Larry C. Lands

Effect of Azithromycin on Pulmonary Function in Patients With Cystic Fibrosis Uninfected With Pseudomonas aeruginosa: A Randomized Controlled Trial

CONTEXT Azithromycin is recommended as therapy for cystic fibrosis (CF) patients with chronic Pseudomonas aeruginosa infection, but there has not been sufficient evidence to support the benefit of azithromycin in other patients with CF. OBJECTIVE To determine if azithromycin treatment improves lung function and reduces pulmonary exacerbations in pediatric CF patients uninfected with P. aeruginosa. DESIGN, SETTING, AND PARTICIPANTS A multicenter, randomized, double-blind placebo-controlled trial was conducted from February 2007 to July 2009 at 40 CF care centers in the United States and Canada. Of the 324 participants screened, 260 were randomized and received study drug. Eligibility criteria included age of 6 to 18 years, a forced expiratory volume in the first second of expiration (FEV(1)) of at least 50% predicted, and negative respiratory tract cultures for P. aeruginosa for at least 1 year. Randomization was stratified by age of 6 to 12 years vs 13 to 18 years and by CF center. INTERVENTION The active group (n = 131) received 250 mg (weight 18-35.9 kg) or 500 mg (weight > or = 36 kg) of azithromycin 3 days per week (Monday, Wednesday, and Friday) for 168 days. The placebo group (n = 129) received identically packaged placebo tablets on the same schedule. MAIN OUTCOME MEASURES The primary outcome was change in FEV(1). Exploratory outcomes included additional pulmonary function end points, pulmonary exacerbations, changes in weight and height, new use of antibiotics, and hospitalizations. Changes in microbiology and adverse events were monitored. RESULTS The mean (SD) age of participants was 10.7 (3.17) years. The mean (SD) FEV(1) at baseline and 168 days were 2.13 (0.85) L and 2.22 (0.86) L for the azithromycin group and 2.12 (0.85) L and 2.20 (0.88) L for the placebo group. The difference in the change in FEV(1) between the azithromycin and placebo groups was 0.02 L (95% confidence interval [CI], -0.05 to 0.08; P = .61). None of the exploratory pulmonary function end points were statistically significant. Pulmonary exacerbations occurred in 21% of the azithromycin group and 39% of the placebo group. Participants in the azithromycin group had a 50% reduction in exacerbations (95% CI, 31%-79%) and an increase in body weight of 0.58 kg (95% CI, 0.14-1.02) compared with placebo participants. There were no significant differences between groups in height, use of intravenous or inhaled antibiotics, or hospitalizations. Participants in the azithromycin group had no increased risk of adverse events, but had less cough (-23% treatment difference; 95% CI, -33% to -11%) and less productive cough (-11% treatment difference; 95% CI, -19% to -3%) compared with placebo participants. CONCLUSION In children and adolescents with CF uninfected with P. aeruginosa, treatment with azithromycin for 24 weeks did not result in improved pulmonary function. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00431964.

Long-term pulmonary sequelae of severe bronchopulmonary dysplasia.

OBJECTIVE To evaluate the long-term pulmonary sequelae of survivors of bronchopulmonary dysplasia (BPD) of sufficient severity to have required supplemental oxygen for at least 1 month after term. STUDY DESIGN Fifteen patients with a mean age of 1.1 years were matched to preterm infants of similar gestational age and age at time of study. Pulmonary function testing included spirometry, plethysmographic lung volumes, carbon monoxide diffusion capacity, and in 9 of 15 subjects with BPD, measurement of lung static elastic recoil pressures. RESULTS The subjects with BPD had a mean expiratory volume in 1 second (FEV1) of 64% +/- 21% predicted (4 had an FEV1 < 50% predicted) compared with 85% +/- 11% (P < .01) for the preterm children in the control group. Subjects with BPD had a significant degree of gas trapping with a residual volume to total lung capacity ratio of 37% +/- 13% compared with 25% +/- 4% for the control group (P < .01). An inverse relationship was seen between the FEV1 and the time on supplemental oxygen (r = -0.84, P < .0001), with 3 of the 4 children whose FEV1 was < 50% requiring oxygen for more than 900 days. Those with the greatest degree of airflow limitation and gas trapping had the greatest abnormalities in both shape and position of the pressure volume curves of the lung. CONCLUSION Severe BPD may result in moderate to severe long-term abnormalities in pulmonary function tests.

Prevalence of Low Bone Mass and Deficiencies of Vitamins D and K in Pediatric Patients With Cystic Fibrosis From 3 Canadian Centers

OBJECTIVE. In this cross-sectional observational study, we assessed both vitamins D and K status and bone health in pancreatic insufficient pediatric patients with cystic fibrosis from 3 Canadian cystic fibrosis centers. METHODS. Eighty-one patients who had cystic fibrosis and were clinically stable for at least 3 months were enrolled. At the time of the clinic visit, anthropometric variables, lung function, pubertal status, intake of calcium and vitamins D and K, and physical activity were assessed. Blood was taken for analysis of biochemical biomarkers of bone turnover and status of vitamins D and K, and a urine sample was obtained for calcium, creatinine, sodium, and deoxypyridoline analyses. Whole-body bone mineral content and lumbar spine (L1–L4) bone mineral density were measured. RESULTS. The children were relatively well nourished and had moderate to mild lung disease. Low bone mineral mass defined as a z score between −1.0 and −2.0, for gender and age was detected in 38% of the children for whole body and in 28% for lumbar spine. z score less than −2.0 was observed in 7 children for both bone measures. Suboptimal vitamin D status occurred in 95% of patients; suboptimal vitamin K status occurred in 82% of patients. Measures of plasma osteocalcin and carboxy-terminal propeptide type 1 procollagen and urinary deoxypyridoline compared with reference values for age, gender, and pubertal status reflected a state of suppressed bone formation and elevated bone resorption in a large proportion of the patients. CONCLUSIONS. Bone mass of the whole body and spine was lower than expected for chronological age in approximately one third of pediatric patients with cystic fibrosis irrespective of gender or age. This may be explained by the observation of low bone turnover for developmental stage as indicated by bone biomarkers. Suboptimal status of vitamins D and K may be key causative factors of the low bone status for age.

Improved glutathione status in young adult patients with cystic fibrosis supplemented with whey protein

BACKGROUND The lung disease of cystic fibrosis is associated with a chronic inflammatory reaction and an over abundance of oxidants relative to antioxidants. Glutathione functions as a major frontline defense against the build-up of oxidants in the lung. This increased demand for glutathione (GSH) in cystic fibrosis may be limiting if nutritional status is compromised. We sought to increase glutathione levels in stable patients with cystic fibrosis by supplementation with a whey-based protein. METHODS Twenty-one patients who were in stable condition were randomly assigned to take a whey protein isolate (Immunocal, 10 g twice a day) or casein placebo for 3 months. Peripheral lymphocyte GSH was used as a marker of lung GSH. Values were compared with nutritional status and lung parameters. RESULTS At baseline there were no significant differences in age, height, weight, percent ideal body weight or percent body fat. Lymphocyte GSH was similar in the two groups. After supplementation, we observed a 46.6% increase from baseline (P < 0.05) in the lymphocyte GSH levels in the supplemented group. No other changes were observed. CONCLUSION The results show that dietary supplementation with a whey-based product can increase glutathione levels in cystic fibrosis. This nutritional approach may be useful in maintaining optimal levels of GSH and counteract the deleterious effects of oxidative stress in the lung in cystic fibrosis.

A randomized double blind, placebo controlled phase 2 trial of BIIL 284 BS (an LTB4 receptor antagonist) for the treatment of lung disease in children and adults with cystic fibrosis.

BACKGROUND Airway inflammation, mediated in part by LTB4, contributes to lung destruction in patients with cystic fibrosis (CF). LTB(4)-receptor inhibition may reduce airway inflammation. We report the results of a randomized, double-blind, placebo-controlled study of the efficacy and safety of the leukotriene B(4) (LTB(4))-receptor antagonist BIIL 284 BS in CF patients. METHODS CF patients aged ≥6 years with mild to moderate lung disease were randomized to oral BIIL 284 BS or placebo once daily for 24 weeks. Co-primary endpoints were change in FEV(1) and incidence of pulmonary exacerbation. RESULTS After 420 (155 children, 265 adults) of the planned 600 patients were randomized, the trial was terminated after a planned interim analysis revealed a significant increase in pulmonary related serious adverse events (SAEs) in adults receiving BIIL 284 BS. Final analysis revealed SAEs in 36.1% of adults receiving BIIL 284 BS vs. 21.2% receiving placebo (p = 0.007), and in 29.6% of children receiving BIIL 284 BS vs. 22.9% receiving placebo (p = 0.348). In adults, the incidence of protocol-defined pulmonary exacerbation was greater in those receiving BIIL 284 BS than in those receiving placebo (33.1% vs. 18.2% respectively; p = 0.005). In children, the incidence of protocol-defined pulmonary exacerbation was 19.8% in the BIIL 284 BS arm, and 25.7% in the placebo arm (p = 0.38). CONCLUSIONS While the cause of increased SAEs and exacerbations due to BIIL 284 BS is unknown, the outcome of this trial provides a cautionary tale for the administration of potent anti-inflammatory compounds to individuals with chronic infections, as the potential to significantly suppress the inflammatory response may increase the risk of infection-related adverse events.

Effect of Azithromycin on Systemic Markers of Inflammation in Patients With Cystic Fibrosis Uninfected With Pseudomonas aeruginosa

BACKGROUND While the mechanism of action by which azithromycin exerts positive effects inpatients with cystic fibrosis remains unclear, evidence suggests that azithromycin may act as an immunomodulatory agent. We examined changes in systemic inflammatory markers in a doubleblind, randomized, controlled trial of oral azithromycin in patients 6-18 years of age with cystic fibrosis who were uninfected with Pseudomonas aeruginosa. METHODS WBC counts and differential, serum myeloperoxidase (MPO), high-sensitivity C reactive protein (hsCRP), intracellular adhesion molecule 1, IL-6, calprotectin, serum amyloid A (SAA),and granulocyte colony-stimulating factor (G-CSF) were measured at baseline and after 28 and 168 days of treatment in patients receiving either oral azithromycin or placebo. RESULTS Inflammatory markers were similar in both groups at baseline. HsCRP, MPO, SAA, calprotectin,and the absolute neutrophil count (ANC) significantly decreased from baseline today 28 in the azithromycin group compared with the placebo group ( P < .05). This treatment effect was sustained at day 168 for ANC, calprotectin, and SAA ( P < .05). Changes in hsCRP, calprotectin,and SAA at day 28 were negatively correlated with changes in FEV 1 (L) and FEV 1(% predicted), as well as both absolute and relative changes in weight ( P < .05). Except for weight (%),the associations remained significant for calprotectin; FEV 1 (L) and weight (%) remained significantly correlated with the 168-day change in hsCRP. The 168-day change in ANC was significantly correlated with changes in lung function, but not in weight; the change in G-CSF was significantly correlated with the change in weight (%) only. CONCLUSIONS In patients not infected with P aeruginosa , oral azithromycin significantly reduced neutrophil counts and serum inflammatory markers within 28 days of initiating treatment. TRIAL REGISTRY ClinicalTrials.gov; No.: NCT00431964; URL: www.clinicaltrials.gov

Long-Term Impact of Bronchopulmonary Dysplasia on Pulmonary Function

BACKGROUND Bronchopulmonary dysplasia (BPD) and the longterm respiratory consequences of prematurity are unfamiliar to adult respirologists and remain under-recognized entities to adult caregivers. In Canada, the incidence of preterm births and its main chronic respiratory complication, BPD, have increased over the past 25 years. OBJECTIVE To describe the posthospitalization morbidity, medication use, health care use and pulmonary function tests of a large cohort of individuals with preterm birth complicated by BPD. METHODS A retrospective review of the hospital records of 322 preterm infants with BPD was conducted. Outcome variables were compared across levels of disease severity. Differences between groups were tested with one-way ANOVA for continuous variables and the Mantel-Haenszel chi-squared test for ordinal variables. RESULTS Outcomes after the initial hospitalization that were associated with the initial severity of BPD were as follows: hospital readmissions in the first two years of life, the presence of developmental delay, forced expiratory volume in 1 s and forced vital capacity on pulmonary function tests in patients between eight and 15 years of age. CONCLUSION Initial BPD severity was an important predictor of pulmonary function abnormality and health care use during childhood.

Reliability and validity of the habitual activity estimation scale (HAES) in patients with cystic fibrosis

To understand potential benefits of exercise in the cystic fibrosis (CF) population, there needs to be accurate methods to quantify it. The Habitual Activity Estimation Scale (HAES) questionnaire has been shown to be a feasible tool to measure physical activity however the reliability and validity have yet to be determined in the CF population.

Evaluation of a School-Based Tuberculosis-Screening Program and Associate Investigation Targeting Recently Immigrated Children in a Low-Burden Country

CONTEXT. In countries with a low incidence of tuberculosis (TB), screening programs targeting recent immigrants from TB-endemic countries have been shown to be effective in further reducing TB incidence; however, evaluative data on some aspects of these programs remain sparse. OBJECTIVE. We sought to retrospectively evaluate a school-based screening program targeting children at high risk for TB infection in Montreal, Canada, as well as subsequently investigate family and household associates of the schoolchildren with latent TB infection (LTBI), based on adherence to LTBI therapy and cost-benefit analysis. DESIGN, SETTING, AND PARTICIPANTS. Newly arrived immigrant children (aged 4–18 years) in selected schools were screened for LTBI by using the tuberculin skin test (TST). The TST was defined as positive at an induration of ≥10 mm. Each child who tested positive on the TST was referred for medical evaluation. Family and household associates of the TST-positive child also were screened for LTBI. Classroom attendance sheets and medical charts were reviewed for 16 elementary and secondary schools that comprised the school-screening program of the Montreal Childrens Hospital from 1998 to 2003. Medical charts of the child associates (<18 years old) who were screened were reviewed also. MAIN OUTCOME MEASURES. The main outcome measures were TST-positivity rate, rate of adherence to LTBI therapy, estimation of factors associated with adherence, and net cost/benefit of the school-screening and associate-investigation programs, both respectively and as a combined program, compared with the cost of passive treatment of TB disease. RESULTS. Of 2524 immigrant children screened, 542 (21%) were TST-positive. Of 342 children started on therapy, 316 (92%) demonstrated adequate adherence. The only predictor of adherence among the schoolchildren was having ≥2 family members brought in for TB screening (adjusted odds ratio: 2.0; 95% confidence interval: 1.3–3.3). There were 599 associates investigated from the 484 TST-positive schoolchildren seen at the TB clinic. Of 555 associates with TST results, 211 (38%) were found to be TST-positive. Of 136 TST-positive child associates, 131 were seen at the Montreal Childrens Hospital TB clinic and had their chart reviewed. Of these, 108 (82%) were started on LTBI therapy, and 78 (79%) of 99 of those children with information complied adequately with their therapy. We found net benefits from both school-based screening and associate investigation, both as stand-alone programs and as 1 coordinated, targeted TB-screening program. CONCLUSION. We demonstrated the effectiveness, including cost-effectiveness, of a targeted, school-based screening program in a low-burden country and the extra benefit given by adding associates to such a program.

Long-term multicentre randomised controlled study of high frequency chest wall oscillation versus positive expiratory pressure mask in cystic fibrosis

Background Positive expiratory pressure (PEP) is the most commonly used method of airway clearance (AC) in Canada for patients with cystic fibrosis (CF) whereas, in some countries, high frequency chest wall oscillation (HFCWO) is the preferred form of AC. There have been no long-term studies comparing the efficacy of HFCWO and PEP in the CF population. Objectives To determine the long-term efficacy of HFCWO compared with PEP mask therapy in the treatment of CF as measured by the number of pulmonary exacerbations (PEs). Methods A randomised controlled study was performed in 12 CF centres in Canada. After a 2-month washout period, subjects were randomised to perform either HFCWO or PEP mask therapy for 1 year. Results 107 subjects were enrolled in the study; 51 were randomised to PEP and 56 to HFCWO. There were 19 dropouts within the study period, of which 16 occurred prior to or at the time of randomisation. There were significant differences between the groups in the mean number of PEs (1.14 for PEP vs 2.0 for HFCWO) and time to first PE (220 days for PEP vs 115 days for HFCWO, p=0.02). There was no significant difference in lung function, health-related quality of life scores or patient satisfaction scores between the two groups. PEP mask therapy required a shorter treatment time. Conclusions The results of this study favour PEP and do not support the use of HFCWO as the primary form of AC in patients with CF. Clinical Trial Registration number NCT00817180.