A retrospective study of the relationship between childhood asthma and respiratory infection during gestation

BACKGROUND: Wheeze in children has been found to be associated with prior antepartum haemorrhage and raised levels of IgE in cord blood, and acute wheezing episodes are intimately linked with respiratory viral infections. OBJECTIVE: To assess the relationship between maternal presentation with respiratory tract infections in pregnancy and childhood asthma, taking into account factors which could affect presentation. METHODS: This was a case-control study of 200 asthmatic children, 5-16-year-old, age-matched with one control, having no recorded history of wheeze. Data on respiratory tract infections, maternal wheeze, atopy and smoking was collected from primary care records. Deprivation score was assessed according to small residential areas and subjects were equally distributed between four general practices in Plymouth, UK. RESULTS: Presentation with respiratory tract infections during pregnancy was significantly associated with childhood asthma (OR 1.69, 95% confidence interval 1.05-2.77, P = 0.03). The association was marginally stronger for infections in the first trimester (OR 2.30, 95% CI 1.05-5.41, P = 0.04) and for those with cough during pregnancy (OR 2.24, 95% CI 1.23-4.22, P = 0.007). The associations remained significant after allowing for the effect of the independent variables (gender, maternal smoking, maternal wheeze, allergic rhinitis, eczema, asthma treatment in pregnancy and deprivation [Townsend] score), using multiple logistic regression analysis (ORs and 95% CIs 1.91, 1.14-3.22; 2.32, 1.01-5.34 and 2.29, 1.17-4.48, respectively). There was also an association between numbers of presentations with respiratory infections and childhood asthma (test for trend, P = 0.02). CONCLUSIONS: This study has shown an association between presentation with respiratory infection during gestation and childhood asthma. The results were not affected by the other independent variable factors studied and therefore provide some evidence to support the theory that respiratory viruses may be implicated in the aetiology of asthma.     

Animal models of virus-induced chronic airway disease

There is increasing evidence that experiencing viral wheezing illnesses early in life, especially in conjunction with allergic sensitization, is an important risk factor for the onset of asthma. In this review, the potential advantages and disadvantages of using rodent models of virus-induced chronic airway dysfunction to investigate the mechanisms by which early-life viral respiratory tract infections could initiate a process leading to chronic airway dysfunction and the asthmatic phenotype are discussed. The potential usefulness of rodent models for elucidating the viral, host, environmental, and developmental factors that might influence these processes is emphasized. There is a need for the continued development of rodent models of early-life viral respiratory tract infections that include the development of chronic airway dysfunction, the capacity to add components of allergic sensitization and allergic airway inflammation, and the ability to address both immunologic and physiologic consequences. Investigation of these rodent models should complement the research from pediatric cohort studies and begin to bring us closer to understanding the role of viral respiratory tract infections in the inception of childhood asthma.     

Rhinoviruses, allergic inflammation, and asthma

Viral infections affect wheezing and asthma in children and adults of all ages. In infancy, wheezing illnesses are usually viral in origin, and children with more severe wheezing episodes are more likely to develop recurrent episodes of asthma and to develop asthma later in childhood. Children who develop allergen-specific immunoglobulin E (allergic sensitization) and those who wheeze with human rhinoviruses (HRV) are at especially high risk for asthma. In older children and adults, HRV infections generally cause relatively mild respiratory illnesses and yet contribute to acute and potentially severe exacerbations in patients with asthma. These findings underline the importance of understanding the synergistic nature of allergic sensitization and infections with HRV in infants relative to the onset of asthma and in children and adults with respect to exacerbations of asthma. This review discusses clinical and experimental evidence of virus-allergen interactions and evaluates theories which relate immunologic responses to respiratory viruses and allergens to the pathogenesis and disease activity of asthma. Greater understanding of the relationship between viral respiratory infections, allergic inflammation, and asthma is likely to suggest new strategies for the prevention and treatment of asthma.     

Post-viral atopic airway disease: pathogenesis and potential avenues for intervention

Introduction: In early childhood, wheezing due to lower respiratory tract illness is often associated with infection by commonly known respiratory viruses such as respiratory syncytial virus (RSV) and human rhinovirus (RV). How respiratory viral infections lead to wheeze and/or asthma is an area of active research.

Areas covered: This review provides an updated summary of the published information on the development of post-viral induced atopy and asthma and the mechanisms involved. We focus on the contribution of animal models in identifying pathways that may contribute to atopy and asthma following respiratory virus infection, different polymorphisms that have been associated with asthma development, and current options for disease management and potential future interventions.

Expert commentary: Currently there are no prophylactic therapies that prevent infants infected with respiratory viruses from developing asthma or atopy. Neither are there curative therapies for patients with asthma. Therefore, a better understanding of genetic factors and other associated biomarkers in respiratory viral induced pathogenesis is important for developing effective personalized therapies.     

The role of viral infections in the natural history of asthma

Viral infections have been related to the inception of recurrent wheezing illnesses and asthma in infants and are probably the most frequent cause of exacerbations of established disease in older children and adults. The well-recognized clinical effects of viral infections are mainly caused by virus-induced immune responses. Clinical studies of natural and experimentally induced viral infections have led to the identification of mechanisms of inflammation that could be involved in producing airway obstruction and lower airway symptoms. In addition, host factors that are associated with more vigorous viral replication or severe clinical illness are beginning to be identified. Advances in molecular virology and our understanding of immune responses to viral infections may lead to the development of new strategies for the prevention and treatment of virus-induced respiratory disorders.     

Number of offspring and maternal allergy

The consistent association seen between family size and childhood allergy has led to the 'hygiene hypothesis', namely that a lower frequency of infections in early childhood is associated with an increased risk of asthma and hay fever. Maternal atopy, however, is a strong predictor of childhood asthma and hay fever. If maternal atopy is inversely related to the number of siblings then the role of siblings in the development of childhood atopy, the basic tenet of the 'hygiene hypothesis', is challenged. We evaluated the association between number of pregnancies and number of live births with lifetime occurrence of maternal wheeze, asthma, allergic rhinitis, and allergic conjunctivitis in a cross-sectional study in four areas in Italy. A total of 1755 (35-74 year old) nonsmoking women filled a questionnaire on reproductive history as well as on lifetime occurrence of symptoms/diseases. The number of live births was inversely related to lifetime allergic rhinitis (P-value for trend=0.031) and allergic conjunctivitis (P-value for trend=0.011). The odds ratios for those with 4+ children (in comparison with those having 0-1) were: 0.53 (95% CI: 0.27-1.04) and 0.42 (95% CI: 0.22-0.81), respectively. A similar trend was seen for number of pregnancies, although not statistically significant. No association was found between number of pregnancies and number of live births with wheeze or asthma. The results may be interpreted as an indication that maternal atopy influences pregnancy outcomes or that pregnancy itself has an effect on maternal atopy.     

Childhood infections, the developing immune system, and the origins of asthma

Asthma is an immune-mediated inflammatory condition characterized by increased responsiveness to bronchoconstrictive stimuli. Viruses have been shown to play an important role in asthma, with viral infection being present during about 85% of exacerbations. However, the role they play in the onset of asthma is more controversial. Some respiratory viral infections might be protective, but there is a strong association between respiratory syncytial virus-induced bronchiolitis in infancy and recurrent wheeze up to 12 years of age. Both the respiratory tract and the immune system undergo rapid maturation during the first year of life, and it seems that postnatal development is affected by and affects responses to viral infections. Understanding postnatal developmental changes in the immune system might help to explain the origins and pathogenesis of asthma and thus the effectiveness or ineffectiveness of specific asthma therapies.     

Respiratory viral infections and asthma pathogenesis: a critical role for dendritic cells?

BACKGROUND: Respiratory viral infections can influence the course of asthma at different time points. Severe respiratory viral infections during early age are associated with a higher prevalence of asthma in later childhood. In established asthma, viral infections are a frequent cause of asthma exacerbation. OBJECTIVES: The present review focuses on epidemiological and experimental animal data that can illuminate the mechanisms by which viral infections can lead to sensitization to antigen, and exacerbate ongoing allergic airway inflammation and focuses on the role played by dendritic cells (DCs). RESULTS: In experimental rodent models of asthma, respiratory viral infection at the time of a first inhaled antigen exposure is described to induce Th2 sensitization and to enhance the allergic response to a second encounter with the same antigen. Virus infections can modulate airway dendritic cell function by upregulation of costimulatory molecule expression, enhanced recruitment, and by inducing an inflammatory environment, all leading to an enhanced antigen presentation and possibly changing the normal tolerogenic response to inhaled antigen into an immunogenic response. In established asthma, respiratory viral infections attract several inflammatory cells, alter receptor expression on airway smooth muscle and modulate neuroimmune mechanisms, possibly leading to exacerbation of disease. CONCLUSIONS: Animal data suggest that the link between respiratory viral infections and increased asthma is causally related, the viral infection acting on the immune and structural cells to enhance antigen presentation and inflammatory cell recruitment.     

The impact of respiratory viral infection on wheezing illnesses and asthma exacerbations

The etiology and morbidity associated with asthma are thought to stem from both genetic factors and potentially modifiable environmental factors, such as viral infections. Although it is unclear whether respiratory viral infections cause asthma, observational studies have demonstrated a high rate of asthma in children with a history of severe viral lower respiratory tract infections during infancy, and viruses are associated with the majority of asthma exacerbations among both children and adults. This article discusses the pathogens associated with virus-induced wheezing illnesses during infancy and early childhood, the association of bronchiolitis during infancy with an increased risk of childhood asthma, and the association of respiratory viruses with asthma exacerbations in older children and adults.     

Effects of anti-inflammatory therapies on recurrent and low-grade respiratory syncytial virus infections in a murine model of asthma.

BACKGROUND: Recurrent and subclinical viral respiratory tract infections could immunologically exacerbate allergic airway inflammation. However, the most appropriate treatment for virus-induced asthma exacerbation is yet to be established. The effects of glucocorticoids in virus-induced acute asthma are controversial. OBJECTIVE: To determine the effects of representative anti-inflammatory therapies for asthma--glucocorticoids and leukotriene receptor antagonists (LTRAs)--in mite allergen-sensitized and repeatedly low-grade respiratory syncytial virus (RSV)--infected mice. METHODS: Dermatophagoides farinae-sensitized mice were inoculated twice with low-grade RSV and subcutaneously injected with either a glucocorticoid or an LTRA for 4 consecutive days. Lung inflammation, cytokine profiles, LT production, and viral RNA in lung tissues were compared in 5 groups of 8 mice each: controls, D farinae allergen sensitized, D farinae sensitized and RSV infected, D farinae sensitized and RSV infected with dexamethasone, and D farinae sensitized and RSV infected with pranlukast, an LTRA. RESULTS: Allergic airway inflammation in D farinae mice was significantly enhanced by recurrent and low-grade RSV infections (RLRIs). The glucocorticoid attenuated allergic airway inflammation, which was associated with interleukin 5 (IL-5) and interferon-gamma (IFN-gamma) suppression in lung-draining lymph nodes without affecting viral quantity. The LTRA also attenuated allergic airway inflammation in D farinae-RSV mice with concomitant inhibition of IL-5 but not IFN-gamma. Dermatophagoides farinae allergen sensitization significantly increased LTs in the airway, whereas RLRIs did not further enhance LT production. CONCLUSIONS: Glucocorticoids and LTRAs significantly inhibit RLRI-induced exacerbation of allergic airway inflammation by distinct pathways. Dexamethasone suppressed nonspecific cytokines, whereas viral RNA did not increase via suppression of immunity. In contrast, pranlukast specifically inhibited IL-5 but not IFN-gamma.     

Interferon-gamma levels in nasopharyngeal secretions of infants with respiratory syncytial virus and other respiratory viral infections

Respiratory syncytial virus (RSV) infection, one of the most common causes of hospitalization of children in developed countries, has been implicated as a cause of asthma. We aimed to characterize the cytokine profile in nasopharyngeal aspirates (NPAs) taken from infants during upper respiratory tract infection to investigate whether RSV induced a unique immune response as compared with other viruses. Additionally, we sought to determine whether this profile was influenced by the infants' atopic status. A prospective birth cohort of babies at high risk of atopy was recruited. Ratios of a T-helper 1 (Th1) cytokine, interferon gamma (IFN-gamma) and a T-helper 2 (Th2)-like cytokine, interleukin-10 (IL-10), in NPAs were determined during episodes of respiratory tract infections in the first year. The viral aetiology of the respiratory tract infections was determined using polymerase chain reaction (PCR), culture and immunofluorescence. Atopic status was ascertained at 1 year of age using skin prick tests. Participants were recruited antenatally and subsequently followed in the community. Sixty babies with one or both parents atopic were enrolled into the study. IFN-gamma : IL-10 ratios in NPAs during upper respiratory tract infections and their correlation with viral aetiology and atopic status were the main outcome measures. The mean IFN-gamma : IL-10 ratio was significantly lower (due to lower IFN-gamma) during RSV infections than during infections with other viruses (P = 0.035). The cytokine ratio, however, did not differ between infants with or without wheeze during URTIs (P = 0.44), or between infants who were atopic or non-atopic (P = 0.49). This study suggests that RSV is associated with lower IFN-gamma production in young babies, regardless of their atopic status, compared to upper respiratory tract infections where either another virus is detected or where no viral identification is made.     

Relationship between childhood atopy and wheeze: what mediates wheezing in atopic phenotypes?

BACKGROUND: The nature of the relationship between childhood wheeze and atopy remains uncertain. OBJECTIVE: To characterize childhood wheeze among atopic phenotypes in a longitudinal birth cohort study. METHODS: A whole population birth cohort (N = 1,456) was recruited in 1989. Children were seen at birth and at 1, 2, 4, and 10 years of age to obtain information on asthma and allergic disease development and relevant risk factors for these states. Skin prick testing at ages 4 (n = 980) and 10 (n = 1,036) years was used to define atopic phenotypes. Wheezing in these states was characterized, and logistic regression was used to identify independent risk factors for wheeze onset in different atopic phenotypes. RESULTS: Wheeze ever occurred in 37% of never atopics, 38% of early childhood atopics, 65% of chronic childhood atopics, and 52% of delayed childhood atopics. Chronic childhood atopics had significant wheezing morbidity and bronchial hyperresponsiveness. Their wheezing was associated with male sex, early eczema, family history of eczema, and early tobacco exposure. Never atopic wheeze was related to maternal asthma, parental smoking, and respiratory tract infections. Exclusive breastfeeding protected against early childhood atopic wheeze. Maternal asthma, family history of urticaria, and dog ownership increased delayed childhood atopic wheeze. CONCLUSIONS: In many respects, chronic childhood atopy is the atopic phenotype associated with the most significant forms of childhood wheezing. In such children, heritable drive, allergens, and synergy with other environmental triggers seem to be crucial determinants of wheeze onset. Where such sensitization is absent, numerous environmental factors plus genetic predisposition may assume importance for wheezing.     

Risk factors for asthma and atopy

PURPOSE OF REVIEW: The aim of this article is to provide information on risk factors associated with the development of atopy and asthma in childhood. RECENT FINDINGS: Several gene polymorphisms have been associated with susceptibility to asthma and allergy; complex gene-environmental interactions, however, appear to play a key role in the development of the disease. Early life sensitization to aeroallergens, presence of atopic dermatitis or allergic rhinitis, maternal smoking during pregnancy and children's environmental exposure to tobacco smoke, lower respiratory tract infections with respiratory syncytial virus and potentially with other viruses including rhinovirus and metapneumovirus, exposure to air pollutants, several perinatal factors other than maternal smoking, are among factors associated with an increased risk for development of chronic asthma. SUMMARY: The prevalence of asthma and allergic diseases is increasing progressively. Those who are involved in the care of young children should be prepared to recognize risk factors for development of these diseases and to appreciate the role of gene-environment interactions. Preventive measures established at an early age may modify the natural history of asthma and other allergic diseases.     

The role of respiratory virus infections in childhood asthma inception

Viral respiratory illnesses associated with wheezing are extremely common during early life and remain a frequent cause of morbidity and hospitalization in young children. Although many children who wheeze with respiratory viruses during infancy outgrow the problem, most children with asthma and reductions in lung function at school age begin wheezing during the first several years of life. Whether symptomatic viral infections of the lower respiratory tract are causal in asthma development or simply identify predisposed children remains a controversial issue. Wheezing illnesses caused by respiratory syncytial virus (RSV), particularly those severe enough to lead to hospitalization, have historically been associated with an increased risk of asthma at school age. However, with the development of molecular diagnostics, human rhinovirus (HRV) wheezing illnesses have been recognized more recently as a stronger predictor of school-age asthma than RSV. In this article, the authors review the impact of virus infections during early life, focusing primarily on RSV and HRV, and their potential roles in asthma inception.     

Epidemiology of asthma and recurrent wheeze in childhood

To summarize, wheeze is common throughout childhood, although it decreases as children age. However, the characteristics of wheeze, its relations with asthma, and its risk factors all change with age. Longitudinal studies have shown that "transient early wheezing" predominates during the first years of life. The principal risks for this type of wheezing are largely mechanical, relating to small airways, and infectious, relating to the risk of becoming infected with respiratory viruses. Associated with passive exposure to cigarette smoke, exposure to other children, and not being breastfed, this form of wheezing was unrelated to increased airway liability or atopy in the child. For the majority of children, particularly those with low lung function at birth, wheezing with early LRIs is a benign condition, not associated with subsequent wheeze or risk for asthma. During the middle part of the first decade of life, wheezing appears to reflect a mix of infectious and allergic wheezing. By 6 yr of age, some children have already wheezed persistently. This group is more likely to have high total IgE levels, to be skin-test positive, and to be given a diagnosis of asthma. Further, their immunologic response to their early LRIs was consistent with a Th2 bias: persistent wheezers produced high levels of IgE, and did not demonstrate the normal pattern of decreased eosinophils. Nevertheless, the children who wheeze in middle childhood are a mixed group, with some being less allergic. Thus, although markers of allergy become increasingly important predictors of wheezing for the group as a whole, wheezing in middle childhood is not associated with later methacholine hyperresponsiveness (42). Finally, persistent allergic wheezing, usually associated with a diagnosis of asthma, predominates by the end of the first decade of life. Wheezing at this age is associated with methacholine responsiveness, peak-flow variability, and markers of atopy, such as total IgE and allergy skin-test response. Although children who wheezed early in life are more likely to wheeze later, early wheeze does not increase the risk of atopy, suggesting that early LRIs are markers of increased risk rather than causes. The gender differences in wheeze disappear, with boys becoming less likely to wheeze and to have asthma, whereas both conditions appear to increase in girls. Finally, some of the risk factors for early LRIs, such as exposure to other children in infancy, appear to be associated with protection from later allergic wheezing. Clearly, asthma and wheeze during childhood are complex entities, presenting with different characteristics at different ages, and implicating varied and changing causes. Genetic factors are important determinants of the intermediate phenotypes. However, environmental factors operating at different developmental stages also appear to influence the development of asthma. Additional research regarding these relationships is essential, both to elucidate possible causal mechanisms and to provide insight into the primary prevention of asthma.     

Risk factors for asthma in children in Lódź region

The incidence of asthma and other allergic diseases continues to increase. In addition to genetic factors, environmental influences are thought to play an important role. The aim of this study was to identify factors that influence and drive the atopic march from atopic sensitization to asthma in children from Lód?. METHODS: 800 atopic children, aged 5-18 years, were included to our study. Parents filled in questionnaires and gave interviews about their children's diseases. 405 (43%) children have diagnosis of asthma. RESULTS: A significant association was observed between asthma and male sex, parents' history of atopy, parental highest school grade, maternal smoking during pregnancy, maternal chronic disease (especially chronic renal diseases), maternal allergen-sensitizing diet during breast-feeding, increased exposure to indoor humidity and moulds. Similar effect was seen for episodes of wheeze occurring in the first 3 years of life as followed: wheezing during an airway infection, wheezing not connected with respiratory tract infection, wheezing not related with physical exercise. Child's daycare attendance (nursery school) was associated with decreased risk of asthma.     

Allergic rhinitis and its impact on otorhinolaryngology

Allergic rhinitis (AR) is a disease with growing impact on everyday medical practice, as its prevalence has steadily increased during the last decades. Immunoglobulin-E (IgE)-mediated airway inflammation may manifest itself as AR, asthma or both. Allergic inflammation in upper and lower airways is now considered as one airway disease, with manifestation of symptoms in upper, lower or global airway. This insight into allergic inflammation of the whole respiratory tract has consequences for the diagnostic and therapeutic approach of affected patients, as highlighted in the ARIA document. In contrast to asthma, the link between AR and associated conditions in the upper airways like rhinosinusitis, nasal polyps, recurrent viral infections, adenoid hypertrophy, tubal dysfunction, otitis media with effusion and laryngitis remains less explored. It is however of utmost importance to consider the aetiological role of IgE-mediated inflammation of the nasal mucosa in several diseases of the upper respiratory tract, as they represent a large body of patient population seen by the general practitioner as well as the paediatrician, allergologist and otorhinolaryngologist. We here aim at reviewing the current literature on the relationship between AR and conditions in upper airways frequently encountered in everyday clinical practice, and highlight the need for further studies exploring the role of allergic inflammation in the development of these diseases.     

Early-life rotavirus and norovirus infections in relation to development of atopic manifestation in infants

Background The increase in incidence of atopic diseases (ADs) in the developed world over the past decades has been associated with reduced exposure of childhood infections.
Objective To investigate the relation between early intestinal viral infections in relation to the development of atopic symptoms (eczema, wheeze and atopic sensitization) in the first and second year(s) of life.
Methods In the KOALA Birth Cohort Study, we assessed IgG seropositivity for rota- and norovirus (GGI.1 and GGII.4) at 1 year of age. This was related to allergic sensitization [specific immunoglobulin E (IgE)] at 1 and 2 years, and parent reported eczema and wheeze in the first 2 years, using logistic regression analysis adjusted for confounders.
Results Rotavirus seropositivity (39%) was associated with an unexpected higher risk of recurrent wheeze in the first and second year of life [adjusted odds ratio (OR) 3.1 and 95% confidence intervals (CI) 1.1–9.1] and persistent and new recurrent wheeze (adjusted OR 2.7 and 95% CI 1.1–6.2). No further associations were found between intestinal viral seropositivity and atopic manifestations.
Conclusion Our data did not show a clear protection by enteric viral infections in young children on development of IgE response to allergens, but rotavirus infection in the first year was a risk factor for wheeze. However, this needs to be followed up to older ages in order to establish the true importance of intestinal viral infections and especially cumulative effects in AD aetiology. Exposure to rotavirus may offer a new and interesting focus on infant wheeze and later asthma development.     

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

BACKGROUND: Severe lower respiratory infections (LRIs) and atopic sensitization have been identified as independent risk factors for asthma. OBJECTIVE: The nature of potential interactions between these risk factors was the subject of this study. METHODS: A community-based cohort of 198 children at high atopic risk was followed from birth to 5 years. All episodes of acute respiratory illness in the first year were recorded and postnasal aspirates were collected for viral identification. History of wheeze and asthma was collected annually, and atopy was assessed at 6 months, 2 years, and 5 years. RESULTS: A total of 815 episodes of acute respiratory illness were reported, and 33% were LRIs. Viruses were detected in 69% of aspirates, most commonly rhinoviruses (48.3%) and respiratory syncytial virus (10.9%). At 5 years, 28.3% (n = 56) had current wheeze, and this was associated with wheezy [odds ratio (OR), 3.4 (1.2-9.7); P = .02] and/or febrile LRI [OR, 3.9 (1.4-10.5); P = .007], in particular those caused by respiratory syncytial virus or rhinoviruses [OR, 4.1 (1.3-12.6); P = .02]. Comparable findings were made for current asthma. Strikingly these associations were restricted to children who displayed early sensitization (< or =2 years old) and not observed in nonatopic patients or those sensitized later. CONCLUSION: These data suggest viral infections interact with atopy in infancy to promote later asthma. Notably the occurrence of both of these events during this narrow developmental window is associated with maximal risk for subsequent asthma, which suggests a contribution from both classes of inflammatory insults to disease pathogenesis. CLINICAL IMPLICATIONS: Protection of "high-risk" children against the effects of severe respiratory infections during infancy may represent an effective strategy for primary asthma prevention. The potential benefits of these strategies merit more careful evaluation in this age group.     

Viral respiratory tract infections and asthma in early life: cause and effect?

Interactions between viral respiratory tract infections in infancy and childhood, and asthma development and exacerbation, are complex and intriguing. This review aims to unravel some of these complexities. Does severe respiratory viral infection early in life predispose to later asthma development, or is it indicative of a predisposition to allergic respiratory disease? How could variables such as age and severity of viral infection affect the interaction between respiratory viral infections and asthma? How could respiratory viral infection drive allergic sensitization? Here, we review the evidence surrounding these questions, and discuss current and future research and therapeutic approaches targeting the interplay between viral respiratory tract infection and asthma.