Pediatr Infect Dis J, 2003;22:S7682 Copyright 2003 by Lippincott Williams & Wilkins, Inc.

Vol. 22, No. 2 Printed in U.S.A.

Respiratory syncytial virus bronchiolitis and the pathogenesis of childhood asthma

FERNANDO D. MARTINEZ, MD

There is now convincing evidence that children who develop lower respiratory symptoms during infection with respiratory syncytial virus (RSV) in early life are at increased risk of developing asthma-like symptoms during the school years. What determines this association is not well-understood, but increased likelihood of allergic sensitization plays a minor role, if any, as a determinant of post-RSV wheeze. Current evidence suggests that both genetic and environmental factors determine the type of immune response to the acute RSV infection and that this response, in turn, may affect the development of the control mechanisms involved in the regulation of airway tone. Many different cytokines appear to play a role in this acute immune response, including interferon-gamma; interleukins 8, 10 and 12; and cytokines produced by T helper (Th) 1 and Th2 cells. Because asthma is a heterogeneous condition, future studies will need to determine the potentially different role of RSV infection as a risk factor for these different asthma phenotypes. It is likely, however, that strategies for the prevention of RSV infection may play a role in the prevention of the subsequent development of persistent wheezing and asthma-like symptoms in childhood.
INTRODUCTION

Compelling epidemiologic evidence supports the concept that in a majority of cases, symptoms of asthma appear during the first years of life and that for individuals with symptomatic asthma in early adulthood, symptoms and alterations in pulmonary function are already present during their first decade of life, in particular before the age of 3 years. Asthma is a heterogeneous disease, with both interindividual and intraindividual variability in its signs and symptoms. Genetic and environmental factors that influence the expression and progression of the disease are protean and include genetic predisposition to asthma and/or atopy, viral infections, prematurity, maternal smoking during pregnancy, postnatal exposure to tobacco smoke, maternal asthma, growth and development of the respiratory system and early sensitization to aeroallergens, to name a few.3 Although important differences exist between the manifestation of asthma in adults and children, the various forms of the disease share essential components of airway inflammation, airway hyperresponsiveness and bronchial obstruction. Despite these consistent characteristics, the mechanisms by which the pathogenesis of pediatric asthma evolves, in particular in association with certain predisposing factors to its development, such as RSV disease, require further elucidation.
EFFECTS OF GROWTH AND DEVELOPMENT ON LUNG FUNCTION

Asthma is the most common chronic disease of childhood, afflicting nearly 5 million children in the United States and 155 million individuals worldwide. According to a recent estimate on the economic burden of asthma in the United States, the cost of treating this disease approaches $13 billion dollars annually, in 1998 dollars.1, 2

From the Arizona Respiratory Center, University of Arizona College of Medicine, Tucson, AZ. Key words: Asthma phenotypes, methacholine, peak flow variability, interleukin-10, interleukin-12, peripheral blood mononuclear cell; 15-hydroxyeicosatetraenoic acid. Address for reprints: Fernando D. Martinez, M.D., Arizona Respiratory Center, Post Office Box 245030, 1501 N. Campbell Avenue, Room 2349, Tucson, AZ 85764. Fax 520-626-6623; E-mail fernando@resp-sci.arizona.edu.

Pulmonary diseases that affect the airways early in life may disrupt normal developmental processes of both large and small airways, immune and inflammatory host responses and neural control mechanisms. Yet, the process by which airway hyperresponsiveness develops in infancy eludes definitive identification and description. Prenatal interactions between maternal and child immune systems, altered patterns of postnatal maturation of respiratory and immune systems in early life and augmentation of cytokine production with upregulation of inflammatory cell function secondary to viral infection have been proposed as potential inducers of change in both lung structure and function. It has been proposed that in a genetically susceptible individual, the cytokine response to virus infection S76

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with high gene expression of interleukin (IL)-4 and IL-5, accompanied by low gene expression of IL-2 and interferon-gamma (IFN-gamma, may contribute to increased airway inflammation, pulmonary function deficits and influence long term outcomes, including postbronchiolitic wheezing and asthma.4 This hypothesis requires further elucidation.
ASTHMA PHENOTYPES

To examine the relationship between wheezing during viral respiratory infection and its relation to later development of asthma, the Tucson Childrens Respiratory Study enrolled 1246 newborns between May 1980 and October 1984. The study collected prospective, follow-up data on serum IgE levels, pulmonary function before any lower respiratory tract illness and skin allergy testing at age 6 and 11 years. Of the 1246 enrolled, 826 children with complete data were assigned to 4 categories according to their history of wheezing during the first 3 years of life: Those who had never wheezed; those with at least 1 wheezing lower respiratory tract illness during the first 3 years of life, but no wheezing at age 6 years, described as transient early wheezers; those who had no wheezing lower respiratory tract illness during the first 3 years of life, but who experienced wheezing episodes at 6 years of age, collectively termed late onset wheezers; and those who had at least 1 lower respiratory tract illness with wheezing in the first 3 years of life and who also experienced wheezing at 6 years of age, known as persistent wheezers (Fig. 1). Findings demonstrated that children with transient early wheezing had significantly lower length-adjusted values for V max functional residual capacity (FRC) in infancy than all other groups. The primary risk for this phenotype appears to be decreased pulmonary function before the development of any lower respiratory tract illness. Rather than increased airway lability, mechanical pulmonary characteristics, such as reduced airway resistance or increased dynamic compliance may contribute to transient wheezing.3, 6 In addition maternal smoking during pregnancy and postnatal exposure to tobacco smoke were significantly associated with transient wheezing in children younger than 3 years of age, a risk that may be mediated, in part, by the congenitally smaller airways seen in children of women who smoke.6 Further, at age 6 years the lower height-adjusted V max FRC values persisted in the transient early wheezers despite their current lack of symptoms and compared with those who had never wheezed. Late onset wheezing was associated with maternal asthma, male gender and episodes of rhinitis in the first year of life. Atopy was significantly more prevalent in both late onset wheezers and in the persistent wheezing groups than in those who had never wheezed.

FIG. 1. Asthma phenotypes: wheezing phenotypes in children. Hypothetical yearly peak prevalence of wheezing for the three different wheezing phenotypes in children. Prevalence for each age interval should be the sum of the areas under each curve. This classification of wheezing phenotypes should not imply that groups are exclusive. Dashed lines suggest that wheezing can present different curve shapes many factors, including overlap of groups. Reprinted from Stein et al.7 with permission from the BMJ Publishing Group.

As for persistent wheezers, the study found that these children had initial V max FRC values not significantly different from those of children who had never wheezed but were almost 50% higher than those of transient early wheezers. Elevated serum IgE levels at 9 months of age directly correlated with the risk of persistent wheezing, suggesting a form of IgEmediated sensitization during the first year of life. Such levels may be associated with chronic airway inflammation, persistent bronchial hyperresponsiveness and abnormal development of lung function, predisposing this group to asthma in later life. Persistent wheezers were more likely to experience significantly reduced pulmonary function at 6 years of age and were as likely as children with late onset wheezing to become sensitized to common, local aeroallergens. Unlike transient early wheezers, the deterioration in airway function among persistent wheezers appeared to reflect a chronic disease process targeting the bronchi, rather than diminished postnatal lung function in the newborn period.6 Data presented by Zeiger et al.7 for the Childhood Asthma Management Program supports the contention that early initiation of symptoms is associated with worse prognosis in children who will have persistent wheezing. They showed that duration of asthma was significantly and independently associated with multiple markers of disease severity, including lower lung

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function, prebronchodilator percent predicted forced expiratory volume at 1 s (FEV1), both prebronchodilator and postbronchodilator FEV1/forced vital capacity, greater methacholine responsiveness, increased asthma symptomatology and more frequent use of albuterol. Working with a cohort of 754 enrollees in the original Tucson Childrens Respiratory Study, Stein et al.5 examined the relationship of peak flow variability, methacholine challenge, total serum IgE and skin test reactivity to common allergens at age 11 years, compared with wheezing before 3 years of age. The study found that neither positive peak flow variability nor methacholine hyperresponsiveness at age 11 years were associated with transient early wheezing. However, both methacholine hyperresponsiveness and positive peak flow variability at 11 years of age were associated with persistent wheezing at both 6 and 11 years. Among atopic subjects, methacholine hyperresponsiveness was associated with wheezing at age 11 years, irrespective of wheezing at age 6 years.5 Whereas peak flow variability was unrelated to skin test reactivity at ages 6 and 11 and to serum IgE levels at ages 9 months, 6 years and 11 years, methacholine responsiveness was strongly associated with skin test reactivity to allergens and with total serum IgE levels measured concurrently at ages 11 and 6 years.5 It appears that different risk factors underscore different wheezing phenotypes, a hypothesis that supports the observations of Wilson et al. that many pre-school wheezers do not exhibit the same kind of atopy-related inflammatory airway response characteristic of older asthmatics, as evidenced by various, and at times divergent, patterns of response for peak flow variability and methacholine challenge at different ages.5, 8 Additionally although RSV lower respiratory tract infection poses a risk for subsequent wheezing and impaired lung function in early childhood, in most children postbronchiolitic wheezing resolves by 13 years of age. For the subgroup of persistent wheezers, early allergic sensitization increases the prevalence of respiratory symptoms, chronic airway inflammation and the risk of declining pulmonary function.
ROLE OF HOST AND ENVIRONMENTAL FACTORS IN THE DEVELOPMENT OF CHILDHOOD ASTHMA

Nafstad et al.9 assessed the contribution of early respiratory infection to the subsequent development of bronchial obstruction in the first 2 years of life and asthma by age 4 years. A total of 2531 children enrolled in the Oslo Birth Cohort were followed for outcomes of current asthma as diagnosed by a physician with symptoms occurring during the previous 12 months. As a secondary mea-

sure bronchial obstruction was defined as 2 episodes characterized by 3 of 5 observable symptoms of wheezing, chest retraction, tachypnea, rhonchi during auscultation and forced expiration, or a single episode that persisted for 1 month during the first 2 years of life. Parents completed a respiratory questionnaire when enrollees were 6, 12, 18 and 24 months old and again at 4 years of age. Six month and 1-year data were collected on otitis media, croup, common cold and lower respiratory tract infections, defined as an episode of bronchiolitis (including RSV), bronchitis or pneumonia. Covariate analyses were performed on potential confounders of gender; parental atopy defined as a history of maternal or paternal asthma or hay fever; maternal age at delivery; maternal education; family income; single parenthood; length of breastfeeding, categorized into 0 to 6 months and 6 months; and environmental tobacco smoke exposure at birth, defined as living together with 1 or more smokers. Findings indicated that children who had experienced any of the four types of infections incurred considerably higher risk for both bronchial obstruction and asthma by age 4 years, compared with children who had not had the corresponding infection, i.e. common cold, croup, lower respiratory tract infection or otitis media.9 Experience of lower respiratory tract infection during either the first 6 or 12 months of life was the strongest factor associated with subsequent bronchial obstruction. Although bronchial obstruction during the first 2 years of life itself was strongly associated with the risk of asthma, of the 225 children who had experienced bronchial obstruction, only 76 (33.8%) developed symptomatic asthma at the age of 4 years. However, respiratory infections in infancy increased the risk of asthma at age 4 years, irrespective of a prior episode of bronchial obstruction.9 Further, each type of infection had an independent effect on the risk of asthma, for both the first 6 and the first 12 months of life. These results suggest that the association between respiratory infections in infancy on the subsequent development of asthma symptoms by age 4 years is not mediated through early bronchial obstruction.9 Nafstads group9 proposed that varying degrees of genetic propensity and environmental exposure contribute to the relationship of respiratory infection during the first year of life with the development of a heterogeneous disease such as asthma. Although the presence of older siblings and day care attendance at a young age increased the risk of bronchial obstruction, older siblings tended to decrease the risk of asthma at the age of 4 years, independent of a higher frequency of early respiratory infections. Krawiec et al.10 examined the cellular composition and specific lipid mediators in the airways of 20 young

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children who wheezed (WC) and compared them with 6 nonwheezing controls (NC). The median age of the wheezing group was 14.9 months vs. a somewhat older 23.3 months for the normal controls. Patients who had experienced episodes of wheezing for 2 months within a 6-month period received diagnostic bronchoscopy with bronchoalveolar lavage. Nonwheezing patients identified as controls for the study had been scheduled for elective surgery with general anesthesia. Bronchoalveolar lavage fluid (BALF) was analyzed for common bacterial and viral pathogens, cell counts and differentials. Competitive enzyme immunoassay was performed to quantitate leukotriene (LT) B4, LTC4, prostaglandin (PG) D2, PGE2 and 15-hydroxyeicosatetraenoic acid (HETE). Results indicated that wheezing children had a 3fold increase in both total cells and in all cell types compared with normal controls, with the largest difference occurring in lymphocyte counts (P 0.007).10 Although lymphocytes have been implicated in adult asthma, in particular with respect to the Th2 phenotype, their contribution to childhood wheezing is not well-understood. Total numbers of both macrophages and neutrophils were also increased in the WC group, compared with normal controls (P 0.02). Although statistically significant differences were observed in the total number of eosinophils (P 0.04), such differences were the least significant compared with other cell types. In contrast to older patients, the comparatively modest elevation in eosinophils suggests that this cell type may not be the predominant inflammatory cell in young wheezers.10 Increases in overall cell numbers rather than in individual cell types imply a nonspecific inflammatory process in young wheezing children, without one or more specific cell types predominating and without alterations in normal airway cellular patterns (Fig. 2).10 BALF analysis for mediator levels showed statistically significant elevations in 15-HETE, PGE2, LTE4 and LTB4 in the WC compared with the NC group.10 It has been suggested that 15-HETE plays an antiinflammatory role in asthma. LTB4, produced by both macrophages and neutrophils, is a potent chemoattractant for neutrophils. No differences were observed in PGD2 and beta-tryptase levels between the wheezing and nonwheezing groups. These mediators, derived from mast cells, are commonly associated with adult asthma.10 Results from this and other studies support the position that wheezing in childhood represents a spectrum of heterogeneous conditions, which share a common expression of airway obstruction, characterized by

FIG. 2. Significant elevations in lymphocytes (LYMPH), epithelial cells (EPI) and polymorphonuclear cells (PMN) in WC compared with NC. Lymphocytes, epithelial cells and polymorphonuclear cells are expressed as cells 104/ml in WC compared with NC. The median is shown as a single black line. Each circle, triangle and diamond represents one individual. Reprinted from Krawiec et al.,10 with permission.

signs and symptoms that vary between patients, within the individual patient and over time.
CELLULAR IMMUNITY AND AIRWAY FUNCTION

Respiratory syncytial virus promotes a cell-mediated defense by initially infecting respiratory epithelial cells, resident macrophages and monocytes in the airways. Monocytes and macrophages internalize viral proteins, present them on their cell membranes and release increased numbers of viral particles. Monocytes and macrophages play a role in the acute inflammatory process that accompanies RSV bronchiolitis. In the front lines of the immune response cascade, monocytes and macrophages produce a number of cytokines, including IL-12 and IL-10. Interleukin-12 initiates the antiviral immune response, promotes differentiation of naive CD4 T cells to the Th1 phenotype and enhances the capacity of T cells and natural killer (NK) cells to produce IFNgamma and IL-2.11 Interleukin-10 down-regulates cytokine production by Th1-like T cells, inhibits antigen presentation by antigen-presenting cells and influences recurrent wheezing, possibly by activating cytokine networks, resulting in an asthma-inducing immune response on subsequent challenge with both aspecific and allergic stimuli.12 Alveolar macrophages and monocytes directly interact with T helper cells and cytotoxic T cells. The lymphocyte subsets Th1 and Th2 can be differentiated on the basis of their respective cytokine profiles, although such a clear differentiation is not always possible in humans, and these two seem to be more poles of Th cell development than true cell subtypes.

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Th1 cells typically promote cell-mediated immunity by secreting IFN-gamma, an inhibitor of IL-4-induced IgE production, and interleukin-2, an immunomodulatory cytokine known to increase the proliferation of CD4 cells and to act as a growth factor for CD8 cytolytic T cells.11 Th2 cells elaborate IL-4, an interleukin that stimulates isotype switching to IgE antibody production, and IL-5, which plays a role in immediate-type hypersensitivity reactions. Respiratory syncytial virus induces monocyte activation and results in immune activation with increased production of proinflammatory mediators, such as tumor necrosis factor, IL-1, IL-6, IL-8, IL-10, plateletactivating factor and prostaglandin E2. In addition to cytokines, other factors, including the dose of antigen, the type of antigen-presenting cell and the major histocompatibility complex Class II haplotype, can influence the differentiation of CD4 T cells into specific Th subsets.12 Roman et al.13 compared the peripheral blood mononuclear cell subpopulations of 15 confirmed RSVpositive infants hospitalized for acute lower respiratory tract illness with 17 healthy controls to determine the type of immune response that develops during an episode of acute respiratory disease with bronchial obstruction. The group found that infants infected naturally with RSV exhibited a predominantly humoral Th2 type immune response to infection with an increased number of B cells, decreased number of CD8 T cells and CD8/CD25-activated cells and functional depression of Th1 cells, characterized by the absence of IFN-gamma, the presence of IL-4 and a significantly elevated ratio of IL-4 to IFN-gamma.13 Other investigators have assessed the monocyte and lymphocyte cytokine responses to infection with RSV in an attempt to determine whether such responses possess predictive value for the development of recurrent wheezing. Bont et al.11 measured the levels of IL-10, IFNgamma and IL-4 during the acute and convalescent phases of RSV bronchiolitis in 50 hospitalized children 13 months of age and confirmed RSV-positive by immunofluorescence of nasopharyngeal secretions. Twenty-seven uninfected children served as agematched controls. One year postdischarge follow-up data were collected on episodes of cough and recurrent wheeze. Whole blood culture stimulated with lipopolysaccharide and IFN-gamma was used to induce maximal monocyte IL-10 production, and phytohemagglutinin was added to culture to induce lymphocyte cytokine production of IFN-gamma and IL-4. Supernatant concentrations of IL-10, IL-12, IL-4 and IFN-gamma were

measured by enzyme-linked immunosorbent assay (ELISA). Findings indicated that during the acute phase of RSV disease, patients produced significantly lower concentrations of IL-12 than did control subjects. During convalescence IL-12 responses in RSV-infected patients increased to levels that did not differ significantly from those of the control group.11 During the acute phase of RSV disease, lower levels of both IL-4 and IFN-gamma were observed in patients vs. controls, whereas during convalescence both responses returned to levels similar to those of the control subjects. Additionally differences in neither IL-4 and IFN-gamma responses nor in IFN-gammaIL-4 ratios were found between subsequent wheezing and nonwheezing infants.11 In contrast to IL-12 the amount of IL-10 produced during the acute phase of RSV illness did not differ significantly from those of the control subjects. However, during the convalescent phase IL-10 production was significantly higher than in the acute phase (P 0.001) and when compared with that of control subjects (P 0.001). Further, IL-10 responses during the convalescent phase were significantly higher in infants with subsequent recurrent wheezing than in those without recurrent wheezing (P 0.006) and in infants with and without physician-diagnosed asthma (P 0.004) (Fig. 3).11 Moreover an augmented monocyte IL-10 response during the convalescent phase of RSV bronchiolitis positively correlated with the development of recurrent wheeze during a 1-year follow-up interval and was significantly associated with the number of wheezing episodes. Direct infection, local production of cytokines and other mediators by epithelial cells and macrophages and the potential difference in local vs. systemic immune responses might explain the mechanisms by which peripheral blood mononuclear cell cytokine responses alter during RSV lower respiratory tract infection. This raises the possibility that increased IL-10 production in vivo may suppress antigen presentation by pulmonary macrophages, promote decreased antiviral immunity and permit progression of upper respiratory tract infection to lower respiratory tract illness accompanied by wheezing and lower airway inflammation.11 In a related study Bont et al.14 further explored the relationship between specific monocyte-produced cytokines and severity of RSV bronchiolitis. Thirty infants 13 months of age with confirmed RSV infection needed ventilatory support for respiratory insufficiency. Blood samples were obtained from each patient and cultured with lipopolysaccharide and IFN-gamma to induce monocyte IL-10, IL-12 and IL-8 production. Cytokine concentrations were measured by ELISA.

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FIG. 3. Response during the convalescent phase in infants with recurrent wheezing and in those without recurrent wheezing. Relationship between ex vivo IL-10 production and number of wheezing episodes during a 1-year follow-up period. Blood was obtained from patients with RSV bronchiolitis 3 to 4 weeks after admission (convalescent phase). Data represent individual values. Reprinted with permission from Bont et al.11

FIG. 4. Relationship of genotype to in vitro production of IL-8. IL-8 production against time for each 251 genotype. The concentrations, corrected for total white blood cell (WBC) count, are geometric means; error bars, 95% confidence intervals. Reprinted from Hull et al.16 with permission from the BMJ Publishing Group.

The study found that chronologic age, postconceptional age and gender bore no relationship to IL-12 production. However, IL-12 response at the initiation of ventilatory assistance was inversely related to duration of mechanical ventilation, suggesting that the lower the monocyte IL-12 value during acute RSV infection, the greater is the disease severity.14 In contrast to IL-12 neither IL-8 nor IL-10 levels predicted duration of mechanical ventilation. Both IL-12 production and the mean ventilation index appeared to be independent predictors of duration of mechanical ventilation (P 0.001 and P 0.013, respectively). Investigators postulated that respiratory syncytial virus itself could prevent the initiation of an effective antiviral immune response by inhibiting IL-12 production, suggesting that cellmediated immunity participates in both induction of and recovery from RSV lower respiratory tract disease.14
GENETIC INFLUENCE AND SUSCEPTIBILITY FOR RSV INFECTION

The advent of the Human Genome Project has remarkably increased our capacity to study genetic polymorphisms and their role in human disease. The simplest class of polymorphism is a substitution of one nucleotide for another. Single nucleotide polymorphisms occur more frequently than any other type of polymorphism and thus can serve as relatively stable markers when applied to genotype-phenotype associations in the pathophysiology of asthma. Tests of

genetic associations with single nucleotide polymorphisms are based primarily on linkage disequilibrium to investigate the genetic determinants of complex human diseases.15 Hull et al.16 investigated the genetic correlates of disease severity in 83 children hospitalized for RSV bronchiolitis. DNA sequencing on whole blood samples of confirmed RSV-positive infants and healthy controls was performed to determine whether or not a genetic component contributed to RSV pathogenetic processes. Neutrophils comprise the dominant cell type found in the BALF of infants with RSV bronchiolitis, and increased levels of IL-8, a potent neutrophil chemoattractant, distinguish lower respiratory tract infection with RSV. The concentration of IL-8 was measured by ELISA from blood samples of 50 healthy controls. Genomic DNA identified a single nucleotide polymorphism at 251 relative to the transcription start site of IL-8, with nucleotide A in 31 of 72 and nucleotide T in 41 of 72 chromosomes.16 Genotyping of the IL-8-251 polymorphism from 50 healthy blood donors revealed that 12 were AA, 9 were TT and 29 were AT. IL-8 production tended to be highest for the AA group and least for the TT group. The IL-8-251A allele was transmitted to 62% (51) of the affected infants (P 0.014).16 Of 117 families associated with a clinical diagnosis of infantile RSV bronchiolitis, 83 were informative for transmission disequilibrium testing (TDT), with at least one parent heterozygous for the IL-8-251 polymorphism. TDT analyzes whether the transmission of

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an allele to probands from parents who are heterozygous at the genetic marker under investigation departs significantly from an expected value of 50%. Of the 83 infants in families informative for the IL-8-251 polymorphism, 53 (64%) required oxygen therapy, with a treatment duration of 2 days in 66% (35). Seven required mechanical ventilation. Transmission of the IL-8-251 polymorphisms increased to 65% (34) in the families with infants who required supplemental oxygen, to 71% (25) in families of those who required more than 2 days of oxygen therapy and to 70% (5) in families whose infant required ventilatory assistance.16 Excluding the concomitant risk factors of older siblings, prematurity and congenital cardiac disease, the percentage of IL-8-251A transmission increased further to 78%. The findings of Hull et al.16 suggested that the IL-8-251A allele is associated with increased IL-8 production and that elevated IL-8 levels may represent a risk factor for subsequent development of bronchiolitis. Data from this study implicated the IL-8-251A allele with severity of RSV bronchiolitis, as evidenced by supplemental oxygen requirement and duration of oxygen therapy in affected infants. Use of the TDT permitted estimation of a genetic susceptibility to infectious disease in families and provided a possible link between a single nucleotide polymorphism, severe RSV lower respiratory tract infection and subsequent persistent wheezing illness, in particular in individuals with no other risk factors for RSV bronchiolitis (Fig. 4).16
CONCLUSION

pulmonary and immune systems, chronologic age and time of disease onset to exert its greatest influence on long term outcomes of an acute infectious process.
REFERENCES
1. Redd SC. Asthma in the United States: burden and current theories. Environ Health Perspect 2002;110:557 60. 2. Smith DH, Malone DC, Lawson KA, et al. A national estimate of the economic costs of asthma. Am J Respir Crit Care Med 1997;156:78793. 3. Martinez FD. Development of wheezing disorders and asthma in preschool children. Pediatrics 2002;109:3627. 4. Busse WW, Banks-Schlegel SP, Larsen GL. Effects of growth and development on lung function. Am J Respir Crit Care Med 1997;156:314 9. 5. Martinez FD, Wright AL, Taussig LM, et al. Asthma and wheezing in the first six years of life. N Engl J Med 1995;332: 133 8. 6. Zeiger RS, Dawson C, Weiss S, and the Childhood Asthma Management Program (CAMP) Research Group. Relationships between duration of asthma and asthma severity among children in the Childhood Asthma Management Program (CAMP). J Allergy Clin Immunol 1999;103:442 4. 7. Stein RT, Holberg CJ, Morgan WJ, et al. Peak flow variability, methacholine responsiveness, and atopy as markers for detecting different wheezing phenotypes in childhood. Thorax 1997;52:946 52. 8. Wilson NM, Bridge P, Silverman M. Bronchial responsiveness and symptoms in 5 6 year old children: a comparison of a direct and indirect challenge. Thorax 1995;50:339 45. 9. Nafstad P, Magnus P, Jaakkola JJK. Early respiratory infections and childhood asthma. Pediatrics 2000;106:e38. 10. Krawiec ME, Westcott JY, Chu HW, et al. Persistent wheezing in very young children is associated with lower respiratory inflammation. Am J Respir Crit Care Med 2001;163: 1338 43. 11. Bont L, Heijnen CJ, Kavelaars A, et al. Monocyte IL-10 production during respiratory syncytial virus bronchiolitis is associated with recurrent wheezing in a one-year follow-up study. Am J Respir Crit Care Med 2000;161:1518 23. 12. Kimpen JLL. Respiratory syncytial and asthma: the role of monocytes. Am J Respir Crit Care Med 2001;163:S13. 13. Roman M, Calhoun WJ, Hinton KL, et al. Respiratory syncytial virus infection in infants is associated with predominant Th-2-like response. Am J Respir Crit Care Med 1997; 156:190 5. 14. Bont L, Kavelaars A, Heijnen CJ, et al. Monocyte interleukin-12 production is inversely related to duration of respiratory failure in respiratory syncytial virus bronchiolitis. J Infect Dis 2000;181:16725. 15. Palmer LJ, Cookson W OCM. Using single nucleotide polymorphisms as a means to understanding the pathophysiology of asthma. Respir Res 2001;2:10212. 16. Hull J, Thomson A, Kwiatkowski D. Association of respiratory syncytial virus bronchiolitis with the interleukin 8 gene region in UK families. Thorax 2000;55:10237.

Genetic predisposition, neurogenic inflammation, virus-induced activation of cell-mediated immunity and elaboration of proinflammatory cytokines represent only a few of the interactive components that may combine forces in the development of respiratory diseases of childhood, in particular RSV. Underpinning a dynamic system of illness and recovery, genetic susceptibility of the pediatric host to postbronchiolitic sequelae of recurrent wheezing and asthma may depend on the relative immaturity of