Karen McKay

Inhaled mannitol improves lung function in cystic fibrosis

BACKGROUND The airways in patients with cystic fibrosis (CF) are characterized by the accumulation of tenacious, dehydrated mucus that is a precursor for chronic infection, inflammation, and tissue destruction. The clearance of mucus is an integral component of daily therapy. Inhaled mannitol is an osmotic agent that increases the water content of the airway surface liquid, and improves the clearance of mucus with the potential to improve lung function and respiratory health. To this end, this study examined the efficacy and safety of therapy with inhaled mannitol over a 2-week period. METHODS This was a randomized, double-blind, placebo-controlled, crossover study. Thirty-nine subjects with mild-to-moderate CF lung disease inhaled 420 mg of mannitol or placebo twice daily for 2 weeks. Following a 2-week washout period, subjects were entered in the reciprocal treatment arm. Lung function, respiratory symptoms, quality of life, and safety were assessed. RESULTS Mannitol treatment increased FEV(1) from baseline by a mean of 7.0% (95% confidence interval [CI], 3.3 to 10.7) compared to placebo 0.3% (95% CI, - 3.4 to 4.0; p < 0.001). The absolute improvement with mannitol therapy was 121 mL (95% CI, 56.3 to 185.7), which was significantly more than that with placebo (0 mL; 95% CI, - 64.7 to 64.7). The forced expiratory flow in the middle half of the FVC increased by 15.5% (95% CI, - 6.5 to 24.6) compared to that with placebo (increase, 0.7%; 95% CI, - 8.3 to 9.7; p < 0.02). The safety profile of mannitol was adequate, and no serious adverse events related to treatment were observed. CONCLUSIONS Inhaled mannitol treatment over a period of 2 weeks significantly improved lung function in patients with CF. Mannitol therapy was safe and well tolerated. TRIAL REGISTRATION (ClinicalTrials.gov) Identifier: NCT00455130.

Airway smooth muscle thickness in asthma is related to severity but not duration of asthma

Asthma is characterised by an increased airway smooth muscle (ASM) area (ASMarea) within the airway wall. The present study examined the relationship of factors including severity and duration of asthma to ASMarea. The perimeter of the basement membrane (PBM) and ASMarea were measured on transverse sections of large and small airways from post mortem cases of fatal (n = 107) and nonfatal asthma (n = 37) and from control subjects (n = 69). The thickness of ASM (ASMarea/PBM) was compared between asthma groups using multivariate linear regression. When all airways were considered together, ASMarea/PBM (in millimetres) was increased in nonfatal (median 0.04; interquartile range 0.013–0.051; p = 0.034) and fatal cases of asthma (0.048; 0.025–0.078; p<0.001) compared with controls (0.036; 0.024–0.042). Compared with cases of nonfatal asthma, ASMarea/PBM was greater in cases of fatal asthma in large (p<0.001) and medium (p<0.001), but not small, airways. ASMarea/PBM was not related to duration of asthma, age of onset of asthma, sex or smoking. No effect due to study centre, other than that due to sampling strategy, was found. The thickness of the ASM layer is increased in asthma and is related to the severity of asthma but not its duration.

Normal Development of the Lung and Premature Birth

The following review focuses on the normal development of the lung from conception to birth. The defined periods of lung development-Embryonic, Pseudoglandular, Canalicular, Saccular and Alveolar-will be explored in detail in relation to gestational age. Cellular differentiation, formation of the conducting airways and respiratory zone and development of the alveoli will be reviewed. Pulmonary vascular development will also be examined within these periods to relate the formation of the blood-air barrier to the lungs for their essential function of gas exchange after birth. The development of the surfactant and cortisol systems will also be discussed as these need to be mature before the lungs are able to take on their role of respiration following birth. It is clear that premature birth interrupts normal lung development so the effect of preterm birth on lung development will be examined and the respiratory consequences of very preterm birth will be briefly explored.

The mechanism of action of endothelin in human lung

1 The peptides endothelin‐1 (ET‐1) and endothelin‐2 (ET‐2) elicited potent and sustained contractions of human isolated bronchus and pulmonary artery. 2 ET‐1 is one of the most potent contractile agonists investigated in these tissues with an EC50 value of 18.3 nm (95% confidence interval: 12.9, 25.9 nm; n = 26) in bronchus and 3.2 nm (95% confidence interval: 0.4, 23.9 nm; n = 5) in the arterial preparation. 3 ET‐1 is 2.5 times more potent than ET‐2 in both the airway and vascular tissues, and both forms of the peptide have geometric mean EC50 values 5 times greater in the isolated bronchial tissue than in the pulmonary artery. 4 Neither pretreatment with the voltage‐dependent calcium (VDC) channel antagonist verapamil (10 μm) nor with indomethacin (25 μm) significantly altered the response curve to ET‐1 in human isolated bronchus. Removal of calcium from the Krebs‐Henseleit solution did not affect ET‐1‐induced responses. 5 Specific binding on the smooth muscle of human airway and pulmonary arterial tissue to both ET‐1 and ET‐2 was detected in autoradiographic studies. There appeared to be no difference between the peptides in the location nor the density of binding sites. 6 We conclude that contraction of human bronchial tissue by ET‐1 is not dependent upon influence of extracellular calcium nor release of prostaglandins or thromboxane A2. It is likely that the action of ET‐1 in this tissue is due to binding of this peptide to specific receptors located on the smooth muscle.

Improved survival in cystic fibrosis patients diagnosed by newborn screening compared to a historical cohort from the same centre

Background Newborn screening (NBS) for cystic fibrosis (CF) is associated with improved early nutritional outcomes and improved spirometry in children. The aim of this study was to determine whether early diagnosis and treatment of CF with NBS in New South Wales in 1981 led to better clinical outcomes and survival into early adulthood. Methods Retrospective observational study comprising two original cohorts born in the 3 years before (‘non-screened cohort’, n=57) and after (‘screened’; n=60) the introduction of NBS. Patient records were assessed at transfer from paediatric to adult care by age 19 years and survival was documented to age 25 years. Results Non-screened patients (n=38) when compared with screened patients (n=41) had a higher rate and lower age of Pseudomonas aeruginosa acquisition at age 18 years (p≤0.01). Height, weight and body mass index (BMI) z scores (all p<0.01) and forced expiratory volume in 1 s (FEV1)% were better in the screened group (n=41) (difference: 16.7±6.4%; p=0.01) compared to non-screened (n=38) subjects on transfer to adult care. Each 1% increase in FEV1% was associated with a 3% (95% CI 1% to 5%; p=0.001) decrease in risk of death and each 1.0 kg/m2 increase in BMI contributed to a 44% (95% CI 31% to 55%; p<0.001) decrease in risk of death. This accumulated in a significant survival difference at age 25 years (25 vs 13 deaths or lung transplants; p=0.01). Conclusion NBS for CF leads to better lung function, nutritional status and improved survival in screened patients in early adulthood.

Low lung volume alters contractile properties of airway smooth muscle in sheep

Breathing at volumes lower than functional residual capacity (FRC) can induce changes in nonasthmatic airways consistent with the behaviour of asthmatic airways. This study investigated the chronic effect of breathing at volumes lower than FRC on the contractility of airway smooth muscle and myosin light chain kinase (MLCK) content and activity. Sheep of three age groups (neonate, adolescent and adult) had their FRC reduced by ∼25% for 4 weeks using a leather corset. Contractile responses to carbachol were then recorded in isolated tracheal strips and bronchial rings. MLCK content and activity were assessed by immunoblotting. The rate of stress generation increased in the bronchial smooth muscle of both adult and adolescent but not neonatal corseted sheep: adolescent corseted versus control, 65.0±4.1 versus 103.4±7.0 s (to reach 50% maximum stress), respectively; and adult corseted versus control, 57.0±6.4 versus 93.4±8.2 s, respectively. This was not due to increases in either bronchial or tracheal smooth muscle amount or MLCK content and activity. The present results indicate that chronic breathing at low lung volumes increases the rate of stress generation in airway smooth muscle.

The impact of meconium ileus on the clinical course of children with cystic fibrosis

The present study was designed to compare the clinical course of children diagnosed with cystic fibrosis (CF) in infancy due to the presence of meconium ileus (MI) with children diagnosed by way of a newborn screening programme (non-MI). A matched case-control study design was used. Matching was performed on the basis of sex and date of birth. All children born in New South Wales, Australia after 1980 and who had attended the CF clinic at The Childrens Hospital at Westmead since diagnosis were included as possible cases or controls. Parameters pertaining to the clinical course were compared in 39 matched pairs. MI children had a significantly worse pulmonary status. The forced expiratory volume in one second was 16.3 +/- 5.2% higher (p<0.001, n=21 pairs) and the forced vital capacity value 10.5 +/- 4.7%, higher (p<0.05, n=21 pairs) in non-MI children. The difference between the pairs (18.6 +/- 4.4 MI and 20.5 +/- 3.4 non-MI) in the Shwachman chest radiograph score was statistically significant (p<0.05, n=39 pairs). There were no significant differences in any other assessed parameters, such as height, weight, the presence of liver function abnormalities, the frequency of hospitalization or airway microbial colonization. Meconium ileus may be an early indication of a more severe phenotype of cystic fibrosis. This was suggested by the significantly lower pulmonary function found in children with a history of meconium ileus compared to age- and sex-matched children who did not have meconium ileus.

Distribution of airway smooth muscle remodelling in asthma: Relation to airway inflammation

Pathological phenotypes of asthma have been based predominantly on inflammation, rather than airway wall remodelling. Differences in the distribution of airway smooth muscle (ASM) remodelling between large and small airways may affect clinical outcomes in asthma. The aim of this study was to examine the distribution of ASM remodelling and its relation to airway inflammation.

Pseudomonas aeruginosa genotypes acquired by children with cystic fibrosis by age 5-years.

BACKGROUND We describe Pseudomonas aeruginosa acquisitions in children with cystic fibrosis (CF) aged ≤5-years, eradication treatment efficacy, and genotypic relationships between upper and lower airway isolates and strains from non-CF sources. METHODS Of 168 CF children aged ≤5-years in a bronchoalveolar lavage (BAL)-directed therapy trial, 155 had detailed microbiological results. Overall, 201/271 (74%) P. aeruginosa isolates from BAL and oropharyngeal cultures were available for genotyping, including those collected before and after eradication therapy. RESULTS Eighty-two (53%) subjects acquired P. aeruginosa, of which most were unique strains. Initial eradication success rate was 90%, but 36 (44%) reacquired P. aeruginosa, with genotypic substitutions more common in BAL (12/14) than oropharyngeal (3/11) cultures. Moreover, oropharyngeal cultures did not predict BAL genotypes reliably. CONCLUSIONS CF children acquire environmental P. aeruginosa strains frequently. However, discordance between BAL and oropharyngeal strains raises questions over upper airway reservoirs and how to best determine eradication in non-expectorating children.

Cystic fibrosis in Australia, 2009: results from a data registry

Objectives: To describe the demographics, clinical features and outcomes among people with cystic fibrosis (CF) in Australia and to estimate incidence of the disease.