Tiina M. Reijonen

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

Abstract 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. (J Allergy Clin Immunol 2003;111:66-71.)

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.

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. Pediatr Pulmonol.

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.

Bronchial asthma after early childhood wheezing: a follow‐up until 4.5–6 years of age

Over a period of 12 months from 1981 to 1982, 83 patients aged less than 2 years were treated in hospital for acute bronchiolitis. The children were followed‐up prospectively; 68 (83%) completed the study until 4.5–6.0 years of age. At this age, 17 (25%) of the 68 children with bronchiolitis still suffered from wheezing attacks. These 17 asthmatics suffered from both atopic dermatitis (29 versus 6%) and allergic rhinitis (29 versus 8%) more frequently than non‐asthmatic children. In contrast, positive results in the skin prick tests were almost equally common (29 and 20%) in asthmatic and non‐asthmatic children. In these tests, allergies to birch pollen, timothy grass pollen and house dust mite were most common; asthma was particularly associated with house dust mite allergy. The presence of atopic dermatitis, elevated immunoglobulin E values and repeated wheezing episodes between I and 2 years of age were significant risk factors for later asthma. In conclusion, the risk for later asthma is increased after early childhood bronchiolitis; the frequency of asthma was 25% in the present study. Our results confirm that atopics are at a greater risk of developing asthma later in childhood than non‐atopics; the risk was significant from 1 year of age onwards.

One-year follow-up of young children hospitalized for wheezing: the influence of early anti-inflammatory therapy and risk factors for subsequent wheezing and asthma†

We investigated the 1‐year outcome of children hospitalized for wheezing, paying special attention to the effect of early anti‐inflammatory therapy. In addition, we identified risk factors for recurrent wheezing and asthma. Eighty‐eight children under 2 years old treated in the hospital for wheezing were followed for 1 year. Nebulized anti‐inflammatory therapy was given for 16 weeks: 31 patients received budesonide, 29 patients cromolyn sodium, and 28 control patients received no therapy. The number of subsequent physician‐diagnosed wheezing episodes was recorded.

Serum eosinophil cationic protein as a predictor of wheezing after bronchiolitis

We have evaluated the role of eosinophil cationic protein (ECP) concentrations in serum in predicting wheezing after bronchiolitis, during infancy and early childhood. A prospective study at a university hospital serving all pediatric patients in a defined area was designed. Serum ECP concentrations were measured in 92 infants under the age of 2 years on admission for acute bronchiolitis, and 6 and 16 weeks after hospitalization. Nebulized anti‐inflammatory therapy was initiated during hospitalization: 32 patients received cromolyn sodium and 32 patients received budesonide for 16 weeks; 30 control patients received no maintenance therapy. The numbers of subsequent physician‐diagnosed wheezing episodes and hospital admissions for obstructive airway disease were recorded during 16 weeks of follow‐up.

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.

Lung function and bronchial hyper‐responsiveness 11 years after hospitalization for bronchiolitis

Aim: Atopic infants hospitalized for wheezing not caused by respiratory syncytial virus (RSV) carry the highest risk for later asthma. In the present paper, early risk factors for later lung function abnormalities and for bronchial hyper‐responsiveness (BHR) were evaluated in 81 children, hospitalized for bronchiolitis in infancy, at the median age of 12.3 years.

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.