The prevalence of asthma varies from country to country. The ISAAC study 2 is a world-wide, questionnaire-based, multicentre study of the prevalence of asthma, allergic rhinitis and atopic dermatitis in 463,801 children aged 13-14 years from 155 centres in 56 countries. The countries with the highest prevalence of asthma symptoms are the UK, Australia, New Zealand and the Republic of Ireland, followed by North, Central and South America; the lowest prevalences are found in Eastern Europe, Indonesia, Greece, China, Taiwan, Uzbekistan, India and Ethiopia. There was a 20-fold difference (1.6-36.8%) reported between centres with the highest and lowest rates and an 8-fold variation between the 10th and 90th centiles (3.9-30.6%).
In general, asthma is most common in the industrialised nations with a 'Western' life-style. von Mutius has studied the role of cultural and environmental differences in disease prevalence in East and West Germany following re-unification in 1989 3 . Children living in East Germany had a lower prevalence of asthma and hayfever despite being exposed to higher levels of atmospheric pollution, but higher rates of bronchitis. By the mid 1990s, the prevalence of hayfever and atopic sensitisation had increased whilst the prevalence of asthma had remained stable 4 .
The reasons for such differences are not clear. Possible factors in the aetiology of asthma include ethnic origin, childhood respiratory diseases, allergen exposure, diet and socio-economic differences. It has been suggested that improved hygiene in the Western world has resulted in a different exposure to infectious diseases with one consequence being an increased tendency to atopic responses to environmental allergens 5 .
The recent epidemic of atopic disease and asthma may have occurred as a consequence of a decline in certain childhood infections or a more general lack of exposure to a broad range of infectious agents in the first years of life. This idea is supported by studies of children in environments that would be expected to lead to increases in viral infections. Ball et al 6 investigated 1035 children as part of the Tucson Children's Respiratory Study. Children with older siblings at home or who attended day care and, therefore, were more likely to be exposed to respiratory virus infections, were more likely to have frequent wheezing (more than 3 episodes in the preceding year) at age 2 years, but were less likely to have frequent wheezing from ages 6-13 years (Fig. 1) . Such children have a reduced risk of atopic sensitisation and asthma at school age 7 .
Illi 8 and other members of the Multicentre Allergy Study (MAS) Group have shown that, in German children, repeated upper respiratory tract infection and infection with non-respiratory viruses such as herpes simplex in infancy may reduce the risk of asthma developing up to school age.
Measles infection appears to inhibit atopic disease. Amongst children in Guinea-Bissau, Shaheen et al have shown that those who have recovered from natural measles infection have half the incidence of atopy and positive responses to house dust compared to children who have been vaccinated 9 . In a study of Scottish schoolchildren, Bodner et al 10 have also shown a reduction in atopic disease, in this case allergic rhinitis in those children with a history of measles. In contrast, a study by Paunio et al 11 from Finland found a positive association between measles infection and atopy. Children with established atopic diseases may demonstrate remission of disease during measles infection with recurrence of symptoms following recovery.
Matricardi et al 12 have shown that respiratory allergy in Italian air force cadets is less frequent after heavy exposure to orofaecal and foodborne microbes as demonstrated by positive serology for Toxoplasma gondii, Helicobacter pylori and hepatitis A. A Westernised, semisterile diet may facilitate atopy by influencing the overall pattern of commensals and pathogens that stimulate the gut-associated lymphoid tissue.
A number of additional possible non-viral protective infectious influences have been proposed 13 . These include prenatal or perinatal bacterial infections, exposure to endotoxin 14 and differences in intestinal microflora. Children of farmers in rural areas have a lower prevalence of symptoms of allergic rhinitis and of allergen specific IgE than those in non-farming families 15, 16 . Children with tuberculin test evidence for natural exposure to tuberculosis have fewer symptoms of asthma, eczema, and rhinitis 17 .
Hopkin 18 has shown that treatment with oral antibiotics before the age of 2 years is associated with subsequent atopic disease. The mechanism of this effect is unclear, but it may be that antibiotics are associated with a disruption of the normal bowel flora necessary for maturation of the immune system. Alternatively, eliminating a pathogen by antibiotic therapy may limit the beneficial effects on maturation of the immune system of that infection.
It has been suggested that exposure to viruses and other infectious agents in early life is protective against the development of atopy and asthma. Of course such infections are themselves associated with significant morbidity and mortality, and this has been dramatically reduced by preventive strategies such as improvements in public health and measles vaccination. It is possible that some infections help the immune system to mature from an early predominantly Th2-biased state 19 towards a Th1-biased state and that in their absence, in individuals predisposed by genetic or additional environmental factors such as allergen exposure or maternal cigarette smoking, that this fails to happen. The consequence is atopic disease, including asthma, characterised by inflammation with a Th2 phenotype. The use of immunomodulatory drugs 20 to inhibit Th2 cell function may help to deviate the immune system away from a state where atopic disease and asthma are likely to develop. Such a strategy would require the identification of individuals at high risk and treatment in early life. There are significant ethical problems in human trials of such drugs in infants and young children, and the possible harmful effects of immune deviation are unknown.
In spite of the possible protective influence of a wide range of infectious agents (including some of the respiratory viruses) on the subsequent development of atopy and asthma, infection by respiratory viruses is a common cause of wheezing episodes in infancy and, as discussed below, of exacerbations in asthmatic children. Some 70% of wheezing episodes in the first year are associated with viral respiratory infection 21 . Respiratory syncytial virus (RSV), rhinovirus and influenza B are the most frequently cultured 22 . In some children, RSV causes bronchiolitis, a potentially serious lower respiratory tract illness with a significant mortality.
Of the respiratory viruses, RSV has most often been associated with subsequent asthma. Sigurs et al reported that infants suffering wheezing RSV infections requiring hospitalisation were more likely than prospectively identified control subjects to have allergen-specific IgE and Childhood respiratory diseases asthma by the age of 3 years 23 . Other studies have failed to demonstrate a relationship between RSV infection and asthma 24, 25 .
Martinez and colleagues 26 have studied the relationship between childhood respiratory disorders, their prognosis and the development of asthma in the Tucson Children's Respiratory Study. A total of 1246 newborn babies were recruited and studied in the first 6 years of life. Those children who suffered wheezing early in life before age 3 years could be divided into two groups. Persistent wheezers (those who still had episodes of wheezing at age 6 years) had higher levels of IgE, higher prevalence of atopic dermatitis and a higher prevalence of maternal asthma. Transient wheezers (those without wheezing by age 6 years) were more likely to have small airways and impaired lung function at birth rather than factors associated with atopy. Differences were observed between these two groups in the response at the time of the first infective wheezing episode, which occurred at around 1 year and which was due to RSV in two-thirds of episodes. Persistent wheezers showed an increase in serum IgE not seen in transient wheezers. Eosinopenia was observed in transient wheezers and in children with lower respiratory tract illness without wheezing; eosinophil counts were maintained in persistent wheezers. Such episodes were also observed to be more severe in persistent wheezers. It has been suggested that persistent wheezers will, therefore, be over-represented in studies of children hospitalised with RSV infection, and this may explain why such studies show such a strong association with subsequent asthma 27 .
Stein 28 further examined the relationship between lower respiratory tract illness before the age of 3 years and the prevalence of childhood atopy and wheeze in the Tuscon cohort. Those children with lower respiratory tract infection due to RSV had an increased risk of wheezing in the first 6 years, but this increased risk had disappeared by age 11 years. Similar increased risk was observed with other pathogens and indeed with lower respiratory tract infection with negative tests (which in this study may indicate rhinovirus infection since sensitive methods for detection were not included). No association was found between infection by RSV or other pathogens and the subsequent development of atopy.
Whether respiratory viruses actually cause subsequent asthma is unclear. Infants and young children who wheeze with acute respiratory virus infection appear to be at risk of wheeze later in childhood. This may be because such children have other factors such as small airways or deficient type 1 immunity which predispose them to wheeze during virus infections in both early and late childhood and may also predispose them to develop subsequent asthma. Roman 29 has shown low IL-4 and IFN-γ responses and significantly lower IFN-γ/IL-4 ratios in PBMC from children hospitalised with RSV relative to PBMC from control children. Respiratory viruses may simply identify predisposed Viruses in asthma children in infancy since they respond to infection by wheezing. They may or may not influence the development of asthma or the progression of asthmatic airway disease.
The link between respiratory infection and asthma exacerbations is well established although incompletely understood. In the 1950s, this association was attributed to bacterial allergy 30 , but it is now clear that the majority of exacerbations are due to viral rather than bacterial infection.
The viruses implicated in causing primarily respiratory disease include influenza, parainfluenza, enteroviruses, adenovirus, respiratory syncytial virus (RSV), rhinovirus and coronavirus. These viruses were first isolated between 1933 (influenza) 31 and the early 1960s (rhinoviruses 32,33 and coronaviruses 34, 35 ) . It is likely that additional viruses exist, but have not yet been identified. A recent study of children in The Netherlands has identified a new human metapneumovirus 36 causing symptoms similar to RSV ranging from upper respiratory tract disease to severe bronchiolitis and pneumonia. Serology demonstrated that human metapneumovirus has been circulating in humans for at least 50 years and that virtually all children in The Netherlands have been exposed to this virus. Viral respiratory tract infections are a major cause of wheezing in infants and children. Their role may have been underestimated in early epidemiological studies because of difficulties in isolation and identification 37 . Studies carried out in the 1970s and 1980s were limited to viral culture and serology, and did not always include sensitive methods for detection of rhinoviruses and coronaviruses. The introduction of molecular biology techniques (RT-PCR) to such studies has implicated viral infection in the majority of asthma exacerbations.
Apart from the method of detection used, study design also influences the frequency of detection of respiratory viruses. Asthma exacerbations often occur following a preceding history of common cold symptoms. If clinical sampling is delayed until the child is brought to the GP or accident and emergency department, then samples will be taken at a time when virus shedding is falling and isolation becomes more difficult. In an early study, it was found that 33% of specimens obtained in the first 5 days of illness were positive, but this fell to 18% if specimens were not taken until after the first 5 days 38 . The highest rates of virus Childhood respiratory diseases detection are found in prospective studies where children are followed closely and samples are taken as soon as symptoms commence.
Indirect evidence from population studies has established a significant correlation between the seasonal variation in wheezing episodes in young children and peaks of virus identification 39 . In a study of schoolchildren in Southampton, UK, specimens were obtained during respiratory infection or when there was a drop in peak expiratory flow rate. Seasonal patterns of identification of respiratory viruses in this cohort were associated with peaks in local hospital admissions for children with asthma indicating a role for such infections in severe asthma attacks 40 .
Direct evidence implicating viral infection in asthma exacerbations has been provided by studies showing an increased rate of virus detection in individuals suffering asthma attacks. Such studies fall into two main types: cross-sectional studies 22, 38, [41] [42] [43] [44] [45] [46] [47] [48] [49] [50] [51] [52] and prospective studies 39, 46, [53] [54] [55] [56] [57] [58] [59] . Viruses have been identified in 10-85% of asthma exacerbations in children.
The highest rates of identification are in those studies where subjects are followed prospectively allowing collection of clinical specimens early in the course of the illness, where PCR-based methods of diagnosis are used in addition to serology and culture, and where the methodology used allows for detection of rhinoviruses.
In Southampton 55 , 108 children aged 9-11 years were identified by questionnaire as suffering symptoms of asthma. These children were then followed prospectively over a period of 13 months. Diary cards and peak flow monitoring were used to identify episodes of fall in peak flow, upper respiratory symptoms, cough or wheeze. Nasal samples were taken early during such episodes. A combination of culture and RT-PCR detected viruses in 85% of episodes, the most frequent being rhinovirus.
Rakes et al 42 have recently reported the results of a cross-sectional study of 70 infants and children with severe wheezing attending the emergency department in Virginia, USA. This study used both RT-PCR and viral culture to detect a range of viruses including rhinovirus, RSV, coronavirus, enterovirus, influenza and adenovirus in nasal wash samples. Respiratory viruses were detected in 82% of wheezing infants below the age of 2 years and in 83% of older wheezing children. The predominant pathogens were RSV in infants (68%) and rhinovirus in older children (71%). After the age of 2 years, wheezing was most frequent in those with a positive RT-PCR for rhinovirus together with a positive serum RAST for aero-allergens, nasal eosinophilia or elevated nasal ECP.
Freymuth et al 52 have similarly used a mixture of conventional and molecular methods for detection of rhinovirus, enterovirus, RSV, adenovirus, coronavirus, influenza, parainfluenza, Chlamydia pneumoniae and Mycoplasma pneumoniae in nasal aspirates from 75 infants and children hospitalised for a severe attack of asthma. Overall, a pathogen was detected in 81.8% of those studied, the most frequently identified Viruses in asthma being rhinovirus (46.9%) and RSV (21.2%). The use of RT-PCR in this study increased the detection rates for rhinovirus and RSV 5.8-fold and 1.6-fold, respectively.
The rate of detection of viruses between exacerbations when individuals are asymptomatic is only of the order of 3-12% 60 . In contrast, a study of transtracheal aspirates in adult asthmatics during exacerbations 61 yielded sparse bacterial cultures with no correlation to clinical illness and no difference from those of normal subjects. In almost all studies of asthmatics, the predominant viruses are rhinoviruses, RSV and parainfluenza viruses. Rhinoviruses alone are detected in around 50% of virusinduced asthma attacks. Adenoviruses, enteroviruses and coronaviruses are also detected but less frequently. Influenza is only found during annual epidemics.
If a child with asthma develops an infection in which a rhinovirus, coronavirus or RSV is cultured, the likelihood of an associated asthma attack is around 50-70% in prospective studies 37 .
This is a complex area that has been reviewed by a number of authors [62] [63] [64] and will only be considered briefly here. As yet, our knowledge remains incomplete. Much of the data concerning the mechanisms of virus-induced wheezing and asthma are derived from experimental virus infection in mild adult asthmatics, usually with specific serotypes of rhinovirus, from in vitro work on virus infection in epithelial cell culture systems or from animal studies. These data may or may not be relevant to virus-induced wheezing in infants and children.
Whereas other respiratory viruses (such as influenza, parainfluenza, RSV and adenovirus) are well recognised causes of lower airway syndromes such as pneumonia and bronchiolitis and are capable of replication in the lower airway, there has been uncertainty as to whether rhinovirus infection occurred in the lower airway as well as in the upper respiratory tract. Although the possibility of nasopharyngeal contamination cannot be ruled out, rhinovirus has been detected in lower airway clinical specimens such as sputum 49 , tracheal brushings 65 , and BAL 66 by both RT-PCR and culture. Rhinovirus has been cultured in cell lines of bronchial epithelial cell origin 67 and replication has been demonstrated in primary cultures of bronchial epithelial cells 68, 69 . Finally, the use of in situ hybridisation has demonstrated rhinovirus in bronchial biopsies of subjects following experimental infection 68 . These data confirm that rhinovirus infection of the lower airway does occur and directly implicate lower airway infection in the pathogenesis of asthma exacerbations.
The interaction of respiratory virus infection and chronic asthmatic airway inflammation results in respiratory symptoms that are more severe than those suffered by non-asthmatic individuals. The detailed immunological mechanisms underlying this interaction are currently unclear. The disease syndrome following infection by virus is a consequence both of direct harmful effects of the virus itself and of immunopathology resulting from the host immune response, some of which may be unavoidable if the virus is to be eliminated. In an asthmatic individual, exacerbation may occur because of functional interaction between viral pathology and asthmatic pathology (i.e. through different mechanisms with the same end effect on function), or by sharing the same pathogenetic mechanism in an additive or even in a synergistic fashion. Pre-existing asthmatic inflammation might interfere with an effective antiviral response and thus allow the virus itself to cause increased airway damage. Alternatively, virus infection might increase the sensitivity of the asthmatic airway to trigger factors such as allergen exposure. In fact, it is likely that virus-induced asthma exacerbations occur because of a combination of these four types of interaction.
The virally infected epithelial cell is an important component of the antiviral immune response, producing cytokines and chemokines (IL-6, IL-8, RANTES, IL-11, IL-1β, MCP-1, MIP-1α) capable of activating and recruiting a variety of other cells including lymphocytes, eosinophils and neutrophils. Efficient clearance of virus is orchestrated by antibodies and by T-cells producing type 1 cytokines. The asthmatic airway is rich in type 2 cytokines and this may result in virus-specific T cells with type 2 or mixed type 1/type 2 character. If this is the case, then virus infection could be followed by both an inefficient antiviral immune response with delayed viral clearance and by amplification of on-going asthmatic inflammation; the consequence of this interaction is severe, often prolonged viral illness and exacerbation of asthma.
The success of vaccination to prevent respiratory virus infections has been limited by significant variation within the major virus types causing disease. There are 102 serotypes of rhinovirus and no effective vaccine has been introduced. The influenza viruses display antigenic shift and drift. New vaccines must be developed every 2-3 years to cover the strains prevalent at the time. When a new pandemic strain arises, there is a delay before sufficient quantities of vaccine can be made available. Vaccination against RSV experienced a major setback in the 1960s when the use of formalin inactivated virus in young babies resulted in increased disease severity following subsequent virus infection 70 
Viruses in asthma vaccinated children, 80% required hospitalisation when subsequently infected with RSV, as compared to 5% of controls. The lungs of two vaccinated children who died contained eosinophilic infiltrates. It has been suggested that formalin inactivation may have modified epitopes within the RSV G and F surface glycoproteins, resulting in a modified immune response to subsequent infection with enhanced immunopathology 71 . Vaccinated individuals demonstrate a number of differences from individuals who have suffered natural RSV infection including a lack of specific mucosal antibodies and deficient neutralising and fusion-inhibiting serum antibodies 72 . There are also differences in the cell-mediated immune response with some vaccinated individuals demonstrating peripheral eosinophilia and exaggerated lymphocytic proliferative responses to RSV 73 . To protect against RSV infection, a successful vaccine would need to provide more effective protection than natural infection, which is itself frequently followed by re-infection 74 , and would have to be administered early in infancy to have an effect on infant bronchiolitis.
There are two main approaches to therapy for a viral exacerbation. The first is to use antiviral agents with direct actions against the virus itself. Because of the large number of viruses producing similar clinical syndromes, the use of specific antiviral drugs requires rapid accurate diagnostic methods such as PCR.
An alternative approach is to treat virus-induced inflammation, perhaps by strategies that promote type 1 responses in individuals with excessive type 2 responses. Understanding the complexities of the antiviral immune response, in particular how it may be altered in the context of pre-existing chronic airway diseases such as asthma, is an essential first step. Further work is needed to elucidate the important sites of interaction between the immunological networks of asthma and of virus infection. Greater knowledge is required if we are to identify key targets for therapeutic intervention, the aim of which will be to minimise immunopathology whilst maintaining or enhancing the host antiviral immune response.
Currently, much of the treatment of infective exacerbations of asthma is symptomatic, consisting of increased bronchodilators, or supportive in the form of oxygen and, in severe cases, non-invasive or invasive ventilatory measures. Corticosteroids are widely used in inhaled or oral form for their anti-inflammatory actions and have a major role in asthma. The effects of corticosteroids are the result of actions at many points in various inflammatory cascades 75 . Whilst this undoubtedly contributes to their beneficial effects, it also results in significant side-effects, in particular if systemic steroid treatment is prolonged or frequent. In addition, systemic steroids may interfere with the antiviral immune response resulting in reduced viral clearance 76 .
Specific antiviral agents exist for the influenza viruses including amantidine, rimantidine and the more recently developed neuraminidase inhibitors, zanamivir and oseltamivir. Their use is currently restricted to adults. Influenza is a relatively unusual cause of asthma exacerbations in children, especially outside epidemics.
Ribavirin is a nucleoside analogue, active against RSV in vivo and also against influenza in vitro. Nebulised ribavirin therapy is licensed for use in hospitalised infants and children in the first 3 days of RSV bronchiolitis. It is, however, expensive and of unproven benefit on clinical outcome.
RSV-enriched immunoglobulin is effective as prophylaxis for infants at high risk of RSV bronchiolitis 77 , and trials with RSV neutralising monoclonal antibodies are in progress.
Rhinoviruses are a major target for drug treatment. It has been estimated that rhinoviruses result in 6-10 colds per year in young children As yet, no effective agent is available for clinical use. Capsid binding/canyon inhibitors block the binding of rhinoviruses to their host cell receptor (ICAM-1 in the case of the major group). One example in phase 3 clinical trials is pleconaril (Picovir). These drugs can be extremely potent, but their clinical usefulness is often limited by serotype specificity and the rapid development of resistance. Alternative targets include soluble ICAM-1 which inhibits major rhinovirus infection in vitro and conserved viral enzymes such as protein 3D, the RNA-dependent RNA transcriptase, protein 2C, the associated ATP-helicase, and the cysteine protease 3C.
The role of infection in the aetiology of asthma is complex. Current evidence suggests that the overall load of infectious agents, including respiratory viruses, encountered early in life is an important factor influencing maturation of the immune system from a type 2 bias at birth towards predominantly type 1 responses, thus avoiding atopic diseases. The 'hygiene hypothesis' is that the relatively sterile environment present in industrialised Western countries has, therefore, contributed to the recent epidemic of asthma and atopy.
Whether specific infections are of greater or lesser protective value is unclear. This is an important question if strategies are to be derived to mimic the beneficial effects of childhood infection whilst avoiding morbidity and potential mortality of the natural pathogens 78 .
There is no convincing evidence that specific infections cause atopy or asthma. There is, however, a strong association between severe wheezing episodes in infancy (commonly due to virus infection, in particular RSV) and subsequent wheezing or asthma later in life, particularly in those children with features of atopy.
Infection by respiratory viruses is a common trigger of wheezing in infants and of exacerbations of asthma in older children. Viruses are detected in up to 85% of such episodes. Rhinovirus is common in all age Viruses in asthma groups, RSV is most important in infants and young children. Our knowledge of the immunopathogenetic mechanisms involved remains incomplete.
Current therapy for virus-induced exacerbations of asthma relies on increased treatment of pre-existing disease. Corticosteroids form the major anti-inflammatory component of such therapy, but their use can be associated with significant side-effects, especially if used systemically and in high doses. Antiviral agents do exist, in particular for influenza viruses, but the effective use of such drugs in asthma requires viral diagnosis and commencement of treatment early in the course of an exacerbation or the targeting of high-risk groups for prophylaxis. Clinically effective broad spectrum agents are not yet available for the rhinoviruses which are the commonest cause of exacerbations. Alternative strategies for drug development may involve the identification of key factors common to exacerbations induced by a range of different viruses. Increased knowledge of the host-virus interaction is required to design treatments that will increase virus clearance and minimise immunopathology.
• The vast majority of asthma exacerbations in school-age children are precipitated by acute respiratory viral infection
• The failure to develop adequate type 1 immunity is associated with an increased risk of development of atopy and asthma • A high overall load of infectious disease early in life (including viral upper respiratory tract infections) protects against atopy and asthma, presumably by augmenting type 1 immunity
• Unnecessary use of antibiotics in the first years of life should be avoided for this reason • Individual severe viral infections (such as RSV) in those at increased risk (with relatively deficient type 1 immunity) are associated with wheeze in early life and the later development of atopy and asthma