Eosinophil activity in infants hospitalized for wheezing and risk of persistent childhood asthma.

Eosinophilic inflammation has a central role in the pathogenesis of asthma. We aimed to elucidate whether elevated blood eosinophil count (B-EOS), eosinophil cationic protein in serum (S-ECP) or in nasopharyngeal aspirate (NPA-ECP) predict later asthma after hospitalization for wheezing in infancy. In 1992-1993, 100 infants aged <24 months were hospitalized for wheezing associated with respiratory infection. B-EOS, S-ECP and NPA-ECP were measured on admission. Asthma status was evaluated at the follow-up visits at the median ages of 4.0, 7.2 and 12.3 yr. Twenty (25%) of 81 children had asthma at all three visits and were considered to have persistent childhood asthma (PCA). Children with B-EOS >or= 0.450 x 10(9) cells/l had a 2.9-fold PCA risk compared with other children. The risk was 6.1-fold when S-ECP was >or=20.0 microg/l and 6.7-fold when NPA-ECP was >or=815.0 ng/g. By these cut-off limits, all these markers were specific (75-93%), but not very sensitive (30-58%) in predicting PCA. At least one marker was elevated in 75% of the children with PCA. The respective figure for NPA-ECP alone was 58%. In adjusted analyses, only elevated NPA-ECP was an independent risk factor for PCA (OR 4.09). In conclusion, eosinophil activity in early life predicts the development of childhood asthma after hospitalization for wheezing in infancy. The results highlight NPA-ECP as an independent predictor of the persistence of asthma at school age.

Use of inhaled corticosteroids decreases hospital admissions for asthma in young children.

BACKGROUND: An active use of inhaled corticosteroids for asthma has been associated with less asthma exacerbations and hospital admissions in children aged more than 2 years. The present study aimed to investigate hospital admission rates in young children from two populations in relation to the age-specific use of maintenance medication for asthma. METHODS: Annual data on children aged less than 24 months treated for asthma, including data on the use of maintenance medication based on the purchases of prescribed medications, and annual numbers of admissions to hospital and proportions of readmissions, were collected from 1995 to 1999 in two provinces of Finland. The inclusion criteria, three or more doctor-diagnosed wheezing episodes, were individually checked by the authors in each case. The mean number of children aged less than 24 months during the years of the study was 5490 in Kuopio and 9914 in Oulu area. RESULTS: In the Kuopio area, during the years of the study, 16.5/1000 children aged less than 24 months were on maintenance medication for asthma, and 90% of them were receiving inhaled corticosteroids. In the Oulu area, the respective figures were 13.5/1000 (P<0.001) and 99%. The average admission rate was 7.9/1000 in the Kuopio area and 8.7/1000 in the Oulu area (P<0.05). The readmissions indicated the higher admission rates in the Oulu (40% of all admissions) than in the Kuopio (28%) area (P<0.01). CONCLUSION: Active use of maintenance therapy by inhaled corticosteroids was associated with a decreased need of hospital treatment in young children <24 months old with asthma, mainly because of less readmissions.

Wheezing due to rhinovirus infection in infancy: Bronchial hyperresponsiveness at school age.

BACKGROUND: Characteristics related to decreased lung function and increased bronchial responsiveness after early childhood wheezing requiring hospitalization are not fully established. METHODS: Seventy-nine children with wheezing requiring hospitalization at age <2 years were prospectively followed up and re-investigated at age 5.6-8.8 years when the measurements of baseline lung function and bronchial responsiveness to exercise were performed. RESULTS: At early school age, 23% of children had decreased lung function, and 13% had increased bronchial responsiveness to exercise. Predictors of decreased lung function were maternal history of smoking during pregnancy (odds ratio [OR], 12.8; 95% confidence interval [CI]: 1.2-139.6), parental history of asthma (OR, 4.3; 95%CI: 1.1-17.1), and female gender (OR, 4.0; 95%CI: 1.2-13.7). Increased bronchial responsiveness was associated with rhinovirus infection-induced wheezing in infancy (OR, 6.5; 95%CI: 1.2-36.3), and early cat or dog exposure leading to sensitization (OR, 26.6; 95%CI: 1.3-525.2). Inhaled anti-inflammatory therapy was common in children with rhinovirus infection-induced wheezing in infancy (n = 13/19; P = 0.001 vs children with other/no confirmed virus infection etiology for wheezing in infancy, n = 16/60), which may have improved lung function and attenuated bronchial responsiveness in them. CONCLUSIONS: After early childhood wheezing requiring hospitalization, one-fourth of children will have decreased lung function and one-eighth of children will show increased bronchial responsiveness at school age. Gender, heredity of asthma, and antenatal exposure to tobacco smoke are predictors of decreased lung function, whereas rhinovirus infection etiology of wheeze and early animal exposure leading to sensitization are associated with increased bronchial responsiveness later in childhood.

Responses to inhaled bronchodilators in infancy are not linked with asthma in later childhood.

Many doctors consider wheezing infants and young children who respond to beta-adrenergic agents to be asthmatics, or at least at risk for later asthma. The aim of this study was to compare responses to inhaled albuterol and racemic epinephrine in infancy between children with and without asthma later in childhood. In a crossover study setting, 100 acutely wheezing infants aged less than 24 months were randomized to receive inhalations of either racemic epinephrine and placebo, or albuterol and placebo. Clinical evaluation consisted of measurements of respiratory rate, heart rate, and oxygen saturation, and clinical assessment of the respiratory distress assessment instrument (RDAI) score, consisting of wheezing and chest indrawings. The asthma status of the children was evaluated at three clinical follow-up visits, at 4.0, 7.2, and 12.3 (median) years of age. Responses to bronchodilating agents, when respiratory rates and RDAI scores were used as outcome measures, were not different in future asthmatics compared to nonasthmatics. However, oxygen saturation was significantly higher after albuterol inhalation in children who had asthma at all three visits (92.67% confidence interval (CI), 91.39-93.96) than in those without asthma at these visits (92.52% CI, 91.79-93.25), but lower, correspondingly, after racemic epinephrine (91.97% CI, 90.74-93.19 vs. 93.04% CI, 92.29-93.79) and placebo (91.38% CI, 90.49-92.28 vs. 93.12% CI, 92.60-93.65) inhalations (P = 0.04). In conclusion, we were not able to confirm that future asthmatics respond better than future nonasthmatics to bronchodilating agents during wheezing in infancy. More studies are needed to characterize the subset of infants who benefit from bronchodilating treatment in infancy.

Sodium cromoglycate therapy in wheezing infants: preliminary evidence of beneficial outcome at early school age.

BACKGROUND: In order to affect the natural course of childhood wheezing and asthma, anti-inflammatory therapy is often prescribed for young wheezing children, but there is lack of long-term follow-up data. METHODS: Eighty-two of the original 100 children, hospitalized for wheezing under the age of 2 years in 1992-1993, were re-examined at school age in 1999. The children had participated in an open, randomized, parallel-group trial including a 4-month intervention with inhaled sodium cromoglycate (SCG) or budesonide (BUD). The baseline data, including data on atopy, eosinophilia and viral etiology, were prospectively collected on admission. RESULTS: At early school age (median 7.2 years), asthma was present in 33 (40%) children. There was less asthma in the original SCG (21%) than in the control group (54%) (OR 0.23; 95% CI 0.07-0.77). The figure was 46% in the BUD group. When the analyses were performed separately for atopic and non-atopic infants, the difference was significant only among atopics. The lowered risk for asthma in the SCG group remained significant in the multivariate logistic regression analysis when adjusted for age, sex and atopy, and further when adjusted for earlier episodes of wheezing and respiratory syncytial virus identification. However, after adjustment for blood eosinophilia, the significance was lost, albeit the risk for asthma remained low (OR 0.21; 95% CI 0.04-1.12). A sensitivity analysis, which was done by including the six drop-outs of the SCG group as unfavorable and the 12 drop-outs of other groups as favorable outcomes in the model, did not change the direction of the result (OR 0.70; 95% CI 0.26-1.89). CONCLUSIONS: An early SCG intervention in infants hospitalized for wheezing was associated with a lowered risk for early school-age asthma, especially in infants with evidence of atopy.

Teenage asthma after severe early childhood wheezing: an 11-year prospective follow-up.

The role of factors related to early wheezing and their associations with subsequent development of asthma are controversial. We reevaluated 81 children who had been prospectively followed up since hospitalization for wheezing at less than 2 years of age. The baseline data on characteristics of the children, family-related factors, and viral causes of wheezing were collected on entry into the study. At the median age of 12.3 years, current symptoms suggestive of asthma and allergy were recorded. As part of the clinical examination, an outdoor exercise challenge test and skin prick tests to common inhalant allergens were performed. Asthma, as indicated by current inhaled anti-inflammatory medication or repeated wheezing and positive result in the challenge test, was present in 32 (40%) children, and 90% of them were sensitized to at least one allergen. Early asthma-predictive factors were atopic dermatitis (odds ratio (OR), 3.5; 95% confidence interval (CI), 1.2-10.1) and the presence of specific IgE to inhalant allergens (OR, 11.3; 95% CI, 1.9-67.6). Respiratory syncytial virus (RSV) identification during wheezing in infancy was relatively rare (20%) among later asthmatics compared with other or no viral identification (52%) or rhinovirus identification (58%). Since the prevalence of childhood asthma in our area is 4.0-5.0%, we conclude that the increased risk of asthma persists until the teenage years after hospitalization for wheezing in infancy. The risk was about 5-fold after respiratory syncytial virus-induced wheezing, and more than 10-fold after rhinovirus-induced wheezing in the present study.

Respiratory syncytial virus infection in children hospitalized for wheezing: virus-specific studies from infancy to preschool years.

AIM: To evaluate whether the presence of immunoglobulin G (IgG) antibodies against respiratory syncytial virus (RSV) in early childhood is associated with later asthma, and to evaluate a new diagnostic test for RSV, reverse-transcription polymerase chain reaction (RT-PCR), comparing it to the antigen and antibody assays initially used in RSV diagnostics in the present cohort. METHODS: At the start of the study in 1992-1993, RSV was studied by antigen detection (using time-resolved fluoroimmunoassay) and complement-fixing antibody assay. Advances in methodology allowed us to supplement RSV studies by RT-PCR in frozen nasopharyngeal aspirates obtained on admission, and by specific IgG antibodies (using enzyme immunoassay) in frozen serum samples obtained during the follow-up. RESULTS: On admission, 29 of the 100 children hospitalized for wheezing at <2 y of age were RSV positive. When compared with conventional methods, the sensitivity of RT-PCR was 83% (100% w.r.t. antigen detection) and its specificity was 92% in diagnosing RSV infection. RSV-specific IgG antibody concentrations rose with age, but were not predictive of asthma at any age. In the present cohort, wheezing without RSV was particularly associated with increased risk for later childhood asthma. CONCLUSION: Hospitalization for wheezing in infancy is associated with increased risk for later childhood asthma, particularly in children without RSV infection on admission, although children with RSV have also slightly increased risk for later asthma. However, mere serological evidence of RSV infection is not associated with the development of asthma. In addition to RSV, more attention should be paid to less virulent agents in order to find those wheezing infants who are at particular risk of later childhood asthma.

Rhinovirus-associated wheezing in infancy: comparison with respiratory syncytial virus bronchiolitis.

BACKGROUND: There is increasing evidence that rhinoviruses (RV) are able to cause lower airway infections and to induce wheezing in young children. There are few data on the clinical characteristics of RV infections in infants. OBJECTIVE: The aim of the study was to compare clinical characteristics of infantile RV infection associated with wheezing and respiratory syncytial virus (RSV) bronchiolitis. MATERIAL AND METHODS: During a 22-month study period in 1992-1993, 100 children younger than 24 months old were hospitalized with respiratory tract infection-associated wheezing. Viral etiology was originally assessed by antibody and antigen assays. Etiologic studies were later supplemented by polymerase chain reaction for RVs (in 2000) and for RSV (in 2002), studied in frozen respiratory samples. There were 81 children with adequate determinations for both RVs and RSV. Twenty-six children had RV and 24 had RSV infection, and these 50 cases form the material of the present study. Atopic dermatitis, oxygen saturation, respiratory rates and clinical scores based on wheezing and retractions and total serum IgE concentrations and blood eosinophil counts were studied in all cases on admission. RESULTS: The children with RV infection, compared with RSV patients, were older (median, 13 versus 5 months), presented more often with atopic dermatitis (odds ratio, 16.7; 95% confidence interval, 2.22-100) and blood eosinophilia (odds ratio, 2.22; 95% confidence interval, 1.04-50). The groups did not differ from each other with regard to total serum IgE. Oxygen saturation values were lower in children with RSV infection. There were no significant differences in respiratory rates or scores combining wheezing and retractions. CONCLUSION: RV-associated wheezing and RSV bronchiolitis, although having rather similar clinical characteristics, differ significantly with regard to age, presence of atopic dermatitis and eosinophilia during infection.

Allergen-specific immunoglobulin E antibodies in wheezing infants: the risk for asthma in later childhood.

OBJECTIVE: To evaluate whether the measurement of specific immunoglobulin E (IgE) antibodies to food and/or inhalant allergens in infants who are hospitalized for wheezing can be used to predict later asthma. METHODS: Eighty-two children who were hospitalized for wheezing at <2 years of age were followed prospectively until early school age. The baseline data and the characteristics of infancy had been collected at enrollment. At school age, the children were evaluated for asthma and allergic manifestations, including skin prick tests to common inhalant allergens. Frozen serum samples obtained during the index episode of wheezing were available for 80 children for determination of food and inhalant allergen-specific serum IgE antibodies by fluoroenzyme-immunometric assay, UniCAP, applying the Phadiatop Combi allergen panel. RESULTS: Asthma was present in 32 (40%) children at school age. Food-specific IgE antibodies of >or=0.35 kU/L were found in 37 (46%) wheezing infants, but only specific IgE to wheat and to egg white at the level of >or=0.35 kU/L were significantly associated with later asthma. In regard to specific IgE to the mixture of food allergens, the cutoff level of >or=0.70 proved to be significant. Inhalant allergen-specific IgE of >or=0.35 kU/L was found only in 14 cases (18%), but when present, it was significantly predictive of asthma. Elevated levels of specific IgE antibodies to food or inhalant allergens were significantly associated with allergic rhinitis and skin-test reactivity at school age. CONCLUSIONS: When present in wheezing infants, specific IgE of >or=0.35 kU/L to wheat, egg white, or inhalant allergens are predictive of later childhood asthma. Consequently, detection of those specific IgE antibodies in wheezing infants may facilitate the early diagnosis of asthma, especially in cases with no clinically evident atopic manifestations.

Rhinovirus-induced wheezing in infancy--the first sign of childhood asthma?

BACKGROUND: Although known as common causes of upper respiratory infections, rhinoviruses, enteroviruses, and corona-viruses are poorly studied as inducers of wheezing in infants, and their possible role in the development of childhood asthma has not been investigated. OBJECTIVE: The purposes of this study were to assess the occurrence of RV, enterovirus, and coronavirus infections in wheezing infants and to evaluate the association of these viral findings with early school-age asthma. METHODS: In 1999, outcome in relation to asthma was studied in 82 of 100 initially recruited children who had been hospitalized for wheezing in infancy during the period 1992-1993. In 2000, etiologic viral studies regarding the index episode of wheezing were supplemented by rhinovirus, enterovirus, and coronavirus detection by RT-PCR from frozen nasopharyngeal aspirates in 81 of the children for whom adequate samples were available. Of these children, 66 had participated in the follow-up in 1999. RESULTS: Rhinoviruses were identified in 27 (33%) of the 81 children, enteroviruses in 10 (12%), and coronaviruses in none. Rhinoviruses were present as single viral findings in 22 (81%) of the 27 rhinovirus-positive cases, and rhinovirus infections were associated with the presence of atopic dermatitis in infancy. Enteroviruses were commonly encountered in mixed infections and had no association with atopy. As single viral findings, rhinoviruses were associated with the development of asthma (P =.047; odds ratio, 4.14; 95% CI, 1.02-16.77 versus rhinovirus-negative cases [by logistic regression adjusted for age, sex, and atopic dermatitis on entry)]. CONCLUSION: Our results present rhinoviruses as important inducers of wheezing even in infancy. The association with atopy and subsequent asthma calls for reevaluation of the role of rhinoviruses in the development of asthma.

Wheezing requiring hospitalization in early childhood: predictive factors for asthma in a six-year follow-up.

Although asthma is common after wheezing in early childhood, the risk factors for and the prevention of later asthma are poorly understood. During the present follow-up study, a range of possible predictive factors for school-age asthma was evaluated. The study group consisted of 82 children hospitalized for wheezing at age < 2 years in 1992-93. The baseline data were collected on entry to the study. In 1999, the children were re-examined at the median age of 7.2 years. A structured questionnaire was applied to chart the symptoms suggestive of asthma, and the children were examined clinically. An exercise challenge test, as well as skin prick tests (SPT) to common inhalant allergens, was performed. Asthma was present in 33 (40%) children, 30 (91%) having continuous medication for asthma. The significant asthma-predictive factors, present on entry to the study, were blood eosinophilia (p = 0.0008), atopic dermatitis (p = 0.0089), elevated total serum immunoglobulin E (IgE) (p = 0.0452), and a history of earlier episodes of wheezing in infancy (p = 0.0468). SPT positivity in early childhood was also associated with school-age asthma (p = 0.002). In contrast, respiratory syncytial virus (RSV) identification during the index episode of wheezing played a minor role as a predictive factor for asthma. In conclusion, if hospitalization for wheezing occurs in infancy, more than every third child will suffer from asthma at early school age; the risk is significantly increased with recurrent wheezing in infancy and the development of allergic manifestations.