The role of respiratory viruses in adult patients with cystic fibrosis receiving intravenous antibiotics for a pulmonary exacerbation

BackgroundRespiratory viruses have become increasingly recognised as important agents in pulmonary exacerbations in infants and children with CF. The aim of this study was to determine the prevalence of respiratory viruses during acute pulmonary exacerbations in adults and compare the severity of these exacerbations with non-viral associated exacerbations.MethodsThis was a retrospective case control study. Viral throat swabs were taken from all patients presenting with an acute pulmonary exacerbation requiring intravenous antibiotic treatment over a 12 month period.ResultsThere were 432 pulmonary exacerbations in 180 adults. A positive viral PCR in 42 exacerbations indicated a prevalence of 9.7%. The commonest virus isolated was rhinovirus (n = 29, 69%) with influenza A/H1N1 in seven patients (16.7%). Exacerbations associated with a positive viral PCR had a greater fall in lung function at presentation with higher levels of inflammatory markers. They received more days of intravenous antibiotics, showed less response to treatment and had a shorter time to next pulmonary exacerbation compared to matched controls.ConclusionViral associated pulmonary exacerbations in adults with CF are associated with more severe pulmonary involvement and respond less well to standard treatment.     

A smartphone application for reporting symptoms in adults with cystic fibrosis improves the detection of exacerbations: Results of a randomised controlled trial

BackgroundRespiratory exacerbations impair lung function and health-related quality of life in people with CF, with delayed identification of exacerbations often resulting in worse outcomes. We developed a smartphone application (app) for adults with CF to report symptoms to the CF team, and investigated its impact on antibiotic use and other outcomes.MethodsParticipants were randomised to intervention (use of the app weekly or sooner if symptoms had worsened) or control (usual care). The app comprised questions relating to symptoms suggestive of an exacerbation. If worsening symptoms were reported, the participant was contacted by the nurse practitioner. The primary outcome measure was the number of courses and days of intravenous (IV) antibiotics.ResultsSixty participants (29 female, aged [mean ± SD] 31 ± 9 years, FEV₁ 60 ± 18% predicted) were recruited, with 29 (48%) allocated to the intervention group. Over the 12-month follow-up, there was no clear effect of the app on the number of courses of IV antibiotics (incidence rate ratio [IRR] 1; 95% confidence interval [CI] 0.6 to 1.7), however number of courses of oral antibiotics increased (IRR 1.5; 95% CI 1.0 to 2.2). The median [IQR] time to detection of exacerbation requiring oral or IV antibiotics was shorter in the intervention group compared with the control group (70 [123] vs. 141 [140] days; p = .02). No between-group differences were observed in other outcomes.ConclusionThe use of an app reduced time to detect respiratory exacerbations that required antibiotics, however did not demonstrate a clear effect on the number of courses of IV antibiotics.     

Design and powering of cystic fibrosis clinical trials using pulmonary exacerbation as an efficacy endpoint

Background

Reduction in pulmonary exacerbations is an important efficacy endpoint for CF clinical studies. Powering exacerbation endpoints requires estimation of the future exacerbation incidence in CF study populations, but rates differ across the population.

Methods

We have estimated exacerbation rates for Epidemiologic Study of CF subpopulations stratified by age, FEV₁% predicted, sex, weight-for-age percentile, respiratory signs and symptoms, and history of exacerbation and bacterial culture. Sample sizes required to attain 80% power to detect exacerbation reductions of 20% to 80% in 1:1 randomized studies of 3 to 12 month duration were determined. Exacerbation treatments with “any” antibiotic (new oral quinolone, new inhaled antibiotic, or intravenous (IV) antibiotic) and with IV antibiotics were studied.

Results

At all ages, decreased FEV₁, female sex, exacerbation history, and Pseudomonas aeruginosa culture history were associated with increased treatment for exacerbation.

Conclusions

These data should assist investigators in the design of future CF exacerbation studies.     

Efficacy and safety of intravenous meropenem and tobramycin versus ceftazidime and tobramycin in cystic fibrosis.

BACKGROUND: Cystic fibrosis (CF) is characterized by chronic bacterial broncho-pulmonary infection. Although intravenous (i.v.) antibiotic therapy is regarded as standard treatment in CF, only few randomised trials comparing different antibiotic compounds exist. METHODS: We report on a prospective multicenter interventional trial of i.v. meropenem (120 mg/kg/day) or i.v. ceftazidime (200-400 mg/kg/day), each administered together with i.v. tobramycin (9-12 mg/kg/day). Outcome measures were changes in lung function, microbiological sputum burden and blood inflammatory marker. Liver and renal function values were measured to assess safety. RESULTS: One hundred eighteen patients (59/59) were included into the study with the following indications: first infection of P. aeruginosa (n=6), acute pulmonary exacerbation (n=34) and suppression therapy of chronic P. aeruginosa colonization (n=78). Both treatments improved lung function measures, bacterial sputum burden and CRP levels with no differences between treatment groups observed. A significant higher elevation for alkaline phosphatase (p<0.0001) was observed for patients in the meropenem/tobramycin group. CONCLUSIONS: i.v. antibiotic therapy in CF patients with meropenem/tobramycin is as effective as with ceftazidime/tobramycin regarding lung function, microbiological sputum burden and systemic inflammatory status. Hepato-biliary function should be monitored carefully during i.v. treatment, possibly important in CF patients with pre-existing liver disease.     

Measuring and improving respiratory outcomes in cystic fibrosis lung disease: Opportunities and challenges to therapy

Cystic fibrosis (CF) is a life-shortening disease with significant morbidity. Despite overall improvements in survival, patients with CF experience frequent pulmonary exacerbations and declining lung function, which often accelerates during adolescence. New treatments target steps in the pathogenesis of lung disease, such as the basic defect in CF (CF Transmembrane Conductance Regulator [CFTR]), pulmonary infections, inflammation, and mucociliary clearance. These treatments offer hope but also present challenges to patients, clinicians, and researchers. Comprehensive assessment of efficacy is critical to identify potentially beneficial treatments. Lung function and pulmonary exacerbation are the most commonly used outcome measures in CF clinical research. Other outcome measures under investigation include measures of CFTR function; biomarkers of infection, inflammation, lung injury and repair; and patient-reported outcomes. Molecular diagnostics may help elucidate the complex CF airway microbiome. As new treatments are developed for patients with CF, efforts should be made to balance treatment burden with quality of life. This review highlights emerging treatments, obstacles to optimizing outcomes, and key future directions for research.     

Randomized controlled study of aerosolized hypertonic xylitol versus hypertonic saline in hospitalized patients with pulmonary exacerbation of cystic fibrosis

BackgroundCystic fibrosis (CF) lung disease is characterized by chronic bacterial infection and recurrent pulmonary exacerbations. Xylitol is a 5-carbon sugar that can lower the airway surface salt concentration and augment innate immunity. We examined the safety and efficacy of aerosolized xylitol use for 2 weeks in subjects hospitalized with a pulmonary exacerbation of CF.MethodsIn a 2-week study, 60 subjects with cystic fibrosis and FEV₁ > 30% predicted were enrolled to receive aerosolized 7% hypertonic saline (4 ml) or 15% xylitol (5 ml) twice a day for 14 days. Outcomes assessed included change from baseline in FEV₁% predicted, change in sputum microbial density, revised CF quality of life questionnaire including the respiratory symptom score, time to next hospitalization for a pulmonary exacerbation, and frequency of adverse events.Results59 subjects completed the study (one subject in the saline group withdrew before any study product administration). No significant differences were noted between the 2 arms in mean changes in lung function, sputum microbial density for Pseudomonas aeruginosa and Staphylococcus aureus, body weight, quality of life, and frequency of adverse events.ConclusionsAerosolized hypertonic xylitol was well-tolerated among subjects hospitalized for CF pulmonary exacerbation. Future studies examining efficacy for long term use in patients with CF lung disease would be worthwhile.The clinical trial registration number for this study is NCT00928135.     

The role of respiratory viruses in cystic fibrosis

BACKGROUND: Previous studies have suggested a role played by respiratory viruses in the exacerbation of cystic fibrosis (CF). However, the impact of respiratory viruses could have been underestimated because of the low detection rate by conventional laboratory methods. METHODS: Children with CF had nasal swabs and sputum samples obtained on a routine basis and when they developed respiratory exacerbations. Nucleic Acid Sequence Based Amplification (NASBA) was used to detect respiratory viruses from nasal swabs. The definition of a respiratory exacerbation was when the symptom score totalled to 4 or more, or if the peak expiratory flow fell by more than 50 l/min from the child's usual best value, or if the parent subjectively felt that the child was developing a cold. RESULTS: 71 patients had 165 reported episodes of respiratory exacerbations. 138 exacerbation samples were obtained of which 63 (46%) were positive for respiratory viruses. In contrast, 23 of 136 asymptomatic nasal swabs (16.9%) were positive for respiratory viruses. There was significantly more viruses being detected during respiratory exacerbations, in particular influenza A, influenza B and rhinovirus (p<0.05). Upper respiratory symptoms significantly correlated with positive respiratory viral detection (p<0.05). This study also showed that viral respiratory exacerbations in CF could be independent from bacterial infections. CONCLUSIONS: Respiratory viruses are associated with exacerbations in CF and upper respiratory symptoms are strong predictors for their presence. 'Real-time' NASBA has a rapid turn-around time and has the potential to aid clinical decision making, such as the use of anti-virals and administration of antibiotics.     

Evaluating assumptions of definition-based pulmonary exacerbation endpoints in cystic fibrosis clinical trials

BackgroundCystic fibrosis (CF) pulmonary exacerbations can be serious respiratory events and reduction in exacerbation rate or risk are important efficacy endpoints for CF therapeutic trials. Variability in exacerbation diagnoses and treatment have led drug developers to employ “objective” exacerbation definitions combining antimicrobial treatment (AT) and the presence of ≥4 of 12 respiratory criteria (first published by Fuchs et al. [NEJM 1994;331(10):637–42]). Assumptions underlying this approach have yet to be formally evaluated.MethodsRespiratory events (RE) observed during a 48-week trial of ataluren (NCT02139306), a read-through agent for premature nonsense codons, were compared across six exacerbation definitions: any AT, intravenous AT (IVAT), ≥4 Fuchs criteria present, AT plus ≥4 Fuchs criteria, IVAT plus ≥4 Fuchs criteria, and investigator assessment. Fuchs definitions were evaluated by assessing missingness of individual criteria and associations between criteria presence and clinician exacerbation assessment.ResultsAmong 751 RE, more than one third had ≥4 Fuchs criteria present but were not assessed as exacerbations by investigators. Data for ≥1 and for 4 Fuchs criteria, respectively, were missing for ~ 90% and >30% of RE. Only 6/12 Fuchs criteria were present more often when investigators assessed RE as exacerbations than when they did not.Conclusions“Objective” definitions have shortcomings inconsistent with their purpose of optimizing exacerbation capture in clinical trials : 1) they capture events clinicians do not consider exacerbations, 2) are prone to data missingness which can bias the likelihood of meeting the definition, and 3) employ criteria that are not associated with investigator assessment of exacerbation.     

Relation of sputum inflammatory markers to symptoms and lung function changes in COPD exacerbations

BACKGROUND: Although it is presumed that exacerbations of chronic obstructive pulmonary disease (COPD) are associated with increased airway inflammation, there is little information available on inflammatory markers during an exacerbation and the relationship with severity or time course of recovery. A study was undertaken to investigate the sputum cell and cytokine characteristics of COPD when stable and during an exacerbation. METHODS: Induced sputum samples from 57 patients with moderate to severe COPD were analysed (44 samples were taken during a stable period and 37 during an exacerbation). The patients recorded daily symptoms on diary cards. Cell counts and sputum levels of interleukin (IL)-6 and IL-8 were measured. RESULTS: Patients with >/=3 exacerbations/year had higher median stable sputum levels of IL-6 (110 (95% CI 11 to 215) pg/ml) and IL-8 (6694 (95% CI 3120 to 11995) pg/ml) than those with 相似文献   

Fatty Acid Supplementation Improves Respiratory,Inflammatory and Nutritional Parameters in Adults with Cystic Fibrosis

Introduction and aimsChronic inflammation plays a major role in lung deterioration in cystic fibrosis (CF) patients and anti-inflammatory strategies have beneficial effects. To study the changes seen after a oneyear course of low-dose dietary supplements with a mixture of fatty acids in adult patients with CF in chronic inflammation, pulmonary status (lung function, respiratory exacerbations and antibiotic consumption), quality of life and anthropometric parameters.Patients and methodSeventeen adult subjects with CF received 324mg of eicosapentaenoic, 216mg of docosahexaenoic, 480mg of linoleic and 258mg of gammalinolenic acid daily. We assessed inflammation markers, spirometry parameters, number and severity of respiratory exacerbations, antibiotic consumption, quality of life (St George's QoL), anthropometric parameters and serum phospholipid fatty acid composition.ResultsAt the end of the treatment period TNF alpha levels fell significantly and its soluble receptors (60 and 80) rose significantly. Levels of IgG and IgM anti-oxidised LDL antibodies fell significantly. Spirometry improved significantly. Annual respiratory exacerbations and days of antibiotic treatment fell significantly. The improvement in QoL was not significant. Serum levels of docosahexaenoic, total omega-3 and linoleic acid rose significantly and more favourable profiles were seen in monoenoic acids, arachidonic acid and the arachidonic/docosahexaenoic ratio. The fat-free mass and hand grip dynamometry improved significantly.ConclusionsLow-dose supplements of n-3 and gammalinolenic fatty acids over a long period (one year) appears to improve pulmonary status (lung function, respiratory exacerbations and antibiotic consumption), inflammatory and anthropometric parameters in adults with CF.     

Effect of endoscopic sinus surgery on pulmonary status of adults with cystic fibrosis

Objective Functional endoscopic sinus surgery (FESS) provides symptomatic relief of sinus disease in patients with cystic fibrosis (CF), but it is unclear whether it has beneficial effects on lung disease in this population. This study assessed the effect of FESS on the respiratory status of adult patients with CF. Study Design Retrospective chart review. Setting Tertiary medical center. Subjects Thirty-two adult patients with CF who underwent 45 operative cases. Methods Clinical information retrieved for the 12-month periods preceding and following to determine the effect of FESS on the rate of decline in lung function, as well as intravenous antibiotic use and hospitalization for pulmonary exacerbation. Results The rate of decline in forced expiratory volume in 1 second and forced vital capacity was not significantly different in the 12 months before and after FESS. Functional endoscopic sinus surgery did not reduce days hospitalized or days on intravenous antibiotics for a respiratory exacerbation in the pre- vs postoperative period. Limiting the analysis to the 30 surgeries that were performed in patients with concomitant respiratory symptoms (ie, excluding the 15 surgeries performed for sinus symptoms alone) did not significantly alter the results. Covariates of importance in CF, including CFTR genotype, gender, or microbiology, did not affect the study results. Conclusion These results did not demonstrate an effect of FESS on progression of lung disease in patients with CF, but further research is needed because low statistical power has made some of the negative findings inconclusive.     

Aerosolized lancovutide in adolescents (≥12 years) and adults with cystic fibrosis – a randomized trial

BackgroundLancovutide activates a chloride channel (TMEM-16A) other than the cystic fibrosis (CF) transmembrane conductance regulator protein and could benefit CF patients.MethodsIn this randomized, multi-center, double-blind, placebo-controlled, parallel-group trial 161 patients ≥12 years with a confirmed diagnosis of CF were randomized to either placebo (saline) or active drug in 3 different dosing schemes of 2.5mg inhaled lancovutide (once daily, every other day or twice a week) for eight weeks. The primary endpoint was the change in the forced expiratory volume in 1 second (FEV1) percent predicted. Secondary endpoints included further lung function parameters (FEV1 (absolute), functional vital capacity percent predicted, forced expiratory flow percent predicted, pulse oximetry), quality of life assessment, pulmonary exacerbations, hospitalization due to pulmonary exacerbations, time to first pulmonary exacerbation, duration of anti-inflammatory, mucolytic or antibiotic treatment, and safety.ResultsThere was no significant difference in the change in FEV1 percent predicted, quality of life, other lung function parameters, pulmonary exacerbations or requirement of additional treatment between groups. Overall, the inhalation of lancovutide was safe although a higher rate of adverse events, especially related to the respiratory system, occurred as compared to placebo.ConclusionsLancovutide did not improve FEV1 percent predicted when compared to placebo (NCT00671736).     

Exacerbations in cystic fibrosis: 2 . prevention

The life span of people with cystic fibrosis (CF) has increased dramatically over the past 50 years. Many factors have contributed to this improvement. Respiratory exacerbations of CF lung disease are associated with the need for hospitalisation and antibiotic treatment, reduction in the quality of life, fragmented sleep and mortality. A number of preventive treatment strategies have been developed to reduce the frequency and severity of respiratory exacerbations in CF including mucolytic agents, physiotherapy and exercise, antibiotics, nutritional strategies, anti-inflammatory treatments and vaccinations against common respiratory pathogens. The evidence for each of these treatments and their potential impact is discussed.     

Why, when and how to propose noninvasive ventilation in cystic fibrosis?

Cystic fibrosis (CF) lung disease is characterized by progressive airflow obstruction, due to mucus plugging and inflammation within the bronchial walls, and destruction of the lung parenchyma secondary to bronchiectasis. These alterations result in an increase of the work of breathing, leading to alveolar hypoventilation predominantly during sleep, exercise and acute respiratory exacerbations. Noninvasive positive pressure ventilation (NPPV) has been shown to unload the respiratory muscles in patients with CF, which increases alveolar ventilation and improves gas exchange. NPPV has been shown to reduce oxygen desaturation during sleep, exercise and chest physiotherapy and may facilitate the recovery of a severe hypercapnic respiratory exacerbation. Several ventilatory modes may be used in cystic fibrosis patients but the most physiological mode is pressure support. However, validated criteria to start NPPV as well as data on long term outcome, notably in terms of improved survival and quality of life, are lacking and should be assessed in the future.     

Temocillin in cystic fibrosis: A retrospective pilot study

BackgroundTemocillin is currently used in the treatment of acute pulmonary exacerbations caused by Burkholderia cepacia complex and multi-resistant Pseudomonas aeruginosa in cystic fibrosis (CF) patients despite little published clinical data. This study assessed if intravenous (IV) antibiotic therapy including temocillin was equivalent to standard combination therapy for an acute exacerbation.MethodsA retrospective, pilot cross-over study. Adult patients attending two CF centres between 1997 and 2006 who had received a course of IV antibiotics including temocillin (TIV) and a further IV course (within ± 1 year) which did not include temocillin (NTIV) were included. Outcome measures at the start and end of each IV course were recorded (FEV₁%, FVC%).ResultsTwenty six patients had received temocillin. Baseline values of FEV₁% predicted were comparable for both groups (TIV: 37(18%), NTIV: 39(20%)). FEV₁% increased by 7.12(11.67)% after TIV (p < 0.01) and 6.65(7.62)% after NTIV (p < 0.01). There was no significant difference between the IV courses in mean %change in lung function TIV versus NTIV (FEV₁ 0.46% [95%CI: − 4.55 to 5.48%]).ConclusionThese data suggest equivalence in the lung function outcome of IV antibiotic therapy includingtemocillin versus standard IV antibiotic therapy.     

Glucocorticoids as an adjuvant treatment to intravenous antibiotics for cystic fibrosis pulmonary exacerbations: a UK Survey.

Oral glucocorticoids are widely used to treat exacerbations of asthma and COPD. A role for their use in treating exacerbations in Cystic Fibrosis (CF) is not proven. We describe the current practice, amongst UK adult CF physicians, of oral glucocorticoid use as an adjuvant to intravenous (IV) antibiotic treatment during CF pulmonary exacerbation (P EX). The survey also examined whether physicians thought a randomised controlled trial (RCT) was necessary and their willingness to participate patients in such a trial. Eighty one percent of physicians replied. All of them used corticosteroids with P EX. Most physicians supported the need for a RCT and would be willing to enroll consenting patients in the trial. This survey highlighted the need for a RCT which would examine the role of adjuvant corticosteroids to IV antibiotics in CF P EX.     

What is the clinical significance of filamentous fungi positive sputum cultures in patients with cystic fibrosis?

In patients with cystic fibrosis (CF), the isolation of filamentous fungi, in particular Aspergillus spp. in the respiratory secretions is a common occurrence. Most of these patients do not fulfil the clinical criteria for a diagnosis of allergic bronchopulmonary aspergillosis (ABPA). The clinical relevance of filamentous fungi and whether antifungal therapy should be started in patients with persistent respiratory exacerbations who do not respond to two or more courses of appropriate oral or intravenous antibiotics and in whom no other organisms are isolated from respiratory secretions is a dilemma for the CF clinician. In this article, we review the epidemiology and clinical significance of filamentous fungi in the non-ABPA CF lung, with an emphasis on Aspergillus spp. colonisation (AC), the clinical relevance of Aspergillus spp. positive respiratory cultures and the outcome following antifungal therapy in these patients.     

Withdrawal of dornase alfa increases ventilation inhomogeneity in children with cystic fibrosis

BackgroundThe lung clearance index (LCI) is increasingly used as an outcome in clinical trials of patients with mild cystic fibrosis (CF) lung disease. Yet, understanding the impact of standard CF respiratory therapy on LCI is needed. We assessed to what degree withdrawal of nebulised dornase alfa affected LCI in school-age children with CF not receiving CFTR modulators or hydrator therapy.MethodsA single-centre, randomised, controlled, parallel group study to determine effects of one month's withdrawal of nebulised dornase alfa (intervention) in 5-18 years old children with CF. Remaining chronic maintenance therapy stayed unchanged. Outcome measures were assessed at two visits one month apart. Primary outcome was absolute change in LCI. Secondary outcomes were FEV₁, FEF_25–75 and CF Questionnaire-revised (CFQ-R) respiratory symptom score. Possible harmful effects were assessed by comparing the occurrence of pulmonary exacerbations between groups.ResultsTwenty-eight children (median age 10.4 [interquartile range: 7.6; 13.5] years) with CF received standard care (n = 14) or intervention (n = 14). Compared with the control group, LCI increased (worsened) 1.74 (95% confidence interval: 0.62; 2.86) during withdrawal of dornase alfa, while FEV₁ (-6.8% predicted) and FEF_25–75 (-13.1% predicted) decreased significantly. Change in CFQ-R respiratory symptom score and the occurrence of pulmonary exacerbations did not differ significantly between groups.ConclusionsOne month's withdrawal of dornase alfa caused increasing ventilation inhomogeneity and deteriorating FEV₁ and FEF_25–75 in school-age children with mild CF. Hence, adherence to dornase alfa optimally needs to be addressed when using LCI and spirometric parameters as endpoints, even in short-term clinical trials.     

Treatment of lung infection in patients with cystic fibrosis: Current and future strategies

In patients with cystic fibrosis (CF) lung damage secondary to chronic infection is the main cause of death. Treatment of lung disease to reduce the impact of infection, inflammation and subsequent lung injury is therefore of major importance. Here we discuss the present status of antibiotic therapy for the major pathogens in CF airways, including prophylaxis against infection, eradication of early infection, suppression of chronic infection, and the treatment of infective exacerbations. We outline measures to optimize maintenance treatment for infection in the light of novel antibiotic drug formulations. We discuss new developments in culture-independent microbiological diagnostic techniques and the use of tools for monitoring the success of antibiotic treatment courses. Finally, cost-effectiveness analyses for antibiotic treatment in CF patients are discussed.