Abstract
Rhinovirus (RV) infections occur early and recurrently in life, imposing a significant burden of disease on infants and young children. They are the most frequent causative agents of both upper and lower respiratory tract infections in this age group and are associated with a broad variety of clinical outcomes, ranging from asymptomatic infections to severe respiratory disease requiring hospitalisation. In addition to their impact on short-term morbidity, RVs are also debated as important pathogens in the development of recurrent wheeze and/or asthma. Several studies in infants at high-risk for atopy and asthma and in hospitalised children have demonstrated that recurrent wheezing illnesses induced by RVs early in life are a risk factor for the development of asthma later in childhood. However, underlying mechanisms are poorly understood. The question whether RVs are directly involved in the development of childhood wheeze and asthma, or whether symptomatic RV infections only represent a proxy for infants prone to develop obstructive lung diseases, is still open. In this review we provide an overview on the role of RVs as important disease-causing agents from infancy to early childhood and discuss their contribution to the subsequent development of childhood wheeze and/or asthma.
Acute respiratory tract infections (ARTIs) are the most frequent infections worldwide and represent a major public health problem. They are the leading cause of acute illnesses in all age groups and a major contributing factor of childhood morbidity and mortality [1, 2]. Infants and young children are particularly vulnerable to ARTIs as their immunity is still developing and not fully in place to defend against most of the respiratory pathogens they are exposed to. ARTIs in young children are very common and usually of viral origin, due to the abundance of circulating viruses and their ease in transmission among hosts. Viral ARTIs in childhood result in a wide-range of disease severity; from the common cold to severe life-threatening respiratory tract infections [3]. Thus, they impose considerable burden on healthcare systems and account for a large proportion of emergency visits to hospital and hospitalisations [4].
A large number of community-based studies have characterised the frequency, seasonality, age specificity and clinical features of viral ARTIs in childhood and have determined which pathogens are most commonly involved with children [5–7]. These are the: respiratory syncytial virus (RSV) [8], influenza virus [9], parainfluenza virus [10], adenovirus [11], rhinovirus (RV) [12], and coronavirus [13]. Recent advances in the development of diagnostic techniques, and specifically of molecular biology tools [14–16], have led to the identification of additional viruses associated with ARTIs in childhood, amongst them are the human metapneumovirus [17], the coronaviruses NL63 and HKU1 [18, 19], bocavirus [20] and different subgroups of RVs [21], and of emerging viruses such as severe acute respiratory syndrome coronavirus [22] and the H5N1 and H1N1 influenza viruses [23, 24]. Whereas the role of RSV, influenza virus, parainfluenza virus, adenovirus and more recently the human metapneumovirus in causing ARTIs in infants and children have been intensively studied and are widely accepted [6, 25], the contribution of RVs to respiratory morbidity in childhood is subject to debate [26, 27].
The aim of this review is to provide an overview of the increasingly recognised role of RVs as important disease-causing agents from infancy to early childhood, to portray their impact on short-term and long-term morbidity, and to depict their role in the development of childhood wheeze and asthma.
CHARACTERISTICS, EPIDEMIOLOGY AND DETECTION OF RVs
First discovered in the 1950s, RVs belong to the family Picornaviridae. They are small, non-enveloped viruses with a single-stranded, positive-sense RNA genome. To date, there are >100 identified serotypes, which are classified according to the receptor they bind to at the surface of the epithelial cells within the respiratory tract [28]. Strains binding to intercellular adhesion molecule (ICAM)-1 belong to the so-called major-group RVs, in contrast to the minor-group RVs, which consist of ∼10 strains and bind to the low-density lipoprotein receptor [29]. According to sequence variations, RVs are further classified into two main phylogenetic species, RV-A and RV-B [30, 31]. Recently, a novel RV species distributed worldwide, namely RV-C, was identified [21, 32–35]. One of the striking characteristics of RVs when compared with many other respiratory viruses is that they replicate rapidly and demonstrate high mutation rates, resulting in distinct genetic diversity [36, 37]. Infections caused by certain genetic RV sublineages seem to be more prevalent in the general population, occurring during specific seasons, and are also more often associated with symptomatic respiratory diseases in children when compared to other sublineages [38, 39], e.g. RV-C was shown to cause nearly half of all RV-induced ARTIs with clinical and age-related differences compared to RV-A or RV-B [40, 41].
The mode of RV transmission has been vividly discussed. Most probably, RVs are transmitted both by direct or indirect contact [28]. Infections caused by RVs have been shown to occur throughout the year [42, 43], but most reports suggest that there is a seasonal variability with peaks during cold and rainy seasons. The peak incidence of RV infections varies annually and geographically [44], most probably depending on the seasonal distribution of specific strains [45–47]. Compelling evidence shows higher rates of RV infections occurring during the crowding of children returning to school after their holidays [48–51]. Observations on virus transmission, infection patterns and immune responses suggest that due to a temporary lack of exposure during holidays, a transitory window of susceptibility to RV infections develops afterwards [52].
There are four principal ways in which RVs can be diagnosed: virus culture [53, 54], serology [53], immunofluorescence [55, 56] and nucleic acid/PCR-based tests [57]. Virus culture is labour-intensive and time-consuming procedure, and culture results may only be available when clinical symptoms have already disappeared. Serology, which has long been the main diagnostic tool for RV infections, relies on the detection of an immune response towards the virus and thus only provides a delayed and indirect picture of the infection itself. Further, serology is insensitive, as some RV serotypes lack a common group antigen, making the possibility of broadly reacting antibodies unlikely [58, 59]. Therefore, it is no longer used in routine diagnostics, but only for study purposes, such as epidemiological studies aimed at following the natural course of an infection [57]. Due to the lack of sensitive detection methods, the prevalence of RV infections has been under estimated in early studies. The availability of new PCR-based molecular diagnostic techniques for the detection of viruses [60] has provided evidence that RVs are the leading agents of the common cold and wheezing illnesses in infants and young children compared to any other virus affecting the respiratory tract [61–67]. However, the high sensitivity of PCR is also a limitation, as the presence of virus nucleic acid in respiratory secretions of a patient with respiratory symptoms does not prove that the virus is the cause of the symptoms. PCR may overestimate RV burden because of a high proportion of positive results in asymptomatic children [64, 68–71]. Furthermore, PCR may detect remnants of previous viral infections or replication defective viral sequences. Indeed, the RV genome may be detected by PCR even weeks after an acute viral infection [65]. Finally, a high co-detection rate, with on average of ∼20% of respiratory samples being positive for two or more viruses during an ARTI [3, 72], adds to the difficulty of differentiating RVs as true pathogens from innocent bystanders. Due to its lower sensitivity, and possibly higher specificity for clinically relevant RV infections, rapid RV detection with immunfluorescence has been proposed as an alternative to PCR, both for clinical and research applications [43, 56, 73, 74].
CLINICAL FEATURES OF RV INFECTIONS
RVs and their impact on short-term morbidity: upper respiratory tract infection and the “common cold”
RVs are the most common pathogens associated with ARTIs in all age groups, and they account for the vast majority of upper respiratory tract infections (URTIs) [75–78]. Together with coronaviruses, they are the main causative agents of the common cold [44, 78]. The common cold is the colloquial expression for a self-limited URTI of a median duration of 9–10 days with the most prevalent symptoms being a runny nose, nasal stuffiness, sneezing, a sore throat and cough. Besides the common cold, RVs can also cause other URTIs with a range of mild to more-severe symptoms, such as acute otitis media, sinusitis, pharyngitis and croup [4, 78, 79].
RVs and their role in lower respiratory tract infections: more than just a “common cold”
RVs replicate best at temperatures slightly below body temperature (33–34°C) and, therefore, RV infections were long assumed to be restricted to the upper airways. Recent breakthroughs in molecular diagnostics have provided data on RVs as important causes of lower respiratory tract infections (LRTIs) and of acute virus-induced wheez in children. RVs were shown to have the capacity to infect the lower respiratory tract and to replicate effectively in lower airway cells even at core temperatures of 37°C, although greater viral yields are obtained at lower temperatures [80–83]. In line with these findings, studies using sensitive molecular viral detection methods have shown that RVs are a common cause of LRTI in infants and young children; including wheezing disorders, bronchiolitis, and pneumonia with potential subsequent hospitalisations [65–67, 84–92]. Both prevalence and severity of LRTI induced by RVs are further increased in high-risk groups, especially in infants and young children with underlying chronic lung disease, such as those with bronchopulmonary dysplasia [93, 94], asthma [66, 90, 95, 96] and cystic fibrosis [97–101]. Co-infection with other viruses, mainly with RSV, occurs in approximately one-third of RV-infected children and has been linked to more severe respiratory symptoms [40, 86, 102, 103].
RVs and their role in the very young
Infections with RVs occur very early in life. Whereas older children experience on average one RV infection per year, this occurs up to two to three times more frequently in infants and younger children [42, 47]. As reported in several studies including in- and outpatient follow-up [47, 62–64, 67, 86, 87, 89, 90, 92, 104–107], as well as in prospective birth cohorts of otherwise healthy infants [66, 91, 108–111], RVs represent the most common pathogens associated with URTIs, LRTIs and wheeze in the first year of life (table 1). The mean age at the first symptomatic RV infection is 4–6 months compared with >6 months for other viruses, such as RSV [67, 91]. By the age of 6 months, >20% of children have already experienced their first RV infection, by the age of 2 yrs RVs can be identified in almost 80% of children with ARTIs, and 90% of children have antibodies against RVs [108]. Re-infections occur regularly and are usually caused by different viral strains [67]. Up to 30% of all hospitalisations due to respiratory symptoms in children <5 yrs of age are caused by RVs (this relates to five hospitalisations per 1,000 children) [90]. The highest incidence was found in children with a personal history of wheeze and/or suspected asthma with up to 45%, only second to RSV in children younger than 12 months of age [62, 86, 87, 89, 106]. At the same frequency, and especially among atopic infants older than 6 months, RV infections were found to be associated with ARTIs or wheeze [66, 107, 110, 112]. This was also confirmed in studies from developing countries, which showed increased prevalence of RV infection and frequent association with wheeze in infants aged from 2–6 months [105, 111]. All these studies highlight the predominant role of RV as a respiratory pathogen in early life.
RVs AND THEIR ROLE DURING ASTHMA DEVELOPMENT: CAUSING OR UNMASKING ASTHMA?
Current evidence
RV infections not only constitute the most common cause of acute illnesses and wheezing during infancy, but they have also been debated [113–116] as important pathogens with regard to the development of subsequent recurrent wheeze and asthma (table 2) [104, 110, 112, 117–121]. In the Childhood Origins of Asthma study, a birth cohort study of high-risk infants (where at least one parent had a history of doctor-diagnosed hay fever, asthma or eczema), Lemanske et al. [112] and Jackson et al. [110] identified moderate-to-severe RV-induced wheezing illnesses in the first years of life as the strongest predictors and risk factors for subsequent wheeze at the age of 3 yrs and 6 yrs, respectively. Almost 90% of high-risk children who wheezed with RVs at the age of 3 yrs had asthma at school age [110]. These findings are corroborated by data of an Australian birth cohort study of children at high risk for asthma development, in which Kusel and co-workers [119, 120] found that RV-induced wheezing illnesses in infancy were associated with asthma at the age of 5 yrs and 10 yrs. Also Finnish studies [117, 118, 121] showed that infants hospitalised because of RV-induced wheezing exhibited a considerably higher risk for childhood and adolescent asthma when compared with infants hospitalised because of LRTIs associated with other viruses. Taken together, high frequency and severe RV infections during infancy, especially in high-risk infants with an atopic background, seem to increase the risk for subsequent wheeze/asthma in childhood.
Possible mechanisms
The precise mechanisms through which RV-induced illnesses are involved in the pathogenesis of subsequent childhood wheeze and the development of asthma are unknown. Although the majority of children are infected with RV at the age of 2 yrs, only one-third of infants undergoing recurrent RV-induced illnesses will go on to develop asthma later in life [28]. The question whether RV infections are directly involved in the development of childhood wheeze and asthma, for instance through damage of the airway epithelium and the induction of inflammatory and remodelling processes, or whether they unveil infants prone to developing obstructive lung diseases, is subject to debate [122]. In fact, both scenarios are not mutually exclusive.
As RVs have the ability to invade lower airways and escape immunity [58], they may promote exaggerated inflammatory responses towards further stimuli, such as allergens, and lead to enhanced airway responsiveness, possibly promoting the development of asthmatic features [123–126]. Evidence from animal studies further suggests that viral infections are important environmental stimuli for airway inflammation, injury and remodelling [126–128]. Infancy is a period of profound growth and development for the pulmonary and immune systems [129, 130], and recurrent RV infections and associated inflammatory and remodelling processes during this time may thus inter- and disrupt normal processes of lung growth. Infants repeatedly undergoing severe RV infections might, therefore, develop recurrent wheezing as a consequence of airway remodelling and impaired lung growth.
Alternatively, symptomatic RV infections might only represent a proxy for infants prone to developing obstructive lung diseases. Indeed, important determinants for the occurrence of wheezing illness including RV-associated wheezing during the first year of life have been recently described. An already reduced premorbid lung function shortly after birth was shown to predispose infants to more frequent and severe LRTIs [131–133]. Further studies have demonstrated that timing and frequency of RV-induced wheezing illnesses, respectively, play an important role in asthma pathogenesis [110, 134, 135]. The age at which RV-induced wheeze occurs has a prognostic value, with later wheeze playing a more important role than early wheeze [110, 112].
Interplay with other risk factors for developing asthma
Several risk factors for developing asthma, including non-viral risk factors, have been identified in clinical and population-based studies.
Intrinsic factors include epigenetic [136, 137] and genetic factors [137–139], the stage of infant development, airway size [131–133, 138], immune function [138], male sex [138], stress [140], disease severity [120], airway hyperresponsiveness and atopic predisposition [138, 141–145]. Amongst extrinsic factors, environmental and lifestyle factors, such as various exposures in utero and in early life, e.g. indoor and outdoor air pollutants [138, 146, 147], environmental and parental/maternal tobacco smoke [138, 144, 148, 149], older siblings and early daycare attendance [138, 143] are known to be relevant. It has also been shown, for example, that traffic-related air pollution impairs lung development and influences the frequency of asthma exacerbations in older children [150]. There is also evidence for a significant impact of air pollution and environmental tobacco smoke exposure on lung development during pregnancy and early life [151], with a clear connection to asthma development [150].
The interesting question is: which of these factors might denote a link to viral infections and their impact on asthma risk? One such factor is atopy. The highest risk to develop asthma was observed for children having both recurrent viral infections during infancy and atopic features, such as atopic dermatitis or a family history of allergy [110, 112, 119, 152, 153]. Moreover, it was recently demonstrated that allergic sensitisation precedes RV-associated wheezing [142], suggesting that allergic sensitisation leads to more severe RV-induced illnesses. These findings support a causal role for allergic sensitisation in this developmental pathway, but underlying mechanisms are poorly understood. It might be that the innate antiviral immune system of atopic children is additionally activated in an atopy-dependent way upon respiratory viral infections, which would amplify and sustain airway inflammation via enhancement of atopy-associated immune cascades, e.g. by increasing up-regulation of specific high-affinity immunoglobulin E receptors involving T-helper type 2 cells [145, 154]. Additional contributors and determinants of the risk might be polymorphisms in genes encoding cytokines or other mediators of the immune system [139], or genes that have been associated with asthma [155–158]. Some protective factors have been reported as well, in particular the allergy-protective farm exposure [159] and the presence of commensal bacteria [160]. Both factors are important for normal cellular immune maturation and further control of allergic airway inflammation. However, their role in preventing infants from RV-induced wheezing illnesses and further prevention of subsequent development of childhood asthma remains unclear. To summarise, viral aetiology, illness severity, timing, allergic sensitisation and genetic predisposition all probably contribute as synergistic factors to the risk of developing asthma.
CONCLUSION AND OUTLOOK
Recent advances in molecular diagnostic tools have led to an improved understanding of the impact of RV infections in infancy and childhood. RV infections occur early and recurrently in life and impose a large burden of disease on the very young. RVs are not only the most frequent pathogens of URTIs and LRTIs in this age group, but have been shown to represent an important pathogenic factor for the development of recurrent wheeze and asthma. However, most of the studies that have highlighted the role of RVs in causing acute illness and identified them as possible contributors in asthma development have involved hospitalised and high-risk infants or infants from selected populations with a wide age range. Thus, little is known about the true impact of RVs on both short- and long-term morbidity in otherwise healthy infants. In particular, knowledge concerning the occurrence of asymptomatic RV infections early in life and their relationship with for example early bacterial acquisition or atopy is poor. Carefully conducted prospective and longitudinal population-based studies in unselected healthy infants and young children are needed to more precisely define underlying mechanisms of RV-induced wheezing episodes in early life and their complex interactions with atopy, age and maturity of the immune system on asthma development. A better understanding and characterisation of these relationships might enable the identification and close follow-up of children who have a higher risk for severe RV infections and asthma development. This might also help to develop better preventive and therapeutic measures for these conditions, such as immunisations or antiviral therapies against RVs.
Footnotes
Statement of Interest
None declared.
- Received November 21, 2011.
- Accepted June 4, 2012.
- ©ERS 2013
