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

Currently, the life expectancy for cystic fibrosis (CF) lung disease is less than 40 years due to decreasing lung function despite significant advances in the care and treatment of these patients. As patients live longer, the preservation of healthy lung tissue becomes of paramount importance to improve patient quality of life and increase life span. To do this, an understanding of the early disease processes is needed as is an ability to monitor the efficacy of therapeutic interventions early in life. CF lung disease, similar to other lung diseases, is a regional disease causing local dysfunction in the lung tissue and changes in lung anatomy. It is important for any monitoring or diagnostic tool to be sensitive to early regional disease which current methods (spirometry) are not. This lack of sensitivity to regional disease limits the ability of physicians and researchers to track the earliest stages of disease and assess treatment efficacy in these initial disease stages, ideally in infants and young children. Three dimensional imaging presents a unique solution to this problem by providing a non-invasive, volumetric investigation of the lung tissue. Computed tomography has long been the first choice in clinical lung imaging offering excellent resolution and fast imaging times but results in repeated exposure to ionizing radiation. Because the patient populations of interest are infants and children, avoidance of unnecessary, repeated radiation exposure during longitudinal monitoring is desirable. This combination of clinical and research need has led us to the exploration of rapid MRI techniques for lung imaging. We are interested in developing a novel, robust quantitative Magnetic Resonance Imaging technique that allows for 3D investigation of the lung tissue and is sensitive to early disease changes. Our hypothesis is that quantitative imaging will be able to detect changes in regional lung anatomy as an indication of early disease before disease is detected by standard methods. To accomplish this goal, we are proposing the implementation of multiple advanced quantitative MRI techniques including T1-mapping using Saturation-Recovery Look-Locker mapping and simultaneous multiple parameter mapping (combinations of T1, T2, T2*) using the recently developed Magnetic Resonance Fingerprinting method. An ultra-short echo time acquisition will be used to ensure imaging of the rapidly decaying MRI signal in the lung is possible. Using a radial acquisition, we plan to include an undersampled acquisition to reduce imaging time and generate an imaging method that is rapid and insensitive to patient motion. Our goal is to initially apply these quantitative measures in a mouse model of cystic fibrosis to establish the ability of the imaging methods to be sensitive to regional disease in CF mice. We expect to see changes in the quantitative parameters in areas that correspond to diseased areas of the lung upon histological investigation. These quantitative measurements should give unambiguous indications of disease and allow identification of changes in lung anatomy early in the disease process. This work will lay the foundation for translation of clinical CF monitoring in a pediatric population. Translational studies such as these will hopefully provide a measurement of disease progression and provide a new opportunity to evaluate early disease therapeutics offering insight into the earliest manifestations of CF lung disease.

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Increase of survival and improvement of the prognosis with new therapies for the treatment of cystic fibrosis

Annals of Physical and Rehabilitation Medicine ◽

10.1016/j.rehab.2018.05.916 ◽

2018 ◽

Vol 61 ◽

pp. e393

Author(s):

M.J. Buzzetta Devis ◽

M.E. Martinez Rodriguez ◽

A. Lamas Ferrero ◽

J.C. Estupiñan ◽

D. Pozo Crespo ◽

...

Keyword(s):

Cystic Fibrosis ◽

New Therapies

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Oral cysteamine as an adjunct treatment in cystic fibrosis pulmonary exacerbations: An exploratory randomized clinical trial

PLoS ONE ◽

10.1371/journal.pone.0242945 ◽

2020 ◽

Vol 15 (12) ◽

pp. e0242945

Author(s):

Graham Devereux ◽

Danielle Wrolstad ◽

Stephen J. Bourke ◽

Cori L. Daines ◽

Simon Doe ◽

...

Keyword(s):

Clinical Trial ◽

Cystic Fibrosis ◽

Randomized Clinical Trial ◽

Outcome Measures ◽

Leukocyte Count ◽

Bacterial Load ◽

Adjunct Treatment ◽

Dosing Regimens ◽

Pulmonary Exacerbations ◽

Blood Leukocyte

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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Longitudinal imaging studies in schizophrenia: the relationship between brain morphology and outcome measures

Epidemiologia e Psichiatria Sociale ◽

10.1017/s1121189x00001123 ◽

2010 ◽

Vol 19 (3) ◽

pp. 207-210 ◽

Cited By ~ 12

Author(s):

Marcella Bellani ◽

Nicola Dusi ◽

Paolo Brambilla

Keyword(s):

Longitudinal Studies ◽

Outcome Measures ◽

Brain Morphology ◽

Imaging Studies ◽

Longitudinal Imaging ◽

The Relationship ◽

Worse Prognosis

AbstractImaging studies have tried to identify morphological outcome measures of schizophrenia in the last two decades. In particular, longitudinal studies have reported a correlation between larger ventricles, decreased prefrontal volumes and worse outcome. This would potentially allow to isolate subtypes of schizophrenia patients with a worse prognosis and more evident biological impairments, ultimately helping in designing specific rehabilitation interventions.

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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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