key: cord-0715943-gv4cwgrf
authors: Ortega, Hector; Nickle, David; Carter, Laura
title: Rhinovirus and asthma: Challenges and opportunities
date: 2020-11-20
journal: Rev Med Virol
DOI: 10.1002/rmv.2193
sha: 1beb03ae701d97ab1dcd3671680e7592163a1894
doc_id: 715943
cord_uid: gv4cwgrf

Human rhinoviruses (RVs) are the primary aetiological agent of the common cold. Generally, the associated infection is mild and self‐limiting, but may also be associated with bronchiolitis in infants, pneumonia in the immunocompromised and exacerbation in patients with pulmonary conditions such as asthma or chronic obstructive pulmonary disease. Viral infection accounts for as many as two thirds of asthma exacerbations in children and more than half in adults. Allergy and asthma are major risk factors for more frequent and severe RV‐related illnesses. The prevalence of RV‐induced wheezing will likely continue to increase given that asthma affects a significant proportion of the population, with allergic asthma accounting for the majority. Several new respiratory viruses and their subgroups have been discovered, with various degrees of relevance. This review will focus on RV infection in the context of the epidemiologic evidence, genetic variability, pathobiology, clinical studies in the context of asthma, differences with other viruses including COVID‐19 and current treatment interventions.

considering the prevalence of asthma, with an allergic component accounting for the majority of cases. 7 It is important to emphasize that respiratory viruses act as triggers of wheezing. Despite improvements in asthma management and advances in therapeutics, the reported incidence of asthma exacerbations has not declined.

Data from controlled clinical trials indicate that the development of asthma exacerbations in children as well as in adults are predictive of future exacerbations. 2,7-10 Therefore, strategies enabling the management and control of viral-induced events represent a priority to counter exacerbations linked to viral disease.

Children may be infected with RVs from 8 to 12 times per year, while adults may be infected 2-3 times per year, with peaks of infection observed throughout the year. 11 While mild and self-limiting in immunocompetent hosts, RV infection is associated with bronchiolitis in infants, pneumonia in the immunosuppressed and exacerbation of pre-existing pulmonary conditions such as asthma or chronic obstructive pulmonary disease (COPD). 12, 13 Bronchiolitis, acute wheezing illnesses and asthma are major clinical management challenges representing an unmet medical need.

RSV is the primary cause of bronchiolitis in infants less than 6 months of age. RV becomes more common later in infancy and is a much more common cause of wheezing in the second and third year of life than RSV. 3, 4 The reasons for age-specific manifestations and outcomes are poorly understood and may involve complex interactions between the host and intrinsic pathogenicity of the virus.

Data have demonstrated that transient wheezing (from infancy up to age 3 years) may be linked to RSV infection. 8 In addition to asthma exacerbations, severe respiratory illness induced by RSV or RV has been associated with subsequent development of asthma. In fact, RSV-induced wheezing during infancy may affect respiratory health for years. 14 There is evidence that RSV-induced bronchiolitis can damage the airways and promote airway obstruction with recurrent wheezing. 8, 14 While RV likely causes less structural damage, it remains a significant contributor to wheezing illnesses in young children. Because RV infections are common and a major cause of exacerbations in paediatric and adult patients with lung disease, interactions between viral virulence factors, personal risk factors (e.g., atopy, genetic susceptibility and age) and environmental exposures (e.g., allergen exposure and seasonality) promote more severe wheezing illnesses and the risk for progression to asthma. [4] [5] [6] The prevalence of bronchiolitis is approximately 20%-30% in the first year and 10%-20% in the second year of life. 15 Up to 50% of children have acute wheezing at least once before school age. Of these, about 35% will have recurrent wheezing. Once asthma is established, exposure to allergens and RV, with a potential synergistic effect, are important triggers of asthma exacerbation. 16 A seasonal pattern of paediatric asthma exacerbation is well established. [17] [18] [19] In particular, a peak in asthma exacerbations and related hospitalizations occurring in September has been observed in children in the Northern Hemisphere. There is considerable evidence to support a causal link between viral respiratory tract infection and asthma exacerbation in children, with respiratory viruses detected up to 80% of paediatric patients who experience asthma exacerbation. 20, 21 A retrospective cohort study by Suruki et al. using US healthcare claims data reported the frequency and type of exacerbation in 734,114 paediatric patients with asthma. 22 The investigators analysed the annual frequency of and seasonal trends for exacerbation in real-world clinical practice. The mean annual exacerbation frequency was 1.4; 86% of these exacerbations were defined by systemic corticosteroid use. A consistent trend of increased exacerbation incidence in the fall and early winter was observed. In addition, a high proportion of asthma-related hospitalizations occurred in patients of a younger age. This study further supports the epidemiological association of seasonal exacerbations linked to viral exposures that tend to occur between fall and winter. 

More than 160 strains of RV have been identified and classified into three genetic clades (A, B and C) according to sequence similarity, including 80 RV-A, 32 RV-B and 65 RV-C genotypes 23, 24 while crossprotection appears to be limited. Molecular epidemiologic studies suggest that the dominant species are RV-A and RV-C, while RV-B is rarely detected. RV-A and RV-C are not only associated with wheezing illnesses in early childhood, but also these viruses are more often associated with exacerbations of asthma compared with RV-B.

RV-C might be more strongly associated with more severe exacerbations, including those requiring hospitalization. 25, 26 This could be due to faster replication rate and induction of more robust cellular responses, based on data from cultures of differentiated airway epithelial cells. In cohort studies, RV-B infections do not increase the risk for exacerbations, but they might slightly increase the risk of exacerbation in children with severe asthma.

Competition assays for cellular binding sites have further grouped RVs into major or minor group viruses depending on the use of intercellular adhesion molecule 1 (ICAM-1), low-density lipoprotein (LDL) and cadherin-related family member 3 (CDHR3) as receptors. 24 While these advances in the understanding of the virus are encouraging, the unique structural and genetic variability of RVs has inhibited efforts to develop effective therapies.

To build a context of the genetic variation of RV, it is important to understand how it fits in the world of genetic variation among other viruses. For example, the human immunodeficiency virus (HIV) 27 exhibits one of the fastest evolving genomes ever observed. 28 Within a single patient, the envelope gene evolves at an astounding rate of 1% per year. 29 After approximately 4 years of within-patient evolution, the viral population no longer has coalescent events that reach back to the infection time frame; this means that none of the nodes that existed near the time of infection are present. Serially sampled populations of viruses tend to cluster temporally, giving rise to a 'ladder' like phylogeny. 29 Interestingly, among patients with influenza phylogenetic trees are ladder like as well. 30, 31 This means that early assumptions, to estimate the timing of ancestral events that occur on the phylogeny. 32 One of the most important demographic factors is the effective population size. 33 In both cases, among patient influenza and within patient HIV, the total mutation at any one slice of time reaches back about 5 and 3 years, respectively. 30, 34 The concept of effective population size (or Ne) is central to population genetics. Recombination events can drive the appearance of extremely high Ne in a phylogenetic context ( Figure 3 ). 35 Although RV is seasonal, it must maintain its genetic variation by a continuously infecting many people throughout time.

There is a relationship between Ne and the difficulty in developing a vaccine, such that, the larger the Ne the harder it is to generate a durable immune response with a vaccine. As such, some of the challenges in developing a RV vaccine are not simply due to the mutation rate. Influenza has a very similar mutation rate, yet yearly vaccines are possible because the Ne is sufficiently small. However, RV vaccine efforts do not enjoy these low Ne and thus vaccine efforts have largely failed in part due to the vast variation of the current circulating strains through human populations.

The plasticity of viral genomes allows for the generation of enormous numbers of viable mutants, resulting in circulating sequences that can differ by more than 30% in the maximally variable genes of viruses. Since the genetic diversity of viruses, RV in particular, will continue to increase, it is critical to understand the genetic variation in a phylogenetic sense in an effort to develop effective antiviral or vaccine strategies.

RV is transmitted mainly through direct contact with aerosolized particles and replicate in ciliated epithelial cells of the upper airways and in medium-to large-sized lower airways. 36 Viruses attach to unique cellular receptors: ICAM-1 used by RV-B and most RV-As, LDL receptor used by some RV-As, and cadherin-related family member 3 (CDHR3) used by RV-C. 37 After RV attachment, infected cells recognize RV pathogen-associated molecular patterns through interaction with two different families of pattern recognition receptors: Toll-like receptor (TLR) 2, TLR3, TLR7 and TLR8 and retinoic acid-inducible gene I-like (RIG-1) receptors. 38, 39 These receptors activate transcription factors (e.g., interferon regulatory transcription factor 7 and nuclear factor kB) that promote the expression of Figure 4 illustrates the combined effects of the virus and the inflammatory response leading F I G U R E 2 Tree pattern of changes in sequences collected overtime. The tree on the left is a set of sequences collected from a single individual approximately every 6 months who was not on effective therapy. The tree on the right is a selection of N1H1 Influenza viruses where the earliest sequences are from the 1918 Influenza Pandemic and the most recent are from the 2019 to 2020 flu season. Note that both tree shapes appear to shift from one population to the next suggesting that the effective population size at any one time is relatively small. Each of these trees are rooted by the earliest time points F I G U R E 3 Evolutionary rate based off dated tips of rhinovirus A with an estimated divergence rate. Rhinovirus A has very deep evolutionary nodes, indicating that the population has a very high Ne. (a) Dated tip phylogeny can be used to estimate the dates of all the nodes on a tree including the date of the Most Recent Common Ancestor (MRCA). (b) These dates can be used to assess the maximum likelihood estimate of the divergence rate (2.90e-03). Importantly, recombination events can drive the appearance of extremely high Ne in a phylogenetic context to epithelial damage and sloughing, mucus production and ultimately airway obstruction. [42] [43] [44] There is evidence that viruses and bacteria interact in patients with respiratory illnesses; viral infection may be associated with transient detection of common bacterial pathogens such as Moraxella catarrhalis, Streptococcus pneumoniae and Haemophlius influenzae. 45 Disrupted airway epithelium favours RV replication by allowing access to deeper layers in tissue in which RV replicates most actively and by increasing the number of ICAM1 receptors as shown in in vitro studies. 46 The damaged barrier function of the airway epithelium can also enhance engagement of aeroallergens or bacterial pathogens through the airway wall. 47 RVs also may contribute to airway remodelling by inducing vascular endothelial growth factor, TGF-β, and other mediators into airway smooth muscle cells. 41, 48 It is possible that these effects are more pronounced in early life. 6, 10, 14, 49 Thus, repeated RV infections that extend to the lower airways may cause damage that subsequently leads to remodelling of the airways.

Eosinophils exert prominent cytotoxic properties that damage the respiratory mucosa and attenuate lung function during stable asthma and during exacerbation. Using an experimental human exposure model of mild asthma, Sabogal Piñeros et al. reported that RV16-inoculation induced loss of asthma control with a strong correlation with CD69 expression by eosinophils. 50 Interestingly, eosinophils from patients with asthma displayed a reduced capacity to bind the virus, suggesting that human eosinophils may be important scavengers of virus in the respiratory mucosa, preventing viral F I G U R E 4 Inflammatory response following viral infection. Rhinovirus (RV) is transmitted mainly through direct contact and aerosolized particles and replicates in ciliated epithelial cells of the upper and lower airways. The viruses attach to unique cellular receptors. After attachment, infected cells recognize RV pathogen-associated molecular patterns through interaction with two different families of pattern recognition receptors, that is, Toll-like receptors. These receptors activate transcription factors that promote the expression of type I and type III interferons and several inflammatory cytokine genes. Early innate immune responses, such as type I interferons, occur rapidly after infection. RV induce cytokines, chemokines and growth factors that activate and attract granulocytes, dendritic cells and monocytes at the site of infection and trigger an inflammatory response and induce an asthma exacerbation ORTEGA ET AL. Although RV-induced wheezing was an independent asthma risk factor, allergen sensitization significantly increases the RV-associated risk of asthma. [5] [6] [7] A study by Tan Respiratory symptoms typically develop 1-2 days after inoculation in studies, and uncomplicated RV symptoms usually peak 2-4 days after inoculation. The median duration of RV colds is 1 week, but up to 25% last more than 2 weeks. 3 During illness caused by RV, viral shedding occurs naturally for up to 21 days, but predominantly over an initial 3-to 4-day period.

Recent data suggest that people who present with symptoms of respiratory illness at an emergency department, and who are subsequently diagnosed with a common respiratory virus, are in fact coinfected with the COVID-19 virus. 55 York state documented a rate of asthma of 12.5%, slightly higher than the prevalence of current adult asthma (10.1%) in that state. 56 This finding is consistent with another report from Ireland, where review of medical records of 193 consecutive admissions who were SARSCoV-2-positive found that 8.8% had a physician diagnosis of asthma which is slightly higher than the prevalence of current asthma of 7.0% in adults in Ireland. 57 While these findings suggest that patients with asthma are not at a higher risk of SARS-CoV-2, recent data 58 using air-liquid interface cultures from nasal tissues 

There are multiple on-going efforts to address the unmet need in patients reactive to viral-induced exacerbations. Here are some examples to illustrate these efforts:

Targeting ICAM-1 in transgenic mice engineered to overexpress extracellular domains 1 and 2 of human ICAM-1 has been shown to prevent the cellular entry of two major groups of RVs, RV16 and RV14. 60 Reduced cellular inflammation, pro-inflammatory cytokine production and virus load were also observed in this model. However, targeting and blockage of other receptors used by minor group RV, such as the LDL receptor, has been challenging. 60 This is also the case in the context of the development of a universal anti-RV antibody, which is problematic due to the antigenic diversity of circulating RV.

In addition, there are significant challenges associated with the identification of new antigenic variants plus the fact that approximately 90% of RV serotypes cannot bind to the murine ICAM-1 T A B L E 1 Virology from mucus sample collection in children 4-11 years of age with asthma receptor. 61 Ultimately, development of novel therapeutics that interferes with RV binding, entry and replication in the host cell could yield promising results.

In vitro studies have shown that exogenous delivery of interferons (IFN-α, IFN-β, IFN-λ1 or IFN-λ2) reduced RV1A viral copies in human primary bronchial epithelial cells (HPBECs). 62 Interestingly, the addition of IFN-β also suppressed RV16 and RV1B replication in HPBECs isolated from healthy and asthmatic individuals. 63 A study by Djukanovic et al. 64 

Viral bronchiolitis in children

Respiratory viruses and exacerbations of asthma in adults

Epidemiology of virus-induced asthma exacerbations: with special reference to the role of human rhinovirus

Bronchiolitis: age and previous wheezing episodes are linked to viral etiology and atopic characteristics

Early-life respiratory viral infections, atopic sensitization, and risk of subsequent development of persistent asthma

Wheezing rhinovirus illnesses in early life predict asthma development in high-risk children

Rhinovirus and serum IgE are associated with acute asthma exacerbation severity in children

Martinez FD. Tucson children's respiratory study: 1980 to present

Epidemiology of respiratory viruses in patients hospitalized with near-fatal asthma, acute exacerbations of asthma, or chronic obstructive pulmonary disease

Evidence for a causal relationship between allergic sensitization and rhinovirus wheezing in early life

Role of viral respiratory infections in asthma and asthma exacerbations

Environmental factors affecting seasonality of ambulance emergency service visits for exacerbations of asthma and COPD

Role of viral infections in the development and exacerbation of asthma in children

Managing childhood asthma: challenge of preventing exacerbations

The first wheezing episode: respiratory virus etiology, atopic characteristics, and illness severity

Experimental rhinovirus challenges in adults with mild asthma: response to infection in relation to IgE

Epidemiology of asthma exacerbations

Seasonal risk factors for asthma exacerbations among inner-city children

The September epidemic of asthma exacerbations in children: a search for etiology

Rhinovirus detection in symptomatic and asymptomatic children: value of host transcriptome analysis

Rhinovirus infections in the first 2 years of life

Retrospective cohort analysis of healthcare claims in the United States characterising asthma exacerbations in paediatric patients

Proposals for the classification of human rhinovirus species A, B and C into genotypically assigned types

Human rhinoviruses

Human rhinovirus species C infection in young children with acute wheeze is associated with increased acute respiratory hospital admissions

Community study of role of viral infections in exacerbations of asthma in 9-11 year-old children

Pacing a small cage: mutation and RNA viruses

Consistent viral evolutionary changes associated with the progression of human immunodeficiency virus type 1 infection

Strength and tempo of selection revealed in viral gene genealogies

Positive Darwinian evolution in human influenza A viruses

Tree time: maximum-likelihood phylodynamic analysis

Evolution in Mendelian populations

Estimating mutation parameters, population history and genealogy simultaneously from temporally spaced sequence data

Automated phylogenetic detection of recombination using a genetic algorithm

Quantitative and qualitative analysis of rhinovirus infection in bronchial tissues

Cadherin related family member 3, a childhood asthma susceptibility gene product, mediates rhinovirus C binding and replication

Toll-like receptor 2-expressing macrophages are required and sufficient for rhinovirus induced airway inflammation

Co-ordinated role of TLR3, RIG-I and MDA5 in the innate response to rhinovirus in bronchial epithelium

Interferon regulatory factor 7 regulates airway epithelial cell responses to human rhinovirus infection

Human rhinovirus infection enhances airway epithelial cell production of growth factors involved in air way remodeling

Infantile respiratory syncytial virus and human rhinovirus infections: respective role in inception and persistence of wheezing

Respiratory syncytial virus, human metapneumovirus and parainfluenza viruses

Respiratory viral infections in infants: causes, clinical symptoms, virology, and immunology

Detection of pathogenic bacteria during rhinovirus infection is associated with increased respiratory symptoms and asthma exacerbations

Basal cells of differentiated bronchial epithelium are more susceptible to rhinovirus infection

Rhinovirus disrupts the barrier function of polarized airway epithelial cells

Human rhinovirus infection of epithelial cells modulates airway smooth muscle migration

Neonatal rhinovirus Induces mucous metaplasia and airways hyperresponsiveness through IL-25 and type 2 innate lymphoid cells

Eosinophils capture viruses, a capacity that is defective in asthma

Differential gene expression of lymphocytes stimulated with rhinovirus A and C in children with asthma

Rhinovirus illnesses during infancy predict subsequent childhood wheezing

The association between seasonal asthma exacerbations and viral respiratory infections in a pediatric population receiving inhaled corticosteroid therapy with or without long-acting beta-adrenoceptor agonist: a randomized study

Prevalence of respiratory viral infection in children hospitalized for acute lower respiratory tract diseases, and association of rhinovirus and influenza virus with asthma exacerbations

Higher Co-infection Rates

Clinical characteristics of Covid-19

Prevalence of comorbid asthma in COVID-19 patients

RV infections in asthmatics increase ACE2 expression and cytokine pathways implicated in COVID-19

An anti-human ICAM-1 antibody inhibits rhinovirus-induced exacerbations of lung inflammation

Human Th1 and Th2 cells targeting rhinovirus and allergen coordinately promote allergic asthma

Antiviral therapeutic approaches for human rhinovirus infections

Interferon-beta induces a long-lasting antiviral state in human respiratory epithelial cells

Modeling of the human rhinovirus C capsid suggests possible causes for antiviral drug resistance

The Effect of inhaled IFN-β on worsening of asthma symptoms caused by viral infections

Dynamics of IFN-β responses during respiratory viral infection: Insights for therapeutic strategies

Phase II, randomized, double-blind, placebo-controlled studies of ruprintrivir nasal spray 2-percent suspension for prevention and treatment of experimentally induced rhinovirus colds in healthy volunteers

Cross-serotype immunity induced by immunization with a conserved rhinovirus capsid protein

In vitro activity of pleconaril and AG7088 against selected serotypes and clinical isolates of human rhinoviruses

Oral pleconaril treatment of picornavirus associated viral respiratory illness in adults: efficacy and tolerability in phase II clinical trials

Rhinovirus chemotherapy

Relationship of pleconaril susceptibility and clinical outcomes in treatment of common colds caused by rhinoviruses

Meeting the challenge of vaccine design to control HIV and other difficult viruses

Rhinovirus and asthma: challenges and opportunities

The authors would like to thank Jill Luer, PharmD for her support reviewing and editing the manuscript.

The authors report no conflict of interest.

Hector Ortega: writing original draft, reviewing and editing; David Nickle: writing, reviewing and editing; Laura Carter: reviewing and editing.

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.

https://orcid.org/0000-0002-2632-6370