Christopher H. Goss

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.

Incidence of acute lung injury in the United States

OBJECTIVE Recent estimates of acute respiratory distress syndrome (ARDS) incidence have varied from 1.3 to 22 per 100,000 person years (105 person.years); the incidence of acute lung injury (ALI) has varied from 17.9 to 34 cases per 105 person.years. Potential reasons for this wide range include differences in the definition of the syndrome, in the populations sampled, and in the assumptions made to estimate incidence. We hypothesized that careful, prospective, protocol-driven case identification that included the milder hypoxemia criterion for ALI would yield incidence numbers greater than previously reported. DESIGN Prospective cohort study with extrapolation to the U.S. population. SETTING National Heart, Lung, and Blood Institute-sponsored ARDS Network composed of 20 hospitals. PATIENTS As part of the National Institutes of Health-sponsored ARDS network, 20 hospitals prospectively identified patients with ALI from 1996 to 1999. Screening logs from this study were used to estimate ALI rates per intensive care unit (ICU) bed per year. We used the registry and data from the American Hospital Association to estimate the incidence of ALI in the United States. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS The ALI per ICU bed incidence in the ARDS network registry varied from 0.7 to 5.8 cases of ALI per ICU bed per year with an average of 2.2 cases of ALI per ICU bed per year. We tested the robustness of the incidence estimate by performing a variety of sensitivity analyses. When we used the conservative assumptions that the ARDS network screening logs were complete at each of the participating hospitals and that ALI cases are limited to academic hospitals with > or =20 adult ICU beds, the incidence of ALI in adults in the United States is 22.4 cases per 105 person.years. Under the less conservative assumption that ALI cases occurred only at hospitals with > or =20 ICU beds, regardless of their academic status, the incidence of ALI in the United States is estimated at 64.2 cases per 105 person.years. CONCLUSIONS Based on this analysis, which used prospective clinical trial screening data and conservative assumptions about where patients with ALI are cared for, the incidence of ALI in the United States appears to be higher than previously reported.

Exacerbations in cystic fibrosis · 1: Epidemiology and pathogenesis

With the improving survival of patients with cystic fibrosis (CF), the clinical spectrum of this complex multisystem disease continues to evolve. One of the most important clinical events for patients with CF in the course of this disease is an acute pulmonary exacerbation. Clinical and microbial epidemiology studies of CF pulmonary exacerbations continue to provide important insight into the course, prognosis and complications of the disease. This review provides a summary of the pathophysiology, clinical epidemiology and microbial epidemiology of a CF pulmonary exacerbation.

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.

Clinician statements and family satisfaction with family conferences in the intensive care unit

Objectives:The quality of family-clinician communication in the intensive care unit is often inadequate, but little is known about specific clinician communication behaviors that might improve family satisfaction. In this exploratory analysis, we hypothesized that clinicians’ communication behaviors providing emotional support to families during intensive care unit conferences would be associated with increased family satisfaction. Design:We audiotaped 51 intensive care unit family conferences in which withholding or withdrawing life support was discussed or bad news was delivered. Emotional support techniques used by clinicians during each conference were identified and coded using grounded theory. Setting:Four Seattle hospitals. Subjects:Family members of critically ill patients. Interventions:Questionnaires rating satisfaction with communication were completed by 169 family members. Measurements and Main Results:Linear regression with generalized estimating equation methods was used to analyze the association between the frequency of clinicians’ emotionally supportive statements and family satisfaction. Increasing frequency of three types of clinicians’ statements during family conferences was associated with increased family satisfaction: a) assurances that the patient will not be abandoned before death (p = .015); b) assurances that the patient will be comfortable and will not suffer (p = .029); and c) support for family’s decisions about end- of-life care, including support for family’s decision to withdraw or not to withdraw life-support (p = .005). Conclusions:Most family members participating in this study were quite satisfied with the communication in the family conferences. Specific clinician communication behaviors are associated with increased family satisfaction during family conferences among family members who are willing to have a family conference recorded. Our results suggest that clinicians in the intensive care unit may improve the experiences of families of critically ill patients by providing explicit support for decisions made by a family with regard to end-of-life care and by assuring families continuity of high-quality care with particular attention to the patient’s comfort.

Pulmonary exacerbations are associated with subsequent FEV1 decline in both adults and children with cystic fibrosis

Patients with cystic fibrosis (CF) frequently experience pulmonary exacerbations that may lead to a faster subsequent decline in pulmonary function; however, this relationship has not been clearly established. The purpose of this study was to determine the association between the frequency of pulmonary exacerbations and subsequent forced expiratory volume in 1 sec (FEV1) decline in adults and children with CF.

Longevity of Patients With Cystic Fibrosis in 2000 to 2010 and Beyond: Survival Analysis of the Cystic Fibrosis Foundation Patient Registry

Context Cystic fibrosis (CF) is a life-shortening disease, but care has improved. An updated assessment of survival is important for patients and their families and to plan for the health care needs of an increasing number of patients with CF living to adulthood. Contribution The survival of patients with CF enrolled in a national registry increased between 2000 and 2010. Conservative estimates assuming no further improvements suggest that median survival of a patient born and diagnosed in 2010 would be about 39 years. Implication The prognosis of patients with CF has improved, and more of these patients can be expected to need adult care. The Editors Cystic fibrosis (CF) is a heritable, life-shortening disease in which dysfunction of the CF transmembrane conductance regulator (CFTR) epithelial chloride channel dehydrates secretions in the airways, the pancreatic ducts, and elsewhere in the body, causing progressive organ damage (1). In 1966, the Cystic Fibrosis Foundation Patient Registry (CFFPR) was established to track the natural history of the disease, the effect of treatments, and patient health status and to design clinical trials. Registry data have been used to describe survival in CF and the role of specific clinical features in outcomes (25). Approximately 30000 persons in the United States have CF (2), and slightly more than 26000 living persons were represented in the CFFPR in 2010. In the earliest years of the CFFPR, persons with CF did not live to attend elementary school (6). By 2010, almost half of the patients in the registry were aged 18 years or older (6, 7). Advances in pulmonary and nutritional therapies continue to extend the life span of patients with CF. Daily regimens include airway clearance therapy; inhaled mucoactive agents and antibiotics; and a high-calorie, high-fat diet (8, 9). Early identification and management of CF-related diabetes (CFRD) has also been emphasized as a standard of care (10). In addition, universal newborn screening for CF, which has been linked to overall improved health by enabling earlier initiation of treatment (11), was instituted in all 50 states by 2009. Of persons diagnosed in 2010, 57.5% were diagnosed by newborn screening compared with only 8.0% of those diagnosed in 2000 (12). As new therapies emerge and patients with CF live longer, estimating survival is essential to providing an accurate prognosis to parents of newly diagnosed infants. Understandably, parents of children diagnosed with the disease want to provide the best possible care for their child and seek to understand what their childs future will hold (13). Because adults with CF are increasingly apt to pursue life-defining activities, such as marriage, parenthood, higher education, and employment (7, 14), parents may also need to reassess their supportive roles, such as during the period of transition from pediatric to adult care (15). Updated survival estimates will also inform the medical needs of an expanding population of adults with CF (16, 17). Decades of exposure to aminoglycosides are likely to result in increased vestibular (18) and renal dysfunction (19) in the older CF patient population. The prevalence of microvascular complications from CFRD (microalbuminuria, peripheral neuropathy, and retinopathy) increases with the duration of CFRD and should therefore inform screening efforts in older adults (20). Clinicians must also remain vigilant for depression and anxiety (21) among aging patients with CF. Additional unanticipated complications may emerge as the CF patient population continues to age. Recent evaluations of survival in the United Kingdom suggest that children diagnosed with CF since 2000 can anticipate a median survival greater than 50 years (22). Our objective in this study was to characterize survival in the United States between 2000 and 2010 in order to project survival for children born and diagnosed with CF in 2010 and thereby improve the clarity of prognostic dialogue and inform adult care needs. Methods The CFFPR is an institutional review boardapproved observational study at 110 Cystic Fibrosis Foundationaccredited care centers, encompassing more than 260 adult, pediatric, and affiliate programs. Data on patients with CF who have provided consent are collected through a secure Web-based portal. Findings on clinical presentation (such as respiratory symptoms, failure to thrive, and positive newborn screening result confirmed as CF); age at diagnosis; and encounter-based measures of nutritional status, pulmonary function, respiratory cultures, prescribed therapies, and CF-related complications are collected. Our analyses used data from patients in the CFFPR between 1 January 2000 and 31 December 2010 with a confirmed diagnosis of CF based on genotype and phenotype (including sweat chloride, pulmonary function, pancreatic status, and respiratory microbiology) (23). We sought to describe survival between 2000 and 2010, with analysis of mortality according to age, age at diagnosis, gender, race or ethnicity, F508del mutation status, and calendar year, and to project survival of children born and diagnosed with CF in 2010. Statistical Analysis We assessed trends in mortality between 2000 and 2010 by using multivariable Cox proportional hazards models. Calendar year was included as a time-dependent covariate, both as a continuous variable to estimate the rate of change over the decade and as a categorical indicator variable to estimate the rate relative to the year 2000. The time scale in the Cox proportional hazards models was age, with left truncation at entry into the registry or the year 2000, whichever occurred later. We adjusted for gender, race or ethnicity, F508del mutation status, presence of symptoms at diagnosis, and age at diagnosis (24, 25) because these patient characteristics are known at diagnosis (time-independent), are not modifiable by clinical care, and have been shown to be important predictors of survival in CF (24, 25). Therefore, these factors will be most relevant to clinicians who are providing information on prognosis to parents of children with the disease. We adjusted for F508del mutation status because it is an important predictor of survival (26) and its distribution in the CFFPR decreased during the study period. Furthermore, the F508del mutation accounts for approximately 70% of abnormal CFTR alleles, and approximately half of persons with CF are homozygous for this mutation (27). We estimated absolute annual mortality as a function of age, gender, and F508del mutation status for the period from 2000 to 2010 by smoothing age-specific rates with a triangular kernel with a radius of 5 years. Further details on the Cox proportional hazards models, the smoothed estimate of mortality, and subgroup analyses can be found in Appendix 1. We projected survival of children born and diagnosed with CF in 2010 because most future diagnoses will be made early in life due to universal newborn screening. Diagnoses made beyond infancy will probably be in persons with residual CFTR function and a milder phenotype. We present overall results and those stratified by gender and F508del mutation status using the mortality hazards estimated with data from 2000 to 2010 (additional information is provided in Appendix 2). We derived projections assuming that mortality does not change from the rate observed in 2010, mortality decreases at the same rate observed between 2000 and 2010 (1.8%), and mortality decreases at half the rate observed between 2000 and 2010 (0.9%). Institutional review board approval to conduct these analyses was obtained from the Dartmouth Committee for the Protection of Human Subjects. We used R, version 2.15.1, for the analyses, specifically the libraries survival and quantreg. Role of the Funding Source This project was funded by the Cystic Fibrosis Foundation. The funding source had no role in the design, conduct, or analysis of the study but provided access to the CFFPR data and contributed to the interpretation of the findings and the manuscript. Results Table 1 shows characteristics of all 34547 unique patients in the CFFPR from 2000 to 2010. Of these, we excluded patients with missing genotype data (11.9%) and those with missing data on gender, age at diagnosis, or age at entry into the registry (0.4%) from further analyses. Fewer than 4000 individuals (approximately 2.0% per year) were lost to follow-up, with no death date recorded. Between 2000 and 2010, the median age of the cohort increased from 14.3 to 16.7 years and the proportion of patients aged 18 years or older increased from 39% to 48%. Among newly diagnosed patients (that is, those with incident disease), the median age at diagnosis decreased from 6 months in 2000 to 1 month in 2010. The proportion of persons in the CFFPR who were homozygous for the F508del mutation decreased from 51% to 48%. Forty-two percent of patients entering the CFFPR in 2000 were homozygous for the F508del mutation compared with 36% of those entering in 2010. Table 1. Characteristics of Patients in the Cystic Fibrosis Foundation Patient Registry Mortality rate ratios from 2000 to 2010 with respect to calendar year, age at diagnosis, presentation at diagnosis, race or ethnicity, gender, and F508del mutation status are shown in Table 2. Mortality decreased with increasing age at diagnosis; for example, patients diagnosed between ages 5 and 9 years had a 21% (95% CI, 9% to 31%) lower adjusted risk for death than those diagnosed before age 1 year. Males had a 19% (CI, 13% to 24%) lower adjusted risk for death than females. Compared with patients who were homozygous for the F508del mutation, those with 1 copy of the mutation and those with no copies had a 14% (CI, 7% to 20%) and 25% (CI, 15% to 34%) lower adjusted risk for death, respectively. As reported in Table 2, the adjusted hazard ratio for the 10-year change in calendar year (2000 to 2010) was 0.83 (CI, 0.75 to 0.93), which equates to a 17%

The Cystic Fibrosis Foundation Patient Registry. Design and Methods of a National Observational Disease Registry

RATIONALE The Cystic Fibrosis Foundation Patient Registry (CFFPR) is an ongoing patient registry study that collects longitudinal demographic, clinical, and treatment information about persons with cystic fibrosis (CF) in the United States. CF is a life-shortening genetic disorder that occurs in approximately 1 in 3,500 births in the United States. High-quality observational data is important for clinical research, quality improvement, and clinical management. OBJECTIVES To describe the data collection, patient population, and key limitations of the CFFPR. METHODS Inclusion criteria for the CFFPR include diagnosis with CF or a CFTR-associated disorder, care at an accredited care center program, and provision of informed consent. Data from clinic visits and hospitalizations are collected through a secure website. Loss to follow-up and generalizability were examined using several methods. The accuracy of CFFPR data was evaluated with an audit of 2012 CFFPR data compared to the medical record. MEASUREMENTS AND MAIN RESULTS Since 1986, the CFFPR contains the records of 48,463 individuals with CF. Participation among individuals seen at accredited care centers is high, and loss to follow-up is low. An audit of 2012 CFFPR data suggests that the CFFPR contains 95% of clinic visits and 90% of hospitalizations found in the medical record for these patients, and nearly all of the audited fields were highly accurate. CONCLUSIONS Registries such as the CFFPR are important tools for research, clinical care, and tracking incidence, mortality and population trends.

Phase II studies of nebulised Arikace in CF patients with Pseudomonas aeruginosa infection

Rationale Arikace is a liposomal amikacin preparation for aerosol delivery with potent Pseudomonas aeruginosa killing and prolonged lung deposition. Objectives To examine the safety and efficacy of 28 days of once-daily Arikace in cystic fibrosis (CF) patients chronically infected with P aeruginosa. Methods 105 subjects were evaluated in double-blind, placebo-controlled studies. Subjects were randomised to once-daily Arikace (70, 140, 280 and 560 mg; n=7, 5, 21 and 36 subjects) or placebo (n=36) for 28 days. Primary outcomes included safety and tolerability. Secondary outcomes included lung function (forced expiratory volume at one second (FEV1)), P aeruginosa density in sputum, and the Cystic Fibrosis Quality of Life Questionnaire—Revised (CFQ-R). Results The adverse event profile was similar among Arikace and placebo subjects. The relative change in FEV1 was higher in the 560 mg dose group at day 28 (p=0.033) and at day 56 (28 days post-treatment, 0.093L±0.203 vs −0.032L±0.119; p=0.003) versus placebo. Sputum P aeruginosa density decreased >1 log in the 560 mg group versus placebo (days 14, 28 and 35; p=0.021). The Respiratory Domain of the CFQ-R increased by the Minimal Clinically Important Difference (MCID) in 67% of Arikace subjects (560 mg) versus 36% of placebo (p=0.006), and correlated with FEV1 improvements at days 14, 28 and 42 (p<0.05). An open-label extension (560 mg Arikace) for 28 days followed by 56 days off over six cycles confirmed durable improvements in lung function and sputum P aeruginosa density (n=49). Conclusions Once-daily Arikace demonstrated acute tolerability, safety, biologic activity and efficacy in patients with CF with P aeruginosa infection.

Monitoring Influenza Activity in the United States: A Comparison of Traditional Surveillance Systems with Google Flu Trends

Background Google Flu Trends was developed to estimate US influenza-like illness (ILI) rates from internet searches; however ILI does not necessarily correlate with actual influenza virus infections. Methods and Findings Influenza activity data from 2003–04 through 2007–08 were obtained from three US surveillance systems: Google Flu Trends, CDC Outpatient ILI Surveillance Network (CDC ILI Surveillance), and US Influenza Virologic Surveillance System (CDC Virus Surveillance). Pearsons correlation coefficients with 95% confidence intervals (95% CI) were calculated to compare surveillance data. An analysis was performed to investigate outlier observations and determine the extent to which they affected the correlations between surveillance data. Pearsons correlation coefficient describing Google Flu Trends and CDC Virus Surveillance over the study period was 0.72 (95% CI: 0.64, 0.79). The correlation between CDC ILI Surveillance and CDC Virus Surveillance over the same period was 0.85 (95% CI: 0.81, 0.89). Most of the outlier observations in both comparisons were from the 2003–04 influenza season. Exclusion of the outlier observations did not substantially improve the correlation between Google Flu Trends and CDC Virus Surveillance (0.82; 95% CI: 0.76, 0.87) or CDC ILI Surveillance and CDC Virus Surveillance (0.86; 95%CI: 0.82, 0.90). Conclusions This analysis demonstrates that while Google Flu Trends is highly correlated with rates of ILI, it has a lower correlation with surveillance for laboratory-confirmed influenza. Most of the outlier observations occurred during the 2003–04 influenza season that was characterized by early and intense influenza activity, which potentially altered health care seeking behavior, physician testing practices, and internet search behavior.