Viral upper respiratory infections have been implicated as a major cause of asthma exacerbations among school age children. Regular hand washing is the most effective method to prevent the spread of viral respiratory infections but, effective hand washing practices are difficult to establish in schools.
This randomized controlled trial evaluated whether a standardized regimen of hand washing plus alcohol-based hand sanitizer could reduce asthma exacerbations more than schools’ usual hand hygiene practices.
This was a two year, community-based, randomized controlled crossover trial. Schools were randomized to usual care then intervention (Sequence 1) or intervention then usual care (Sequence 2). Intervention schools were provided with alcohol-based hand sanitizer, hand soap, and hand hygiene education. The primary outcome was the proportion of students experiencing an asthma exacerbation each month. Generalized estimating equations were used to model the difference in the marginal rate of exacerbations between sequences while controlling for individual demographic factors and the correlation within each student and between students within each school.
527 students with asthma were enrolled among 31 schools. The hand hygiene intervention did not reduce the number of asthma exacerbations as compared to the schools’ usual hand hygiene practices (p=0.132). There was a strong temporal trend as both sequences experienced fewer exacerbations during Year 2 as compared to Year 1 (p<0.001).
While the intervention was not found to be effective, the results were confounded by the H1N1 influenza pandemic that resulted in substantially increased hand hygiene behaviors and resources in usual care schools. Therefore, these results should be viewed cautiously.
asthma; schools; children; hand hygiene; hand sanitizer
Asthma is a highly prevalent chronic respiratory disease affecting 300 million people worldwide. A significant fraction of the cost and morbidity of asthma derives from acute care for asthma exacerbations. In the United States alone, there are approximately 15.0 million outpatient visits, 2 million emergency room visits, and 500,000 hospitalizations each year for management of acute asthma. Common respiratory viruses, especially rhinoviruses, cause the majority of exacerbations in children and adults. Infection of airway epithelial cells with rhinovirus causes the release of pro-inflammatory cytokines and chemokines, as well as recruitment of inflammatory cells, particularly neutrophils, lymphocytes, and eosinophils. The host response to viral infection is likely to influence susceptibility to asthma exacerbation.
Having had at least one exacerbation is an important risk factor for recurrent exacerbations suggesting an “exacerbation-prone” subset of asthmatics. Factors underlying for the “exacerbation-prone” phenotype are incompletely understood but include extrinsic factors: cigarette smoking, medication noncompliance, psychosocial factors, and co-morbidities such as gastroesophageal reflux disease, rhinosinusitis, obesity, and intolerance to non-steroidal anti-inflammatory medications; as well as intrinsic factors such as deficient epithelial cell production of the anti-viral type I interferons (IFN-α and IFN-β). A better understanding of the biologic mechanisms of host susceptibility to recurrent exacerbations will be important for developing more effective preventions and treatments aimed at reducing the significant cost and morbidity associated with this important global health problem.
Asthma exacerbations are seasonal with the greatest risk in elementary-age students occurring shortly after returning to school following summer break. Recent research suggests that this seasonality in children is primarily related to viral respiratory tract infections. Regular hand washing is the most effective method to prevent the spread of viral respiratory infections; unfortunately, achieving hand washing recommendations in schools is difficult. Therefore, we designed a study to evaluate the effect of hand sanitizer use in elementary schools on exacerbations among children with asthma.
To describe the process of redesigning the trial in response to changes in the safety profile of the hand sanitizer as well as changes in hand hygiene practice in the schools.
The original trial was a randomized, longitudinal, subject-blinded, placebo-controlled, community-based crossover trial. The primary aim was to evaluate the incremental effectiveness of hand sanitizer use in addition to usual hand hygiene practices to decrease asthma exacerbations in elementary-age children. Three events occurred that required major modifications to the original study protocol: (1) safety concerns arose regarding the hand sanitizer’s active ingredient; (2) no substitute placebo hand sanitizer was available; and (3) community preferences changed regarding hand hygiene practices in the schools.
The revised protocol is a randomized, longitudinal, community-based crossover trial. The primary aim is to evaluate the incremental effectiveness of a two-step hand hygiene process (hand hygiene education plus institutionally provided alcohol-based hand sanitizer) versus usual care to decrease asthma exacerbations. Enrollment was completed in May 2009 with 527 students from 30 schools. The intervention began in August 2009 and will continue through May 2011. Study results should be available at the end of 2011.
The changed design does not allow us to directly measure the effectiveness of hand sanitizer use as a supplement to traditional hand washing practices.
The need to balance a rigorous study design with one that is acceptable to the community requires investigators to be actively involved with community collaborators and able to adapt study protocols to fit changing community practices.
Background Asthma exacerbations are seasonal with
the greatest risk in elementary-age students occurring shortly after returning
to school following summer break. Recent research suggests that this seasonality
in children is primarily related to viral respiratory tract infections. Regular
hand washing is the most effective method to prevent the spread of viral
respiratory infections; unfortunately, achieving hand washing recommendations in
schools is difficult. Therefore, we designed a study to evaluate the effect of
hand sanitizer use in elementary schools on exacerbations among children with
Purpose To describe the process of redesigning the
trial in response to changes in the safety profile of the hand sanitizer as well
as changes in hand hygiene practice in the schools.
Methods The original trial was a randomized,
longitudinal, subject-blinded, placebo-controlled, community-based crossover
trial. The primary aim was to evaluate the incremental effectiveness of hand
sanitizer use in addition to usual hand hygiene practices to decrease asthma
exacerbations in elementary-age children. Three events occurred that required
major modifications to the original study protocol: (1) safety concerns arose
regarding the hand sanitizer’s active ingredient; (2) no substitute placebo hand
sanitizer was available; and (3) community preferences changed regarding hand
hygiene practices in the schools.
Results The revised protocol is a randomized,
longitudinal, community-based crossover trial. The primary aim is to evaluate
the incremental effectiveness of a two-step hand hygiene process (hand hygiene
education plus institutionally provided alcohol-based hand sanitizer) versus
usual care to decrease asthma exacerbations. Enrollment was completed in May
2009 with 527 students from 30 schools. The intervention began in August 2009
and will continue through May 2011. Study results should be available at the end
Limitations The changed design does not allow us to
directly measure the effectiveness of hand sanitizer use as a supplement to
traditional hand washing practices.
Conclusions The need to balance a rigorous study
design with one that is acceptable to the community requires investigators to be
actively involved with community collaborators and able to adapt study protocols
to fit changing community practices.
Associations between respiratory infections and asthma inception and exacerbations are well established. Infant respiratory syncytial virus and rhinovirus infections are known to be associated with an increased risk of asthma development, and among children with prevalent asthma, 85% of asthma exacerbations are associated with viral infections. However, the exact nature of this relationship remains unclear. Is the increase in severity of infections an epiphenomenon, meaning respiratory infections just appear more severe in individuals with underlying respiratory disease, or instead a reflection of altered host susceptibility among persons with asthma and atopic disease? The main focus of this review is to summarize the available levels of evidence supporting or refuting the notion that persons with asthma or atopic disease have an altered susceptibility to selected pathogens, as well as discussing the biological mechanism(s) that might explain such associations. Finally, we will outline areas in need of further research, as understanding the relationships between infections and asthma has important implications for both asthma prevention and treatment, including potential new pathways that might target host immune response to select pathogens.
Asthma; viral infections; bacterial infections; allergy; allergic rhinitis; atopic disease; immune function; immune system
The rising worldwide prevalence of asthma has intensified interest in the natural history of asthma. An improved understanding of the genetic, environmental, and developmental factors contributing to the inception and exacerbation of asthma will be crucial to efforts to devise effective preventive and therapeutic interventions. There is increasing evidence that the complex interplay of early life respiratory viral infections and allergic sensitization is important in the development of asthma. Major causes of asthma exacerbations are respiratory viral infections and aeroallergen exposure, which may have interactive co-morbid effects. This review describes the potential role of thymic stromal lymphopoietin (TSLP) as a connection between the innate immune response to respiratory viral infections and the type-2 adaptive immune response in the development and exacerbation of asthma.
Thymic stromal lymphopoietin (TSLP); virus infection; atopy; asthma
Each year, approximately 20% of asthmatics in the United States experience acute symptom exacerbations, which commonly result from pulmonary viral infections. The majority of asthma exacerbations in very young children follow infection with respiratory syncytial virus (RSV). However, pathogenic mechanisms underlying induction of asthma exacerbations by RSV are not well understood. We therefore investigated the effect of post-sensitization RSV infection on lung function in ovalbumin (OVA)-sensitized BALB/c mice as a model of RSV asthma exacerbations. OVA sensitization of uninfected female BALB/c mice increased bronchoalveolar lavage fluid (BALF) eosinophil levels and induced airway hyperresponsiveness to the muscarinic agonist methacholine, as measured by the forced-oscillation technique. In contrast, intranasal infection with replication-competent RSV strain A2 for 2–8 days reduced BALF eosinophil counts and reversed airway hyperresponsiveness in a pertussis toxin-sensitive manner. BALF levels of the chemokine keratinocyte cytokine (KC; a murine homolog of interleukin-8) were elevated in OVA-sensitized, RSV-infected mice and reversal of methacholine hyperresponsiveness in these animals was rapidly inhibited by KC neutralization. Hyporesponsiveness could be induced in OVA-sensitized, uninfected mice by recombinant KC or the Gαi agonist melittin. These data suggest that respiratory syncytial virus induces KC-mediated activation of Gαi, resulting in cross-inhibition of Gαq-mediated M3-muscarinic receptor signaling and reversal of airway hyperresponsiveness. As in unsensitized mice, KC therefore appears to play a significant role in induction of airway dysfunction by respiratory syncytial virus. Hence, interleukin-8 may be a promising therapeutic target to normalize lung function in both asthmatics and non-asthmatics with bronchiolitis. However, the OVA-sensitized, RSV-infected mouse may not be an appropriate model for investigating the pathogenesis of viral asthma exacerbations.
Asthma exacerbations may be triggered by a number of atmospheric and domiciliary environmental factors as well as by those encountered in schools and workplaces. The majority of exacerbations, particularly in children, coincide with respiratory viral infections, most commonly rhinovirus. As most respiratory viruses and many aeroallergens appear in seasonal patterns, asthma exacerbations, particularly those requiring emergency treatment, show analogous seasonal cycles which differ in form in children and adults. While similar in form between the sexes, they differ in amplitude, with boys having higher risks of exacerbation in childhood and women in adult life. Simultaneous exposure of asthmatics with respiratory viral infections to allergens or air pollutants may significantly increase the risks of exacerbation. Access to and compliance with inhaled corticosteroid treatment is an important predictor of the likelihood of asthma exacerbations occurring, including those that occur during respiratory viral infections. Epidemiologically, the degree of asthma control achieved by asthmatics is an important predictor of the likelihood of disease exacerbation including respiratory failure, death, and health service consumption.
asthma; exacerbation; epidemiology; seasons; allergen; anti‐asthmatic drugs
Viral respiratory tract infections are frequent and usually self-limited illnesses. For patients at risk for asthma, or with existing asthma, viral respiratory tract infections can have a profound effect on the expression of disease or loss of control. New evidence has shown that wheezing episodes early in life with the common cold virus, human rhinovirus, is a major risk factor for the later diagnosis of asthma at age six years. For those with existing asthma, exacerbations are a major cause of morbidity, need for acute care and, rarely, death. Viral respiratory tract infections, most frequently with rhinovirus, are the predominant microorganisms associated with asthma exacerbations. Evidence is also emerging that deficiencies in antiviral activity and the integrity of the airway epithelial barrier may make individuals with asthma more likely to have severe viral respiratory infections of the lower airway, and thus increase the risk of exacerbation. Given the influences of respiratory viruses on many aspects of asthma, efforts to understand the mechanisms and risk factors by which these airway infections cause changes in airway pathophysiology are a first step in improved treatment.
Viral respiratory infection has long been known to influence the occurrence of asthma exacerbations. Over the last twenty years much effort has been put into clarifying the role that viral respiratory infections play in the eventual development of asthma.
Scope of Review
In this review we give a general background of the role of viruses in the processes of asthma exacerbation and asthma induction. We review recent additions to the literature in the last three years with particular focus on clinical and epidemiologic investigations of influenza, rhinovirus, bocavirus, respiratory syncytial virus, and metapneumovirus.
The development of asthma emerges from a complex interaction of genetic predisposition and environmental factors with viral infection likely playing a significant role in the effect of environment on asthma inception.
Further understanding of the role that viruses play in asthma exacerbation and inception will contribute to decreased asthma morbidity in the future.
asthma; viral infection; influenza; 2009 H1N1 influenza; rhinovirus; bocavirus; respiratory syncytial virus; human metapneumovirus
The role of viral respiratory tract infections in acute exacerbations of asthma was studied prospectively in 31 patients with atopic asthma aged 15-56 years. Patients recorded symptom scores for asthma and peak expiratory flow rate daily for 11 months. In addition, they reported for detailed clinical, functional, and virological study every four weeks and as soon as possible after the onset of worsening asthma or symptoms suggesting a respiratory tract infection. Thirty viral identifications were made, of which 18 (60%) were associated with an exacerbation of asthma. Viral respiratory tract infection was identified in 18 (10%) of the 178 exacerbations of asthma, and in 10 (36%) of the 28 severe exacerbations. The frequency of viral identifications in 16 non-asthmatic, control subjects during the same period was similar. It is concluded that viral respiratory tract infections may cause or be associated with exacerbations of asthma in adults, and that they are an important factor in severe exacerbations.
Rationale: Human rhinoviruses (HRV) are the leading cause of upper respiratory infections and have been postulated to trigger asthma exacerbations. However, whether HRV are detected during crises because upper respiratory infections often accompany asthma attacks, or because they specifically elicit exacerbations, is unclear. Moreover, although several hypotheses have been advanced to explain virus-induced exacerbations, their mechanism remains unclear.
Objectives: To determine the role of HRV in pediatric asthma exacerbations and the mechanisms mediating wheezing.
Methods: We prospectively studied 409 children with asthma presenting with upper respiratory infection in the presence or absence of wheezing. Candidate viral and immune mediators of illness were compared among children with asthma with different degrees of severity of acute asthma.
Measurements and Main Results: HRV infections specifically associated with asthma exacerbations, even after adjusting for relevant demographic and clinical variables defined a priori (odds ratio, 1.90; 95% confidence interval, 1.21–2.99; P = 0.005). No difference in virus titers, HRV species, and inflammatory or allergic molecules was observed between wheezing and nonwheezing children infected with HRV. Type III IFN-λ1 levels were higher in wheezing children infected with HRV compared with nonwheezing (P < 0.001) and increased with worsening symptoms (P < 0.001). Moreover, after adjusting for IFN-λ1, children with asthma infected with HRV were no longer more likely to wheeze than those who were HRV-negative (odds ratio, 1.18; 95% confidence interval, 0.57–2.46; P = 0.66).
Conclusions: Our findings suggest that HRV infections in children with asthma are specifically associated with acute wheezing, and that type III IFN-λ1 responses mediate exacerbations caused by HRV. Modulation of IFN- λ1 should be studied as a therapeutic target for exacerbations caused by HRV.
asthma; interferon-λ; rhinovirus; children; asthma exacerbation
Inhaled corticosteroids (ICS) are the most effective anti-inflammatory drugs for the treatment of persistent asthma in children. Treatment with ICS decreases asthma mortality and morbidity, reduces symptoms, improves lung function, reduces bronchial hyperresponsiveness and reduces the number of exacerbations. The efficacy of ICS in preschool wheezing is controversial. A recent task force from the European Respiratory Society on preschool wheeze defined two different phenotypes: episodic viral wheeze, wheeze that occurs only during respiratory viral infections, and multiple-trigger wheeze, where wheeze also occurs in between viral episodes. Treatment with ICS appears to be more efficacious in the latter phenotype. Small particle ICS may offer a potential benefit in preschool children because of the favourable spray characteristics. However, the efficacy of small particle ICS in preschool children has not yet been evaluated in prospective clinical trials. The use of ICS in school children with asthma is safe with regard to systemic side effects on the hypothalamic–pituitary–adrenal axis, growth and bone metabolism, when used in low to medium doses. Although safety data in wheezing preschoolers is limited, the data are reassuring. Also for this age group, adverse events tend to be minimal when the ICS is used in appropriate doses.
Inhaled corticosteroids; Asthma; Children; Preschool; Safety; Wheeze
The etiology and morbidity associated with asthma are thought to stem from both genetic factors and potentially modifiable environmental factors, such as viral infections.[1-7] 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 the associated with the majority of asthma exacerbations among both children and adults. This review will discuss 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.
viruses; respiratory tract infections; 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 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.
rhinovirus; virus; allergy; asthma; inflammation
Acute respiratory illness (ARI) due to various viruses is not only the most common cause of upper respiratory infection in humans but is also a major cause of morbidity and mortality, leading to diseases such as bronchiolitis and pneumonia. Previous studies have shown that respiratory syncytial virus (RSV), human rhinovirus (HRV), human metapneumovirus (HMPV), human parainfluenza virus (HPIV), and human enterovirus infections may be associated with virus-induced asthma. For example, it has been suggested that HRV infection is detected in the acute exacerbation of asthma and infection is prolonged. Thus it is believed that the main etiological cause of asthma is ARI viruses. Furthermore, the number of asthma patients in most industrial countries has greatly increased, resulting in a morbidity rate of around 10-15% of the population. However, the relationships between viral infections, host immune response, and host factors in the pathophysiology of asthma remain unclear. To gain a better understanding of the epidemiology of virus-induced asthma, it is important to assess both the characteristics of the viruses and the host defense mechanisms. Molecular epidemiology enables us to understand the pathogenesis of microorganisms by identifying specific pathways, molecules, and genes that influence the risk of developing a disease. However, the epidemiology of various respiratory viruses associated with virus-induced asthma is not fully understood. Therefore, in this article, we review molecular epidemiological studies of RSV, HRV, HPIV, and HMPV infection associated with virus-induced asthma.
molecular epidemiology; virus-induced asthma; respiratory syncytial virus; human rhinovirus; human metapneumovirus; respiratory viruses
Asthma inception is associated with respiratory viral infection, especially infection with respiratory syncytial virus (RSV) and/or human rhinovirus (HRV), in the vast majority of cases. However, the reason why RSV and HRV induce the majority of bronchiolitis cases during early childhood and why only a small percentage of children with RSV- and HRV-induced bronchiolitis later develop asthma remains unclear. A genetic association study has revealed the important interaction between viral illness and genetic variants in patients with asthma. Severe RSV- and HRV-induced bronchiolitis may be associated with a deficiency in the innate immune response to RSV and HRV. RSV and HRV infections in infants with deficient innate immune response and the dysfunction of regulatory T cells are considered to be a risk factor for the development of asthma. Sensitization to aeroallergens, beginning in the first year of life, consistently predisposes children to HRV-induced wheezing illnesses, but the converse is not true. Some evidence of virus specificity exists, in that allergic sensitization specifically increased the risk of wheezing in individuals infected with HRV, but not RSV. Administration of Palivizumab, a humanized monoclonal antibody that targets the A antigenic site of the Fusion-protein of RSV, decreases the risk of hospitalization in high-risk infants and the risk of recurrent of wheezing. However, palivizumab did not have any effect on subsequent recurrent wheezing in children with a family history of atopy. These findings suggest that infection with RSV and infection with HRV might predispose individuals to recurrent wheezing through an atopy-independent and an atopy-dependent mechanism, respectively. Respiratory virus-induced wheezing illnesses may encompass multiple sub-phenotypes that relate to asthma in different ways.
respiratory syncytial virus; human rhinovirus; virus-induced asthma; cellular immunity; humoral immunity
Viral respiratory infections can have a profound effect on many aspects of asthma including its inception, exacerbations, and, possibly, severity. Of the many viral respiratory infections that influence asthma, the common cold virus, rhinovirus, has emerged as the most frequent illness associated with exacerbations and other aspects of asthma. The mechanisms by which rhinovirus influences asthma are not fully established, but current evidence indicates that the immune response to this virus is critical in this process. Many airway cell types are involved in the immune response to rhinovirus, but most important are respiratory epithelial cells and possibly macrophages. Infection of epithelial cells generates a variety of proinflammatory mediators to attract inflammatory cells to the airway with a subsequent worsening of underlying disease. Furthermore, there is evidence that the epithelial airway antiviral response to rhinovirus may be defective in asthma. Therefore, understanding the immune response to rhinovirus is a key step in defining mechanisms of asthma, exacerbations, and, perhaps most importantly, improved treatment.
Asthma; exacerbation; rhinovirus; immune response to virus; pathogenesis
Rationale: Acute asthma exacerbations, precipitated by viral infections, are a significant cause of morbidity, but not all patients with asthma are equally susceptible.
Objectives: To explore susceptibility factors for asthma exacerbations, we considered a role for histoblood group antigens because they are implicated in mechanisms of gastrointestinal viral infection, specifically the O-secretor mucin glycan phenotype. We investigated if this phenotype is associated with susceptibility to asthma exacerbation.
Methods: We performed two consecutive case-control studies in subjects with asthma who were either prone or resistant to asthma exacerbations. Exacerbation-prone cases had frequent use of prednisone for an asthma exacerbation and frequent asthma-related healthcare utilization, whereas exacerbation-resistant control subjects had rarely reported asthma exacerbations. The frequency of different mucin glycan phenotypes, defined by the presence or absence of H (O), A, B, or AB antigens, was compared in cases and control subjects.
Measurements and Main Results: In an initial study consisting of 49 subjects with asthma (23 cases and 26 control subjects), we found that having the O-secretor phenotype was associated with a 5.8-fold increase in the odds of being a case (95% confidence interval, 1.7–21.0; P = 0.006). In a replication study consisting of 204 subjects with asthma (101 cases and 103 control subjects), we found that having the O-secretor phenotype was associated with a 2.3-fold increased odds of being a case (95% confidence interval, 1.2–4.4; P = 0.02).
Conclusions: The O-secretor mucin glycan phenotype is associated with susceptibility to asthma exacerbation.
Clinical trial registered at www.clinicaltrials.gov (NCT00201266).
asthma; mucins; fucosylation; H antigen; blood groups
Infections of the respiratory tract were studied in a group of families each containing a patient with chronic bronchitis or with asthma. A wide variety of infective agents may be associated with exacerbations in susceptible subjects, but the types of organism to which patients are most at risk differ according to the family structure. Exacerbations in the susceptible subject are more likely to be related to viral infections when the family contains children than when it does not.
Two patients with asthma experienced frequent respiratory infections, many of which provoked attacks of asthma.
Viruses are the predominant infectious cause of asthma exacerbations in the developed world. In addition, recent evidence strongly suggests that viral infections may also have a causal role in the development of childhood asthma. In this article, we will briefly describe the general perception of how the link between infections and asthma has changed over the last century, and then focus on very recent developments that have provided new insights into the contribution of viruses to asthma pathogenesis. Highlighted areas include the contribution of severe early life viral infections to asthma inception, genetic determinants of severe viral infections in infancy, the differences in innate and adaptive immune system cytokine responses to viral infection between asthmatic and nonasthmatic subjects, and a potential vaccine strategy to prevent severe early life virally-induced illness.
OBJECTIVE--To study the association between upper and lower respiratory viral infections and acute exacerbations of asthma in schoolchildren in the community. DESIGN--Community based 13 month longitudinal study using diary card respiratory symptom and peak expiratory flow monitoring to allow early sampling for viruses. SUBJECTS--108 Children aged 9-11 years who had reported wheeze or cough, or both, in a questionnaire. SETTING--Southampton and surrounding community. MAIN OUTCOME MEASURES--Upper and lower respiratory viral infections detected by polymerase chain reaction or conventional methods, reported exacerbations of asthma, computer identified episodes of respiratory tract symptoms or peak flow reductions. RESULTS--Viruses were detected in 80% of reported episodes of reduced peak expiratory flow, 80% of reported episodes of wheeze, and in 85% of reported episodes of upper respiratory symptoms, cough, wheeze, and a fall in peak expiratory flow. The median duration of reported falls in peak expiratory flow was 14 days, and the median maximum fall in peak expiratory flow was 81 l/min. The most commonly identified virus type was rhinovirus. CONCLUSIONS--This study supports the hypothesis that upper respiratory viral infections are associated with 80-85% of asthma exacerbations in school age children.
Childhood asthma in the Caribbean is advancing in prevalence and morbidity. Though viral respiratory tract infections are reported triggers for exacerbations, information on these infections with asthma is sparse in Caribbean territories. We examined the distribution of respiratory viruses and their association with seasons in acute and stable asthmatic children in Trinidad.
In a cross-sectional study of 70 wheezing children attending the emergency department for nebulisation and 80 stable control subjects (2 to 16 yr of age) in the asthma clinic, nasal specimens were collected during the dry (n = 38, January to May) and rainy (n = 112, June to December) seasons. A multitarget, sensitive, specific high-throughput Respiratory MultiCode assay tested for respiratory-virus sequences for eight distinct groups: human rhinovirus, respiratory syncytial virus, parainfluenza virus, influenza virus, metapneumovirus, adenovirus, coronavirus, and enterovirus.
Wheezing children had a higher [χ2 = 5.561, p = 0.018] prevalence of respiratory viruses compared with stabilized asthmatics (34.3% (24) versus (vs.) 17.5% (14)). Acute asthmatics were thrice as likely to be infected with a respiratory virus (OR = 2.5, 95% CI = 1.2 – 5.3). The predominant pathogens detected in acute versus stable asthmatics were the rhinovirus (RV) (n = 18, 25.7% vs. n = 7, 8.8%; p = 0.005), respiratory syncytial virus B (RSV B) (n = 2, 2.9% vs. n = 4, 5.0%), and enterovirus (n = 1, 1.4% vs. n = 2, 2.5%). Strong odds for rhinoviral infection were observed among nebulised children compared with stable asthmatics (p = 0.005, OR = 3.6, 95% CI = 1.4 – 9.3,). RV was prevalent throughout the year (Dry, n = 6, 15.8%; Rainy, n = 19, 17.0%) and without seasonal association [χ2 = 0.028, p = 0.867]. However it was the most frequently detected virus [Dry = 6/10, (60.0%); Rainy = 19/28, (67.9%)] in both seasons.
Emergent wheezing illnesses during childhood can be linked to infection with rhinovirus in Trinidad's tropical environment. Viral-induced exacerbations of asthma are independent of seasons in this tropical climate. Further clinical and virology investigations are recommended on the role of infections with the rhinovirus in Caribbean childhood wheeze.
Asthma is characterized as a chronic inflammatory disease associated with significant tissue remodeling. Patients with asthma are more susceptible to virus-induced exacerbation, which subsequently can lead to increased rates of hospitalization and mortality. While the most common cause of asthma-related deaths is respiratory viral infections, the underlying factors in the lung environment which render asthmatic subjects more susceptible to viral exacerbation are not yet identified. Since transforming growth factor β (TGF-β) is a critical cytokine for lung tissue remodeling and asthma phenotype, we have focused on the effects of TGF-β on viral replication and virus-induced inflammation. Treatment of human epithelial cells with TGF-β increased respiratory syncytial virus (RSV) replication by approximately fourfold. Tumor necrosis factor alpha (TNF-α) mRNA and protein expression were also significantly increased above levels with RSV infection alone. The increase in RSV replication and TNF-α expression after TGF-β treatment was concomitant with an increase in virus-induced p38 mitogen-activated protein kinase activation. Our data reveal a novel effect for TGF-β on RSV replication and provide a potential mechanism for the exaggerated inflammatory response observed in asthmatic subjects during respiratory viral infections.
Respiratory syncytial virus (RSV) infects all children early in life, is the most common cause of infant lower respiratory tract infections, and causes disease exacerbations in children with asthma. Episodes of lower respiratory tract infection in early life are associated with asthma development. Whether RSV infection early in life directly causes asthma or simply identifies infants who are genetically predisposed to develop subsequent wheezing is debatable. Recent studies suggest that these two explanations are not mutually exclusive, and are likely both important in asthma development. An open-label study of RSV immunoprophylaxis administered to preterm infants reduced recurrent wheezing by 50%. Clinical trials of infant RSV prevention, delay or severity reduction on the outcome of childhood asthma would confirm the causal relationship between RSV infection and asthma, and offer a primary prevention strategy.
asthma; bronchiolitis; lower respiratory tract infection; recurrent wheezing; respiratory syncytial virus