In this issue of Acta Paediatrica Heather Elphick and coworkers publish a follow-up to age three of 36 of 56 children hospitalised with Respiratory Syncytial Virus (RSV) lower respiratory tract infection before age one in comparison to a control group of 77 of 94 children recruited in infancy (1). They found an increased frequency of respiratory symptoms in the RSV group compared to the controls but no increase in allergic sensitisation except in a small subgroup of nine RSV infected children. Most children are infected by RSV before age two (2). Some children only get symptoms from the upper airways but many infants develop lower respiratory tract disease (3,4). One to two percent of previously healthy infants are hospitalised with RSV bronchiolitis, characterised by tachypnea, feeding difficulties, hypoxia, cough, and on auscultation widespread crackles, wheezes or both (2–5). Risk factors for severe bronchiolitis are age below 6 months, prematurity, cardiac or chronic lung disease (2–5). The study by Elphick et al. as well as most other studies shows that recurrent wheezing is common many years after an early RSV infection (1–9). It is a question of debate whether this recurrent wheezing is mainly a non-allergic condition with a good prognosis or an early onset of allergic asthma or a combination of both (2–6). Pullan et al. found a higher rate of wheeze but no increase in allergic sensitisation at a follow-up 10 years after hospitalisation for RSV lower respiratory tract infection in the first year of life when compared to controls (7). In the Tucson study of non-

High intra-subject variability in lung dose achieved when using aerosol delivery systems may impact on the efficacy of treatment in clinical practice. While the dose delivered by metered dose inhalers (pMDIs) is highly reproducible when tested in vitro, the variability in dose delivered to the lungs is known to be high. It has been suggested that newer delivery systems such as dry powder inhalers (DPIs) or breath actuated pMDIs significantly reduce the intra-subject variability in lung dose, but this remains untested. The 30-min urinary salbutamol technique was used to assess intra-subject variability in lung dose for five portable inhaler devices. Thirteen healthy adult subjects inhaled salbutamol from five different devices. Each device was used at five separate study days, a total of 25 visits. The devices studied were the Evohaler pMDI, a pMDI with Volumatic (pMDI + HC), the Easibreath, the Accuhaler and the Turbohaler. Subjects inhaled 400 microg of salbutamol and produced a urine sample exactly 30 min later. Quantities of salbutamol contained in the urine were determined using an HPLC technique. The mean coefficient of variation (CV% and range) for lung dose were 31.8% (20.1-87.4) for the pMDI + HC, Easi-breathe 35.9% (10.4-66.2), Accuhaler 40.4% (15.6-75.2), Turbohaler 42.4% (20.7-74.2), and 52.0% (27.1-49.3) for the pMDI alone. There was no significant statistical significant difference between any of the devices. In seven of 13 subjects, the greatest lung dose was achieved with the Volumatic. The observed intra-subject in health volunteers is similar to the reported intra-subject variability of bioavailability for a number of oral medications. Though there was trend towards higher variability when using the pMDI, this was not statistically significant and was largely attributable to one subject in with a poor technique.

The aim of this pilot study was to compare a the HaloLite Paediatric Nebulizer (HPN) with a pressurized metered dose inhaler and valved holding chamber (pMDI VHC, Aerochamber™) in terms of drug delivery, adherence to treatment, compliance with device, true adherence, and acceptability. Fourteen children aged 11–36 months with asthma on regular treatment with inhaled corticosteroids were enrolled into an open, randomized, crossover trial. They received budesonide for 2 weeks with each delivery system. Both devices incorporated a datalogger which recorded information on how the device was used. The HPN was preprogrammed to deliver 25 μg of budesonide to the patient. A single actuation of budesonide 200 μg was used with the pMDI VHC. The median delivered dose of budesonide was 36 μg (range, 31–45 μg; CV, 15%) for the HPN and 53 μg (range, 17–85 μg; CV, 47%) for the pMDI VHC. The median adherence was 68% (range, 11–96%) with the HPN and 71% (range, 11–100%) with the pMDI VHC. The median device compliance was 30% and 51% and the median true adherence was 23% and 36%, respectively. The shape, size, and weight of the HaloLite Paediatric Nebulizer were generally less acceptable than the shape, size, and weight of the pMDI VHC with datalogger. These results indicate that reproducible quantities of drug can be delivered to very young children using AAD™ technology such as that incorporated into the HPN. Drug delivery with the pMDI VHC was more variable, but parents preferred this device. Pediatr Pulmonol. 2004; 37:311–317. © 2004 Wiely‐Liss, Inc.

Guidelines suggest that pressurized metered dose inhalers (pMDI) plus spacers are the delivery system of choice for children. However, they are bulky, which makes them inconvenient. It was suggested that the smaller dry-powder inhalers (DPIs) may be suitable for delivering short-acting bronchodilators to preschool children. This study considered whether preschool children could reliably generate sufficient inspiratory flows to use the Clickhaler DPI. Twenty-seven asthmatic and 34 nonasthmatic children, aged 2-5 years, were recruited. Following training, they were asked to inhale four times through a Clickhaler flow monitoring system, twice "steadily" and twice "forcefully." Inspiratory flow data were collected during each inhalation. Of the 3-, 4-, and 5-year-old asthmatics, 62.5, 100, and 100%, respectively, could reliably differentiate between inhaling and exhaling through the DPI. For nonasthmatics, the figures were 66, 60, and 88%, respectively. All but one of the children who understood the instructions generated a PIF of greater than 15 l/min (range, 13.9-88.3 l/min and 21.2-84.5 l/min in asthmatic and nonasthmatic children, respectively). These data indicate that the majority of children aged 3 years and above could reliably inhale rather than exhale through a dry-powder inhaler, and that they generate inspiratory flows sufficient to use the Clickhaler effectively. The results indicate that the device could be a suitable delivery system for beta(2)-agonists in preschool children.

Computerised breath sounds analysis was used to assess the response of infants with wheeze and ruttles to the drug ipratropium bromide. A mean decrease in breath sounds intensity occurred in infants with ruttles after five minutes (20.5 dB), but not until 20 minutes in those with wheeze (8.1 dB). This differential response may be related to different underlying pathophysiology.

Large numbers of neutrophils in the airway of infants infected by respiratory syncytial virus (RSV) are recruited by chemokines, such as interleukin-8, and specific inflammatory molecules can delay apoptosis increasing their longevity. The aim of this study was to investigate whether airway secretions in RSV bronchiolitis contain factors that influence neutrophil apoptosis. Nasal lavage fluid (NLF) was obtained from 24 infants with RSV bronchiolitis (31 infant controls and 12 adults). Neutrophils isolated from healthy adult volunteers were incubated with the NLF in Dulbecco modified Eagle medium (DMEM) for 24 h, and apoptosis and necrosis were quantified using Hoechst 33342 and propidium iodide viability dyes. The presence of putative factors that delay neutrophil apoptosis was investigated using inhibitors to leukotriene-B4, lipopolysaccharide and the IL-8 receptor CXCR2, and blocking antibodies to granulocyte-monocyte colony-stimulating factor. Characterisation of NLF involved tests of thermal instability, proteolysis, deoxyribonuclease digestion and molecular filtration. NLF from infants with RSV bronchiolitis and controls significantly delayed neutrophil apoptosis, whereas NLF from healthy adults did not. None of these inhibitor molecules blocked this delay in apoptosis but activity was heat liable and >3 kDa. The study showed that nasal lavage fluid from infants significantly delays neutrophil apoptosis. The speculation is that the prolonged survival of neutrophils in the infant airway contributes to the characteristic accumulation of neutrophils in the airways of infants with respiratory infections.

BACKGROUND Exhaled nitric oxide levels are low in patients with cystic fibrosis (CF), despite the chronic inflammation present in the airways. This study aimed to determine whether levels of exhaled nitric oxide were reduced prior to the onset of respiratory symptoms in infants with CF. METHODS The levels of exhaled nitric oxide were measured using a chemiluminescence analyser in five infants with CF and 11 healthy control subjects, both groups having a mean age of 48.6 days. RESULTS Mean levels of exhaled nitric oxide were significantly lower in infants with CF than in the control group (4.9 ppb v 12.1 ppb; p=0.01). CONCLUSIONS This finding may be the key to understanding the inflammatory processes in early cystic fibrosis and may lead to novel treatment approaches.

Epidemiological studies indicate that the prevalence of "wheeze" is very high in early childhood. However, it is clear that parents and clinicians frequently use the term "wheeze" for a range of audible respiratory noises. The commonest audible sounds originating from the lower airways in infancy are ruttles, which differ from classical wheeze in that the sound is much lower in pitch, with a continuous rattling quality and lacking any musical features. The aim of this study was to clearly differentiate wheeze and ruttles objectively using acoustic analysis. Lung sounds were recorded in 15 infants, seven with wheeze and eight with ruttles, using a small sensitive piezoelectric accelerometer, and information relating to the respiratory cycle was obtained using inductive plethysmography. The acoustic signals were analysed using a fast fourier transformation technique (Respiratory Acoustics Laboratory Environment programme). The acoustic properties of the two noises were shown to be quite distinct, the classical wheeze being characterized by a sinusoidal waveform with one or more distinct peaks in the power spectrum display; the ruttle is represented by an irregular nonsinusoidal waveform with diffuse peaks in the power spectrum and with increased sound intensity at a frequency of <600 Hz. It is important for clinicians and epidemiologists to recognize that there are distinct types of audible respiratory noise in early life with characteristic acoustic properties.