Pulmonary aspiration in preschool children with cystic fibrosis.

Pulmonary aspiration of gastric refluxate (PAGR) has been demonstrated in association with pulmonary inflammation in school aged children with Cystic Fibrosis (CF). We sought to determine if similar findings were present in preschool children. Pepsin was measured in Broncho-alveolar lavage (BAL) fluid collected from clinically stable preschool children with CF and controls. Elevated pepsin levels were found in a subgroup of children with CF, but this was not found to be associated with pulmonary infection, pulmonary inflammation or respiratory or gastrointestinal symptoms.

Vitamin D receptor variants and uncontrolled asthma.

Summary: Background. Asthma is a common childhood respiratory disease, affecting around 20% of Irish children. In other populations, vitamin D receptor (VDR) polymorphisms have been associated with asthma risk. We aimed to investigate the association between 2 VDR polymorphisms and uncontrolled paediatric asthma. Methods. 44 asthmatic children and 57 healthy volunteers were studied. The VDR TaqI gene variant in exon 9 (T/C) (rs731236) and ApaI (rs7975232) in intron 8 (C/T) were determined, using TaqMan® Assays. The lung function, serum 25-hydroxyvitamin D (25OHD) levels and other biomarkers of allergy, immunity, airway and systemic inflammation were as-sessed. Results. The distribution of T and C alleles and genotype frequencies differed significantly between asthmatics and controls for both polymorphisms (p < 0.05). A significant association was found between both TaqI [OR = 2.37, 95% CI (1.27 - 4.45), p = 0.007] and ApaI polymorphisms, and asthma risk [OR = 2.93, 95% CI (1.62 - 5.3), p = 0.0004]. No association was observed between genotypes and 25OHD levels, lung function and other biomarkers, with the exception of Interleukin-10 (IL-10) and white blood cells count (WBC). IL-10 levels were lower in asthmatics with TC genotype for TaqI polymorphism (p < 0.01) and were higher in patients with TT genotype for ApaI (p < 0.01). WBC were higher in patients with TC and CC genotypes for TaqI (p < 0.05) and lower in TT genotype for ApaI (p < 0.05). Conclusion. TaqI and ApaI polymorphisms are associated with asthma in Irish children. Further studies are warranted to investigate the importance of decreased IL-10 levels in paediatric asthmatics with specific genotypes.

Diagnosis and treatment of sleep related breathing disorders in children: 2007 to 2011.

Sleep related breathing disorders (SRBD) have historically been under-recognised and under-treated. Obstructive sleep apnoea (OSA) affects approximately 3% of children. In line with the increased recognition of SRBD there has been an increase in demand for diagnostic services. We determined the awareness of SRBD amongst Irish paediatricians, examined the provision of sleep services to children throughout the country between 2007 and 2011 and audited diagnostic sleep services in a tertiary centre in 2011. Amongst respondents there was an awareness of SRBD but a poor understanding of diagnostic evaluation with 31/46 (67) referring to inappropriate services. There has been a sharp increase in both diagnostic sleep tests (433-1793 [414]) and in the use of non-invasive ventilation (NIV) (31-186 [627]) for treatment of SRBD between 2007 and 2011. Paediatric sleep services are organized in an ad-hoc manner nationally with significant service variation. The use of domiciliary overnight oximetry reduced the requirement for more formal polysomnography by 70%.

Physical activity and cardiovascular disease risk factors in urban school children.

Although the clinical signs of cardiovascular disease (CVD) are not evident until adulthood, many of the risk factors have their roots in early childhood. The aim of this study was to examine physical activity levels (PA) and the incidence of CVD risk factors in a small population (n=102) of primary school children in Dublin. Risk factors measured included overweight/obesity, blood lipids, blood pressure (BP), physical fitness and PA levels. Over a quarter of the group were overweight/obese (n = 29, 28%). Despite relatively good fitness levels, PA levels were low with less than half the group (n = 44, 46%) participating in the recommended 1 hour/day. Fewer girls reported spending > 1 hour/day at PA compared to boys (n = 14 v n = 30). Six children had elevated cholesterol levels and five children had higher than normal BP values. Sixteen children demonstrated clustering of CVD risk factors and in those who were inactive the risk was greater. Our data suggest that in children as young as 10 years significant risk factors already exist. Furthermore, the low level of PA in girls provides a target for health promotion programmes.

The changing epidemiology of the bronchiolitis epidemic in Tallaght Hospital.

Bronchiolitis affects one third of babies in their first year of life. We investigated all bronchiolitis admissions to Tallaght Hospital in the last five years, with the hope of providing an insight into the epidemic in an Irish population. We analysed these 1,202 admissions on the basis of time of year (busiest being December at 24.20%), length of stay (mean 2.92 days), gender (62% male) and age (mean 30.29 weeks). There was a 102% increase in the average incidence of bronchiolitis in the first six months of 2011 and 2012 (186) compared to the previous four years (92.25). P value was statistically significant at 0.0469. Our findings were backed up by comparable data from OLCH, Crumlin (149.5 for 2011-2012 vs 36.25 for 2007-2010). There has been in a significant shift in the timing and incidence of bronchiolitis in Tallaght Hospital in the last two years. We explored the possible reasons for this, with special attention to RSV incidence, climate causes and vaccine programs.

Vitamin D receptor agonists inhibit pro-inflammatory cytokine production from the respiratory epithelium in cystic fibrosis.

BACKGROUND: 1,25-Dihydroxycholecalciferol (1,25(OH)(2)D(3)) has been shown to mitigate epithelial inflammatory responses after antigen exposure. Patients with cystic fibrosis (CF) are at particular risk for vitamin D deficiency. This may contribute to the exaggerated inflammatory response to pulmonary infection in CF. METHODS: CF respiratory epithelial cell lines were exposed to Pseudomonas aeruginosa lipopolysaccharide (LPS) and Pseudomonas conditioned medium (PCM) in the presence or absence of 1,25(OH)(2)D(3) or a range of vitamin D receptor (VDR) agonists. Levels of IL-6 and IL-8 were measured in cell supernatants, and cellular total and phosphorylated IκBα were determined. Levels of human cathelicidin antimicrobial peptide (hCAP18) mRNA and protein were measured in cells after treatment with 1,25(OH)(2)D(3). RESULTS: Pretreatment with 1,25(OH)(2)D(3) was associated with significant reductions in IL-6 and IL-8 protein secretion after antigen exposure, a finding reproduced with a range of low calcaemic VDR agonists. 1,25(OH)(2)D(3) treatment led to a decrease in IκBα phosphorylation and increased total cellular IκBα. Treatment with 1,25(OH)(2)D(3) was associated with an increase in hCAP18/LL-37 mRNA and protein levels. CONCLUSIONS: Both 1,25(OH)(2)D(3) and other VDR agonists significantly reduce the pro-inflammatory response to antigen challenge in CF airway epithelial cells. VDR agonists have significant therapeutic potential in CF.

High concentrations of pepsin in bronchoalveolar lavage fluid from children with cystic fibrosis are associated with high interleukin-8 concentrations.

BACKGROUND: Gastro-oesophageal reflux is common in children with cystic fibrosis (CF) and is thought to be associated with pulmonary aspiration of gastric contents. The measurement of pepsin in bronchoalveolar lavage (BAL) fluid has recently been suggested to be a reliable indicator of aspiration. The prevalence of pulmonary aspiration in a group of children with CF was assessed and its association with lung inflammation investigated. METHODS: This was a cross-sectional case-control study. BAL fluid was collected from individuals with CF (n=31) and healthy controls (n=7). Interleukin-8 (IL-8), pepsin, neutrophil numbers and neutrophil elastase activity levels were measured in all samples. Clinical, microbiological and lung function data were collected from medical notes. RESULTS: The pepsin concentration in BAL fluid was higher in the CF group than in controls (mean (SD) 24.4 (27.4) ng/ml vs 4.3 (4.0) ng/ml, p=0.03). Those with CF who had raised pepsin concentrations had higher levels of IL-8 in the BAL fluid than those with a concentration comparable to controls (3.7 (2.7) ng/ml vs 1.4 (0.9) ng/ml, p=0.004). Within the CF group there was a moderate positive correlation between pepsin concentration and IL-8 in BAL fluid (r=0.48, p=0.04). There was no association between BAL fluid pepsin concentrations and age, sex, body mass index z score, forced expiratory volume in 1 s or Pseudomonas aeruginosa colonisation status. CONCLUSIONS: Many children with CF have increased levels of pepsin in the BAL fluid compared with normal controls. Increased pepsin levels were associated with higher IL-8 concentrations in BAL fluid. These data suggest that aspiration of gastric contents occurs in a subset of patients with CF and is associated with more pronounced lung inflammation.

Use of post-exercise laryngoscopy to evaluate exercise induced dyspnea.

We present the case of a child with asthma who continued to have marked exercise induced dyspnea despite appropriate treatment, and in the face of adequate control of all other asthma symptoms. Spirometry showed a marked truncation of inspiratory flow, and laryngoscopy performed immediately after exercise showed laryngomalacia with dynamic, partial inspiratory obstruction. Exercise induced laryngomalacia (EIL) is a rare cause of exercise induced dyspnea which is diagnosed by post exercise flexible laryngoscopy and may require supraglottoplasty.

A decade of non-cystic fibrosis bronchiectasis 1996-2006.

This study aimed to determine the aetiology, clinical presentation, co-morbidity, severity and the lobar distribution of non cystic fibrosis bronchiectasis (NCFB). We performed a retrospective review of clinical, radiological, immunological and microbiological data from 92 non-CF patients with a High resolution thoracic CT (HRCT) diagnosis of bronchiectasis in the three Dublin Children's referral Hospitals for the period 1996-2006. Of 92 patients (50 female), the median age at diagnosis was 6.4 years. The aetiology of bronchiectasis was as follows; idiopathic 29 (32%), post-pneumonia 16 (17%), immune deficiency 15 (16%), recurrent aspiration 15 (16%), primary ciliary dyskinesia 8 (9%), chronic aspiration with immune deficiency 5 (5%), post foreign body inhalation 2 (2%), tracheomalacia 1 (1%) and Obliterative bronchiolitis 1 (1%). Bronchial asthma and gastroesophageal reflux disease (GORD) were concurrently present in 18 (20%) and 10 (11%) respectively. Left lower lobe was commonly involved followed next by the right middle lobe. The common isolates were Haemophilus influenza (50), Streptococcus pneumoniae (34) and Staphylococcus aureus (14), Moraxella catarrhalis (9) and Pseudomonas auerginosa (8). Surgical interventions were performed in 23 (25%) of patients, lobectomy 11 (12%), pneumectomy 2 (2%), laryngeal cleft repair 4 (5%), rigid bronchoscopy for foreign body removal 2 (2%), Nissan's fundoplication 2 (2%), tracheoesophageal fistula repair 2 (2%). We conclude NCFB is under-recognised in Irish children and diagnosis is often delayed and Bronchial Asthma and GORD are common co morbidity. A high index of suspicion and early HRCT can expedite the diagnosis.

Pleuropulmonary blastoma type I following resection of incidentally found congenital lobar emphysema.

Pleuropulmonary blastoma (PPB) is an aggressive tumour accounting for less than 1% of all primary malignant lung tumours in the paediatric population. It can be associated with cystic pulmonary lesions, which may be evident at the time of diagnosis or predate the appearance of the tumour. There are contradictory reports about the value of prophylactic resection of pulmonary cysts in protecting patients from developing PPB. We report an individual case where asymptomatic congenital lobar emphysema was incidentally picked up on CXR. Following a period of surveillance the lesion was resected due to increasing size. The histology of the lesion revealed PPB Type I.

Severe bone demineralisation is associated with higher mortality in children with cystic fibrosis.

Decreased bone mineral density (BMD) is an emerging problem for clinicians who care for children with Cystic fibrosis (CF). The aim of this study was to determine prevalence and assess risk factors for reduced BMD in our adolescent population with CF. All bone densitometry scans (n=99) performed on children (n=79) with a mean age 13.6 (10-19.2) years over a 7 year period (2000-2007) were reviewed. Patient records were reviewed for correlating clinical data. Low BMD is frequently present in adults and children with variable reports (36-66%). In our study, BMD expressed as z score of L2-L4 spine was reduced in a total of 50% children with a preponderance of males. Bone demineralization was strongly associated with increasing age (p=0.03), diminished lung function (p=0.027), reduced body mass index (p=0.001) and treatment with oral corticosteroids (p=0.02).

Voriconazole in the treatment of allergic bronchopulmonary aspergillosis in cystic fibrosis.

Allergic bronchopulmonary aspergillosis (ABPA) can cause a significant clinical deterioration in patients with cystic fibrosis. There is very little research in the current literature with regard to alternatives for treatment, apart from long courses of steroids. We conducted a retrospective review of all our patients with ABPA treated with the antifungal voriconazole and found there was a significant drop in IgE levels post treatment as well as a decrease in steroid dosing. The improvement in FEV was not statistically significant; however there was a very wide variation in pre-treatment levels.

Asthma control and management: a patient's perspective.

Irish asthma guidelines, published in 2000, are based on the Global Initiative for Asthma (GINA) international asthma management guidelines and provide recommendations for optimal asthma management and control. Using the same methodology as employed in the Asthma Insights and Reality in Europe (AIRE) survey, which assessed whether specific goals of asthma management based on GINA were being realised, 400 patients with current asthma in Ireland were interviewed in the Asthma Insights and Reality in Ireland (AIRI) survey to determine their healthcare utilisation, symptom severity, activity limitations and level of asthma control. Of those surveyed, acute services were utilised by a significant number of respondents. Over the previous year, 27% had either an emergency visit to the hospital or their general practitioner (GP) and 7% were hospitalised for asthma. In terms of asthma control, 19% experienced sleep disturbance at least once a week, 29% missed work or school and 37% of respondents experienced symptoms during physical activity over the previous 4-week period. Based on these findings, the level of asthma control and asthma management in Ireland falls short of recommended national and international asthma guidelines.

Peripheral muscle strength in young males with cystic fibrosis.

BACKGROUND: In children with cystic fibrosis there is a decrease in peak work capacity and oxygen consumption on maximal exercise testing when compared to controls. Previous studies have shown that peripheral muscle force is decreased in children with cystic fibrosis even in those with minimal changes in lung function. However, no studies have examined peripheral muscle strength using isokinetic dynamometry which permits measurement of muscle strength throughout range and is considered the gold standard in orthopaedics and sports medicine. METHODS: Isokinetic muscle strength was measured in the knee flexors and extensors and shoulder flexors and extensors at two speeds of movement in children with cystic fibrosis and matched controls. Activity levels in both groups were calculated. RESULTS: Thirteen subjects and 13 age and height matched controls were assessed. Average peak torque was calculated and expressed in terms of body weight. There was a significant difference in peak torque/body weight in children with cystic fibrosis when compared to controls. FEV1 was significantly correlated with knee muscle strength and shoulder flexion at 90 degrees /s in subjects with CF. CONCLUSION: Children with CF had lower muscle strength than control subjects. Airflow limitation was associated with decreased muscle strength. The relationship between muscle strength and exercise tolerance requires investigation.

Bronchoscopically administered recombinant human DNase for lobar atelectasis in cystic fibrosis.

Lobar atelectasis is a common complication of cystic fibrosis. The majority of cases respond to intravenous antibiotics and chest physiotherapy. In a subgroup of patients, atelectasis is resistant to medical therapy, and its persistence in the pediatric population is associated with a poor prognosis. Bronchoscopic instillation of human recombinant DNase expanded atelectatic lobes in three children resistant to at least 2 weeks of medical therapy. This method of administration of DNase has been successful in resistant cases of lobar atelectasis in patients with chronic obstructive pulmonary disease, quadriplegia, and status asthmaticus. Purulent cystic fibrosis sputum has a very high DNA content, and DNA has been shown to become more pourable in vitro when treated with rhDNase. Bronchoscopic instillation of rhDNase should be considered in cases of persistent lobar atelectasis unresponsive to medical therapy.

Altered intracellular pH regulation in neutrophils from patients with cystic fibrosis.

Cystic fibrosis (CF) is a condition characterized by neutrophil-mediated lung damage and bacterial colonization. The physiological basis for reported functional alterations in CF neutrophils, including increased release of neutrophil elastase, myeloperoxidase, and oxidants, is unknown. These processes are, however, regulated by intracellular pH (pH(i)). We demonstrate here that pH(i) regulation is altered in neutrophils from CF patients. Although resting pH(i) is similar, pH(i) after acid loading and activation (N-formyl-methionyl-leucyl-phenylalanine and phorbol 12-myristate 13-acetate) is more acidic in CF cells than in normal cells. Furthermore, patients with non-CF-related bronchiectasis handle acid loading and activation in a fashion similar to subjects with normal neutrophils, suggesting that chronic pulmonary inflammation alone does not explain the difference in pH(i). This is further supported by data showing that normal neutrophils exposed to the CF pulmonary milieu respond by increasing pH(i) as opposed to decreasing pH(i) as seen in activated CF neutrophils. These pH(i) differences in activated or acid-loaded CF neutrophils are abrogated by ZnCl(2) but not by amiloride and bafilomycin A(1), suggesting that passive proton conductance is abnormal in CF. In addition, DIDS, which inhibits HCO(3)(-)/Cl(-) exchange, causes alkalinization of control but not of CF neutrophils, suggesting that anion transport is also abnormal in CF neutrophils. In summary, we have shown that pH(i) regulation in CF neutrophils is intrinsically abnormal, potentially contributing to the pulmonary manifestations of the condition.

Increased elastase release by CF neutrophils is mediated by tumor necrosis factor-alpha and interleukin-8.

Cystic fibrosis (CF) is a lethal, hereditary disorder characterized by a neutrophil-dominated inflammation of the lung. We sought to determine whether neutrophils from individuals with CF release more neutrophil elastase (NE) than neutrophils from normal subjects. Our results showed that peripheral blood neutrophils (PBNs) from normal subjects and individuals with CF contained similar amounts of NE, but after preincubation with CF bronchoalveolar lavage (BAL) fluid, significantly more NE was released by CF PBNs, a release that was amplified further by incubation with opsonized Escherichia coli. To determine which components of CF BAL fluid stimulated this excessive NE release from CF PBNs, we repeated the experiments after neutralization or immunoprecipitation of tumor necrosis factor (TNF)-alpha and interleukin (IL)-8 in CF BAL fluid. We found that subsequent NE release from CF PBNs was reduced significantly when TNF-alpha and IL-8 were removed from CF BAL fluid. When TNF-alpha and IL-8 were used as activating stimuli, CF PBNs released significantly greater amounts of NE compared with PBNs from control subjects and individuals with bronchiectasis. These results indicate that CF PBNs respond abnormally to TNF-alpha and IL-8 in CF BAL fluid and react to opsonized bacteria by releasing more NE. This may help explain the increased NE burden seen in this condition.