Michelle Klingel

Prolongation of antibiotic treatment for cystic fibrosis pulmonary exacerbations.

BACKGROUND Pulmonary exacerbations frequently lead to an irrevocable loss of lung function in cystic fibrosis (CF) patients. Although extended antibiotic duration has not been shown to be associated with improved outcomes in CF overall, it is not known whether there is a subset of patients who may benefit from longer treatment courses. METHODS This was a retrospective cohort study, using the Toronto CF Database from 1997 to 2012, of CF individuals with pulmonary exacerbations requiring intravenous antibiotic treatment. We investigated factors associated with improvement in forced expiratory volume in 1 second (FEV1) in patients treated with ≤14 days and >14 days of antibiotic treatment. RESULTS A total of 538 pulmonary exacerbations in 253 patients were used for these analysis; 39% of these exacerbations fully recovered lung function at follow-up. Exacerbations were more frequently treated with >14 days of antibiotics in older patients with lower FEV1 at exacerbation and higher rates of B. cepacia complex infections. Subjects with exacerbations treated for >14 days had a significantly greater increase in FEV1 from day 14 to follow up compared to those with ≤14 days (p<0.001). On multivariable analysis, smaller changes from days 0 to 14 of antibiotics and treatment duration>14 days were associated with greater increases in FEV1 from day 14 to follow-up. In those who received >14 days of antibiotic therapy, smaller improvements in FEV1 change from day 0 to 14 and younger age at exacerbation were significantly associated with a greater FEV1 response from day 14 to end of treatment. Antibiotic treatment >14 days was not associated with longer time to subsequent exacerbation. CONCLUSIONS This study highlights that in the treatment of pulmonary exacerbations, maximum lung function is not achieved within 14 days in all patients, and that there is continued improvement beyond this period.

A Systematic Approach to Multiple Breath Nitrogen Washout Test Quality

Background Accurate estimates of multiple breath washout (MBW) outcomes require correct operation of the device, appropriate distraction of the subject to ensure they breathe in a manner representative of their relaxed tidal breathing pattern, and appropriate interpretation of the acquired data. Based on available recommendations for an acceptable MBW test, we aimed to develop a protocol to systematically evaluate MBW measurements based on these criteria. Methods 50 MBW test occasions were systematically reviewed for technical elements and whether the breathing pattern was representative of relaxed tidal breathing by an experienced MBW operator. The impact of qualitative and quantitative criteria on inter-observer agreement was assessed across eight MBW operators (n = 20 test occasions, compared using a Kappa statistic). Results Using qualitative criteria, 46/168 trials were rejected: 16.6% were technically unacceptable and 10.7% were excluded due to inappropriate breathing pattern. Reviewer agreement was good using qualitative criteria and further improved with quantitative criteria from (κ = 0.53–0.83%) to (κ 0.73–0.97%), but at the cost of exclusion of further test occasions in this retrospective data analysis. Conclusions The application of the systematic review improved inter-observer agreement but did not affect reported MBW outcomes.

Changes in airway inflammation during pulmonary exacerbations in patients with cystic fibrosis and primary ciliary dyskinesia

Lung disease in patients with both primary ciliary dyskinesia (PCD) or cystic fibrosis (CF) is associated with impaired mucociliary clearance; however, clinical outcomes are typically worse in CF patients. We assessed whether CF and PCD patients differ in inflammatory response in the airways during pulmonary exacerbation. We first studied clinically stable PCD patients with a spectrum of bacterial pathogens to assess inflammatory response to different pathogens. Subsequently, PCD and CF patients with similar bacterial pathogens were studied at the time of a pulmonary exacerbation and after 21 days of antibiotics treatment. Qualitative and quantitative microbiology, cell counts, interleukin-8 concentrations, and neutrophil elastase activity were assessed in sputum samples obtained before and after treatment. In stable PCD patients, no significant differences were found in sputum inflammatory markers between individuals colonised with different bacterial pathogens. Pulmonary exacerbation severity assessed by a pulmonary exacerbation score and lung function decline from their previous baseline did not differ between CF and PCD patients. Bacterial density for Staphylococcus aureus and Haemophilus influenzae was higher in CF versus PCD (p<0.05), but absolute neutrophil counts were higher in PCD patients (p=0.02). While sputum elastase activity was similar in PCD and CF at the time of exacerbation, it decreased with antibiotic therapy in PCD (p<0.05) but not CF patients. PCD patients differ from those with CF in their responses to treatment of pulmonary exacerbations, with higher neutrophil elastase activity persisting in the CF airways at the end of treatment. PCD patients differ from those with CF in their responses to treatment of pulmonary exacerbations http://ow.ly/TtM54

Effect of ivacaftor therapy on exhaled nitric oxide in patients with cystic fibrosis

UNLABELLED Airways of patients with cystic fibrosis are deficient for nitric oxide. Low nitric oxide in cystic fibrosis has been shown to be associated with poor pulmonary function and risk of infection with certain pathogens. Treatment of cystic fibrosis patients with the cystic fibrosis transmembrane conductance regulator (CFTR)-targeting drug ivacaftor results in improved pulmonary function. The effect of ivacaftor on airway nitric oxide has not been assessed. METHODS In this observational trial, fractional exhaled nitric oxide (FE(NO)) was measured before and 4 weeks after initiation of ivacaftor therapy, in patients with cystic fibrosis and a CFTR gating mutation. The effect of ivacaftor on FE(NO) was compared to treatment with inhaled dornase alfa or hypertonic saline for 4 weeks, respectively. RESULTS A total of 15 patients on ivacaftor therapy were studied. Pulmonary function improved significantly and mean (±SD) FE(NO) increased from 8.5±5.0 to 16.2±15.5 ppb. The effect was more pronounced in pediatric compared to adult patients. There was no linear correlation between changes in FE(NO), pulmonary function or sweat chloride concentration. Neither treatment with inhaled dornase alfa (n=15) or hypertonic saline (n=16) resulted in a change in FE(NO). CONCLUSION Therapy with ivacaftor results in an increase in nitric oxide formation in cystic fibrosis airways, while dornase alfa or hypertonic saline has no effect on airway nitric oxide. Some beneficial effects of CFTR targeting therapy in CF may result from improved airway nitric oxide production.

Changes in magnetic resonance imaging scores and ventilation inhomogeneity in children with cystic fibrosis pulmonary exacerbations

Acute pulmonary exacerbations (aPEs) in patients with cystic fibrosis (CF) often result in incomplete recovery of lung function despite treatment, and are associated with lung function decline over time [1, 2]. Monitoring is therefore important to detect aPEs early and to track treatment responses. Recent studies testing pulmonary function with multiple breath washout (MBW) have shown that the lung clearance index (LCI), the main outcome measure of MBW, is a sensitive tool to measure early changes in the CF lung [3, 4]. However, the potential role of MBW and LCI in more advanced CF lung disease is currently unclear. In fact, a recent study demonstrated heterogeneous responses in LCI, with a significant proportion of patients with CF showing worsening of LCI with treatment for aPEs [5]. Resolution of mucus plugging, resulting in recruitment of poorly ventilated areas of the lung to MBW, would potentially explain the discordant changes in pulmonary function testing by spirometry and LCI with treatment. Resolution of mucus plugging may explain worsening LCI during pulmonary exacerbation treatment in children with CF http://ow.ly/LTLm30dp6hS

Lung clearance index response in patients with CF with class III CFTR mutations

Ivacaftor (KALYDECO) is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator that increases transmembrane chloride flux in vitro and leads to significant benefits in patients with cystic fibrosis (CF) with class III gating mutations.1–5 Ivacaftor is associated with sustained improvement in FEV1 and weight as well as reduced time to next pulmonary exacerbation.5–7 It has also been shown that 4 weeks of ivacaftor improves the lung clearance index (LCI) in patients with CF with preserved lung function.8 It is presently unclear whether LCI, a measure of ventilation inhomogeneity, provides additional information among patients with more impaired lung function as well as whether the sustained effectiveness of ivacaftor as demonstrated by improvements in the previously mentioned outcomes is also evident in the LCI response. The aim of this observational study was to assess the LCI before and after initiation of ivacaftor treatment over 6 months in patients with CF with a wider range of …

Longitudinal study of Stenotrophomonas maltophilia antibody levels and outcomes in cystic fibrosis patients

BACKGROUND Previous studies have shown an association between higher Stenotrophomonas maltophilia antibody levels and decreased lung function in patients with cystic fibrosis (CF). The purpose of this study was to assess the serologic response to S. maltophilia over time and to determine whether changes in antibody levels could predict clinical outcomes. METHODS Changes in S. maltophilia antibody levels in adult and pediatric patients with CF from 2008 to 2014 were assessed between groups of infection patterns. Regression models accounting for repeated measures were used to assess whether antibody levels could predict subsequent S. maltophilia microbiological status, and whether they are associated with lung function and subsequent pulmonary exacerbation. RESULTS A total of 409 S. maltophilia antibody samples from 135 CF patients showed that antibody levels did not change significantly between study visits, regardless of infection group. Higher antibody levels were independently associated with future culture positivity (OR 1.62; 95% CI 1.09, 2.41; p=0.02). While higher antibody levels were not independently associated with decreases in FEV1% predicted, they were associated with an increased hazard ratio for subsequent pulmonary exacerbation (HR 1.3; 95% CI 1.1, 1.6; p<0.001). CONCLUSIONS S. maltophilia antibody levels may be helpful to identify individuals at risk of exacerbation who may benefit from earlier antimicrobial treatment.

Pilot trial of tobramycin inhalation powder in cystic fibrosis patients with chronic Burkholderia cepacia complex infection

There is no effective chronic suppressive therapy Burkholderia cepacia complex infection in cystic fibrosis (CF) patients. This was a pilot, open-label clinical trial of tobramycin inhalation powder (TIP) delivered via Podhaler twice daily for 28days in adults and children with CF and chronic B. cepacia complex infection in Toronto, Canada. A total of 10 subjects (4 pediatric, 6 adult patients) were treated. There was a mean drop of 1.4 log (CFU/ml) in sputum bacterial density (p=0.01) and sputum IL-8 levels decreased significantly after 28days of TIP (p=0.04). The mean relative change in FEV1 (L) from Day 0 to Day 28 of TIP administration was a 4.6% increase but this was not statistically significant. The majority of patients (70%) had no or mild adverse events.

Extracorporeal membrane oxygenation (ECMO) as a treatment strategy for severe acute respiratory distress syndrome (ARDS) in the low tidal volume era: A systematic review☆☆☆★★★

Objective: To evaluate the hospital survival in patients with severe ARDS managed with ECMO and low tidal volume ventilation as compared to patients managed with low tidal volume ventilation alone. Methods: Electronic databases were searched for studies of at least 10 adult patients with severe ARDS comparing the use of ECMO with low tidal volume ventilation to mechanical ventilation with a low tidal volume alone. Only studies reporting hospital or ICU survival were included. All identified studies were assessed independently by two reviewers. Results: Of 1782 citations, 27 studies (n = 1674) met inclusion criteria. Hospital survival for ECMO patients ranged from 33.3 to 86%, while survival with conventional therapy ranged from 36.3 to 71.2%. Five studies were identified with appropriate control groups allowing comparison, but due to the high degree of variability between studies (I2 = 63%), their results could not be pooled. Two of these studies demonstrated a significant difference, both favouring ECMO over conventional therapy. Conclusion: Given the lack of studies with appropriate control groups, our confidence in a difference in outcome between the two therapies remains weak. Future studies on the use of ECMO for severe ARDS are needed to clarify the role of ECMO in this disease. HIGHLIGHTSIdentified 27 studies of ECMO for ARDS patients receiving lung protective ventilationFive have appropriate control groups to allow for comparison.High degree of variability between studiesTwo studies show a statistically significant difference, both favouring ECMO.Confidence in a difference in outcomes with the addition of ECMO is weak.

Early detection using qPCR of Pseudomonas aeruginosa infection in children with cystic fibrosis undergoing eradication treatment

BACKGROUND Infection with Pseudomonas aeruginosa (Pa) with a chronic phenotype is associated with antibiotic eradication therapy (AET) failure. Our objective was to determine whether higher levels of Pa (detected using qPCR) prior to culture positivity were associated with AET failure in pediatric CF patients. METHODS Pa-specific qPCR was performed on stored sputa prior to culture positivity in pediatric CF patients with new-onset culture-positive Pa infections undergoing AET with a 28-day course of tobramycin-inhaled solution (TIS). DNA concentrations were compared in patients in whom AET was successful (Eradicated) to those with persistently positive sputum cultures (Persistent). RESULTS Forty-seven patients were included. AET was successful in 32 cases (68%), but failed in 15 cases (32%). Median sputum Pa-specific DNA concentration preceding the positive sputum culture was 2.2 × 10-6 μg/mL in Eradicated cases compared to 3 × 10-5 μg/mL in Persistent cases (p = 0.14). There was no significant difference in DNA concentration in the last sputum sample prior to culture positivity, nor in maximal DNA values. There was also no difference in sputum Pa DNA concentrations in patients who had a mucoid (compared to non-mucoid) Pa infection. CONCLUSIONS Pediatric CF patients with new-onset Pa infections have detectable Pa-specific DNA in the year preceding a positive culture, however, there is no significant difference in Pa DNA concentrations between patients in whom AET is successful compared to those in whom it fails. Therefore, early molecular detection of Pa may not lead to improved eradication success rates.