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1.
Activity of hypothiocyanite and lactoferrin (ALX-009) against respiratory cystic fibrosis pathogens in sputum.
Tunney, MM, Payne, JE, McGrath, SJ, Einarsson, GG, Ingram, RJ, Gilpin, DF, Juarez-Perez, V, Elborn, JS
The Journal of antimicrobial chemotherapy. 2018;(12):3391-3397
Abstract
OBJECTIVES To determine the antimicrobial activity of ALX-009, a combination of bovine lactoferrin and hypothiocyanite, in sputum against Pseudomonas aeruginosa and Burkholderia cepacia complex (Bcc), key pathogens causing infection in the lungs of cystic fibrosis (CF) patients. METHODS The antimicrobial activity of ALX-009 against clinical respiratory P. aeruginosa isolates was determined by time-kill assay. Sputum from CF patients was treated with ALX-009, either alone or in combination with tobramycin, and the effect on P. aeruginosa, Bcc and total sputum density was determined. RESULTS Time-kill assay indicated that ALX-009 was bactericidal at 24 h against 4/4 P. aeruginosa isolates under aerobic conditions, and against 3/4 isolates under anaerobic conditions. ALX-009 was also bactericidal against P. aeruginosa in sputum samples at 6 h (n = 22/24 samples) and 24 h (n = 14/24 samples), and demonstrated significantly greater activity than tobramycin at both timepoints. Activity against Bcc in sputum samples (n = 9) was also demonstrated, but the magnitude of change in Bcc density was less than for P. aeruginosa. To determine the effect of treating sputum with two doses of ALX-009, similar to current regimens for inhaled antibiotics, aliquots of a further 10 sputum samples positive for P. aeruginosa were treated with one (t = 0 h) or two doses (t = 0 h, t = 12 h) of ALX-009; treatment with two doses resulted in bactericidal activity in 7/10 samples at 34 h compared with only 3/10 samples when treatment was with one dose. CONCLUSIONS ALX-009 demonstrates promise as a novel antimicrobial that could be used to decrease P. aeruginosa density in the lungs of people with CF.
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Unmet needs in cystic fibrosis: the next steps in improving outcomes.
West, NE, Flume, PA
Expert review of respiratory medicine. 2018;(7):585-593
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Abstract
Cystic fibrosis (CF) outcomes and survival have improved over the last century primarily due to advancements in antibiotics, nutritional, and pulmonary therapies. Reviewed here are the significant unmet needs that exist for individuals with CF. Areas covered: With the recent development of medications that address the underlying defect in the CF protein, there is hope that there will be continued improvement in CF outcomes. However, there remains a need to prevent or stop progression of CF-related complications, as the CF protein is important to several body systems. As end stage lung disease is the primary cause of mortality in CF, a need exists for advancements in pulmonary therapies to reduce time burden, identification of best practices for the treatment of pulmonary exacerbations, further development of anti-infective and anti-inflammatory therapies, and appropriately timed referral for lung transplantation at end-stage lung disease. Extra-pulmonary complications are increasingly recognized and better understanding of such problems as CF related liver disease is needed. Expert commentary: While CFTR modulators are available for the majority of CF patients, there remains a need for effective therapies to address infection, inflammation, irreversible lung disease, and extrapulmonary complications of CF.
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Pharmacological management of cystic fibrosis related diabetes.
Moheet, A, Moran, A
Expert review of clinical pharmacology. 2018;(2):185-191
Abstract
There are limited data from randomized clinical trials to guide optimal options for pharmacological treatment of cystic fibrosis related diabetes (CFRD). Current guidelines recommend insulin as the only treatment option for CFRD. Areas covered: Current guidelines for screening, diagnosis and pharmacological agents for treatment of impaired glucose tolerance and CFRD in patients with cystic fibrosis are reviewed. Insights from clinical studies examining the role of insulin therapy in CFRD are presented. Expert commentary: CFRD is the most common extra pulmonary complication of cystic fibrosis, and is primarily related to insulin insufficiency. Insulin is the treatment of choice for CFRD. Insulin treatment is associated with improvement in glycemic control, nutritional status and lung function. Current data does not support use of oral hypoglycemic agents for treatment of CFRD.
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Vitamin A and beta (β)-carotene supplementation for cystic fibrosis.
de Vries, JJ, Chang, AB, Bonifant, CM, Shevill, E, Marchant, JM
The Cochrane database of systematic reviews. 2018;(8):CD006751
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Abstract
BACKGROUND People with cystic fibrosis (CF) and pancreatic insufficiency are at risk of a deficiency in fat-soluble vitamins, including vitamin A. Vitamin A deficiency predominantly causes eye and skin problems, while excessive levels of vitamin A can harm the respiratory and skeletal systems in children and interfere with the metabolism of other fat-soluble vitamins. Most CF centres administer vitamin A as supplements to reduce the frequency of vitamin A deficiency in people with CF and to improve clinical outcomes such as growth, although the recommended dose varies between different guidelines. Thus, a systematic review on vitamin A and vitamin A-like supplementation (carotenes or other retinoids) in people with CF would help guide clinical practice. This is an update of an earlier Cochrane Review. OBJECTIVES To determine if supplementation with vitamin A, carotenes or other retinoid supplements in children and adults with CF reduces the frequency of vitamin A deficiency disorders, improves general and respiratory health and affects the frequency of vitamin A toxicity. SEARCH METHODS We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Cystic Fibrosis Trials Register compiled from electronic database searches and handsearching of journals and conference abstract books. Additionally we searched several ongoing trials registries, including ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform and the International Standard Randomised Controlled Trial Number Registry.Most recent database searches: 01 June 2018. SELECTION CRITERIA All randomised or quasi-randomised controlled studies comparing all preparations of oral vitamin A, carotenes or retinoids (or in combination), used as a supplement compared to placebo at any dose, for at least three months, in people with CF (diagnosed by sweat tests or genetic testing) with and without pancreatic insufficiency. DATA COLLECTION AND ANALYSIS Two authors individually assessed study quality and extracted data on outcome measures. The authors assessed the quality of the evidence using the GRADE system. Investigators were contacted to retrieve missing quantitative data. MAIN RESULTS No studies of vitamin A or other retinoid supplementation were eligible for inclusion. However, one randomised study of beta (β)-carotene supplementation involving 24 people with CF who were receiving pancreatic enzyme substitution was included. The study compared successive β-carotene supplementation periods (high dose followed by low dose) compared to placebo. The results for the low-dose supplementation period should be interpreted with caution, due to the lack of a wash-out period after the high-dose supplementation.The included study did not report on two of the review's primary outcomes (vitamin A deficiency disorders and mortality); results for our third primary outcome of growth and nutritional status (reported as z score for height) showed no difference between supplementation and placebo, mean difference (MD) -0.23 (95% confidence interval (CI) -0.89 to 0.43) (low-quality evidence). With regards to secondary outcomes, supplementation with high-dose β-carotene for three months led to significantly fewer days of systemic antibiotics required to treat pulmonary exacerbations, compared to controls, MD -15 days (95% CI -27.60 to -2.40); however, this was not maintained in the second three-month section of the study when the level of β-carotene supplementation was reduced, MD -8 days (95% CI -18.80 to 2.80) (low-quality evidence). There were no statistically significant effects between groups in lung function (low-quality evidence) and no adverse events were observed (low-quality evidence). Supplementation affected levels of β-carotene in plasma, but not vitamin A levels. The study did not report on quality of life or toxicity. AUTHORS' CONCLUSIONS Since no randomised or quasi-randomised controlled studies on retinoid supplementation were identified, no conclusion on the supplementation of vitamin A in people with CF can be drawn. Additionally, due to methodological limitations in the included study, also reflected in the low-quality evidence judged following the specific evidence grading system (GRADE), no clear conclusions on β-carotene supplementation can be drawn. Until further data are available, country- or region-specific guidelines regarding these practices should be followed.
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Treatment for chronic methicillin-sensitive Staphylococcus aureus pulmonary infection in people with cystic fibrosis.
Ahmed, MI, Mukherjee, S
The Cochrane database of systematic reviews. 2018;(7):CD011581
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BACKGROUND Cystic fibrosis is an inherited life-threatening multisystem disorder with lung disease characterized by abnormally thick airway secretions and persistent bacterial infection. Chronic, progressive lung disease is the most important cause of morbidity and mortality in the condition and is therefore the main focus of clinical care and research. Staphylococcus aureus is a major cause of chest infection in people with cystic fibrosis. Early onset, as well as chronic, lung infection with this organism in young children and adults results in worsening lung function, poorer nutrition and increases the airway inflammatory response, thus leading to a poor overall clinical outcome. There are currently no evidence-based guidelines for chronic suppressive therapy for Staphylococcus aureus infection in cystic fibrosis such as those used for Pseudomonas aeruginosa infection. This is an update of a previously published review. OBJECTIVES To assess the evidence regarding the effectiveness of long-term antibiotic treatment regimens for chronic infection with methicillin-sensitive Staphylococcus aureus (MSSA) infection in people with cystic fibrosis and to determine whether this leads to improved clinical and microbiological outcomes. SEARCH METHODS Trials were identified by searching the Cochrane Cystic Fibrosis and Genetic Disorders Group's Cystic Fibrosis Trials Register, MEDLINE, Embase, handsearching article reference lists and through contact with local and international experts in the field. Date of the last search of the Group's Cystic Fibrosis Trials Register: 09 February 2018.We also searched ongoing trials databases. Date of latest search: 20 May 2018. SELECTION CRITERIA Randomised or quasi-randomised controlled trials comparing any combinations of topical, inhaled, oral or intravenous antimicrobials used as suppressive therapy for chronic infection with methicillin-sensitive Staphylococcus aureus compared with placebo or no treatment. DATA COLLECTION AND ANALYSIS The authors independently assessed all search results for eligibility. No eligible trials were identified. MAIN RESULTS The searches identified 58 trials, but none were eligible for inclusion in the current version of this review. AUTHORS' CONCLUSIONS No randomised controlled trials were identified which met the inclusion criteria for this review. Although methicillin-sensitive Staphylococcus aureus is an important and common cause of lung infection in people with cystic fibrosis, there is no agreement on how best to treat long-term infection. The review highlights the need to organise well-designed trials that can provide evidence to support the best management strategy for chronic methicillin-sensitive Staphylococcus aureus infection in people with cystic fibrosis.
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Repurposing excipients as active inhalation agents: The mannitol story.
Anderson, SD, Daviskas, E, Brannan, JD, Chan, HK
Advanced drug delivery reviews. 2018;:45-56
Abstract
The story of how we came to use inhaled mannitol to diagnose asthma and to treat cystic fibrosis began when we were looking for a surrogate for exercise as a stimulus to identify asthma. We had proposed that exercise-induced asthma was caused by an increase in osmolarity of the periciliary fluid. We found hypertonic saline to be a surrogate for exercise but an ultrasonic nebuliser was required. We produced a dry powder of sodium chloride but it proved unstable. We developed a spray dried preparation of mannitol and found that bronchial responsiveness to inhaling mannitol identified people with currently active asthma. We reasoned that mannitol had potential to replace the 'osmotic' benefits of exercise and could be used as a treatment to enhance mucociliary clearance in patients with cystic fibrosis. These discoveries were the start of a journey to develop several registered products that are in clinical use globally today.
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Interventions for preventing distal intestinal obstruction syndrome (DIOS) in cystic fibrosis.
Green, J, Gilchrist, FJ, Carroll, W
The Cochrane database of systematic reviews. 2018;(6):CD012619
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BACKGROUND Cystic fibrosis (CF) is the most common, life-limiting, genetically inherited disease. It affects multiple organs, particularly the respiratory system. However, gastrointestinal problems such as constipation and distal intestinal obstruction syndrome (DIOS) are also important and well-recognised complications in CF. They share similar symptoms e.g. bloating, abdominal pain, but are distinct conditions. Constipation occurs when there is gradual faecal impaction of the colon, but DIOS occurs when there is an accumulation of faeces and sticky mucus, forming a mass in the distal part of the small intestine. The mass may partially block the intestine (incomplete DIOS) or completely block the intestine (complete DIOS). Symptoms of DIOS can affect quality of life and other aspects of CF health, such as airway clearance, exercise, sleep and nutritional status. Treatment of constipation and prevention of complete bowel obstruction are required for gastrointestinal management in CF. However, many different strategies are used in clinical practice and there is a lack of consensus. The importance of this topic was highlighted in a recent research priority setting exercise by the James Lind Alliance. OBJECTIVES To evaluate the effectiveness and safety of laxative agents of differing types for preventing DIOS (complete and incomplete) in children and adults with CF. SEARCH METHODS We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. Date of search: 22 May 2018.We also searched online trial registries. Date of last search: 10 June 2018. SELECTION CRITERIA Randomised and quasi-randomised controlled parallel trials comparing laxative therapy for preventing DIOS (including osmotic agents, stimulants, mucolytics and substances with more than one action) at any dose to placebo, no treatment or an alternative laxative therapy, in people of any age with pancreatic sufficient or insufficient CF and any stage of lung disease. Randomised cross-over trials were judged on an individual basis. DATA COLLECTION AND ANALYSIS Two authors independently assessed trials for inclusion, extracted outcome data and performed a risk of bias assessment for the included data. We judged the quality of the evidence using GRADE criteria. MAIN RESULTS We included one cross-over trial (17 participants) with a duration of 12 months, in which participants were randomly allocated to either cisapride (a gastro-prokinetic agent) or placebo for six months each. The trial had an unclear risk of bias for most domains but had a high risk of reporting bias.Radiograph scores revealed no difference in occurrence of DIOS between cisapride and placebo (narrative report, no data provided). There were no adverse effects. Symptom scores were the only secondary outcome within the review that were reported. Total gastrointestinal symptom scores favoured cisapride with a statistically significant mean difference (MD) of -7.60 (95% confidence interval (CI) -14.73 to -0.47). There was no significant difference at six months between cisapride and placebo for abdominal distension, MD -0.90 (95% CI -2.39 to 0.59) or abdominal pain, MD -0.4 (95% CI -2.05 to 1.25). The global symptom scores (whether individuals felt better or worse) were reported in the paper to favour cisapride and be statistically significant (P < 0.05).We assessed the available data to be very low quality. There was a great deal of missing data from the included trial and the investigators failed to report numerical data for many outcomes. The overall risk of bias of the trial was unclear and it had a high risk for reporting bias. There was also indirectness; the trial drug (cisapride) has since been removed from the market in several countries due to adverse effects, thus it has no current applicability for preventing DIOS. The included trial also had very few participants, which downgraded the quality a further level for precision. AUTHORS' CONCLUSIONS There is an absence of evidence for interventions for the prevention of DIOS. As there was only one included trial, we could not perform a meta-analysis of the data. Furthermore, the included trial compared a prokinetic agent (cisapride) that is no longer licensed for use in a number of countries due to the risk of serious cardiac events, a finding that came to light after the trial was conducted. Therefore, the limited findings from the trial are not applicable in current clinical practice.Overall, a great deal more research needs to be undertaken on gastrointestinal complications in CF, as this is a very poorly studied area compared to respiratory complications in CF.
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Evaluation of continuous constant current and continuous pulsed current in sweat induction for cystic fibrosis diagnosis.
Gomez, CCS, Marson, FAL, Servidoni, MF, Ribeiro, AF, Ribeiro, MÂGO, Gama, VAL, Costa, ET, Ribeiro, JD, Vieira Junior, FU
BMC pulmonary medicine. 2018;(1):153
Abstract
BACKGROUND The sweat test (ST) is the gold standard for the diagnosis of cystic fibrosis (CF). However, little is known about sweat induction using different types of currents and waves. In this context, our objective was to develop a device to induce sweat and compare the use of continuous constant current (CCC) and continuous pulsed current (CPC) in individuals with CF and healthy controls. METHODS A prospective cross-sectional study with experimental intervention. The variables of gender, ethnicity, age, and body mass index (BMI) were considered. The method of Gibson and Cooke was used, and the following markers were evaluated: sweat weight, electrical impedance, sufficient sweat amount, and CF diagnosis. Triangular (TPC) or sinusoidal (SPC) pulsed current was applied to the right arm, and CCC was applied to the left arm. RESULTS The study analyzed 260 individuals, 141/213 (54.2%) were female participants, 135/260 (51.9%) were Caucasians. The distribution of individuals by concentration of chloride at the ST was: (CF) 26/260 (10%); (borderlines) 109/260 (41.9%); (healthy) 97/260 (37.3%); (insufficient weight in sweat) 28/260 (10.8%). No association was observed between the sufficient sweat amount to perform the ST when we compared the currents. However, the SPC showed a higher amount of sweat weight. Using Bland and Altman plot considering the agreement between the sweat chloride values achieved from CPC [SPC and TPC] and CCC, there was no proportional bias and mean values are unrelated and only explain less than 8% of the variation. Moreover, TPC presented higher electrical impedance when compared with SPC and CCC. SPC presented lower electrical impedance and higher sweat weight than CCC. Male participants presented lower electrical impedance and higher sweat weight with CCC and TPC, and higher sweat weight with SPC. CONCLUSIONS The evaluated currents are safe and able to induce and produce sweat in sufficient quantities for the ST. SPC presented lower electrical impedance when compared with other currents. The use of SPC is recommended to induce sweat in patients with sweat problems. Finally, ethnicity, gender, age and BMI did not influence sweat induction at the ST, and no side effect was observed in our study.
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[Gynecological management and follow-up in women with cystic fibrosis].
Rousset-Jablonski, C, Reynaud, Q, Nove-Josserand, R, Durupt, S, Durieu, I
Revue des maladies respiratoires. 2018;(6):592-603
Abstract
INTRODUCTION Most women with cystic fibrosis reach adulthood and should have appropriate gynecological follow-up and contraception. BACKGROUND There is no specific contra-indication to any contraception due to cystic fibrosis itself. Combined estrogen-progesterone contraception can be used in most cases (including transplanted women). In case of transplantation, intra-uterine devices should be used carefully (risk of pelvic inflammatory disease, potential risk of contraceptive failure with copper intra-uterine devices). Hormonal contraceptives may not be effective in women taking corrective treatments aiming to correct the maturation defect of the chloride channel. Screening for cervical cancer is recommended with a pap smear every three years for women aged 25-65, but yearly and starting at a younger age among transplanted women who are at higher risk for cervical dysplasia. Human Papillomavirus vaccination should be offered to all young women. OUTLOOK Women with cystic fibrosis and health care providers should be better informed on screening and on sexual and reproductive health to avoid unplanned pregnancies, to take into account drug interactions and to prevent cervical disease. CONCLUSION Regular and specific gynecological management is mandatory in cases of cystic fibrosis.
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Oral glucose tolerance test and continuous glucose monitoring to assess diabetes development in cystic fibrosis patients.
Clemente León, M, Bilbao Gassó, L, Moreno-Galdó, A, Campos Martorrell, A, Gartner Tizzano, S, Yeste Fernández, D, Carrascosa Lezcano, A
Endocrinologia, diabetes y nutricion. 2018;(1):45-51
Abstract
INTRODUCTION Patients with cystic fibrosis (CF) undergo a slow and progressive process toward diabetes. Oral glucose tolerance test (OGTT) is recommended to diagnose impaired glucose levels in these patients. Continuous glucose monitoring (CGM) measures glucose profiles under real-life conditions. OBJECTIVE To compare OGTT and CGM results in CF patients. METHODS Paired OGTT and 6-day CGM profiles (146.2±9.1h/patient) were performed in 30 CF patients aged 10-18 years. RESULTS According to OGTT, 14 patients had normal glucose tolerance (NGT), 14 abnormal glucose tolerance (AGT), and two cystic fibrosis-related diabetes (CFRD). In 27 patients (13 NGT, 13 AGT, 1 CFRD), CGM showed glucose values ranging from 140 to 200mg/dL during similar monitoring times (2%-14% with NGT, 1%-16.9% with AGT, and 3% with CFRD). Glucose peak levels ≥200mg/dL were seen in seven patients (3 NGT, 3 AGT, 1 CFRD). According to CGM, two patients had all glucose values under 140mg/dL (1 NGT, 1 AGT). Seventeen patients had glucose levels ranging from 140 to 200mg/dL (10 NGT, 6 AGT, 1 CFRD). Ten patients (3 NGT, 7 AGT) had glucose values ≥200mg/dL for ≤1% of the monitoring time and one (CFRD) for >1% of the monitoring time. CONCLUSIONS OGTT results did not agree with those of the CGM. CGM allows for diagnosis of glucose changes not detected by OGTT. Such changes may contribute to optimize pre-diabetes management in CF patients.