Peter J. Mogayzel

Cystic Fibrosis Pulmonary Guidelines: Treatment of Pulmonary Exacerbations

The natural history of cystic fibrosis lung disease is one of chronic progression with intermittent episodes of acute worsening of symptoms frequently called acute pulmonary exacerbations These exacerbations typically warrant medical intervention. It is important that appropriate therapies are recommended on the basis of available evidence of efficacy and safety. The Cystic Fibrosis Foundation therefore established a committee to define the key questions related to pulmonary exacerbations, review the clinical evidence using an evidence-based methodology, and provide recommendations to clinicians. It is hoped that these guidelines will be helpful to clinicians in the treatment of individuals with cystic fibrosis.

Cystic fibrosis pulmonary guidelines: Pulmonary complications: Hemoptysis and pneumothorax

RATIONALE Cystic fibrosis (CF) is a recessive genetic disease characterized by dehydration of the airway surface liquid and impaired mucociliary clearance. As a result, individuals with the disease have difficulty clearing pathogens from the lung and experience chronic pulmonary infections and inflammation. There may be intermittent pulmonary exacerbations or acute worsening of infection and obstruction, which require more intensive therapies. Hemoptysis and pneumothorax are complications commonly reported in patients with cystic fibrosis. OBJECTIVES This document presents the CF Foundations Pulmonary Therapies Committee recommendations for the treatment of hemoptysis and pneumothorax. METHODS The committee recognized that insufficient data exist to develop evidence-based recommendations and so used the Delphi technique to formalize an expert panels consensus process and develop explicit care recommendations. MEASUREMENTS AND MAIN RESULTS The expert panel completed the survey twice, allowing refinement of recommendations. Numeric responses to the questions were summarized and applied to a priori definitions to determine levels of consensus. Recommendations were then developed to practical treatment questions based upon the median scores and the degree of consensus. CONCLUSIONS These recommendations for the management of the patient with CF with hemoptysis and pneumothorax are designed for general use in most individuals but should be adapted to meet specific needs as determined by the individuals, their families, and their health care providers. It is hoped that the guidelines provided in this manuscript will facilitate the appropriate application of these treatments to improve and extend the lives of all individuals with cystic fibrosis.

Longitudinal association between medication adherence and lung health in people with cystic fibrosis

BACKGROUND This study examined the relationship of medication adherence to frequency of pulmonary exacerbation and rate of decline in FEV(1)% predicted (FEV(1)). METHODS 95 CF patients aged 6 years or older and prescribed a pulmonary medication, were enrolled in a longitudinal retrospective review of medication adherence and health outcomes (the occurrence and frequency of intravenous (IV) antibiotic treatments and FEV(1)) over 12-months. Pharmacy refill records were used to calculate a medication possession ratio (MPR). RESULTS Composite MPR predicted the occurrence of at least one pulmonary exacerbation requiring a course of IV antibiotics (IRR=2.34, p=0.05), but not the frequency of exacerbations, after controlling for gender, baseline FEV(1,) and regimen complexity. Composite MPR predicted baseline FEV(1) (estimate=29.81, p=.007), but not decline in FEV(1). CONCLUSIONS These results demonstrate a significant relation between medication adherence and IV antibiotics in CF patients, highlighting the importance of addressing adherence during clinic visits to improve health outcomes.

Multicenter Evaluation of Infant Lung Function Tests as Cystic Fibrosis Clinical Trial Endpoints

RATIONALE The conducting of clinical trials in infants with cystic fibrosis (CF) has been hindered by lack of sensitive outcome measures. OBJECTIVES To evaluate safety, feasibility, and ability to detect abnormalities in lung function of serial pulmonary function tests (PFTs) in infants with CF. METHODS Multicenter observational study using a commercial device, rigorous training, ongoing quality control, and over-reading of data by an independent panel. Raised volume rapid thoracoabdominal compression technique and plethysmography were performed at enrollment and at 6 and 12 months, with an additional 1-month reproducibility visit. MEASUREMENTS AND MAIN RESULTS A total of 342 procedures were performed in 100 infants with CF at 10 centers. FRC measurements were acceptable at a higher proportion of study visits (89%) than raised volume (72%) or fractional lung volume (68%) measurements. Average Z scores for many parameters differed significantly from historical control values. Mean (95% confidence interval) Z scores were: -0.52 (-0.78 to -0.25) for forced expiratory flow at 75% (FEF₇₅) for FVC; 1.92 (1.39-2.45) for FRC; 1.22 (0.68-1.76) for residual volume; 0.87 (0.60-1.13) for FRC/total lung capacity; and 0.66 (0.27-1.06) for residual volume/total lung capacity. For future multicenter clinical trials using infant PFTs as primary endpoints, minimum detectable treatment effects are presented for several sample sizes. CONCLUSIONS In this 10-center study, key PFT measures were significantly different in infants with CF than in historical control subjects. However, infant PFTs do not yet appear ready as primary efficacy endpoints for multicenter clinical trials, particularly at inexperienced sites, based on acceptability rates, variability, and potentially large sample sizes required to detect reasonable treatment effects.

Sleep-disordered breathing in children with achondroplasia

OBJECTIVE Our objective was to characterize sleep-disordered breathing in 88 children with achondroplasia aged 1 month to 12.6 years. RESULTS At the time of their initial polysomnography, five children had previously undergone tracheostomy, and seven children required supplemental oxygen. Initial polysomnography demonstrated a median obstructive apnea index of 0 (range, 0 to 19.2 apneas/hr). The median number of central apneas with desaturation per study was 0.5 (0 to 49), the median oxygen saturation nadir was 91% (50% to 99%), and the median peak end-tidal pCO2 was 47 mm Hg (36 to 87 mm Hg). Forty-two children (47.7%) had abnormal initial study results, usually caused by hypoxemia. Two children with severe obstructive sleep apnea eventually required continuous positive airway pressure therapy, and three additional children required tracheostomies. CONCLUSIONS (1) Children with achondroplasia often have sleep-related respiratory disturbances, primarily hypoxemia. (2) The majority do not have significant obstructive or central apnea; however, a substantial minority are severely affected. (3) Tonsillectomy and adenoidectomy decreases the degree of upper airway obstruction in most but not all children with achondroplasia and obstructive sleep apnea. (4) Restrictive lung disease can present at a young age in children with achondroplasia.

Cystic Fibrosis Foundation Pulmonary Guideline*. Pharmacologic Approaches to Prevention and Eradication of Initial Pseudomonas aeruginosa Infection

DESCRIPTION The Cystic Fibrosis (CF) Foundation developed clinical care guidelines for the prevention of Pseudomonas aeruginosa infection, the treatment of initial P. aeruginosa infection, and the use of bronchoscopy to obtain routine airway cultures in individuals with CF. METHODS A multidisciplinary committee developed questions about the prevention and treatment of initial P. aeruginosa infection and the use of bronchoscopy to obtain routine airway cultures. The outcome measure of interest was cultures without P. aeruginosa growth. Systematic reviews of PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials were conducted in May 2012 and August 2013. Searches combined controlled vocabulary terms and text words for CF and terms relevant to each question. The entire committee reviewed the evidence, and final recommendation statements were graded using the U.S. Preventive Services Task Force system. Recommendation 1: The CF Foundation strongly recommends inhaled antibiotic therapy for the treatment of initial or new growth of P. aeruginosa from an airway culture (certainty of net benefit, high; estimate of net benefit, substantial; grade of recommendation, A). The favored antibiotic regimen is inhaled tobramycin (300 mg twice daily) for 28 days. Recommendation 2: The CF Foundation recommends against the use of prophylactic antipseudomonal antibiotics to prevent the acquisition P. aeruginosa (certainty of net benefit, moderate; estimate of net benefit, zero; grade of recommendation, D). Recommendation 3: The CF Foundation recommends routine oropharyngeal cultures rather than bronchoalveolar lavage cultures obtained by bronchoscopy in individuals with CF who cannot expectorate sputum to determine if they are infected with P. aeruginosa (certainty of net benefit, moderate; estimate of net benefit, moderate; grade of recommendation, B).

Location and Duration of Treatment of Cystic Fibrosis Respiratory Exacerbations Do Not Affect Outcomes

RATIONALE Individuals with cystic fibrosis (CF) are subject to recurrent respiratory infections (exacerbations) that often require intravenous antibiotic treatment and may result in permanent loss of lung function. The optimal means of delivering therapy remains unclear. OBJECTIVES To determine whether duration or venue of intravenous antibiotic administration affect lung function. METHODS Data were retrospectively collected on 1,535 subjects recruited by the US CF Twin and Sibling Study from US CF care centers between 2000 and 2007. MEASUREMENTS AND MAIN RESULTS Long-term decline in FEV₁ after exacerbation was observed regardless of whether antibiotics were administered in the hospital (mean, -3.3 percentage points [95% confidence interval, -3.9 to -2.6]; n = 602 courses of therapy) or at home (mean, -3.5 percentage points [95% confidence interval, -4.5 to -2.5]; n = 232 courses of therapy); this decline was not different by venue using t tests (P = 0.69) or regression (P = 0.91). No difference in intervals between courses of antibiotics was observed between hospital (median, 119 d [interquartile range, 166]; n = 602) and home (median, 98 d [interquartile range, 155]; n = 232) (P = 0.29). Patients with greater drops in FEV₁ with exacerbations had worse long-term decline even if lung function initially recovered with treatment (P < 0.001). Examination of FEV₁ measures obtained during treatment for exacerbations indicated that improvement in FEV₁ plateaus after 7-10 days of therapy. CONCLUSIONS Intravenous antibiotic therapy for CF respiratory exacerbations administered in the hospital and in the home was found to be equivalent in terms of long-term FEV₁ change and interval between courses of antibiotics. Optimal duration of therapy (7-10 d) may be shorter than current practice. Large prospective studies are needed to answer these essential questions for CF respiratory management.

Current Treatment Recommendations for Correcting Vitamin D Deficiency in Pediatric Patients with Cystic Fibrosis Are Inadequate

OBJECTIVES To determine the prevalence of vitamin D deficiency (25-hydroxy vitamin D [25-OHD] levels in plasma <30 ng/mL) in pediatric patients with cystic fibrosis (CF), elucidate contributing factors for vitamin D deficiency, and determine the efficacy of ergocalciferol repletion strategies. STUDY DESIGN Retrospective chart review of 262 pediatric patients from January 2003 to December 2006 with linear and logistic regression analyses. RESULTS Vitamin D deficiency prevalence declined in the years studied from 86.5% to 46.2%. Patients >12 years old were more likely to have deficiency than patients <5 years old (odds ratio [OR], 3.44; 95% CI, 1.73-6.84). Levels obtained in spring and summer were less likely to be deficient compared with those obatained in fall (OR, 0.24; 95% CI, 0.10-0.61; and OR, 0.25; 95% CI, 0.11-0.61; respectively). Success of treatment with 50,000 IU of ergocalciferol once, twice, or 3 times weekly was 33%, 26%, and 43%, respectively. Ergocalciferol, when compared with no treatment, did not significantly increase the proportion of patients with follow-up levels > or =30 ng/mL (chi(2)P value = .80, .34, and .22, respectively). CONCLUSIONS The prevalence of vitamin D deficiency is high, but declined with time. Age, forced expiratory volume in 1 second, and season were associated with 25-OHD levels. Despite 33% of patients responding to 50 000 IU of ergocalciferol once a week, this recommendation does not adequately treat most patients with CF who have vitamin D deficiency.

Increased Mortality After Pulmonary Fungal Infection Within the First Year After Pediatric Lung Transplantation

BACKGROUND Risk factors, morbidity and mortality from pulmonary fungal infections (PFIs) within the first year after pediatric lung transplant have not previously been characterized. METHODS A retrospective, multicenter study from 1988 to 2005 was conducted with institutional approval from the 12 participating centers in North America and Europe. Data were recorded for the first post-transplant year. The log-rank test assessed for the association between PFI and survival. Associations between time to PFI and risk factors were assessed by Cox proportional hazards models. RESULTS Of the 555 subjects transplanted, 58 (10.5%) had 62 proven (Candida, Aspergillus or other) or probable (Aspergillus or other) PFIs within the first year post-transplant. The mean age for PFI subjects was 14.0 years vs 11.4 years for non-PFI subjects (p < 0.01). Candida and Aspergillus species were recovered equally for proven disease. Comparing subjects with PFI (n = 58) vs those without (n = 404), pre-transplant colonization was associated with PFI (hazard ratio [HR] 2.0; 95% CI 0.95 to 4.3, p = 0.067). Cytomegalovirus (CMV) mismatch, tacrolimus-based regimen and age >15 years were associated with PFI (p < 0.05). PFI was associated with any prior rejection higher than Grade A2 (HR 2.1; 95% CI 1.2 to 3.6). Cystic fibrosis, induction therapy, transplant era and type of transplant were not associated with PFI. PFI was independently associated with decreased 12-month survival (HR 3.9, 95% CI 2.2 to 6.8). CONCLUSIONS Risk factors for PFI include Grade A2 rejection, repeated acute rejection, CMV-positive donor, tacrolimus-based regimen and pre-transplant colonization.

Early Eradication of Pseudomonas aeruginosa in Patients with Cystic Fibrosis

Pseudomonas aeruginosa (Pa) is the predominant organism infecting the airways of patients with cystic fibrosis (CF). This organism has an armamentarium of survival mechanisms that allows it to survive in the CF airway. Since colonization and chronic infection with Pa is associated with poorer lung function and increased morbidity and mortality, therapies that can prevent infection could significantly improve the lives of patients with CF. Numerous studies have examined the effects of treatment on the eradication of Pa as a means to ameliorate disease. This article outlines the pathophysiology and clinical implication of Pa acquisition, and reviews the existing treatment regimens aimed at early eradication of Pa in patients with CF.