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Contains fulltext : 171874.pdf (Publisher’s version ) (Open Access) Non-tuberculous mycobacteria (NTM) are ubiquitous environmental organisms that can cause chronic pulmonary infection, particularly in individuals with pre-existing inflammatory lung disease, such as cystic fibrosis (CF). Pulmonary disease (PD) caused by NTM has emerged as a major threat to the health of individuals with CF, but remains difficult to diagnose and problematic to treat. In response to this challenge, the US Cystic Fibrosis Foundation (CFF) and the European Cystic Fibrosis Society (ECFS) convened a panel of 19 experts to develop consensus recommendations for the screening, investigation, diagnosis and management of NTM-PD in individuals with CF. PICO (population, intervention, comparison, outcome) methodology and systematic literature reviews were employed to inform draft recommendations, which were then modified to achieve consensus and subsequently circulated for public consultation within the USA and European CF communities. We have thus generated a series of pragmatic, evidence-based recommendations as an initial step in optimising management for this challenging condition.

Background We previously performed a randomized placebo-controlled trial to examine the effects of azithromycin in children and adolescents 6–18 years of age with cystic fibrosis uninfected with Pseudomononas aeruginosa and demonstrated that while azithromycin did not acutely improve pulmonary function, azithromycin-reduced pulmonary exacerbations, decreased the initiation of new oral antibiotics, and improved weight gain. We now report the results of the open-label, follow-on study to assess durability of response to azithromycin and continued safety and tolerability. Methods Eligible participants were enrolled in a 24-week open-label study of azithromycin to compare efficacy and safety endpoints during the placebo-controlled trial versus open-label study in two groups: participants initially on azithromycin continued azithromycin (azithromycin–azithromycin) and participants initially on placebo who then received azithromycin (placebo–azithromycin). As in the placebo-controlled trial, the azithromycin dose in the open-label study was 250 mg Monday–Wednesday–Friday for participants weighing 18–35.9 kg and 500 mg Monday–Wednesday–Friday for participants weighing 36 kg or greater. Results Of 174 eligible participants, 146 (83.9%) enrolled in the open-label study. No significant improvements in lung function were observed within either group. There were no differences in outcomes in the placebo–azithromycin group during the placebo-controlled versus open-label phase. The azithromycin–azithromycin group had comparable odds of experiencing an exacerbation during the two phases (OR 1.6, CI95 0.8, 3.0) and stable weight gain, but new oral antibiotics were initiated more frequently during the open-label study (OR 1.9, CI95 1.0, 3.5). In both groups, adverse event rates were comparable during the placebo-controlled and open-label study and treatment-emergent pathogens were rare. Conclusions During the open-label study, we observed continued durability of treatment response to azithromycin, as measured by pulmonary exacerbations and continued weight gain, although use of oral antibiotics increased. There were no new safety concerns. Currently available data suggest that azithromycin reduces exacerbations and improves weight gain for 6–12 months among children and adolescents with CF uninfected with P. aeruginosa. Pediatr Pulmonol. 2012; 47:641–648. © 2012 Wiley Periodicals, Inc.

The Division of Lung Diseases of the National Heart, Lung, and Blood Institute (NHLBI) held a workshop to develop recommendations on topics, methodologies, and resources for comparative effectiveness research (CER) that will guide clinical decision making about available treatment options for lung diseases and sleep disorders. A multidisciplinary group of experts with experience in efficacy, effectiveness, implementation, and economic research identified (a) what types of studies the domain of CER in lung diseases and sleep disorders should include, (b) the criteria and process for setting priorities, and (c) current resources for and barriers to CER in lung diseases. Key recommendations were to (1) increase efforts to engage stakeholders in developing CER questions and study designs; (2) invest in further development of databases and other infrastructure, including efficient methods for data sharing; (3) make full use of a broad range of study designs; (4) increase the appropriate use of observational designs and the support of methodologic research; (5) ensure that committees that review CER grant applications include persons with appropriate perspective and expertise; and (6) further develop the workforce for CER by supporting training opportunities that focus on the methodologic and practical skills needed.

Cystic fibrosis–related diabetes (CFRD) is the most common comorbidity in people with cystic fibrosis (CF), occurring in ∼20% of adolescents and 40–50% of adults (1). While it shares features of type 1 and type 2 diabetes, CFRD is a distinct clinical entity. It is primarily caused by insulin insufficiency, although fluctuating levels of insulin resistance related to acute and chronic illness also play a role. The additional diagnosis of CFRD has a negative impact on pulmonary function and survival in CF, and this risk disproportionately affects women (2–4). In contrast to patients with other types of diabetes, there are no documented cases of death from atherosclerotic vascular disease in patients with CFRD, despite the fact that some now live into their sixth and seventh decades. These guidelines are the result of a joint effort between the Cystic Fibrosis Foundation (CFF), the American Diabetes Association (ADA), and the Pediatric Endocrine Society (PES). They are intended for use by CF patients, their care partners, and health care professionals and include recommendations for screening, diagnosis, and medical management of CFRD. This report focuses on aspects of care unique to CFRD. A comprehensive summary of recommendations for all people with diabetes can be found in the ADA Standards of Medical Care, published annually in the January supplement to Diabetes Care (5). In 2009, CFF in collaboration with ADA and PES convened a committee of CF and diabetes experts to update clinical care guidelines for CFRD. Investigators at Johns Hopkins University conducted evidence reviews on relevant clinical questions identified by the guidelines committee. The reviews were provided to the committee to use in developing recommendations. Where possible, the evidence for each recommendation was considered and graded by the committee using the ADA (5) and the U.S. Preventive Services Task Force (USPSTF) (6 …

Cystic fibrosis–related diabetes (CFRD) is the most common comorbidity in subjects with cystic fibrosis (CF). A consensus conference on CFRD was cosponsored by the Cystic Fibrosis Foundation (CFF), the American Diabetes Association (ADA), and the Pediatric Endocrine Society (PES) in September 2009. The committee's evidence-based recommendations for clinical management of CFRD are published in this issue of Diabetes Care . This review article describes the epidemiology, pathogenesis, and prognostic implications of CFRD. ### Epidemiology CFRD is part of a continuum of glucose tolerance abnormalities, ranging from normal glucose tolerance (NGT), to impaired glucose tolerance (IGT), to CFRD without fasting hyperglycemia (CFRD FH−), to CFRD with fasting hyperglycemia (CFRD FH+) (Fig. 1). Unlike patients with type 1 diabetes, those with CFRD do not develop complete absence of insulin secretion. At the other end of the spectrum, few CF patients have truly normal glucose metabolism. Approximately 20% of children who are categorized as having NGT based on their fasting and 2-h oral glucose tolerance test (OGTT) glucose levels have glucose elevation >200 mg/dl (11.1 mmol/l) mid-OGTT, which is termed indeterminate glycemia (INDET) (1). As in the general population where INDET is a risk factor for progression to diabetes (2), INDET in children with CF is associated with early development of CFRD (1). Home continuous glucose monitoring (CGM) has shown that intermittent, asymptomatic hyperglycemia is common even in CF patients whose OGTT is normal, but the prognostic significance of these early impairments in glucose metabolism is unknown (3,4). Impaired fasting glucose has also been described in CF (5,6). Figure 1 The spectrum of glucose tolerance in CF. Unlike patients with type 1 diabetes, insulin secretion is never completely absent in CFRD. Clinical deterioration (pulmonary function, underweight) is associated with worse glucose tolerance status. Abnl CGM = abnormal home continuous glucose monitoring, T1D …

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.This document presents the CF Foundation's Pulmonary Therapies Committee recommendations for the treatment of hemoptysis and pneumothorax.The committee recognized that insufficient data exist to develop evidence-based recommendations and so used the Delphi technique to formalize an expert panel's consensus process and develop explicit care recommendations.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.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.

The authors were given the charge of providing a vision of the future in paediatric respirology. Themes selected for being ripe for this visionary analysis include bronchopulmonary dysplasia (BPD), asthma, cystic fibrosis (CF), lung infections, obstructive sleep disordered breathing (OSDB) and pulmonary diagnostics and monitoring. A profound reduction or elimination of BPD is seen. Given the strong genetic component of this disease, genetic biomarkers will likely be identified that will permit much earlier recognition of BPD susceptibility and potentially the ability to modify disease course by altering gene expression. The ultimate prevention of BPD will be to prevent prematurity, but recognition of both the genetic basis of BPD and the inflammatory background should lead to improved prevention and therapy. A clear understanding and definition of asthma phenotypes will lead to more specific and targeted therapy, earlier detection and prevention, better monitoring of severity and adherence to therapy, lower mortality and decreased inappropriate diagnosis of asthma. The greatest opportunities in asthma care will likely come through tools to improve adherence to effective therapy. Also, areas are identified where better therapies are needed such as in patients with severe mucus hypersecretion (secretory hyperresponsiveness) especially in those with life-threatening asthma. The future of CF is easier to foresee with early successes seen in clinical trials. After the expected ability to correct the CF transmembrane regulator, care will need to change and additional research will be needed. Additionally, the face of CF is changing with more adults than children presently having the disease. This will necessitate changes to our approach to treating this disease in a fortunately aging population. If we are going to affect the worldwide lung health of children, we will need to address respiratory infections particularly pneumonia, tuberculosis and HIV-associated infections. Preventive, diagnostic and treatment strategies will shape the future face of these problems. The availability of inexpensive, readily available, and rapid molecular techniques to identify true infection (including HIV and tuberculosis) may permit earlier use of effective therapy while preventing the inappropriate use of antibiotics for common viral diseases. Sleep medicine will continue to be an important aspect of paediatric pulmonology. The evaluation of OSDB cannot rely on full-night attended polysomnography due to limited access. Identifying reliable markers of end organ dysfunction in children with OSDB may permit more rapid identification of patients in need of intervention like CPAP and assisted breathing. In addition, management options, as an alternative to adenotonsilectomy, are listed with a call for further research. Pulmonary diagnostics and monitoring will see the development and refinement of tools like the lung clearance index and the analysis of exhaled gases, volatiles and dissolved biomarkers of inflammation as techniques that might help clinicians identify both the initiation of inflammation while it is more amenable to therapy, and to identify more readily the early changes associated with chronic lung diseases in children. The authors hope that these visionary articles will generate comments, arguments, inspiration, and perhaps even motivate funding agencies.

Background Cystic fibrosis (CF) patients from Canada have better-reported post-lung transplant survival compared to patients from the United States. We hypothesized the clinical characteristics of CF patients prior to lung transplant differ between the two countries. Methods Population-based cohort study utilizing combined Canadian CF Registry and US CF Foundation Patient Registry data from 1986 to 2013. Demographic and clinical variables were analyzed prior to lung transplant. Results Between 1986 and 2013, 607 (10.2%) CF patients underwent lung transplantation in Canada and 3428 (7.5%) in the United States. A lower proportion of recipients had growth of B. cepacia complex prior to transplant in the United States compared to Canada (0.8% vs 4.3%). Lung function was similar between recipients from the two countries. The proportion of patients classified as underweight was significantly higher in the United States compared to Canada (39.8% vs 28.0%; SD 26.1) despite higher rates of feeding tube use (42.5% vs 28.6%; SD 29.0). Conclusions CF lung transplant recipients from the United States have similar lung function, lower rates of B. cepacia complex, and worse nutritional parameters prior to transplant compared to counterparts in Canada. Future studies are necessary to evaluate the impact of these differences on post-transplant survival.

Newborn screening for cystic fibrosis (CF) offers the opportunity for early medical and nutritional intervention that can lead to improved outcomes. Management of the asymptomatic infant diagnosed with CF through newborn screening, prenatal diagnosis, or sibling screening is different from treatment of the symptomatically diagnosed individual. The focus of management is on maintaining health by preventing nutritional and respiratory complications. The CF Foundation convened a committee to develop recommendations based on a systematic review of the evidence and expert opinion. These guidelines encompass monitoring and treatment recommendations for infants diagnosed with CF and are intended to help guide families, primary care providers, and specialty care centers in the care of infants with CF. (J Pediatr 2009;155:S73–93).

The improved survival in people with cystic fibrosis has led to an increasing number of patients reaching adulthood. This trend is likely to be maintained over the next decades, suggesting a need to increase the number of centres with expertise in the management of adult patients with cystic fibrosis. These centres should be capable of delivering multidisciplinary care addressing the complexity of the disease, in addition to addressing the psychological burden on patients and their families. Further issues that require attention are organ transplantation and end of life management.Lung disease in adults with cystic fibrosis drives most of the clinical care requirements, and major life-threatening complications, such as respiratory infection, respiratory failure, pneumothorax and haemoptysis, and the management of lung transplantation require expertise from trained respiratory physicians. The taskforce therefore strongly reccommends that medical leadership in multidisciplinary adult teams should be attributed to a respiratory physician adequately trained in cystic fibrosis management.The task force suggests the implementation of a core curriculum for trainees in adult respiratory medicine and the selection and accreditation of training centres that deliver postgraduate training to the standards of the HERMES programme.

Studies in cystic fibrosis (CF) report late attention to advance care planning (ACP). The purpose of this study was to examine ACP with patients receiving care at US adult CF care programs.Chart abstraction was used to examine ACP with adults with CF dying from respiratory failure between 2011 and 2013.We reviewed 210 deaths among 67 CF care programs. Median age at death was 29 years (range 18-73). Median FEV1 in the year preceding death was 33% predicted (range 13-100%); 68% had severe lung disease with FEV140% predicted. ACP was documented for 129 (61%), often during hospitalization (61%). Those with ACP had earlier documentation of treatment preferences, before the last month of life (73% v. 35%; p=0.01). Advance directives were completed by 93% of those with ACP versus 75% without (p0.01); DNR orders and health care proxy designation occurred more often for those with ACP. Patients awaiting lung transplant had similar rates of ACP as those who were not (67% v. 61%; p=0.55). The frequency of ACP varied significantly among the 29 programs contributing data from four or more deaths.ACP in CF often occurs late in the disease course. Important decisions default to surrogates when opportunities for ACP are missed. Provision of ACP varies significantly among adult CF care programs. Careful evaluation of opportunities to enhance ACP and implementation of recommended approaches may lead to better practices in this important aspect of CF care.

Objectives Cystic fibrosis-related diabetes (CFRD) has emerged as an important complication of CF. To better understand who is at risk of developing CFRD, to gain insight into the impact of CFRD on pulmonary and nutritional status, and to assess the association of CFRD with various practice patterns and comorbid conditions, we characterized the Epidemiologic Study of Cystic Fibrosis (ESCF) patient population. Study design Analyses were performed on the 8247 adolescents and adults who were evaluated at one of 204 participating sites during 1998. CFRD was defined as the use of insulin or an oral hypoglycemic agent at any time during the year. Results Previously reported risk factors for CFRD including age, gender (female), and pancreatic insufficiency were confirmed in this study. Patients with CFRD had more severe pulmonary disease, more frequent pulmonary exacerbations, and poorer nutritional status as compared with those without diabetes. CFRD also was associated with liver disease. Conclusions CFRD is a common complication in adolescents and adults that is associated with more severe disease.

Background People with cystic fibrosis (CF) are managed differently in the USA and UK providing an opportunity to learn from differences in practice patterns. Objectives To compare cross-sectional demographics, practice patterns and clinical outcomes between US and UK CF patients. Methods This was a cross-sectional study using 2010 data from patients in the US Cystic Fibrosis Foundation and the UK Cystic Fibrosis patient registries. The a priori outcome measures of interest were lung function and nutritional status. Descriptive statistics and two sample comparisons were performed. Stratification and multivariable linear regression were used to adjust for confounding. Results The study cohort included 13 777 children and 11 058 adults from the USA and 3968 children and 3965 adults from the UK. In children, mean body mass index centiles were similar. Lung function (FEV 1 and FVC% predicted) was significantly higher in US patients ages 6–25 years of age. In a regression model adjusted for only age, FEV 1 % predicted was on average 3.31% of predicted (95% CI 2.65 to 3.96) higher in the USA compared with the UK. When adjusted for age, age at diagnosis, gender, pancreatic insufficiency and genotype, FEV 1 % predicted was on average 3.03% of predicted (95% CI 2.37 to 3.69) higher in the USA compared with the UK These differences persisted despite adjustment for possible confounders. Hypertonic saline and dornase alfa were much more commonly prescribed in US children. Conclusions Children and young adults with CF have better lung function in the USA compared with the UK despite similar nutritional status.

Advances in treatments for cystic fibrosis (CF) continue to extend survival. An updated estimate of survival is needed for better prognostication and to anticipate evolving adult care needs.To characterize trends in CF survival between 2000 and 2010 and to project survival for children born and diagnosed with the disease in 2010.Registry-based study.110 Cystic Fibrosis Foundation-accredited care centers in the United States.All patients represented in the Cystic Fibrosis Foundation Patient Registry (CFFPR) between 2000 and 2010.Survival was modeled with respect to age, age at diagnosis, gender, race or ethnicity, F508del mutation status, and symptoms at diagnosis.Between 2000 and 2010, the number of patients in the CFFPR increased from 21,000 to 26,000, median age increased from 14.3 to 16.7 years, and adjusted mortality decreased by 1.8% per year (95% CI, 0.5% to 2.7%). Males had a 19% (CI, 13% to 24%) lower adjusted risk for death than females. Median survival of children born and diagnosed with CF in 2010 is projected to be 37 years (CI, 35 to 39 years) for females and 40 years (CI, 39 to 42 years) for males if mortality remains at 2010 levels and more than 50 years if mortality continues to decrease at the rate observed between 2000 and 2010.The CFFPR does not include all patients with CF in the United States, and loss to follow-up and missing data were observed. Additional analyses to address these limitations suggest that the survival projections are conservative.Children born and diagnosed with CF in the United States in 2010 are expected to live longer than those born earlier. This has important implications for prognostic discussions and suggests that the health care system should anticipate greater numbers of adults with CF.Cystic Fibrosis Foundation.

The 2013 Infection Prevention and Control (IP&C) Guideline for Cystic Fibrosis (CF) was commissioned by the CF Foundation as an update of the 2003 Infection Control Guideline for CF. During the past decade, new knowledge and new challenges provided the following rationale to develop updated IP&C strategies for this unique population:1.The need to integrate relevant recommendations from evidence-based guidelines published since 2003 into IP&C practices for CF. These included guidelines from the Centers for Disease Control and Prevention (CDC)/Healthcare Infection Control Practices Advisory Committee (HICPAC), the World Health Organization (WHO), and key professional societies, including the Infectious Diseases Society of America (IDSA) and the Society for Healthcare Epidemiology of America (SHEA). During the past decade, new evidence has led to a renewed emphasis on source containment of potential pathogens and the role played by the contaminated healthcare environment in the transmission of infectious agents. Furthermore, an increased understanding of the importance of the application of implementation science, monitoring adherence, and feedback principles has been shown to increase the effectiveness of IP&C guideline recommendations.2.Experience with emerging pathogens in the non-CF population has expanded our understanding of droplet transmission of respiratory pathogens and can inform IP&C strategies for CF. These pathogens include severe acute respiratory syndrome coronavirus and the 2009 influenza A H1N1. Lessons learned about preventing transmission of methicillin-resistantStaphylococcus aureus(MRSA) and multidrug-resistant gram-negative pathogens in non-CF patient populations also can inform IP&C strategies for CF.

The purpose of this study was to characterize the utilization of antibiotics for chronic methicillin-resistant Staphylococcus aureus (MRSA) infection in cystic fibrosis (CF) patients with acute pulmonary exacerbations (PEx).An anonymous national cross-sectional survey of CF Foundation accredited care programs was performed using an electronic survey tool.Fifty-eight percent (152/261) CF Foundation accredited programs completed the survey. Ninety-eight percent (149/152) of respondents reported using antibiotics (oral or intravenous) against MRSA. Variability exists in the use of antibiotics amongst the programs and in the dosages utilized. For oral outpatient treatment, sulfamethoxazole/trimethoprim was the most commonly utilized antibiotic by both pediatric (109/287, 38%) and adult (99/295, 34%) respondents, of which, ten percent of reported to use it in combination with rifampin. For inpatient treatment, linezolid (both intravenous (IV) and oral) was most commonly utilized in both pediatric (IV 35/224, 16%; oral 41/224, 18%), and adult (IV 44/235, 19%; oral 38/235, 16%) respondents for inpatient treatment. IV vancomycin was the second most commonly utilized antibiotic by pediatric (70/224, 31%) and adult (71/235, 30%) respondents. Most respondents reported dose titration to achieve a vancomycin trough level of 15-20 mg/L (150/179, 84%). Topical or inhaled antibiotic utilization was reported to be an uncommon practice with approximately 70% of pediatric and adult respondents reporting to use them either rarely or never. The concomitant use of anti-MRSA and anti-pseudomonal antibiotics was common with 96% of pediatric and 99% of adult respondents answering in the affirmative.We conclude that anti-MRSA antibiotics are utilized via various dosage regimens by a majority of CF Foundation accredited care programs for the treatment of chronic MRSA in PEx, and there is no consensus on the best treatment approach.

The objective of this study was to determine the frequency and severity of decreased arterial oxy-hemoglobin saturation during exercise in adults with cystic fibrosis at 1,500 m above sea level. A convenience sample of 50 adults with cystic fibrosis who did not have hypoxemia (oxygen saturation

The objective of this study was to create a 5-year survivorship model to identify key clinical features of cystic fibrosis. Such a model could help researchers and clinicians to evaluate therapies, improve the design of prospective studies, monitor practice patterns, counsel individual patients, and determine the best candidates for lung transplantation. The authors used information from the Cystic Fibrosis Foundation Patient Registry (CFFPR), which has collected longitudinal data on approximately 90% of cystic fibrosis patients diagnosed in the United States since 1986. They developed multivariate logistic regression models by using data on 5,820 patients randomly selected from 11,630 in the CFFPR in 1993. Models were tested for goodness of fit and were validated for the remaining 5,810 patients for 1993. The validated 5-year survivorship model included age, forced expiratory volume in 1 second as a percentage of predicted normal, gender, weight-for-age z score, pancreatic sufficiency, diabetes mellitus, Staphylococcus aureus infection, Burkerholderia cepacia infection, and annual number of acute pulmonary exacerbations. The model provides insights into the complex nature of cystic fibrosis and supplies a rigorous tool for clinical practice and research.

Epidemiologic data demonstrate a dramatic improvement in survival for cystic fibrosis (CF) over the last few decades and projections suggest that trend will continue. Standard therapy works and should be aggressively applied to this patient population. Although the specific therapies have evolved over the years, the basic tenets of CF care remain unchanged and include antibiotics to control infection, airway clearance, and adequate nutrition. This article focuses on treatment of the pulmonary disease and includes a discussion of the following specific components of a standard therapeutic approach to CF: (1) antibiotics, (2) airway clearance and exercise, (3) mucolytics, (4) bronchodilators, (5) oxygen, (6) anti-inflammatory therapies, and (7) nutritional support. Judicious application of these therapies coupled with careful monitoring of pulmonary, nutritional, and metabolic parameters results in most CF patients surviving into adulthood with an acceptable quality of life.

The objective of this study was to describe the pharmacy needs of a group of males infected with human immunodeficiency virus (HIV) and to determine whether those needs were being met. An anonymous survey was used to determine the perceptions of a group of HIV-positive males. Of 62 usable responses, 53.2% of respondents tested positive for HIV more than five years ago and 58.1% reported a CD4 count below 200/mm3, the mean age was 41 years (SD = 8.6). Respondents indicated a need for a pharmacist knowledgeable in HIV disease/treatment (74.5%), a pharmacy that accepts all insurance (66.6%), and information on alternative therapies (29.4%). Most (72.6%) wanted both written and oral information, and more than half expected the pharmacist to provide information on side effects, how medications interact with other medications and with food and how to take the medication. More than 85% indicated satisfaction with pharmacy services. The study concluded that HIV-positive males have certain expectations for pharmacy services, such as the provision of written and oral information, specific medication information, and personal interaction with the pharmacist. These patients are satisfied to varying degrees with different aspects of pharmaceutical care Pharmacists should provide these expected services to increase satisfaction for all patients, especially those who are HIV positive.

OBJECTIVE The purpose of this study was to develop a cystic fibrosis (CF)-specific patient and family experience of care survey that CF care centers could use to inform quality improvement efforts. METHODS A literature search and query of CF care centers was conducted to identify existing surveys. Individuals with CF, their families, and health care professionals were also asked what to include. Following this process, a draft survey was developed and then reviewed by focus groups. Finally, a version was piloted at 25 CF care centers to validate and further refine the instrument. RESULTS No CF-specific surveys were found in the literature. Focus group participants stated that they understood the survey questions and that they covered important aspects of care, particularly infection control. The pilot test of the instrument with 485 participants supported its validity by demonstrating significant differences across centers and that most of the 3 care dimensions had acceptable internal consistency (Cronbach α: adults, 0.71-0.85; children, 0.68-0.79). CONCLUSION A CF-specific patient and family experience of care survey was developed with input from individuals with CF, their families, and health care professionals. The instrument was validated and has been deployed to CF care centers.

Background Current definitions of pulmonary exacerbation (PE) in cystic fibrosis are based on studies in participants with significant lung disease and may not reflect the spectrum of findings observed in younger patients with early lung disease. Methods We used data from a recent trial assessing the efficacy of azithromycin in children to study signs and symptoms associated with PEs and related changes in lung function and weight. Results While increased cough was present in all PEs, acute weight loss and reduction in oxygen saturation were not observed. Changes in lung function did not differ between subjects who did experience a PE and those who were exacerbation-free. Conclusions Cough was the predominant symptom in CF patients with early lung disease experiencing a PE. There was no significant difference in mean 6-month change in lung function or weight among subjects with one or more exacerbations and those without an exacerbation.

Proteinase 3 is a human polymorphonuclear leukocyte serine proteinase that degrades elastin in vitro and causes emphysema when administered by intratracheal insufflation into hamsters. Proteinase 3, stored in the azurophilic granules, is expressed in progenitor cells of myeloid origin. In the present study, the biosynthesis, processing, and intracellular transport of the enzyme was investigated in the human myelomonocytic cell line U937. Proteinase 3 is initially identified as a 35-kDa precursor and converted into the 29-kDa mature form within 3 h. By using a combination of techniques including amino-terminal sequencing, we identified the 35-kDa form as a zymogen containing an activation dipeptide but lacking the amino-terminal 25 residues, presumably the result of cleavage by a signal peptidase. Tunicamycin treatment and alkalinization of acidic cell compartments with NH4Cl did not prevent the processing of the proteinase 3 zymogen into the mature form, suggesting that the enzyme is targeted to the cytoplasmic granules by a mechanism other than the mannose 6-phosphate receptor. Brefeldin A inhibited the zymogen processing, suggesting that the dipeptide cleavage occurred in a post-Golgi organelle. The enzyme responsible for the removal of the dipeptide is a cysteine proteinase since E-64d, a class-specific inhibitor, prevented processing. However, treatment of cells with a dipeptidyl peptidase I inhibitor, Gly-Phe-diazomethyl ketone and with the lysosomotropic agents, NH4Cl and chloroquine, did not prevent dipeptide cleavage, indicating that the processing enzyme for proteinase 3 is not dipeptidyl peptidase I. In contrast, Gly-Phe-diazomethyl ketone inhibited cleavage of the dipeptide from cathepsin G. This indicates that processing of proteinase 3 is distinct from that of cathepsin G. Proteinase 3 is also processed at the COOH-terminal extension. Cleavage takes place next to Arg-222, suggesting that a trypsin-like proteinase is involved in the COOH-terminal processing.

Objective Cystic fibrosis (CF)-related diabetes (CFRD) is associated with increased morbidity and mortality. Improved detection and management may improve outcomes; however, actual practice falls short of published guidelines. We studied efforts to improve CFRD screening and management in the Mountain West CF Consortium (MWCFC). Research design and methods This is a prospective observational cohort study evaluating quality improvement by accredited CF centers in Arizona, Colorado, New Mexico, and Utah performed between 2002 and 2008. After Institutional Review Board (IRB) approval, centers evaluated adherence with CF Foundation guidelines for CFRD. Each center developed and implemented quality improvement plans to improve both screening and management. Centers were reassessed 1 year later. Results Initially, each CF center had low adherence with screening recommendations (26.5% of eligible patients) that did not improve during the study. However, patients with confirmed CFRD markedly increased (141 (12% of MWCFC patients) to 224 (17%), p

BACKGROUND: In 2008 the Cystic Fibrosis (CF) Foundation launched the Respiratory Therapy Mentoring Program, which pairs a respiratory therapist (RT) relatively new to CF (apprentice) with a highly experienced RT (mentor) from a similar CF care center. We wished to determine if we had achieved our short-term goal of increasing CF-specific knowledge among the apprentices who participated in the program. METHODS: Selected apprentices were each matched with a mentor, based on characteristics of CF population, clinical setting, center size, and geographic location of their care centers. Apprentices completed a CF-specific RT knowledge self assessment tool prior to and after a site visit to their mentor's center. Mentors also completed a post site visit knowledge self assessment tool regarding their apprentice. RESULTS: Thirty-seven apprentices completed a pre and post site visit knowledge self assessment tool. The median pre and post site visit scores were 12 and 31 ( P < .001) respectively. The mentors' post site visit scores of their apprentices (median 29, P = .07) did not significantly differ from the apprentices' post site visit scores. CONCLUSIONS: The results of this preliminary evaluation suggest that the RT mentoring program has achieved its short-term goal of increasing CF-specific knowledge among RTs relatively new to CF care.

Background The current lifetable approach to survival estimation is favoured by CF registries. Recognising the limitation of this approach, we examined the utility of a parametric survival model to project birth cohort survival estimates beyond the follow-up period, where short duration of follow-up meant median survival estimates were indeterminable. Methods Parametric models were fitted to observed survivorship data from the US CF Foundation (CFF) Patient Registry 1980–1994 birth cohort. Model-predicted median survival was estimated. The best fitting model was applied to a Cystic Fibrosis Registry of Ireland dataset to allow an evaluation of the model's ability to estimate predicted median survival. This involved a comparison of birth cohort lifetable predicted and observed (Kaplan–Meier) median survival estimates. Results A Weibull model with main effects of gender and birth cohort was developed using a US CFF dataset (n=13 115) for which median survival was not directly estimable. Birth cohort lifetable predicted median survival for male and female patients born between 1985 and 1994 and surviving their first birthday was 50.9 and 42.4 years respectively. To evaluate the accuracy of a Weibull model in predicting median survival, a model was developed for the 1980–1984 Cystic Fibrosis Registry of Ireland birth cohort (n=243), which had an observed (Kaplan–Meier) median survival of 27.7 years. Model-predicted median survival estimates were calculated using data censored at different follow-up periods. The estimates converged to the true value as length of follow-up increased. Conclusions Accurate prognostic information that is clinically critical for care of patients affected by rare, life-limiting disorders can be provided by parametric survival models. Problems associated with short duration of follow-up for recent birth cohorts can be overcome using this approach, providing better opportunities to monitor survival and plan services locally.

Rapid cycle DNA amplification is a polymerase chain reaction technique with improved product specificity and cycle times of 20-60 s, allowing complete 30-cycle reactions in 10-30 min. The presence or absence of the delta F508 deletion and wild-type allele was determined in 104 cystic fibrosis patients by rapid cycle DNA amplification. In separate allele-specific assays, sequences on both sides of the delta F508 locus were amplified with the 3' end of a discriminating primer at the delta F508 locus, with either a 3-bp or a 1-bp mismatch. With rapid cycling (35-s cycles), single-base discrimination was achieved over a broad range of annealing temperatures (50 degrees C or lower); with conventional cycling and "hot starts" (160-s cycles), only annealing temperatures of 61-62 degrees C sufficiently discriminated between alleles. With rapid cycling, genotype could still be assessed with annealing temperatures as low as 25 degrees C. We conclude that faster temperature cycling can improve the results of allele-specific amplification.

Mesothelial cells play a critical role in the remodeling process that follows serosal injury. Although mesothelial cells are known to synthesize a variety of extracellular matrix components including types I, III, and IV collagens, their potential to participate in matrix degradation has not been explored. We now report that human pleural and peritoneal mesothelial cells express interstitial collagenase, 72- and 92-kD gelatinases (type IV collagenases), and the counterregulatory tissue inhibitor of metalloproteinases (TIMP). Our initial characterization of the mesothelial cell metalloenzymes and TIMP has revealed: (a) they are likely identical to corresponding molecules secreted by other human cells; (b) they are secreted rather than stored in an intracellular pool; (c) a primary site of regulation occurs at a pretranslational level; (d) phorbol myristate acetate, via activation of protein kinase C, upregulates expression of collagenase, 92-kD gelatinase, and TIMP, but has no effect on expression of 72-kD gelatinase; and (e) lipopolysaccharide fails to upregulate the biosynthesis of either metalloproteinases or TIMP. Of particular interest is the observation that the state of cellular differentiation has a striking influence on the expression of metalloenzymes and TIMP, such that epitheloid cells display a more matrix-degradative phenotype (increased 92-kD gelatinase and decreased TIMP) than their fibroblastoid counterparts. We speculate that mesothelial cells directly participate in the extracellular matrix turnover that follows serosal injury via elaboration of metalloproteinases and TIMP. Additionally, the reactive cuboidal mesothelium which is characteristic of the early response to serosal injury may manifest a matrix-degenerative phenotype favoring normal repair rather than fibrosis.

From 2002 to 2012, the median predicted survival age for people with cystic fibrosis (CF) increased nearly 10 years—from 31.3 years to 41.1 years.1 ,2 Strategic efforts to improve care for CF marked this remarkable era. These efforts were supported by expert leadership among CF healthcare improvement professionals and resources from the CF Foundation. While process outcomes improved substantially—for example, more timely clinic visits, increased influenza immunisation rates, and more effective screening for associated problems such as depression and diabetes,1 ,2 clinical outcomes improved even more dramatically—notably, pulmonary function, nutritional status and predicted survival. This supplement, Ten Years of Improvement Innovation in Cystic Fibrosis Care , captures the larger perspective of this comprehensive improvement initiative and reports representative CF care centre-level examples. It also identifies strategies to widen the circle of improvement professionals who successfully publish their innovative work in scholarly journals.3 Institution-based …

The purpose of this study was to characterize the utilization of anti-pseudomonal beta-lactam antibiotics in the treatment of acute pulmonary exacerbations (APE) among Cystic Fibrosis Foundation (CFF)-accredited care centers. An anonymous national cross-sectional survey of CFF-accredited care centers was performed using an electronic survey tool (SurveyMonkey.com®). One hundred and twenty-one of 261 centers completed the survey (46%) representing 56% (14,856/26,740) of patients in the CFF Patient Registry. One hundred and nineteen of 121 (98%) respondents reported using beta-lactams for the treatment of APE. Intermittent dosing regimens constituted 155/167 (93%) reported regimens, while extended infusions were 12/167 (7%). Ceftazidime was the most commonly utilized beta-lactam comprising 74/167 (44%) of all infusions (intermittent and extended) of which 70/74 (95%) were intermittent infusions. The majority of intermittent ceftazidime regimens (56/70; 80%) were at doses lower than CFF and European guidelines recommended doses. In conclusion, a great majority of respondents use intermittent anti-pseudomonal beta-lactam antibiotics, with over half of respondents utilizing lower than guidelines recommended doses. While this is of concern, it is not known if optimization of dosing strategies according to guidelines recommendations will result in clinical benefit.

Background Comparing international estimates of survival can be a useful way of highlighting differences in life expectancy between cystic fibrosis (CF) populations. In this study, we compared survival in two CF populations. Methods The current lifetable method takes age-specific mortality rates observed in a given year and applies them to a hypothetical population assuming those rates will remain the same in the future. This was used to compare median predicted survival in the United States (US) and the Republic of Ireland (RoI) (1986–2008). Median age at death among decedents was also examined. Results In both countries, median age at death was lower than median predicted survival. Successive increases in annual median predicted survival were not observed; rather an overall improvement was discerned over time. In the RoI, where absolute numbers of deaths were small, year-on-year fluctuations in age-specific mortality rates resulted in wide-ranging annual median predicted survival estimates. Conclusion Median age at death is not a good measure of CF survival. Though median predicted survival improved in each country over the study period, between-country comparison at a given time point may be misleading for rare disorders like CF. Longitudinal outcomes must be examined.

The authors were given the charge of providing a vision of the future in paediatric respirology. Themes selected for being ripe for this visionary analysis include bronchopulmonary dysplasia (BPD), asthma, cystic fibrosis (CF), lung infections, obstructive sleep disordered breathing (OSDB) and pulmonary diagnostics and monitoring. A profound reduction or elimination of BPD is seen. Given the strong genetic component of this disease, genetic biomarkers will likely be identified that will permit much earlier recognition of BPD susceptibility and potentially the ability to modify disease course by altering gene expression. The ultimate prevention of BPD will be to prevent prematurity, but recognition of both the genetic basis of BPD and the inflammatory background should lead to improved prevention and therapy. A clear understanding and definition of asthma phenotypes will lead to more specific and targeted therapy, earlier detection and prevention, better monitoring of severity and adherence to therapy, lower mortality and decreased inappropriate diagnosis of asthma. The greatest opportunities in asthma care will likely come through tools to improve adherence to effective therapy. Also, areas are identified where better therapies are needed such as in patients with severe mucus hypersecretion (secretory hyperresponsiveness) especially in those with life-threatening asthma. The future of CF is easier to foresee with early successes seen in clinical trials. After the expected ability to correct the CF transmembrane regulator, care will need to change and additional research will be needed. Additionally, the face of CF is changing with more adults than children presently having the disease. This will necessitate changes to our approach to treating this disease in a fortunately aging population. If we are going to affect the worldwide lung health of children, we will need to address respiratory infections particularly pneumonia, tuberculosis and HIV-associated infections. Preventive, diagnostic and treatment strategies will shape the future face of these problems. The availability of inexpensive, readily available, and rapid molecular techniques to identify true infection (including HIV and tuberculosis) may permit earlier use of effective therapy while preventing the inappropriate use of antibiotics for common viral diseases. Sleep medicine will continue to be an important aspect of paediatric pulmonology. The evaluation of OSDB cannot rely on full-night attended polysomnography due to limited access. Identifying reliable markers of end organ dysfunction in children with OSDB may permit more rapid identification of patients in need of intervention like CPAP and assisted breathing. In addition, management options, as an alternative to adenotonsilectomy, are listed with a call for further research. Pulmonary diagnostics and monitoring will see the development and refinement of tools like the lung clearance index and the analysis of exhaled gases, volatiles and dissolved biomarkers of inflammation as techniques that might help clinicians identify both the initiation of inflammation while it is more amenable to therapy, and to identify more readily the early changes associated with chronic lung diseases in children. The authors hope that these visionary articles will generate comments, arguments, inspiration, and perhaps even motivate funding agencies.

Proteinase-3 (PR-3) is a neutral serine proteinase present in the azurophil granules of human polymorphonuclear leukocytes. It degrades a variety of extracellular matrix proteins including elastin in vitro and causes emphysema when administered by tracheal insufflation to hamsters. It is identical to the target autoantigen (c-ANCA) associated with Wegener's granulomatosis and to myeloblastin, a serine proteinase first identified in HL-60 leukemia cells. In this study, the gene encoding PR-3 was cloned and sequenced. The gene spans approximately 6.5 kilobase pairs and consists of five exons and four introns. The genomic organization of PR-3 is similar to that of the other serine proteinases expressed in hemopoietic cells. Each residue of the catalytic triad of PR-3 is located on a separate exon, and the positions of the residues within the exons are similar to those in human leukocyte elastase and cathepsin G. The phase and placement of the introns in the PR-3 gene are also similar to those in human leukocyte elastase and cathepsin G. The 400-base pair (bp) 5‘-flanking sequence of the PR-3 gene contains a TATA box at position 379. There is no CAAT box promoter element. The 3‘-untranslated region is 200 bp, extending from a TGA stop codon to the site of polyadenylation 10 bp after the canonical AATAAA signal. Amplification of PR-3 from a human/hamster hybrid cell line localizes the gene to human chromosome 19. Evidence from Northern analysis suggests that PR-3 expression is primarily confined to the promyelocytic/myelocytic stage of bone marrow development.

Diffuse alveolar damage, presenting clinically as adult respiratory distress syndrome, is characterized initially by widespread intra-alveolar fibrin deposition. Alveolar epithelial cells play a central role in the subsequent repair process. We have recently shown that alveolar epithelial cells have the capacity to promote fibrinolysis (Marshall, B. C., Sageser, D. S., Rao, N. V., Emi, M., and Hoidal, J. R. (1990) J. Biol. Chem. 265, 8198-8204) and may therefore directly participate in the extensive remodeling that follows acute lung injury. Because the tissue repair process occurs in an acute inflammatory setting, we investigated the effects of inflammatory mediators on urokinase-type plasminogen activator (u-PA) expression by pulmonary epithelial cells. We found that interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) upregulated PA activity in A549 human pulmonary epithelial cells. Biosynthetic labeling and immunoprecipitation showed that both cytokines caused marked accumulation of newly synthesized u-PA. Northern blot analyses demonstrated that both IL-1 beta and TNF-alpha induced relatively rapid accumulation of u-PA mRNA which did not require de novo protein synthesis and was substantially inhibited by glucocorticoids. Nuclear run-off transcription studies showed that both cytokines caused rapid transcriptional activation of the u-PA gene. While the effects of IL-1 beta and TNF-alpha were qualitatively similar, some differences emerged. Most notably, TNF-alpha led to a more sustained accumulation of u-PA mRNA than did IL-1 beta. In contrast to their effects on u-PA expression, IL-1 beta and TNF-alpha had minimal effect on PA inhibitor-1 expression. These effects of IL-1 beta and TNF-alpha, mediators known to play a key role in acute lung injury and inflammation, may promote lysis of alveolar fibrin by alveolar epithelium, thereby aiding in restoration of normal lung architecture.

The central importance of xanthine dehydrogenase (XDH) and xanthine oxidase (XO) in the pathobiochemistry of a number of clinical disorders underscores the need for a comprehensive understanding of the regulation of their expression. This study was undertaken to examine the effects of cytokines on XDH/XO activity and gene expression in pulmonary endothelial cells. The results indicate that IFN-gamma is a potent inducer of XDH/XO activity in rat lung endothelial cells derived from both the microvasculature (LMVC) and the pulmonary artery. In contrast, interferon-alpha/beta, tumor necrosis factor-alpha, interleukin-1 or -6, lipopolysaccharide and phorbol myristate acetate have no demonstrable effect. The increase in XDH/XO activity requires new protein synthesis. By Northern analysis, IFN-gamma markedly increases the level of the 5.0-kb XDH/XO mRNA in LMVC. The increase is due, in part, to increased transcription rate of the XDH/XO gene. Transcriptional activation does not require new protein synthesis. The physiologic relevance of these observations was evaluated by administering IFN-gamma to rats. Intraperitoneal administration leads to an increased XDH/XO activity and XDH/XO mRNA level in rat lungs. In sum, IFN-gamma is a potent and biologically relevant inducer of XDH/XO expression; the major site of upregulation occurs at the transcriptional level.

Through early detection, newborn screening (NBS) for cystic fibrosis (CF) offers the opportunity for early intervention and improved outcomes. NBS programs screen for hypertrypsinogenemia and most also identify mutations in the CF transmembrane conductance regulator (CFTR) gene. Individuals identified by NBS are diagnosed with CF if they have an elevated sweat chloride or if they have inherited two disease-causing mutations in the CFTR gene. Mutations in the CFTR gene can cause CF, but not all CFTR mutations are disease-causing. The term CFTR-related metabolic syndrome (CRMS) is proposed to describe infants with hypertrypsinogenemia on NBS who have normal or intermediate sweat chloride values and 2 CFTR mutations, including at least one that is not known to cause CF, and thus do not meet CF Foundation guidelines for the diagnosis of CF. Individuals with one CF-causing mutation, no mutation on the other allele and an intermediate sweat chloride are presumed to be CF carriers. With what is now near-universal CF NBS in the United States, an increasing number of infants with CRMS are being identified. Given our inadequate knowledge of the natural history of CRMS, standards for diagnosis, monitoring and treatment are absent. This document aims to help guide the monitoring and care of individuals with CRMS while our knowledge base on appropriate management evolves.

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.

Numerous improvements in diagnostic and therapeutic strategies for patients with cystic fibrosis (CF) have occurred during the past 2 decades. We hypothesized that these changes could impact trends in respiratory microbiology.Data from the Cystic Fibrosis Foundation Patient Registry were used to examine trends in the incidence and prevalence of bacterial pathogens isolated from patients with CF in the United States from 1995 to 2005.The number of patients with CF in the patient registry increased from 19,735 in 1995 to 23,347 in 2005. During the study period, the reported annual prevalence of Pseudomonas aeruginosa significantly declined from 60.4% in 1995 to 56.1% in 2005 (p0.001). The decline was most marked in children 6 to 10 years old (48.2 to 36.1%) and adolescents 11 to 17 years old (68.9 to 55.5%). Both the incidence (21.7% in 1995 and 33.2% in 2005) and prevalence (37.0% in 1995 and 52.4% in 2005) of methicillin-susceptible Staphylococcus aureus significantly increased and the age-specific prevalence was highest in patients 6 to 17 years old. The prevalence of methicillin-resistant S aureus increased from 0.1% in 1995 to 17.2% in 2005 and from 2002 to 2005 was highest in adolescents 11 to 17 years old. Both the prevalence and incidence of Burkholderia cepacia complex declined, while the prevalence of Haemophilus influenzae, Stenotrophomonas maltophilia, and Alcaligenes xylosoxidans increased.Data from the patient registry suggest that the epidemiology of bacterial pathogens in patients with CF changed during the study period. Future studies should continue to monitor changing trends and define the association between these trends and care practices in CF.

The Cystic Fibrosis Foundation is a voluntary, nonprofit, health organization whose mission is "to assure the development of the means to cure and control cystic fibrosis and to improve the quality of life for those with the disease." While substantial progress has been made, as evidenced by a marked increase in the median predicted age of survival, much work remains to be done. Ongoing medical programs and activities of the Cystic Fibrosis Foundation, which span basic science, drug discovery, drug development, clinical care, patient education, and advocacy, will be described in this article. The key role of respiratory therapists in the cystic fibrosis community will be highlighted.