a clinical trial of inhaled IFN-b initiated at the onset of a
community-acquired respiratory virus infection in subjects with
asthma. Although the overall study was negative, it was possible
to demonstrate modest efficacy in the more severe, poorly
controlled subgroup of patients.86 Although this treatment
approach has not progressed further in asthma, it is now being
investigated in the management of severe coronavirus disease
2019 (COVID-19) infection.87
The macrolide azithromycin has been intensively investigated
for nonantibiotic properties, and there is some promising data to
suggest it may possess some antiviral effects. Gielen et al88
observed that azithromycin enhanced viral-induced type I and
III IFN, leading to reduced RV replication and release following
in vitro infection of primary human bronchial epithelial cells.
Although azithromycin was able to reduce exacerbations by
approximately 1 per year in the AMAZES study, it has not been
demonstrated that this was due to the inhibition of a virus-
induced exacerbation.89
Modifying the airway microbiome
Growing evidence relating wheezing illnesses to combinations
of viral and bacterial pathogens raises the possibility that modi-
fying the airway microbiome could help to prevent acute
wheezing illnesses. Probiotics are now being developed to restore
the physiology of the epithelial environment on the skin for
patients with atopic dermatitis and populate the gastrointestinal
tract with commensal bacteria, promote the development of
tolerance mechanisms, and reduce the risk for developing allergy.
A Cochrane review of oral probiotics concluded that there is low-
quality evidence that treatment of children with oral probiotics
can reduce rates of respiratory illness.90 In a study involving
experimental RV inoculation, probiotic supplementation influ-
enced airway immune responses to RV but did not have
demonstrable antiviral effects.91 Studies in murine models
demonstrated that nasal administration of commensal bacteria
could reduce respiratory virus-induced pathology,92 suggesting
that clinical studies of nasal probiotics are warranted. Other
approaches to altering the nasal microbiota could include
vaccination against airway pathogens. In addition, oral bacterial
extracts (eg, OM-85) have shown promise to prevent severe
wheezing illnesses in children.93 Finally, 2 high-quality studies
have shown evidence that starting azithromycin treatment at the
onset of respiratory illness can prevent severe wheezing illnesses
in preschool children with a history of recurrent wheeze.94,95
Enthusiasm for this approach is dampened by concerns about
overuse of antibiotics leading to resistant organisms, and also by
studies linking antibiotic use in early life to increased risk for
developing asthma.96 Additional studies are warranted to deter-
mine whether there are subgroups of young children who would
benefit from antibiotic treatment for recurrent wheeze.
LESSONS LEARNED FROM THE COVID-19
PANDEMIC
On the background of the well-established relationship be-
tween asthma exacerbations and respiratory viruses, the medical
community and patients with asthma alike faced the COVID-19
pandemic with a heightened sense of concern and trepidation.
Yet, almost 2 years into the pandemic, the question of whether or
J ALLERGY CLIN IMMUNOL PRACT
VOLUME 10, NUMBER 3
not severe acute respiratory syndrome coronavirus 2 actually
causes a conventional asthma exacerbation in the way that RV or
influenza does remains a contentious point of ongoing debate.97
In contrast to RV, seasonal coronaviruses have not generally been
reported as a prominent exacerbation trigger in asthma.44 In
essence, this suggests a fundamental difference in how corona-
viruses and RVs interact with, and stimulate the asthmatic host
immune system. Indeed, rather than the eosinophilia that
frequently accompanies an RV-induced exacerbation of
asthma,47 one of the earliest findings in the blood counts of
patients admitted with COVID-19 has been their eosinopenia.
At present, some data suggest that compared with the general
population, patients with asthma with more severe disease and
those with frequent exacerbations (ie, poor disease control)
appear more likely to be admitted to hospital with COVID-19
and more likely to require intensive care unit admission, after
accounting for major risk factors.98 However, the data remain
difficult to interpret in light of its retrospective nature as well as
other confounding factors. Importantly, Bloom et al98 demon-
strated that these same patients with asthma had a significantly
higher risk of pneumonia and influenza-related admissions, with
similar levels of relative risk to COVID-19.
Perhaps one of the most remarkable outcomes of the
pandemic has been an overall fall in asthma exacerbations.
Several factors could explain this, including a fall in urban air
pollution levels and/or a change in patient behavior leading to an
improvement in adherence to ICSs.99 However, it is possible that
the nonpharmacologic interventions of increased hand washing
and mask wearing, aimed at reducing transmission of severe
acute respiratory syndrome coronavirus 2, will ultimately prove
to be the most effective intervention against seasonal virus-
induced asthma exacerbations since the introduction of ICSs
almost half a century ago. For example, in New Zealand during
the first wave of the pandemic, the usual winter influenza surge
was essentially eliminated, with a 99.9% reduction in influenza
virus detections, and a 74.6% reduction in RV infections as
compared with previous years. When the nonpharmacologic
interventions were relaxed after lockdown, the incidence of RV
increased rapidly.100 Using weekly national hospital admission
data in New Zealand, Fairweather et al101 observed that asthma
admissions initially fell during the period of more stringent re-
strictions, only to sharply rise in parallel with RV detection rates
immediately on dropping the restrictions. Similar falls in asthma
exacerbation rates have been reported in several other countries as
well.102,103 Critically, this raises the question as to whether
improved advice around nonpharmacological measures of hand
washing and face masks should be routinely included in national
and international asthma guidelines long after the COVID-19
pandemic has subsided.
CONCLUSIONS
The relationship between RV infection, asthma inception, and
exacerbation pathogenesis continues to be an area of intense
study. Researchers over the last 3 decades have revealed several
key insights in asthma that underlie this association, including a
genetic predisposition, multiple deficiencies in the antiviral IFN
response, as well as the inappropriate activation of the T2 in-
flammatory cascade in response to infection. Although specific
antiviral approaches have largely failed, the close interrelationship
between IFN and T2 pathways has preordained that treatments
JACKSON AND GERN 679
capable of dampening T2 inflammation including ICSs and
anti-T2 biologics potentially correct many of these antiviral
deficiencies for us. However, even the dramatic responses to anti-
T2 biologics appear to be eclipsed by the success of non-
pharmacological interventions including mask wearing and hand
hygiene in preventing virus-induced exacerbations made evident
by the COVID-19 pandemic.
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