Cystic Fibrosis Foundation and European Cystic Fibrosis Society Survey of cystic fibrosis mental health care delivery.

BACKGROUND: Psychological morbidity in individuals with cystic fibrosis (CF) and their caregivers is common. The Cystic Fibrosis Foundation (CFF) and European Cystic Fibrosis Society (ECFS) Guidelines Committee on Mental Health sought the views of CF health care professionals concerning mental health care delivery. METHODS: An online survey which focused on the current provision and barriers to mental health care was distributed to CF health care professionals. RESULTS: Of the 1454 respondents, many did not have a colleague trained in mental health issues and 20% had no one on their team whose primary role was focused on assessing or treating these issues. Insufficient resources and a lack of competency were reported in relation to mental health referrals. Seventy-three percent of respondents had no experience with mental health screening. Of those who did, they utilized 48 different, validated scales. CONCLUSIONS: These data have informed the decision-making, dissemination and implementation strategies of the Mental Health Guidelines Committee sponsored by the CFF and ECFS.

A cluster of transfusion-associated babesiosis in extremely low birthweight premature infants.

Babesiosis is a parasitic infection of the red blood cells most often acquired by a tick bite. As it has also been known to be transmitted vertically and via transfusion, neonates have occasionally been reported with the infection. Here, we report a series of three premature neonates who acquired babesiosis via blood transfusion from a single donor, one of whom had difficulty clearing the infection and required multiple antimicrobials.

An update on the screening, diagnosis, management, and treatment of vitamin D deficiency in individuals with cystic fibrosis: evidence-based recommendations from the Cystic Fibrosis Foundation.

OBJECTIVE: The objective was to develop evidence-based clinical care guidelines for the screening, diagnosis, management, and treatment of vitamin D deficiency in individuals with cystic fibrosis (CF). PARTICIPANTS: The guidelines committee was comprised of physicians, registered dietitians, a pharmacist, a nurse, a parent of an individual with CF, and a health scientist, all with experience in CF. PROCESS: Committee members developed questions specific to vitamin D health in individuals with CF. Systematic reviews were completed for each question. The committee reviewed and graded the available evidence and developed evidence-based recommendations and consensus recommendations when insufficient evidence was available. Each consensus recommendation was voted upon by an anonymous process. CONCLUSIONS: Vitamin D deficiency is common in CF. Given the limited evidence specific to CF, the committee provided consensus recommendations for most of the recommendations. The committee recommends yearly screening for vitamin D status, preferably at the end of winter, using the serum 25-hydroxyvitamin D measurement, with a minimal 25-hydroxyvitamin D concentration of 30 ng/ml (75 nmol/liter) considered vitamin D sufficient in individuals with CF. Recommendations for age-specific vitamin D intake for all individuals with CF, form of vitamin D, and a stepwise approach to increase vitamin D intake when optimal vitamin D status is not achieved are delineated.

Epidemiology of cystic fibrosis-related diabetes.

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.

Survival effect of lung transplantation among patients with cystic fibrosis.

CONTEXT: Patients with cystic fibrosis (CF) are the second largest group of lung transplant recipients in the United States. The survival effect of transplantation on a general CF population has not previously been measured. OBJECTIVE: To determine the impact of bilateral lung transplantation on survival in patients with CF. DESIGN, SETTING, AND PATIENTS: Retrospective observational cohort study of 11 630 CF patients who did not undergo lung transplantation (controls) and 468 transplant recipients with CF from 115 CF centers in the United States, 1992-1998. Patients were stratified into 5 groups based on a 5-year survival prediction model (survival group 1: <30%; survival group 2: 30 to <50%; survival groups 3-5: 50 to <100%.) MAIN OUTCOME MEASURE: Five-year survival from date of transplantation in 1992-1997 in the transplant group and from January 1, 1993, in the control group. RESULTS: Lung transplantation increased 5-year survival of CF patients in survival group 1. Survival group 2 had equivocal survival effects, and groups 3-5 had negative survival effects from transplantation. From 1994-1997, there was a mean annual prevalence of 238 patients in survival group 1 and mean annual incidence of 154 patients entering the group, approximately 1.5 times the number of lung transplantations performed each year in CF patients (mean, 104). Use of the criterion of forced expiratory volume in 1 second of less than 30% resulted in an equivocal survival benefit and identified 1458 potential candidates for transplantation in 1993. CONCLUSIONS: Cystic fibrosis patients in group 1 have improved 5-year survival after lung transplantation. The majority of patients with CF have equivocal or negative survival effects from the procedure. Selection of patients with CF for transplantation based on group 1 survival predictions maximizes survival benefits to individuals and may reduce the demand for scarce donor organs.

Oxygen saturation in adult cystic fibrosis patients during exercise at high altitude.

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, < 90%) at rest were evaluated. Spirometry was performed according to American Thoracic Society standards, and maximal exercise tests were performed on an electronically braked cycle ergometer using a ramp protocol individualized for each patient. Pulse oximetry was measured every 2 min. When exercising at high altitude, 45 of 50 patients had a decrease in arterial oxy-hemoglobin saturation from baseline to some degree. In 29 patients, oxy-hemoglobin saturation fell below 90%; in 14 patients, it fell below 85%; and in 4 patients, it fell below 80%. Oxy-hemoglobin saturation decreased to < 90% in 12 of 14 patients with severe pulmonary disease (FEV(1) < 40% predicted), in 15 of 26 patients with moderate disease (40% less than or equal to FEV(1) < 70% predicted), in 2 of 6 patients with mild disease (70% less than or equal to FEV(1) < 90% predicted), and in 0 of 4 with normal pulmonary function (FEV(1) greater than or equal to 90%). Percent predicted FEV(1) (r = 0.57; P < 0.0001) and FEV(1)/FVC ratio (r = 0.52; P < 0.0001) most highly correlated with arterial oxy-hemoglobin saturation at peak exercise. We conclude that at 1,500 m above sea level, adult CF patients with obstructive airways disease are at significant risk for decreased arterial oxy-hemoglobin saturation during exercise. A supervised exercise test should be considered prior to recommending an exercise program for such patients.

Predictive 5-year survivorship model of cystic fibrosis.

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.

Bone mineral status in prepubertal children with cystic fibrosis.

OBJECTIVES: To determine whether osteopenia is evident in prepubertal children with cystic fibrosis (CF) and, if so, whether it is caused by a deficiency in bone formation or increased bone resorption. STUDY DESIGN: With the use of a prospective case control study design, we investigated 11 prepubertal children with CF between the ages of 8 and 12 years old and a non-CF control group matched by weight and sex. Bone density at the radius, ulnar, trochanter, femoral neck, and lumbar spine, biochemical markers of bone metabolism, calcium, vitamin D metabolites, and intact parathyroid hormone were measured in all subjects. Comparisons between the 2 groups were performed with Wilcoxon matched pairs and Fisher exact tests. RESULTS: Intake of total calories, calcium, phosphorus, and vitamin D was significantly greater in the CF group than in the control group. Serum 25(OH)vitamin D levels were significantly lower in the CF group: median 22 ng/mL for the CF group and 39 ng/mL for the control group (P =.02). 1,25(OH)(2) vitamin D levels were borderline or low in 7 subjects in the CF group and 2 members of the control group (P =.08, Fisher exact test). Intact parathyroid hormone levels were higher than the upper limit of normal in 4 subjects of the CF group and 1 member of the control group. Despite these biochemical abnormalities, we found no evidence of bone mineral deficiency in the CF group. CONCLUSIONS: Prepubertal children with CF do not have bone mineral deficit compared with a weight- and sex-matched control group; however, their lower vitamin D levels may portend problems with bone mineralization during adolescence and adulthood.

Hepatocyte growth factor attenuates collagen accumulation in a murine model of pulmonary fibrosis.

We investigated the in vivo effects of recombinant human hepatocyte growth factor (HGF) on epithelial cell proliferation in normal mouse lung and on the repair process that follows bleomycin-induced lung injury. Intratracheal administration of 100 micrograms of rhHGF to C57BL/6 mice led to proliferation of bronchial and alveolar epithelial cells as indicated by an increased number of cells staining for proliferating cell nuclear antigen (PCNA). The effect of HGF on the lung repair process was examined by administration of 100 micrograms of rhHGF on Day 3 and Day 6 after intratracheal injection of bleomycin to mice. We found that HGF significantly attenuated collagen accumulation induced by bleomycin as determined by quantitation of hydroxyproline content and by scoring of the extent of fibrosis. To explore the potential mechanisms involved in the beneficial effects of HGF, we performed in vitro studies with A549 pulmonary epithelial cells and found that HGF enhanced cell surface plasmin generation, expression of u-PA activity, and cell migration. In summary, HGF has potent in vivo and in vitro effects on epithelial cells, which suggests it may have a role in the therapy of pulmonary fibrosis.

Decreased intracellular iron availability suppresses epithelial cell surface plasmin generation. Transcriptional and post-transcriptional effects on u-PA and PAI-1 expression.

Iron and iron metabolism are critical in a variety of physiologic and pathophysiologic processes, including lung injury and repair. The plasmin/plasminogen activator (PA) system is involved in the extensive remodeling process that follows acute lung injury, and alveolar epithelial cells play a key role in this repair process. Herein we report that decreased intracellular iron availability markedly suppresses cell-surface plasmin generation by A549 human carcinoma-derived pulmonary epithelial cells. This effect is mediated by concomitant downregulation of urokinase-type PA and upregulation of PA inhibitor-type 1 expression. Northern analyses, runoff transcription assays, and messenger RNA half-life experiments using actinomycin demonstrate that transcriptional and post-transcriptional mechanisms are operative. Given these potent in vitro effects on the plasmin/PA system, we speculate that adequate intracellular iron stores are important for successful repair of acute lung injury.

Intermittent administration of inhaled tobramycin in patients with cystic fibrosis. Cystic Fibrosis Inhaled Tobramycin Study Group.

BACKGROUND AND METHODS: We conducted two multicenter, double-blind, placebo-controlled trials of intermittent administration of inhaled tobramycin in patients with cystic fibrosis and Pseudomonas aeruginosa infection. A total of 520 patients (mean age, 21 years) were randomly assigned to receive either 300 mg of inhaled tobramycin or placebo twice daily for four weeks, followed by four weeks with no study drug. Patients received treatment or placebo in three on-off cycles for a total of 24 weeks. The end points included pulmonary function, the density of P. aeruginosa in sputum, and hospitalization. RESULTS: The patients treated with inhaled tobramycin had an average increase in forced expiratory volume in one second (FEV1) of 10 percent at week 20 as compared with week 0, whereas the patients receiving placebo had a 2 percent decline in FEV1 (P<0.001). In the tobramycin group, the density of P. aeruginosa decreased by an average of 0.8 log10 colony-forming units (CFU) per gram of expectorated sputum from week 0 to week 20, as compared with an increase of 0.3 log10 CFU per gram in the placebo group (P<0.001). The patients in the tobramycin group were 26 percent (95 percent confidence interval, 2 to 43 percent) less likely to be hospitalized than those in the placebo group. Inhaled tobramycin was not associated with detectable ototoxic or nephrotoxic effects or with accumulation of the drug in serum. The proportion of patients with P. aeruginosa isolates for which the minimal inhibitory concentration of tobramycin was 8 microg per milliliter or higher increased from 25 percent at week 0 to 32 percent at week 24 in the tobramycin group, as compared with a decrease from 20 percent at week 0 to 17 percent at week 24 in the placebo group. CONCLUSIONS: In a 24-week study of patients with cystic fibrosis, intermittent administration of inhaled tobramycin was well tolerated and improved pulmonary function, decreased the density of P. aeruginosa in sputum, and decreased the risk of hospitalization.

Basic therapies in cystic fibrosis. Does standard therapy work?

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.

Induction of urokinase-type plasminogen activator receptor by IL-1 beta.

Extensive tissue remodeling occurs in survivors of acute lung injury, leading to nearly normal histology and physiology in the majority of individuals, whereas others suffer significant impairment due to the development of pulmonary fibrosis. Alveolar epithelial cells play a central role in the repair process. They are strategically located to directly participate in the solubilization of intraalveolar fibrin deposits, and have the capacity to promote fibrinolysis. We have previously reported that interleukin-1 beta (IL-1 beta), an important inflammatory mediator in acute lung injury, upregulates urokinase-type plasminogen activator expression by human A549 cells (1). In this work, we show that IL-1 beta increases cell-surface plasmin generation, mediated in part by increased expression of urokinase receptor (u-PAR). Northern blot analyses demonstrated that IL-1 beta rapidly induces accumulation of u-PAR messenger RNA (mRNA) in a dose-dependent fashion, and that this effect is blocked by actinomycin. The IL-1 beta-mediated increase in u-PAR mRNA is inhibited by: (1) the relatively specific protein kinase C (PKC) inhibitors 1-(5-isoquinoline sulfonyl)-2-methylpiperazine (H7) and calphostin C; and (2) prolonged pretreatment of cells with phorbol myristate acetate (PMA), suggesting that PKC is an important component of the signaling pathway. Okadaic acid, an inhibitor of serine/threonine phosphatases, markedly potentiates the effect of IL-1 beta on u-PAR mRNA levels. In contrast, dexamethasone, in concentrations as low as 10(-8) M, completely blocks the IL-1 beta-mediated increase in u-PAR mRNA. Half-life experiments show that dexamethasone has no effect on u-PAR mRNA stability. Aldosterone, at concentrations in which it binds primarily to the mineralocorticoid receptor, has no effect on u-PAR expression, suggesting that the glucocorticoid effect is due to a transrepressive mechanism. In summary, IL-1 beta increases cell-surface plasmin generation in A549 cells by coordinately upregulating urokinase and u-PAR expression. Transcriptional activation of the u-PAR gene involves PKC-dependent mechanisms, and glucocorticoid suppression is probably due to interactions between the glucocorticoid receptor and another transcriptional activating system such as activator protein-1 (AP-1) and/or nuclear factor-kB (NF-kB).

HIV-positive males' satisfaction with pharmacy services.

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.

Tyloxapol inhibits NF-kappa B and cytokine release, scavenges HOCI, and reduces viscosity of cystic fibrosis sputum.

Cystic fibrosis (CF) patients develop progressive cytokine-mediated inflammatory lung disease, with abundant production of thick, tenacious, protease- and oxidant-rich purulent airway secretions that are difficult to clear even with physiotherapy. In the search for a potential treatment, we have tested tyloxapol, an alkylaryl polyether alcohol polymer detergent previously used as a mucolytic agent in adult chronic bronchitis. Tyloxapol inhibits activation of the transcription factor nuclear factor-kappa B (NK-kappa B), reduces resting secretion of the cytokine interleukin-8 (IL-8) in cultured human monocytes, and inhibits lipopolysaccharide (LPS)-stimulated release of tumor necrosis factor-alpha (TNF-alpha), IL-1 beta, IL-6, IL-8, granulocyte-macrophage colony-stimulating factor (GM-CSF), and the eiconsanoids thromboxane A2 and leukotriene B4 (LTB4). We have previously shown that tyloxapol is a potent antioxidant for hydroxyl radicals ( OH). Tyloxapol (0.05 to 0.1% wt/vol) effectively scavenges the oxidant hypochlorous acid (HOCl; 1 to 7.5 mM) in vitro, and protects from HOCl-mediated lung injury in rats. Tyloxapol also reduces the viscosity of CF sputum (from 463 +/- 133 to 128 +/- 52 centipoise). We conclude that tyloxapol is potentially useful as a new antiinflammatory therapy for CF lung disease, and could possibly promote clearance of secretions in the CF airway.

Biosynthesis and processing of proteinase 3 in U937 cells. Processing pathways are distinct from those of cathepsin G.

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.