Recurrent wheezing after respiratory syncytial virus or non-respiratory syncytial virus bronchiolitis in infancy: a 3-year follow-up

Background:  Recent studies have suggested that rhinovirus-associated early wheezing is a greater risk factor for development of recurrent wheezing in children than is early wheezing associated with respiratory syncytial virus (RSV). We determined the development of recurrent wheezing in young children within 3 years after hospitalization for RSV or non-RSV bronchiolitis.
Methods:  We identified retrospectively all children <2 years of age who were admitted to Turku University Hospital because of bronchiolitis in the months of August–December during 1988–2001. The primary outcome was recurrent wheezing that required long-term asthma medication. Data on asthma medications of the individual children were derived from the Social Insurance Institution of Finland.
Results:  Within the first year after hospitalization, 36 of 217 (16.6%) children with non-RSV bronchiolitis developed recurrent wheezing, compared with five of 199 (2.5%) children with RSV bronchiolitis [relative risk (RR) 6.6; 95% confidence interval (CI) 2.6–16.5]. The rates of recurrent wheezing were significantly increased in the non-RSV group also within 2 years (RR 2.9; 95% CI 1.7–5.1) and 3 years (RR 3.4; 95% CI 2.0–5.7) after hospitalization. The increased risk of recurrent wheezing in children with non-RSV-associated bronchiolitis was observed both in boys and girls at all time points of the 3-year follow-up, and it was not explained by the age difference between the RSV and non-RSV groups or any confounding seasonal factors.
Conclusion:  Children hospitalized with bronchiolitis caused by other viruses than RSV develop recurrent wheezing at substantially higher rates during a 3-year follow-up period than do children with RSV-induced bronchiolitis.     

Severe respiratory syncytial virus infection in early life is associated with increased type 2 cytokine production in Gambian children

BACKGROUND: Severe respiratory syncytial virus (RSV) infection in early childhood has been associated with subsequent wheezing and atopy. The aim of this study was to test if severe RSV infection in early life was associated with an increase in type 2 cytokine production and atopy in Gambian children 5 years later. METHODS: A cohort of children with severe RSV infection during the first year of life ('cases', n = 66) and without ('controls', n = 122) was followed-up at 5 years of age. Immediate hypersensitivity to common allergens, airway reactivity, serum IgE concentration and the production of IFN-gamma, IL-5 and IL-13 by lymphocytes activated in vitro with RSV F-G or control antigens was determined. RESULTS: After adjustment for confounders, cases produced significantly higher concentrations of IL-13 in response to RSV F-G and of IL-5 and IL-13 in response to tuberculin. Cases were more likely to have presented with a wheezy lower respiratory tract infection in the first 3 years of life (adjusted odds ratio = 9.9; 95% CI 1.6-61.0), but not thereafter. Cases and controls had similar skin response to allergens, airway reactivity and serum IgE concentrations. CONCLUSION: Severe RSV infection in early life is associated with a higher production of type 2 cytokines in Gambian children at 5 years of age. However this does not appear to result in increased risk of atopy or clinical allergy at that age.     

Prednisolone reduces recurrent wheezing after a first wheezing episode associated with rhinovirus infection or eczema

BACKGROUND: Rhinovirus-induced early wheezing has been suggested as a new important risk factor for recurrent wheezing. OBJECTIVE: We sought to investigate the risk factors for recurrent wheezing and to determine post hoc the efficacy of prednisolone in risk groups. METHODS: We followed for 1 year 118 children (median age, 1.1 years) who had had their first episode of wheezing and had participated in a trial comparing prednisolone with placebo in hospitalized children. Demographics and laboratory data were obtained at study entry. The follow-up outcome was recurrent wheezing (3 physician-confirmed episodes). RESULTS: Recurrent wheezing was diagnosed in 44 (37%) children. Independent risk factors were age < 1 year, atopy, and maternal asthma. The probability of recurrent wheezing was higher in rhinovirus than respiratory syncytial virus (RSV)-affected children among placebo recipients (hazard ratio, 5.05; 95% CI, 1.00-25.41). Prednisolone decreased the probability of recurrent wheezing in children with eczema (0.15; 95% CI, 0.04-0.63) but not in those without eczema (1.89; 95% CI, 0.83-4.29; P = .007 for interaction). Prednisolone was associated with less recurrent wheezing in the rhinovirus group (0.19; 95% CI, 0.05-0.71), but not in the RSV (2.12; 95% CI, 0.46-9.76) or in the RSV/rhinovirus-negative groups (2.03; 95% CI, 0.83-5.00; P = .017 for interaction). CONCLUSION: Rhinovirus-induced early wheezing is a major viral risk factor for recurrent wheezing. Prednisolone may prevent recurrent wheezing in rhinovirus-affected first-time wheezers. The presence of eczema may also influence the response to prednisolone. CLINICAL IMPLICATIONS: A prospective trial is needed to test the hypothesis that prednisolone reduces recurrent wheezing in rhinovirus-affected wheezing children.     

An Interaction of LPS and RSV Infection in Augmenting the AHR and Airway Inflammation in Mice

Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory tract infection (LRTI) in children under 5 years of age, especially infants with severe bronchiolitis. Our preliminary clinical experiments showed that bacterial colonization was commonly observed in children with virus-induced wheezing, particularly in those with recurrent wheezing, suggesting that bacterial colonization with an accompanying viral infection may contribute to disease severity. In most cases, RSV-infected infants were colonized with pathogenic bacteria (mainly Gram-negative bacteria). LPS is the main component of Gram-negative bacteria and acts as a ligand for Toll-like receptor 4 (TLR4). Relevant studies have reported that the TLR family is crucial in mediating the link between viral components and immunologic responses to infection. Of note, TLR4 activation has been associated with disease severity during RSV infection. In the present study, we identified that LPS aggravated RSV-induced AHR and airway inflammation in BALB/c mice using an RSV coinfection model. We found that the airway inflammatory cells and cytokines present in BALF and TRIF in lung tissue play a role in inducing AHR and airway inflammation upon RSV and bacteria coinfection, which might occur through the TRIF-MMP-9-neutrophil-MMP-9 signalling pathway. These results may aid in the development of novel treatments and improve vaccine design.     

Bidirectional interactions between viral respiratory illnesses and cytokine responses in the first year of life

BACKGROUND: Viral infections are the major cause of acute wheezing illnesses in childhood. Variations in immunologic responses at birth may be determinants of the risk of acquiring these illnesses. OBJECTIVES: To determine the immunologic risk factors for virus-induced wheezing in high-risk infants. METHODS: The study involves 285 children with a parental history of asthma and/or respiratory allergies. Mononuclear cells obtained at birth (umbilical cord blood) and at 1 year of age were incubated with phytohemagglutinin, respiratory syncytial virus, or rhinovirus, and supernatants were analyzed for IL-5, IL-10, IL-13, and IFN-gamma. Nasal secretions obtained at well child visits and during respiratory illnesses were analyzed for common respiratory viruses. RESULTS: Respiratory syncytial virus-induced wheezing was associated with reduced phytohemagglutinin-induced IL-13 responses (medians, 213 vs 304 pg/mL; P = .026) from cord blood cells, and similar trends were found for wheezing in general. Furthermore, median IL-13 responses diminished by 28% in non-wheezing children by age 1 year, versus only 3% in wheezing children (P = .013). Children with > or =2 episodes of wheezing had lower phytohemagglutinin-induced IFN-gamma responses and were less likely to have rhinovirus-induced IFN-gamma responses at birth (P < .05). Finally, children with measurable cord blood IFN responses to respiratory syncytial virus were less likely to wheeze in their first year (odds ratio, 0.43 [0.23, 0.79]). CONCLUSION: In children with a family history of allergies and/or asthma, mononuclear cell phytohemagglutinin-induced IL-13 and virus-induced IFN-gamma responses at birth are indicative of the risk for wheezing in the first year of life.     

The role of respiratory virus infections in childhood asthma inception

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

Transmission of respiratory syncytial virus at the paediatric intensive-care unit: a prospective study using real-time PCR

Transmission of respiratory syncytial virus (RSV) from children with lower respiratory tract infection (LRTI) at a paediatric intensive-care unit (PICU) was examined using a highly sensitive real-time PCR. Twenty-four children with RSV LRTI were admitted during the study period (total days of potential transmission: 239). Fortyeight RSV-negative patients were followed up for RSV acquisition every 5 days (total days of exposure: 683). No single RSV transmission was documented with this highly sensitive diagnostic method. Therefore, routine infection control measures of LRTI patients seem to be adequate to prevent RSV transmission at the PICU.     

Serum concentrations of interferon-γ and intercellular adhesion molecule-1 eight years after an early respiratory syncytial virus infection

BACKGROUND: Respiratory syncytial virus (RSV) infection may influence the development of recurrent wheezing and atopy, but the mechanisms are unclear. OBJECTIVE: The purpose was to evaluate serum concentrations of soluble intercellular adhesion molecule-1 (sICAM-1), CD14, IgE, IL-5 and IFN-gamma in children 6-10 years after an RSV infection and their correlation with subsequent asthma and atopy. METHODS: Fifty-one subjects admitted to hospital for RSV infection during the first year of life and controls matched for birth date and sex underwent clinical examinations including lung function, skin prick and blood tests. RESULTS: The RSV subjects had significantly higher serum concentrations of IFN-gamma and sICAM-1 than the controls (for IFN-gamma 224.9 pg/mL (standard deviation (SD) 271.3) vs. 187.1 pg/mL (372.9), difference 37.8 pg/mL, 95% confidence interval (CI) -90.3 to 166.0, P = 0.05; for sICAM-1 170.2 ng/mL (SD 63) vs. 147.8 ng/mL (SD 57), difference 22.4 ng/mL, 95% CI -1.4 to 46.1, P = 0.04). The RSV subjects with asthma had significantly higher concentrations of IFN-gamma than the controls with asthma, and the RSV subjects with wheezing during the previous 12 months had significantly higher concentrations of both IFN-gamma and sICAM-1 than the controls with wheezing. CONCLUSIONS: Children hospitalized for RSV infection in infancy still differ in IFN-gamma and sICAM-1 production 6-10 years after the infection. The data suggest that the pathomechanism of asthma and wheezing after an early RSV infection may be different from that of children without an early RSV infection.     

Genetic predisposition to wheeze following respiratory syncytial virus bronchiolitis

BACKGROUND: The nature of the association between severe respiratory syncytial virus (RSV) bronchiolitis and subsequent wheezing remains unknown. In a previous study, we showed that genetic variation in the IL-8-promoter region is associated with susceptibility to severe bronchiolitis. OBJECTIVE: The purpose of this study was to assess the association between wheezing post-bronchiolitis and the genetic variant of IL-8 gene. METHODS: We collected data from 134 children who had suffered from bronchiolitis, enrolled in our previous study. The occurrence of wheezing post-bronchiolitis was recorded from a questionnaire sent by post. The association between the genotype and wheezing phenotype was assessed by family-based and case-control approaches. RESULTS: Family-based association showed that the IL-8 variant was transmitted significantly more often than expected in the children who wheezed after the episode of bronchiolitis (transmission=56%, P=0.02). This effect was not observed in the group of children who had bronchiolitis but did not go on to wheeze. Moreover, the variant was significantly more frequent in post-bronchiolitis wheezers compared with the general population (odds ratio=1.6, 95% confidence interval 1.0-2.6). CONCLUSION: These preliminary results suggest that there is a genetic predisposition to wheeze following severe RSV bronchiolitis.     

Rhinovirus illnesses during infancy predict subsequent childhood wheezing

BACKGROUND: The contribution of viral respiratory infections during infancy to the development of subsequent wheezing and/or allergic diseases in early childhood is not established. OBJECTIVE: To evaluate these relationships prospectively from birth to 3 years of age in 285 children genetically at high risk for developing allergic respiratory diseases. METHODS: By using nasal lavage, the relationship of timing, severity, and etiology of viral respiratory infections during infancy to wheezing in the 3rd year of life was evaluated. In addition, genetic and environmental factors that could modify risk of infections and wheezing prevalence were analyzed. RESULTS: Risk factors for 3rd year wheezing were passive smoke exposure (odds ratio [OR]=2.1), older siblings (OR=2.5), allergic sensitization to foods at age 1 year (OR=2.0), any moderate to severe respiratory illness without wheezing during infancy (OR=3.6), and at least 1 wheezing illness with respiratory syncytial virus (RSV; OR=3.0), rhinovirus (OR=10) and/or non-rhinovirus/RSV pathogens (OR=3.9) during infancy. When viral etiology was considered, 1st-year wheezing illnesses caused by rhinovirus infection were the strongest predictor of subsequent 3rd year wheezing (OR=6.6; P < .0001). Moreover, 63% of infants who wheezed during rhinovirus seasons continued to wheeze in the 3rd year of life, compared with only 20% of all other infants (OR=6.6; P < .0001). CONCLUSION: In this population of children at increased risk of developing allergies and asthma, the most significant risk factor for the development of preschool childhood wheezing is the occurrence of symptomatic rhinovirus illnesses during infancy that are clinically and prognostically informative based on their seasonal nature.     

Uteroglobulin-related protein 1 and severity of respiratory syncytial virus infection in children admitted to hospital

There are several reports suggesting that genetic factors contribute to the severity of infection with the respiratory syncytial virus (RSV). Infants hospitalized with lower respiratory tract infection (LRTI) due to RSV are at a significantly increased risk for both recurrent wheezing and childhood asthma. Uteroglobin-related protein 1 (UGRP1) is a secretory protein expressed in the airways, and speculated to have anti-inflammatory activity. The presence of the -112G/A polymorphism in the UGRP1 promoter was found to have a significant correlation with asthma phenotype. Also plasma UGRP1 levels were shown to be associated both with this polymorphism and the severity of asthma. The study population consisted of 62 previously healthy infants, ≤12 months of age, who were hospitalized with RSV LRTI, and a control group of 99 healthy adults. Genotyping was performed by restriction fragment length polymorphism. UGRP1 serum levels were determined using ELISA. There were no significant differences in the overall distribution of UGRP1 -112G/A polymorphism genotypes or alleles between the hospitalized infants and healthy adults. A comparison of serum UGRP1 concentration measured at the time of admission and discharge between patients with and without the -112A allele revealed that there was no relation between the presence of the -112A allele and serum UGRP1 in hospitalized infants with RSV infection. Furthermore, there was no relationship between severity of RSV infection and genotype or serum UGRP1 concentration. These results suggest that UGRP1 does not have a major role in the development of severe RSV infection.     

Total serum IgE and its association with asthma symptoms and allergic sensitization among children.

BACKGROUND: Asthma and wheezing during childhood are associated with elevated total serum IgE and with allergic sensitization to local aeroallergens. However, little is known about the longitudinal relationship between total serum IgE and the development of wheezing and allergic sensitization during childhood. OBJECTIVE: The purpose of our investigation was to determine the relationship between total serum IgE and the development of wheezing and allergic sensitization in childhood. METHODS: Our study subjects were participants in the Tucson Children's Respiratory Study who underwent an IgE measurement in at least 1 of 3 surveys (at years 1, 6, and 11) and complete allergy skin tests during the latter 2 surveys. The children's phenotypes were categorized on the basis of skin test response (never, early, and late) and wheezing status (never, early, late, and persistent). Repeated-measures analyses were used, allowing subjects to be included who had unequal numbers of IgE observations (a total of 263 boys and 277 girls). RESULTS: We found that total serum IgE levels track with age: subjects with high serum IgE levels less than 1 year old continued to have high IgE levels at ages 6 and 11 years. Both persistent wheezing and early sensitization were associated with high serum IgE levels at all ages. Boys who had late or persistent wheezing or who were sensitized early or late had high serum IgE levels as early as age 9 months, whereas only girls with persistent wheezing and early sensitization had elevated IgE levels at that age. Children who wheezed only in the first years of life and not after (ie, those with early wheezing) had serum IgE levels that were not different from those of nonwheezing children. CONCLUSION: On the basis of these findings we conclude that although total serum IgE tracks with age, children who are predisposed to persistent wheezing and early sensitization to local aeroallergens already have high levels of IgE at age 9 months. This suggests that the predisposition to respond to environmental stimuli through high levels of IgE precede early allergic sensitization, indicating that there may be a common defect in the development of the immune system involving IgE production and early allergic sensitization.     

Functional polymorphism of the promoter region of the prostacyclin synthase gene and severity of RSV infection in hospitalized children

Prostaglandin I(2) (PGI(2)) protects against RSV-induced illness in mice. A variable-number tandem repeat (VNTR) polymorphism has been detected in the promoter region of the PGI(2) synthase (PGIS) gene. We sought to determine if PGI(2) concentrations or polymorphisms of the PGIS gene correlate with severity of RSV lower respiratory tract infections (LRTI) in human infants. VNTR polymorphisms were studied in 81 previously healthy children between birth and 12 months of age who were hospitalized for LRTI due to RSV and 98 healthy adult control subjects. The severity of RSV infection was quantified using a clinical scoring system, and infant urine samples were collected during the acute illness for measurement of the urinary metabolite of PGI(2). There were no significant differences in the overall distribution of alleles and genotypes between infants with RSV LRTI and the control subjects. The severity of RSV infection significantly inversely correlated with urinary PGI(2) metabolite concentrations. The urinary PGI(2) metabolite concentration correlated with the number of VNTR. The presence of a genotype with a low number VNTR repeats significantly correlated with the most severe RSV LRTI, and genotypes with the highest number of VNTR correlated with the least severe RSV LRTI. A functional polymorphism in the promoter region of the PGIS gene is associated with both significant differences in urinary PGI(2) concentrations during RSV LRTI, and severity of RSV infection in previously healthy infants.     

Decreased interferon-gamma response in respiratory syncytial virus compared to other respiratory viral infections in infants

An inappropriate interferon-gamma response has been implicated in the pathogenesis of severe respiratory syncytial virus (RSV) lower respiratory tract illness (LRTI). To assess whether this is unique for RSV primary LRTI compared to a first non-RSV LRTI, intracellular interferon-gamma was determined by flow cytometry in peripheral blood mononuclear cells from 32 infants with a primary RSV infection, 28 with a first non-RSV LRTI due to adenoviral, parainfluenzaviral and rhinoviral infection and 13 healthy infants. Interferon-gamma responses were increased significantly during adenoviral, parainfluenzaviral and the majority of the rhinoviral infections, but remained low during RSV and severe rhinoviral infection. Low interferon-gamma responses were associated with a more severe clinical course of LRTI. This indicates that depending on the nature of the viral pathogen, respiratory virus infections in infants differ significantly with regard to the quantity of the interferon-gamma production and that this may contribute to the clinical course of the disease.     

Respiratory syncytial virus associated illness in high-risk children and national characterisation of the circulating virus genotype in South Africa.

BACKGROUND: There is limited information about respiratory syncytial virus (RSV) in high-risk children from developing countries or on the genotype characterisation of the circulating virus. OBJECTIVE: To define the proportion of children with RSV associated lower respiratory tract infections (LRTI) that had risk factors for severe disease and to genotype the circulating RSV strains across the country. STUDY DESIGN: A prospective study was performed in four distinct regions. During April 2000-December 2000 (period 1), all children, with LRTI or without underlying high risk factors for severe RSV disease were enrolled. During January to September 2001 (period 2), only children with LRTI with underlying high risk factors were enrolled. Nasopharyngeal aspirates were evaluated for RSV infection using an ELISA test. RSV isolates were also subtyped and genotyped. RESULTS: Fifty three (24%) of 220 children enrolled during period 1 had risk factors for severe RSV disease; in addition to which a further 38 high-risk children were enrolled during 2001. RSV was isolated from 16 (30%) of 53 and 37 (22%) of 167 high-risk and non-high risk children, respectively, P=0.31. High-risk children were more likely to require intensive unit care (25 vs. 2.7%, P=0.02) and were also more likely to be hospitalised for a longer duration (median 7 vs. 5 days, P=0.06) than non high-risk infants. Overall (periods 1 and 2), RSV was isolated from 34 (37.4%) of the 91 high-risk infants enrolled. Among high-risk children, those from whom RSV was isolated were more likely to require hospitalisation (73.5 vs. 54.4%, P=0.07) and admission to an intensive care unit (14.7 vs. 1.8%, P=0.03) than those from whom RSV was not isolated. Of 40 isolates subtyped during period one, 92.5% were subtype A. Further, 27 (83.3%) of 30 subtype A isolates genotyped during period 1 clustered with GA2. CONCLUSION: RSV is an important cause of LRTI among high-risk infants in a developing country such as South Africa. For the season in question, the genotype that was dominant in Johannesburg was isolated throughout the country, suggesting that successful genotypes may have the ability to spread nationwide.     

Regular pattern of respiratory syncytial virus and rotavirus infections and relation to weather in Stockholm, 1984–1993

Objective: To seek the possible epidemiologic relationship between the two dominant pediatric infectious agents, respiratory syncytial virus (RSV) and rotavirus, and to analyze the relationship of RSV to influenza virus infections and climate.
Methods: In the laboratory register, we retrospectively identified pediatric cases less than 5 years of age from the period 1984–93 (including the winter of 1994). RSV was diagnosed by immunofluorescence in nasopharyngeal samples and rotavirus infections by electron microscopy of feces.
Results: We observed a regular and significant pattern of early RSV epidemics (December to February), alternating every other year with later ones (March to April). There were twice as many hospital admissions during early compared to late epidemics. There was a similar but reverse pattern of early and late rotavirus seasons. Influenza A virus outbreaks occurred during the same period as early RSV epidemics. Several weather factors, such as temperature, precipitation, wind force and humidity were analyzed in relation to RSV epidemics without disclosing an important relationship. Cloudiness was, however, found to be associated with RSV peaks.
Conclusions: The possibility of predicting RSV epidemics may be useful for medical planning.     

The immunobiology of respiratory syncytial virus infection

There is increasing evidence that young children with severe respiratory syncytial virus (RSV)-induced bronchiolitis are at high risk of developing allergy and asthma during their later life. The determinants for this association are not well understood. Current studies suggest that both genetic backgrounds and unique characteristics of the virus play critical roles in determining the type of immune responses to RSV infection, leading to altered regulation of airway tone associated with wheezing. In susceptible subjects, RSV may either enhance the Th2 immune response or decrease the Th1 immune response. This altered Th1/Th2 cytokine response associated with RSV infection is not commonly observed among other RNA viruses, suggesting that RSV may have unique characteristics. Multiple clinical studies support the link between severe RSV bronchiolitis and the subsequent development of allergy and asthma. This link will be further tested by the ongoing large studies on the effect of early RSV intervention on the development of allergy. The administration of palivizumab, an anti-RSV monoclonal antibody, seems to be helpful for RSV prevention and treatment at early stage. There are no effective RSV vaccines available, and this is, at least in part, because of the poorly understood immunology and pathogenesis of RSV disease. The use of experimental animal models has led to a better, but not sufficient, understanding of the immunologic basis of RSV-induced disease, particularly asthma. Further studies on the immunopathology of RSV infection with animal models, including the nonhuman primate models, may help develop effective RSV vaccines.     

Moderate local and systemic respiratory syncytial virus-specific T-cell responses upon mild or subclinical RSV infection

Respiratory syncytial virus (RSV) infections are a major cause of severe respiratory disease in infants. It has been shown that there is an increased frequency of childhood wheezing in ex-bronchiolitic preteen children. This was postulated to be mediated by a vigorous virus-specific Th2 response influencing the further development of the immune system. Little is known about the possible role of the immune response to clinically mild RSV infections in this respect. We have studied the RSV-specific cellular immune response in infants with a laboratory-confirmed RSV upper respiratory tract infection (URTI; n = 13, mean age 12 months, range 2-22 months) in comparison with infants with non-RSV mediated URTI (n = 9, mean age 9.3 months, range 4-18 months) or infants with severe RSV bronchiolitis (n = 11, mean age 2.3 months, range 1-6 months). RSV-specific cytokine-producing cells were enumerated using the ELISPOT method in peripheral blood mononuclear cells and nasal brush T-cells, collected during the acute and convalescent phase of the infection. Mixed Th1 (IFN-gamma) and Th2 (IL-4 and IL-13) responses were detected in all three groups. Frequencies of RSV-specific T-cells were lower in both URTI groups than in the RSV bronchiolitis group, and not significantly different between the RSV URTI and the non-RSV URTI group. The absence of vigorous virus-specific Th2 responses upon mild RSV infection does not support the hypothesis that these infections influence the development of the immune system and that they predispose for the development of atopic disease.