Bradley S. Quon

Contemporary Management of Acute Exacerbations of COPD: A Systematic Review and Metaanalysis

BACKGROUND Systemic corticosteroids, antibiotics, and noninvasive positive pressure ventilation (NPPV) are recommended for patients with acute exacerbation of COPD. However, their clinical benefits in various settings are uncertain. We undertook a systematic review and metaanalysis to systematically evaluate the effectiveness of these therapies. METHODS MEDLINE and EMBASE were searched to identify relevant randomized controlled clinical trials published from January 1968 to November 2006. We identified additional studies by searching bibliographies of retrieved articles. RESULTS Compared with placebo, systemic corticosteroids reduced treatment failure by 46% (95% confidence interval [CI], 0.41 to 0.71), length of hospital stay by 1.4 days (95% CI, 0.7 to 2.2), and improved FEV(1) by 0.13 L after 3 days of therapy (95% CI, 0.04 to 0.21). Meanwhile, the risk of hyperglycemia significantly increased (relative risk, 5.88; 95% CI, 2.40 to 14.41). Compared with placebo, antibiotics reduced treatment failure by 46% (95% CI, 0.32 to 0.92) and in-hospital mortality by 78% (95% CI, 0.08 to 0.62). Compared with standard therapy, NPPV reduced the risk of intubation by 65% (95% CI, 0.26 to 0.47), in-hospital mortality by 55% (95% CI, 0.30 to 0.66), and the length of hospitalization by 1.9 days (95% CI, 0.0 to 3.9). CONCLUSIONS For acute COPD exacerbations, systemic corticosteroids are effective in reducing treatment failures, while antibiotics reduce mortality and treatment failures in those requiring hospitalization and NPPV reduces the risk of intubation and in-hospital mortality, especially in those who demonstrate respiratory acidosis.

Systematic Review of Blood Biomarkers in Cystic Fibrosis Pulmonary Exacerbations

BACKGROUND Biomarkers reflective of disease activity in cystic fibrosis (CF) have the potential to improve patient care, particularly during CF pulmonary exacerbations (CFPEs). Although blood-based biomarkers have been studied in CFPE for nearly 3 decades, none have been integrated into routine clinical practice. To facilitate progress in this area, we performed a systematic review evaluating blood-based biomarkers during CFPE. METHODS MEDLINE, EMBASE, and CENTRAL were searched to identify relevant studies published from January 1995 to August 2012. We included all full-text studies examining systemic (blood-based) biomarkers to aid in the diagnosis of CFPE, predict outcomes of CFPE, and/or monitor the response to CFPE treatment. RESULTS Seventy-eight unique blood-based biomarkers have been studied to date, mainly inflammatory cytokines, acute phase reactants, and markers of oxidative stress. C-reactive protein (CRP) consistently correlated with disease activity, with a statistically significant increase from stable to exacerbation state in five of six studies, and changes in response to CFPE treatment, with a statistically significant decrease from the beginning to the end of CFPE treatment in 18 of 20 studies. Other promising biomarkers of CFPE disease activity include neutrophil elastase antiproteinase complex, IL-6, myeloperoxidase (MPO), lactoferrin, and calprotectin. CONCLUSIONS Although there are several blood-based biomarkers with evidence for application within the CFPE setting, CRP has been the most widely studied biomarker demonstrating the potential for clinical usefulness. Further validation studies and clinical trials are required to determine whether blood-based biomarkers can be used to ultimately improve health outcomes in the setting of a CFPE.

New and emerging targeted therapies for cystic fibrosis

Cystic fibrosis (CF) is a monogenic autosomal recessive disorder that affects about 70 000 people worldwide. The clinical manifestations of the disease are caused by defects in the cystic fibrosis transmembrane conductance regulator (CFTR) protein. The discovery of the CFTR gene in 1989 has led to a sophisticated understanding of how thousands of mutations in the CFTR gene affect the structure and function of the CFTR protein. Much progress has been made over the past decade with the development of orally bioavailable small molecule drugs that target defective CFTR proteins caused by specific mutations. Furthermore, there is considerable optimism about the prospect of gene replacement or editing therapies to correct all mutations in cystic fibrosis. The recent approvals of ivacaftor and lumacaftor represent the genesis of a new era of precision medicine in the treatment of this condition. These drugs are having a positive impact on the lives of people with cystic fibrosis and are potentially disease modifying. This review provides an update on advances in our understanding of the structure and function of the CFTR, with a focus on state of the art targeted drugs that are in development.

Disparities in Access to Lung Transplantation for Patients with Cystic Fibrosis by Socioeconomic Status

RATIONALE Although previous studies suggest that access to care for patients with cystic fibrosis (CF) does not vary appreciably by socioeconomic status (SES), disparities with respect to access to lung transplantation for patients with CF are largely unknown. OBJECTIVES To determine whether access to lung transplantation for patients with CF differs according to SES. METHODS Observational study involving 2,167 adult patients with CF from the CF Foundation Patient registry who underwent their first lung transplant evaluation between 2001 and 2009. The primary outcome was acceptance for lung transplant after initial evaluation. The main SES indicator was Medicaid status. Alternate SES indicators included race, educational attainment, ZIP code-level median household income, and driving time from residence to closest lung transplant center. MEASUREMENTS AND MAIN RESULTS The odds that Medicaid recipients were not accepted for lung transplant were 1.56-fold higher (95% confidence interval [CI], 1.27-1.92) than patients without Medicaid, after multivariate adjustment for demographic characteristics, disease severity, and potential contraindications to lung transplant, and before or after use of the lung allocation score. This association was independent of other SES indicators, including race, educational attainment, ZIP code-level median household income, and driving time to closest transplant center (odds ratio [OR] = 1.37; 95% CI, 1.10-1.72). Patients not completing high school (OR = 2.37; 95% CI, 1.49-3.79) and those residing in the lowest (vs. highest) ZIP code median household income category (OR = 1.39; 95% CI, 1.01-1.93) also experienced a higher odds of not being accepted for lung transplant in multivariate analysis. CONCLUSIONS In this nationally representative study of adult patients with CF, multiple indicators of low SES were associated with higher odds of not being accepted for lung transplant.

Risk Factors for Chronic Kidney Disease in Adults with Cystic Fibrosis

RATIONALE Adults with cystic fibrosis (CF) possess multiple potential risk factors for chronic kidney disease, including CF-related diabetes (CFRD) and lifetime nephrotoxic drug exposure. OBJECTIVES To determine whether cumulative intravenous (IV) aminoglycoside exposure and CFRD increase the risk of chronic kidney disease in adults with CF. METHODS This was a cohort study using adults (≥ 18 yr) in the CF Foundation registry from 2001-2008. Chronic kidney disease (stage 3 or greater) was defined by an estimated glomerular filtration rate of less than 60 ml/min/1.73 m(2). Time-dependent multivariable Cox proportional hazards models were used to determine whether cumulative number of acute pulmonary exacerbations (surrogate for IV aminoglycoside exposure) and CFRD requiring insulin increase the risk of chronic kidney disease, adjusting for confounders. MEASUREMENTS AND MAIN RESULTS The study cohort included 11,912 adults with a median follow-up of 4 years. During the study period, 204 subjects had chronic kidney disease, with an annual disease prevalence of 2.3%. Disease prevalence doubled with every 10-year increase in age. CFRD requiring insulin therapy substantially increased the risk of chronic kidney disease (1-4 yr of CFRD requiring insulin vs. no CFRD, hazard ratio [HR] = 2.40, 95% confidence interval [CI] 1.74-3.32; ≥ 5 yr, HR = 4.56, 95% CI 2.84-7.31). Pulmonary exacerbations did not significantly increase the risk of chronic kidney disease (one to five exacerbations vs. none, HR = 0.79, 95% CI 0.56-1.11; six to nine exacerbations, HR = 0.92, 95% CI 0.58-1.46; ≥ 10 exacerbations, HR = 1.16, 95% CI 0.75-1.81). CONCLUSIONS CF-related diabetes is a significant risk factor for chronic kidney disease in adults with CF, but additional studies examining IV aminoglycoside exposure directly are required.

Cystic Fibrosis: What to Expect now in the Early Adult Years

As a testimony to advances in patient care, more individuals with cystic fibrosis are surviving into their adult years than ever before. The clinical epidemiology of this complex multi-organ disease is evolving and has changed dramatically over the past two to three decades. This article discusses the emergence of chronic disease-related co-morbidities such as CF-related diabetes, chronic kidney disease, bone disease, arthropathy, and depression. It also provides an overview of the many challenges confronted by adult CF care providers.

A story of success: continuous quality improvement in cystic fibrosis care in the USA

Background Continuous quality improvement (CQI) in healthcare can be described as a reiterative approach to improving processes to reduce unexpected variation in health outcomes. CQI represents one model to achieve quality improvement (QI) and has long been recognized as a key to success in the manufacturing industry with companies like Toyota leading the way. Objective Healthcare, and specifically pulmonary, critical care and sleep medicine represent ideal settings for the application of CQI. Methods This opinion piece will describe QI and CQI initiatives in the US Cystic fibrosis (CF) population. Results QI in CF care in the United States has been ongoing since inception of the US CF Foundation (CFF) in 1955. This effort has included work to improve the quality of clinical care provided at CF centers and work to improve clinical outcomes in CF. More recently, QI methods have been applied to the conduct of clinical research. Conclusions The CF community has become a leader in the area of QI and has pointed out the opportunities for others to follow in the area of lung diseases.

A systematic review of factors associated with health-related quality of life in adolescents and adults with cystic fibrosis.

RATIONALE As the life expectancy for individuals with cystic fibrosis (CF) continues to improve, an emphasis on optimizing health-related quality of life (HRQoL) has become increasingly important. The Cystic Fibrosis Questionnaire-Revised (CFQ-R 14+) is the most widely accepted method to quantify HRQoL in this patient population. OBJECTIVES Our objective was to systematically review the literature to identify sociodemographic and clinical factors associated with HRQoL among adolescents and adults with CF. METHODS Five major literature databases were searched (MEDLINE, EMBASE, CENTRAL, CINAHL, psychINFO) to identify studies published from January 1989 to April 2014 (n=1,921). We included all full-text studies that: (1) focused on individuals 14 years of age or older, and (2) examined the relationship between sociodemographic (age, sex, body-mass index [BMI], socioeconomic status, and employment) and clinical (FEV1 % predicted, pulmonary exacerbation, comorbidities) factors with the CFQ-R 14+. Effect estimates and levels of statistical significance in the association between sociodemographic and clinical factors with each of the 12 CFQ-R 14+ domains were analyzed, if examined in at least two studies. MEASUREMENTS AND MAIN RESULTS Twenty-eight articles met our inclusion/exclusion criteria, but 5 studies were excluded at the data synthesis stage, leaving 23 articles for analysis. In relation to the CFQ-R 14+, 10 candidate factors were examined in at least two studies. The five most commonly studied factors were FEV1 % predicted (57.1% of 28 studies), sex (32.1%), BMI (28.6%), age (17.6%), and pulmonary exacerbations (13%). In studies incorporating multivariable methods, FEV1 % predicted was positively associated with all CFQ-R 14+ domains with the exception of Digestion, Social Functioning, and Emotional Functioning. Male subjects reported higher Physical Functioning and lower Body Image scores than female subjects, BMI was positively correlated with Body Image and Weight, and age was negatively correlated with Treatment Burden. Pulmonary exacerbations were negatively associated with multiple domains, including Respiratory Symptoms, Physical, and Role Functioning. CONCLUSIONS Although several factors have been found to be associated with the CFQ-R in adolescents and adults with CF, FEV1 % predicted and pulmonary exacerbations have the broadest impact on HRQoL. Further research is required to investigate the impact of age-related comorbidities, psychosocial factors, and treatment-related factors on HRQoL in adolescents/adults with cystic fibrosis.

Risk of Post-Lung Transplant Renal Dysfunction in Adults With Cystic Fibrosis

BACKGROUND Cystic fibrosis (CF) is one of the leading indications for lung transplantation. The incidence and pre-lung transplant risk factors for posttransplant renal dysfunction in the CF population remain undefined. METHODS We conducted a cohort study using adults (≥ 18 years old) in the CF Foundation Patient Registry from 2000 to 2008 to determine the incidence of post-lung transplant renal dysfunction, defined by an estimated glomerular filtration rate of < 60 mL/min/1.73 m(2). Multivariable Cox proportional hazards modeling was used to identify independent pretransplant risk factors for post-lung transplant renal dysfunction. RESULTS The study cohort included 993 adult lung transplant recipients with CF, with a median follow-up of 2 years. During the study period, 311 individuals developed renal dysfunction, with a 2-year risk of 35% (95% CI, 32%-39%). Risk of posttransplant renal dysfunction increased substantially with increasing age (25 to < 35 years vs 18 to < 25 years: hazard ratio [HR], 1.60; 95% CI, 1.15-2.23; vs ≥ 35 years: HR, 2.45; 95% CI, 1.73-3.47) and female sex (HR, 1.56; 95% CI, 1.22-1.99). CF-related diabetes requiring insulin therapy (HR, 1.30; 95% CI, 1.02-1.67) and pretransplant renal function impairment (estimated glomerular filtration rate, 60-90 mL/min/m(2) vs > 90 mL/min/m(2): HR, 1.58; 95% CI, 1.19-2.12) also increased the risk of posttransplant renal dysfunction. CONCLUSIONS Renal dysfunction is common following lung transplant in the adult CF population. Increased age, female sex, CF-related diabetes requiring insulin, and pretransplant renal impairment are significant risk factors.

The Impact of Housestaff Fatigue on Occupational and Patient Safety

Extended-duration work shifts (i.e., greater than 24 hours) for housestaff are a long-standing tradition. However, the resultant sleep deprivation and fatigue caused by these extreme work schedules pose potential threats to both physician and patient safety. We believe it is critical to understand the potential adverse consequences of housestaff fatigue to optimize shift schedules and reduce risks to both staff and patients.