S Brennan

Lung Function in Infants with Cystic Fibrosis Diagnosed by Newborn Screening

RATIONALE Progressive lung damage in cystic fibrosis (CF) starts in infancy, and early detection may aid preventative strategies. OBJECTIVES To measure lung function in infants with CF diagnosed by newborn screening and describe its association with pulmonary infection and inflammation. METHODS Infants with CF (n = 68, 6 weeks to 30 months of age) and healthy infants without CF (n = 49) were studied. Forced vital capacity, FEV(0.5), and forced expiratory flows at 75% of exhaled vital capacity (FEF(75)) were measured using the raised-volume rapid thoracoabdominal compression technique. Forty-eight hours later, infants with CF had bronchoalveolar lavage (BAL) for assessment of pulmonary infection and inflammation. MEASUREMENTS AND MAIN RESULTS In the CF group, the deficit in FEV(0.5) z score increased by -0.77 (95% confidence interval, -1.14 to -0.41; P < 0.001) with each year of age. The mean FEV(0.5) z score did not differ between infants with CF and healthy control subjects less than 6 months of age (-0.06 and 0.02, respectively; P = 0.87). However, the mean FEV(0.5) z score was lower by 1.15 in infants with CF who were older than 6 months of age compared with healthy infants (P < 0.001). FVC and FEF(75) followed a similar pattern. Pulmonary infection and inflammation in BAL samples did not explain the lung function results. CONCLUSIONS Lung function, measured by forced expiration, is normal in infants with CF at the time of diagnosis by newborn screening but is diminished in older infants. These findings suggest that in CF the optimal timing of therapeutic interventions aimed at preserving lung function may be within the first 6 months of life.

Acquisition and eradication of P. aeruginosa in young children with cystic fibrosis

When do infants and young children with cystic fibrosis acquire infection with Pseudomonas aeruginosa? Can this be eradicated when first detected? Children <6 yrs of age participated in an annual bronchoalveolar lavage (BAL)-based microbiological surveillance programme in Perth, Australia. When P. aeruginosa was detected, an eradication programme using combination treatment with i.v., oral and nebulised antibiotics was undertaken. Repeat BAL was performed 3 months following treatment, to assess eradication success. P. aeruginosa was detected in 33 (28.4%) children; median (range) age at detection was 30.5 (3.3–71.4) months. P. aeruginosa was mucoid at detection in six (18.2%) out of 33 patients and associated with respiratory symptoms in 16 (48.5%) out of 33 children. In total, 26 children underwent eradication therapy, with P. aeruginosa eradicated in 20 (77%) out of 26 following one eradication cycle and in three (total 88%) additional children following a second cycle. Eradication was associated with a significant decrease in neutrophil elastase and interleukin-1β in BAL fluid 12 months post eradication. Eradication of Pseudomonas aeruginosa infection is achievable in young children with cystic fibrosis for up to 5 yrs using combination i.v., oral and nebulised antibiotic therapy and is associated with reduced pulmonary inflammation 12 months post eradication.

Correlation of forced oscillation technique in preschool children with cystic fibrosis with pulmonary inflammation

Background: Lung disease in cystic fibrosis (CF) is established in early childhood with recurrent bacterial infections and inflammation. Using spirometry, the effect of this early lung damage cannot be measured until a child is 6 years of age when some irreversible lung damage may already have occurred. Techniques for measurement of lung function in infants and young children include raised volume rapid thoracic compression (RVRTC) and low frequency forced oscillation (LFFOT). The aim of this study was to investigate the role of inflammation and infection on a population of infants and young children with CF and to determine whether lung function in this population (measured by LFFOT) is affected by early lung disease. Methods: Lung function was measured by LFFOT in 24 children undergoing bronchoalveolar lavage (BAL) on 27 occasions as part of an annual programme while still under general anaesthesia. Following lung function testing, three aliquots of saline were instilled into the right middle or lower lobe. The first aliquot retrieved was processed for the detection of microbes, and the remaining aliquots were pooled to assess inflammatory markers (cytology, IL-8, NE, LTB4). Results: Inflammation (percentage and number of neutrophils) was significantly higher in children with infections (p<0.001, p = 0.04, respectively), but not in those with symptoms. Several markers of inflammation significantly correlated with LFFOT parameters (R, G, and η). Conclusion: Infections and inflammation are established before symptoms are apparent. Inflammation is correlated with measures of parenchymal changes in lung function measured by LFFOT.

Evolution of pulmonary inflammation and nutritional status in infants and young children with cystic fibrosis

Introduction Improved nutrition is the major proven benefit of newborn screening programmes for cystic fibrosis (CF) and is associated with better clinical outcomes. It was hypothesised that early pulmonary inflammation and infection in infants with CF is associated with worse nutrition. Methods Weight, height and pulmonary inflammation and infection in bronchoalveolar lavage (BAL) were assessed shortly after diagnosis in infants with CF and again at 1, 2 and 3 years of age. Body mass index (BMI) was expressed as z-scores. Inflammatory cells and cytokines (interleukin 1β (IL-1β), IL-6, IL-8 and tumour necrosis factor α (TNFα)), free neutrophil elastase activity and myeloperoxidase were measured in BAL. Mixed effects modelling was used to assess longitudinal associations between pulmonary inflammation, pulmonary infection (Staphylococcus aureus and Pseudomonas aeruginosa) and BMI z-score after adjusting for potential confounding factors. Results Forty-two infants were studied (16 (38%) male; 39 (93%) pancreatic insufficient); 36 were diagnosed by newborn screening (at median age 4 weeks) and six by early clinical diagnosis (meconium ileus). Thirty-one (74%) received antistaphylococcal antibiotics. More than two-thirds were asymptomatic at each assessment. Mean BMI z-scores were −1.5 at diagnosis and 0.5, −0.2 and −0.1 at 1, 2 and 3 years, respectively. Neutrophil elastase and infection with S aureus were associated with lower BMI, whereas age (p=0.01) and antistaphylococcal antibiotics (p=0.013) were associated with increased BMI. On average, each log10 increase in free neutrophil elastase activity was associated with a 0.43 (95% CI 0.06 to 0.79) reduction in BMI z-score. Discussion Early nutritional status is associated with the underlying pulmonary pathophysiology in CF, and better understanding of these relationships is required. Studies are required to assess whether interventions can decrease pulmonary inflammation and improve nutrition. Early surveillance will enable such targeted interventions with the aim of improving these important clinical outcomes.

Alveolar macrophages and CC chemokines are increased in children with cystic fibrosis

Airway inflammation is an important component of cystic fibrosis (CF) lung disease. We sought to determine whether alveolar macrophages were involved in early CF lung disease. Children with CF (median age 3.1 yrs) participated in a surveillance programme that included annual bronchoalveolar lavage (BAL). Control samples were obtained from non-CF children (median age 3.1 yrs; n = 24) investigated for persistent respiratory symptoms. Pulmonary infection was detected in 31% (16 out of 51) and 38% (nine out of 24) of children from the CF and non-CF groups, respectively. Alveolar macrophages in BAL were increased in CF compared with non-CF in the absence of infection (223×103 versus 85×103 cells·mL−1; p = 0.001) and were associated with elevations in the CC chemokines (macrophage inflammatory protein (MIP)-3α (chemokine (C-C motif) ligand (CCL)20; 355.8 versus 46.0 pg·mL−1; p<0.001), monocyte chemotactic protein-1 (CCL2; 263.5 versus 25.3 pg·mL−1; p<0.001), MIP-1α (CCL3; 38.2 versus 4.9 pg·mL−1; p<0.001) and MIP-1β (CCL4; 326.6 versus 27.5 pg·mL−1; p<0.001)). Total cell counts and neutrophil numbers increased in the presence of infection; however, there was no additional effect of CF. Alveolar macrophages and CC chemokines are elevated in the lungs in young children with CF even in the absence of pulmonary infection. Longitudinal studies are required to determine the clinical relevance of these findings.

Directed neutrophil migration to IL-8 is increased in cystic fibrosis: a study of the effect of erythromycin

BACKGROUND The aim of this study was to compare neutrophil migration in cystic fibrosis (CF) and non-CF populations and to investigate the effect of erythromycin on directed migration of neutrophils (PMNs) in CF. METHODS PMNs were isolated and their migratory capacity in response to interleukin-8 (IL-8) or f-Met-Leu-Phe (fMLP) in the presence or absence of erythromycin (1–100 μg/ml) was assessed. RESULTS CF derived PMNs showed significantly increased migration to IL-8 but not to fMLP compared with non-CF PMNs. Erythromycin had no significant effect on migration responses to IL-8 and in vitro exposure of PMNs to erythromycin had no effect. CONCLUSIONS CF derived PMNs show higher migratory responsiveness to IL-8 but not to fMLP, suggesting that CF PMNs may be “primed” to IL-8 which is significantly increased in CF serum compared with non-CF serum. Treatment with erythromycin had no significant effect on PMN migration in vitro.

Exhaled nitric oxide is not reduced in infants with cystic fibrosis

Fractional exhaled nitric oxide (FeNO) has been reported to be reduced in cystic fibrosis (CF) patients. However, data from young children are conflicting and it is not clear whether this is a primary feature of the disease or a secondary response. The present study compared FeNO between CF and healthy infants using a validated single-breath technique. A total of 23 healthy infants (11 females; mean age 40.1 weeks) and 18 infants with CF (nine females; 64.9 weeks) underwent tests of lung function and FeNO. Bronchoalveolar lavage (BAL) was collected from all CF infants 2–5 days after lung function testing. There was no significant difference in FeNO between the CF and healthy infants (geometric mean: 23.1 parts per billion (ppb) and 17.0 ppb, respectively). There was an inverse relationship between age and FeNO in the CF patients, but not in the healthy group. Within the CF group, there was no association between FeNO and any marker of airway inflammation measured in the BAL. Exhaled nitric oxide is not reduced in cystic fibrosis infants, but does decrease with age. The current data indicate that FeNO is not a good marker of airway inflammation in cystic fibrosis.

Nasal wash as an alternative to bronchoalveolar lavage in detecting early pulmonary inflammation in children with cystic fibrosis

Objective:  The aim of this study was to determine whether nasal inflammation reflects pulmonary inflammation in young children with cystic fibrosis (CF), as assessed by inflammatory markers in nasal wash (NW) and bronchoalveolar lavage (BAL), respectively.

Detecting early lung disease in cystic fibrosis: Are current techniques sufficient?

Use of the multiple breath inert gas washout technique in the early diagnosis of CF The philosophy underlying treatment at most cystic fibrosis (CF) clinics is essentially preventative—that is, early detection, treatment and hopefully resolutions of problems before they become major clinical issues. The introduction of newborn screening programmes around the world is also based on the idea that early detection and treatment will result in an improved outcome for patients. Progressive lung disease represents the greatest threat to the health and well being of patients with CF. The goal of treatment is to prevent or delay progressive lung disease, so early detection and monitoring of effective treatments would be expected to improve the health and life expectancy of children with CF. Lung disease in CF is characterised by a progression from bacterial colonisation to mucosal infection and finally invasive infection. This is accompanied by a host inflammatory response characterised by cytokine secretion and influx of neutrophils. The neutrophils appear to be drawn to the lungs largely by a chemotactic protein, interleukin 8 (IL-8), that is found in increased levels in the sputum and lavage of patients with CF.1,2 Increased numbers of neutrophils result in increased levels of the products of activated neutrophils such as neutrophil elastase (NE). Unbound NE is thought to be responsible for much of the lung damage seen in CF.3 Breakdown products of elastin found in the urine of patients with CF are thought to originate in the lung,3 indicating that lung destruction is occurring. Recent studies provide strong evidence that lung disease begins during early life in most children with CF. Bronchoalveolar lavage (BAL) performed in infants and young children with CF shows evidence of inflammation and …

CD14 C-159T and early infection with Pseudomonas aeruginosa in children with cystic fibrosis

Early acquisition of Pseudomonas aeruginosa is associated with a poorer prognosis in patients with cystic fibrosis. We investigated whether polymorphisms in CD14, the lipopolysaccharide receptor, increase the risk of early infection. Forty-five children with cystic fibrosis were investigated with annual bronchoalveolar lavage (BAL) and plasma sCD14 levels. Plasma sCD14 levels were significantly lower in children from whom P.aeruginosa was subsequently isolated (492.75 μg/ml vs. 1339.43 μg/ml, p = 0.018). Those with the CD14 -159CC genotype had a significantly increased risk of early infection with P.aeruginosa suggesting that CD14 C-159T plays a role in determining the risk of early infection with P.aeruginosa.