B16. CYSTIC FIBROSIS: NOVEL THERAPIES AND OUTCOME MEASURES

Background Emerging data suggests a possible role for cysteamine as an adjunct treatment for pulmonary exacerbations of cystic fibrosis (CF) that continue to be a major clinical challenge. There are no studies investigating the use of cysteamine in pulmonary exacerbations of CF. This exploratory randomized clinical trial was conducted to answer the question: In future pivotal trials of cysteamine as an adjunct treatment in pulmonary exacerbations of CF, which candidate cysteamine dosing regimens should be tested and which are the most appropriate, clinically meaningful outcome measures to employ as endpoints? Methods and findings Multicentre double-blind randomized clinical trial. Adults experiencing a pulmonary exacerbation of CF being treated with standard care that included aminoglycoside therapy were randomized equally to a concomitant 14-day course of placebo, or one of 5 dosing regimens of cysteamine. Outcomes were recorded on days 0, 7, 14 and 21 and included sputum bacterial load and the patient reported outcome measures (PROMs): Chronic Respiratory Infection Symptom Score (CRISS), the Cystic Fibrosis Questionnaire–Revised (CFQ-R); FEV1, blood leukocyte count, and inflammatory markers. Eighty nine participants in fifteen US and EU centres were randomized, 78 completed the 14-day treatment period. Cysteamine had no significant effect on sputum bacterial load, however technical difficulties limited interpretation. The most consistent findings were for cysteamine 450mg twice daily that had effects additional to that observed with placebo, with improved symptoms, CRISS additional 9.85 points (95% CI 0.02, 19.7) p = 0.05, reduced blood leukocyte count by 2.46x109 /l (95% CI 0.11, 4.80), p = 0.041 and reduced CRP by geometric mean 2.57 nmol/l (95% CI 0.15, 0.99), p = 0.049. Conclusion In this exploratory study cysteamine appeared to be safe and well-tolerated. Future pivotal trials investigating the utility of cysteamine in pulmonary exacerbations of CF need to include the cysteamine 450mg doses and CRISS and blood leukocyte count as outcome measures. Clinical trial registration NCT03000348; www.clinicaltrials.gov.

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Mucus plugging, air trapping, and bronchiectasis are important outcome measures in assessing progressive childhood cystic fibrosis lung disease

Pediatric Pulmonology ◽

10.1002/ppul.24646 ◽

2020 ◽

Vol 55 (4) ◽

pp. 929-938 ◽

Cited By ~ 3

Author(s):

Terry E. Robinson ◽

Michael L. Goris ◽

Richard B. Moss ◽

Lu Tian ◽

Peiyi Kan ◽

...

Keyword(s):

Cystic Fibrosis ◽

Lung Disease ◽

Outcome Measures ◽

Cystic Fibrosis Lung ◽

Air Trapping ◽

Cystic Fibrosis Lung Disease

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A systematic review of patient-reported outcome measures (PROMs) in cystic fibrosis

BMJ Open ◽

10.1136/bmjopen-2019-033867 ◽

2020 ◽

Vol 10 (10) ◽

pp. e033867

Author(s):

Irushi Ratnayake ◽

Susannah Ahern ◽

Rasa Ruseckaite

Keyword(s):

Quality Of Life ◽

Cystic Fibrosis ◽

Outcome Measures ◽

Patient Reported Outcome Measures ◽

Patient Reported Outcome ◽

Cochrane Library ◽

Life Questionnaire ◽

Health Measurement ◽

Patient Reported

BackgroundTo determine patient-reported outcome measures (PROMs) which may be suitable for incorporation into the Australian Cystic Fibrosis Data Registry (ACFDR) by identifying PROMs administered in adult and paediatric cystic fibrosis (CF) populations in the last decade.MethodsWe searched MEDLINE, EMBASE, Scopus, CINAHL, PsycINFO and Cochrane Library databases for studies published between January 2009 and February 2019 describing the use of PROMs to measure health-related quality of life (HRQoL) in adult and paediatric patients with CF. Validation studies, observational studies and qualitative studies were included. The search was conducted on 13 February 2019. The COnsensus-based Standards for the selection of health Measurement INstruments Risk of Bias Checklist was used to assess the methodological quality of included studies.ResultsTwenty-seven different PROMs were identified. The most commonly used PROMs were designed specifically for CF. Equal numbers of studies were conducted on adult (32%, n=31), paediatric (35%, n=34) and both (27%, n=26) populations. No PROMs were used within a clinical registry setting previously. The two most widely used PROMs, the Cystic Fibrosis Questionnaire—Revised (CFQ-R) and the Cystic Fibrosis Quality of Life Questionnaire (CFQoL), demonstrated good psychometric properties and acceptability in English-speaking populations.DiscussionWe found that although PROMs are widely used in CF, there is a lack of reporting on the efficacy of methods and timepoints of administration. We identified the CFQ-R and CFQoL as the most suitable for incorporation in the ACFDR as they captured significant effects of CF on HRQoL and were reliable and valid in CF populations. These PROMs will be used in a further qualitative study assessing patients’ with CF and clinicians’ perspectives toward the acceptability and feasibility of incorporating a PROM in the ACFDR.PROSPERO registration numberCRD42019126931.

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Biogeochemical Forces Shape the Composition and Physiology of Polymicrobial Communities in the Cystic Fibrosis Lung

mBio ◽

10.1128/mbio.00956-13 ◽

2014 ◽

Vol 5 (2) ◽

Cited By ~ 68

Author(s):

Robert A. Quinn ◽

Yan Wei Lim ◽

Heather Maughan ◽

Douglas Conrad ◽

Forest Rohwer ◽

...

Keyword(s):

Cystic Fibrosis ◽

Microbial Community ◽

Amino Acid ◽

Nitrogen Cycle ◽

High Throughput Sequencing ◽

Survival Strategies ◽

Novel Therapies ◽

Amino Acid Catabolism ◽

Respiratory Pathway ◽

The Core

ABSTRACTThe cystic fibrosis (CF) lung contains thick mucus colonized by opportunistic pathogens which adapt to the CF lung environment over decades. The difficulty associated with sampling airways has impeded a thorough examination of the biochemical microhabitats these pathogens are exposed to. An indirect approach is to study the responses of microbial communities to these microhabitats, facilitated by high-throughput sequencing of microbial DNA and RNA from sputum samples. Microbial metagenomes and metatranscriptomes were sequenced from multiple CF patients, and the reads were assigned taxonomy and function through sequence homology to NCBI and the Kyoto Encyclopedia of Genes and Genomes (KEGG) database hierarchies. For a comparison, saliva microbial metagenomes from the Human Microbiome Project (HMP) were also analyzed. These analyses identified that functions encoded and expressed by CF microbes were significantly enriched for amino acid catabolism, folate biosynthesis, and lipoic acid biosynthesis. The data indicate that the community uses oxidative phosphorylation as a major energy source but that terminal electron acceptors were diverse. Nitrate reduction was the most abundant anaerobic respiratory pathway, and genes for nitrate reductase were largely assigned toPseudomonasandRothia. Although many reductive pathways of the nitrogen cycle were present, the cycle was incomplete, because the oxidative pathways were absent. Due to the abundant amino acid catabolism and incomplete nitrogen cycle, the CF microbial community appears to accumulate ammonia. This finding was verified experimentally using a CF bronchiole culture model system. The data also revealed abundant sensing and transport of iron, ammonium, zinc, and other metals along with a low-oxygen environment. This study reveals the core biochemistry and physiology of the CF microbiome.IMPORTANCEThe cystic fibrosis (CF) microbial community is complex and adapts to the environmental conditions of the lung over the lifetime of a CF patient. This analysis illustrates the core functions of the CF microbial community in the context of CF lung biochemistry. There are many studies of the metabolism and physiology of individual microbes within the CF lung, but none that collectively analyze data from the whole microbiome. Understanding the core metabolism of microbes that inhabit the CF lung can provide new targets for novel therapies. The fundamental processes that CF pathogens rely on for survival may represent an Achilles heel for this pathogenic community. Novel therapies that are designed to disrupt understudied survival strategies of the CF microbial community may succeed against otherwise untreatable or antibiotic-resistant microbes.

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Cystic fibrosis and the role of gastrointestinal outcome measures in the new era of therapeutic CFTR modulation

Journal of Cystic Fibrosis ◽

10.1016/j.jcf.2015.01.006 ◽

2015 ◽

Vol 14 (2) ◽

pp. 169-177 ◽

Cited By ~ 32

Author(s):

Frank A.J.A. Bodewes ◽

Henkjan J. Verkade ◽

Jan A.J.M. Taminiau ◽

Drucy Borowitz ◽

Michael Wilschanski

Keyword(s):

Cystic Fibrosis ◽

Outcome Measures ◽

New Era

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Use of Lung Imaging Studies as Outcome Measures for Development of New Therapies in Cystic Fibrosis

Proceedings of the American Thoracic Society ◽

10.1513/pats.200611-183ht ◽

2007 ◽

Vol 4 (4) ◽

pp. 359-363 ◽

Cited By ~ 6

Author(s):

B. W. Ramsey

Keyword(s):

Cystic Fibrosis ◽

Outcome Measures ◽

Lung Imaging ◽

Imaging Studies ◽

New Therapies

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P72 Feasibility of recruiting newborn babies with cystic fibrosis diagnosed by newborn screening to a clinical study with invasive outcome measures

Thorax ◽

10.1136/thx.2010.150979.23 ◽

2010 ◽

Vol 65 (Suppl 4) ◽

pp. A107-A108

Author(s):

J. Chudleigh ◽

A.-F. Hoo ◽

S. A. Prasad ◽

D. Ahmed ◽

A. Bush ◽

...

Keyword(s):

Cystic Fibrosis ◽

Clinical Study ◽

Newborn Screening ◽

Outcome Measures

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Animal models for cystic fibrosis: A systematic search and mapping review of the literature – Part 1: genetic models

Laboratory Animals ◽

10.1177/0023677219868502 ◽

2019 ◽

Vol 54 (4) ◽

pp. 330-340 ◽

Cited By ~ 1

Author(s):

Cathalijn HC Leenaars ◽

Rob BM De Vries ◽

Anna Heming ◽

Damian Visser ◽

David Holthaus ◽

...

Keyword(s):

Cystic Fibrosis ◽

Animal Model ◽

Animal Models ◽

Outcome Measures ◽

Reporting Quality ◽

Genetic Models ◽

Suitable Model ◽

Objective Evidence ◽

New Research ◽

New Treatments

Animal models for cystic fibrosis (CF) have enhanced our understanding of the pathology and contributed to the development of new treatments. In the field of CF, many animal models have been developed and described. To our knowledge, thus far, none of the reviews of CF animal models has used a systematic methodology. A systematic approach to creating model overviews can lead to an objective, evidence-based choice of an animal model for new research questions. We searched Pubmed and Embase for the currently available animal models for CF. Two independent reviewers screened the results. We included all primary studies describing an animal model for CF. After duplicate removal, 12,304 publications were left. Because of the large number of models, in the current paper, only the genetic models are presented. A total of 636 publications were identified describing genetic animal models for CF in mice, pigs, ferrets, rats and zebrafish. Most of these models have an altered Cftr gene. An overview of basic model characteristics and outcome measures for these genetic models is provided, together with advice on using these data. As far as the authors are aware, this is one of the largest systematic mapping reviews on genetic animal models for CF. It can aid in selecting a suitable model and outcome measures. In general, the reporting quality of the included publications was poor. Further systematic reviews are warranted to determine the quality and translational value of these models further.

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