Leif Bjarte Rolfsjord

Racemic Adrenaline and Inhalation Strategies in Acute Bronchiolitis

BACKGROUND Acute bronchiolitis in infants frequently results in hospitalization, but there is no established consensus on inhalation therapy--either the type of medication or the frequency of administration--that may be of value. We aimed to assess the effectiveness of inhaled racemic adrenaline as compared with inhaled saline and the strategy for frequency of inhalation (on demand vs. fixed schedule) in infants hospitalized with acute bronchiolitis. METHODS In this eight-center, randomized, double-blind trial with a 2-by-2 factorial design, we compared inhaled racemic adrenaline with inhaled saline and on-demand inhalation with fixed-schedule inhalation (up to every 2 hours) in infants (<12 months of age) with moderate-to-severe acute bronchiolitis. An overall clinical score of 4 or higher (on a scale of 0 to 10, with higher scores indicating more severe illness) was required for study inclusion. Any use of oxygen therapy, nasogastric-tube feeding, or ventilatory support was recorded. The primary outcome was the length of the hospital stay, with analyses conducted according to the intention-to-treat principle. RESULTS The mean age of the 404 infants included in the study was 4.2 months, and 59.4% were boys. Length of stay, use of oxygen supplementation, nasogastric-tube feeding, ventilatory support, and relative improvement in the clinical score from baseline (preinhalation) were similar in the infants treated with inhaled racemic adrenaline and those treated with inhaled saline (P>0.1 for all comparisons). On-demand inhalation, as compared with fixed-schedule inhalation, was associated with a significantly shorter estimated mean length of stay--47.6 hours (95% confidence interval [CI], 30.6 to 64.6) versus 61.3 hours (95% CI, 45.4 to 77.2; P=0.01) - as well as less use of oxygen supplementation (in 38.3% of infants vs. 48.7%, P=0.04), less use of ventilatory support (in 4.0% vs. 10.8%, P=0.01), and fewer inhalation treatments (12.0 vs. 17.0, P<0.001). CONCLUSIONS In the treatment of acute bronchiolitis in infants, inhaled racemic adrenaline is not more effective than inhaled saline. However, the strategy of inhalation on demand appears to be superior to that of inhalation on a fixed schedule. (Funded by Medicines for Children; ClinicalTrials.gov number, NCT00817466; EudraCT number, 2009-012667-34.).

Allergic diseases and the effect of inhaled epinephrine in children with acute bronchiolitis: follow-up from the randomised, controlled, double-blind, Bronchiolitis ALL trial

BACKGROUND Although use of inhaled bronchodilators in infants with acute bronchiolitis is not supported by evidence-based guidelines, it is often justified by the belief in a subgroup effect in individuals developing atopic disease. We aimed to assess if inhaled epinephrine during acute bronchiolitis in infancy would benefit patients with later recurrent bronchial obstruction, atopic eczema, or allergic sensitisation. METHODS In the randomised, double-blind, multicentre Bronchiolitis ALL trial, 404 infants with moderate-to-severe acute bronchiolitis were recruited from eight hospitals in Norway to receive either inhaled epinephrine or saline up to every second hour throughout the hospital stay. Randomisation was done centrally, and the two study medications (20 mg/mL racemic epinephrine or 0.9% saline) were prepared in identical bottles. The dose given depended on the infants weight: 0.10 mL, less than 5 kg; 0.15 mL, 5-6.9 kg; 0.2 mL, 7-9.9 kg; and 0.25 mL, 10 kg or more; all dissolved in 2 mL of 0.9% saline before nebulisation. The primary outcome was the length of hospital stay. In this follow-up study, 294 children were reinvestigated at 2 years of age with an interview, a clinical examination, and a skin prick test for 17 allergens, determining bronchial obstruction, atopic eczema, and allergic sensitisation, on which subgroup analyses were done. Analyses were done by intention to treat. The trial has been completed and is registered at ClinicalTrials.gov (number NCT00817466) and EUDRACT (number 2009-012667-34). FINDINGS Length of stay did not differ between patients who received inhaled epinephrine versus saline in the subgroup of infants who developed recurrent bronchial obstruction by age 2 years (143 [48.6%] of 294 patients; p(interaction)=0.40). However, the presence of atopic eczema or allergic sensitisation by the age of 2 years (n=77) significantly interacted with the treatment effect of inhaled epinephrine (p(interaction)=0.02); the length of stay (mean 80.3 h, 95% CI 72.8-87.9) was significantly shorter in patients receiving inhaled epinephrine versus saline in patients without allergic sensitisation or atopic eczema by 2 years (-19.9 h, -33.1 to -6.3; p=0.003). No significant differences were found in length of hospital stay in response to epinephrine or saline in children with atopic eczema or allergic sensitisation by 2 years (+16.2 h, -11.0 to 43.3; p=0.24). INTERPRETATION Contrary to our hypothesis, hospital length of stay for bronchiolitis was not reduced by administration of inhaled epinephrine in infants who subsequently developed atopic eczema, allergic sensitisation, or recurrent bronchial obstruction. The present study does not support an individual trial of inhaled epinephrine in acute bronchiolitis in children with increased risk of allergic diseases. FUNDING Medicines for Children Network, Norway.

Skin Barrier Function and Staphylococcus aureus Colonization in Vestibulum Nasi and Fauces in Healthy Infants and Infants with Eczema: A Population-Based Cohort Study

Atopic eczema (AE) is associated with Staphylococcus aureus (S. aureus) colonization and skin barrier dysfunction, often measured by increased transepidermal water loss (TEWL). In the present study, the primary aim was to see whether S. aureus colonization in the vestibulum nasi and/or fauces was associated with increased TEWL in infants with healthy skin and infants with eczema. Secondarily, we aimed to investigate whether TEWL measurements on non-lesional skin on the lateral upper arm is equivalent to volar forearm in infants. In 167 of 240 infants, recruited from the general population, TEWL measurements on the lateral upper arm and volar forearm, using a DermaLab USB, fulfilled our environmental requirements. The mean of three TEWL measurements from each site was used for analysis. The infants were diagnosed with no eczema (n = 110), possible AE (n = 28) or AE (n = 29). DNA samples were analysed for mutations in the filaggrin gene (FLG). Bacterial cultures were reported positive with the identification of at least one culture with S. aureus from vestibulum nasi and/or fauces. S. aureus colonization, found in 89 infants (53%), was not associated with increased TEWL (i.e. TEWL in the upper quartile), neither on the lateral upper arm or volar forearm (p = 0.08 and p = 0.98, respectively), nor with AE (p = 0.10) or FLG mutation (p = 0.17). TEWL was significantly higher on both measuring sites in infants with AE compared to infants with possible AE and no eczema. FLG mutation was significantly associated with increased TEWL, with a 47% difference in TEWL. We conclude that S. aureus in vestibulum nasi and/or fauces was not associated with TEWL, whereas TEWL measurements on the lateral upper arm and volar forearm appear equally appropriate in infants.

Children hospitalised with bronchiolitis in the first year of life have a lower quality of life nine months later

Acute bronchiolitis increases the risk of asthma, and reduced quality of life (QoL) is reported in children with asthma and allergy. However, the impact of asthma risk factors on QoL is unclear. This study investigated whether bronchiolitis and common asthma risk factors in infancy had an influence on later QoL.

Vitamin D levels and atopic eczema in infancy and early childhood in Norway: a cohort study.

Epidemiological data and the effect of sun exposure on atopic eczema (AE) suggest that vitamin D (vitD) may be involved in the pathogenesis.

The severity of acute bronchiolitis in infants was associated with quality of life nine months later

Acute bronchiolitis in infancy increases the risk of later asthma and reduced health‐related quality of life (QoL). We aimed to see whether the severity of acute bronchiolitis in the first year of life was associated with QoL nine months later.

Parental severity assessment predicts supportive care in infant bronchiolitis

In infants with acute bronchiolitis, the precision of parental disease severity assessment is unclear. We aimed to determine if parental assessment at the time of hospitalisation predicted the use of supportive care, and subsequently determine the likelihood that the infant with acute bronchiolitis would receive supportive care.

Transepidermal water loss in infancy associated with atopic eczema at 2 years of age: a population‐based cohort study

DEAR EDITOR, Skin barrier function can be evaluated by measuring transepidermal water loss (TEWL). High TEWL is found in children with atopic eczema and in infants with a mutation in the gene encoding profilaggrin, a precursor of filaggrin, which is an important protein for skin barrier function. In a recent study by Kelleher et al., high TEWL at 2 days and 2 months preceded and predicted atopic eczema at 1 year of age, independently of parental atopy and filaggrin mutation status. Using a cohort of infants living in south-east Norway, we aimed to investigate whether TEWL in infants without atopic eczema was associated with atopic eczema at 2 years of age. Ethical approval and informed consent were obtained. The children, recruited from the general population in the cities of Oslo and Fredrikstad, were examined at two visits at a mean age of 6 0 months (min,max 1 2–13 4) and 24 0 months (min,max 17 5–35 2), respectively, within the period 2012– 2014 (Table 1). Maternal or paternal atopy was defined as reports of atopic eczema, asthma or allergic rhinitis by the respective parent. Atopic eczema was diagnosed clinically by experienced physicians based on the criteria of Hanifin and Rajka or on a history of physician-diagnosed atopic eczema. Children with a rash that did not fulfil these criteria were classified as having a rash. Infants with atopic eczema at the first visit were excluded from the study cohort. TEWL was measured on the lateral part of one upper arm, using an open chamber DermaLab USB (Cortex, Hadsund, Denmark) system. The infants, wearing a nappy only, were acclimatized for a minimum of 15 min under standardized environmental conditions of a temperature of 20–25 °C, in line with studies by Kelleher et al., and 20–50% humidity. TEWL measurements performed while the infants were crying were not included. TEWL was reported as the mean of three consecutive measurements. Data on TEWL measurements performed under the required conditions at the first visit and on atopic eczema at the second visit were obtained in 116 of the 196 children (59%) whose characteristics are shown in Table 1. The median TEWL at the first visit was 7 95 g m 2 h 1 (Q1,Q3; 5 51, 10 21). Using the area under the receiver operating characteristic curve, the optimal cut-off value for TEWL was calculated to be 9 33 g m 2 h , defining low and high TEWL in the analyses. At the second visit atopic eczema was diagnosed in 19 of 116 children (16%). Analysing the association between high TEWL at the first visit and atopic eczema at the second visit, Hosmer and Lemeshow’s step-down procedure was performed to adjust for potential confounding variables, that is, paternal or maternal atopy, paternal or maternal ethnicity, parental income, infants’ sex, age, filaggrin mutation, weight for length, vitamin D level and having a rash at the first visit, as well as the season when the first visit was made and the relative ambient humidity, leaving only high TEWL and having a rash in the final model (Table 2). Table 1 Infants without atopic eczema (n = 196) at the first visit, with and without transepidermal water loss (TEWL) data at the first visit or data on atopic eczema at the second visit. Data are presented as numbers (%) unless otherwise stated