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Karcıoğlu O, Ardalı Düzgün S. The Significance of Density Measurement and the Modified Bhalla and Reiff Scores in Predicting Exacerbations and Hospital Admissions in Cystic Fibrosis Patients. MEDICINA (KAUNAS, LITHUANIA) 2025; 61:808. [PMID: 40428766 DOI: 10.3390/medicina61050808] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/24/2025] [Revised: 04/18/2025] [Accepted: 04/24/2025] [Indexed: 05/29/2025]
Abstract
Background and Objective: This study's objective was to determine the impact of the percentage of lung tissue within the normal density range (PLND) on exacerbations and hospitalizations compared with the modified Bhalla and Reiff scores. We also investigated the effects of these measures on pulmonary function tests (PFTs). Materials and Methods: This retrospective analysis involved adult cystic fibrosis (CF) patients who had thoracic computed tomography (CT) while in a stable clinical condition. A dedicated radiologist analyzed CT images and conducted modified Bhalla, Reiff, and PLND assessments. We analyzed the exacerbations and hospitalizations in the year after the CT scan. We also examined PFTs at the time of the CT scan and one year later. Results: This study's population consisted of 63 subjects (33 men), with a median age of 23.2 years. The median modified Bhalla score was 9.0 (IQR: 7.0-12.0), the median Reiff score was 11.0 (IQR: 8.0-15.0), and the median PLND was 79.4% (IQR: 74.5-82.0). The Bhalla score had the strongest relationship with both the number of exacerbations (p < 0.001, r: -0.559) and hospitalizations the following year (p < 0.001, r: -0.636), followed by the PLND score and the Reiff score. Youden's index shows that the optimum cut-off values for hospitalization at ≤2 and >2 are 6.5 for the modified Bhalla score, 13.5 for the Reiff score, and 76.5% for the PLND. Conclusions: The measurement of PLND may serve as a predictor for exacerbation and hospitalization rates, aligning with the modified Bhalla and Reiff scores, and shows potential for application in follow-up assessments.
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Affiliation(s)
- Oğuz Karcıoğlu
- Department of Chest Diseases, School of Medicine, Hacettepe University, Ankara 06100, Turkey
| | - Selin Ardalı Düzgün
- Department of Radiology, School of Medicine, Hacettepe University, Ankara 06100, Turkey
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Hurley MN, Smith S, Flume P, Jahnke N, Prayle AP. Intravenous antibiotics for pulmonary exacerbations in people with cystic fibrosis. Cochrane Database Syst Rev 2025; 1:CD009730. [PMID: 39831540 PMCID: PMC11744767 DOI: 10.1002/14651858.cd009730.pub3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/22/2025]
Abstract
BACKGROUND Cystic fibrosis is a multisystem disease characterised by the production of thick secretions causing recurrent pulmonary infection, often with unusual bacteria. Intravenous (IV) antibiotics are commonly used in the treatment of acute deteriorations in symptoms (pulmonary exacerbations); however, recently the assumption that exacerbations are due to increases in bacterial burden has been questioned. This is an update of a previously published review. OBJECTIVES To establish whether IV antibiotics for the treatment of pulmonary exacerbations in people with cystic fibrosis improve short-term and long-term clinical outcomes. SEARCH METHODS We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched the reference lists of relevant articles and reviews and ongoing trials registers. Date of last search of Cochrane Trials Register: 19 June 2024. SELECTION CRITERIA Randomised controlled trials and the first treatment cycle of cross-over studies comparing IV antibiotics (given alone or in an antibiotic combination) with placebo, or inhaled or oral antibiotics for people with cystic fibrosis experiencing a pulmonary exacerbation. Studies comparing different IV antibiotic regimens were also eligible. DATA COLLECTION AND ANALYSIS We assessed studies for eligibility and risk of bias, and extracted data. Using GRADE, we assessed the certainty of the evidence for the outcomes lung function % predicted (forced expiratory volume in one second (FEV1) and forced vital capacity (FVC)), time to next exacerbation and quality of life. MAIN RESULTS We included 45 studies involving 2810 participants. The included studies were mostly small, and inadequately reported, many of which were quite old. The certainty of the evidence was mostly low. Combined intravenous antibiotics versus placebo Data reported for absolute change in % predicted FEV1 and FVC suggested a possible improvement in favour of IV antibiotics, but the evidence is very uncertain (1 study, 12 participants; very low-certainty evidence). The study did not measure time to next exacerbation or quality of life. Intravenous versus nebulised antibiotics Five studies (122 participants) reported FEV1, with analysable data only from one study (16 participants). We found no difference between groups (moderate-certainty evidence). Three studies (91 participants) reported on FVC, with analysable data from only one study (54 participants). We are very uncertain on the effect of nebulised antibiotics (very low-certainty evidence). In one study, the 16 participants on nebulised plus IV antibiotics had a lower mean number of days to next exacerbation than those on combined IV antibiotics (low-certainty evidence), but we found no difference in quality of life between groups (low-certainty evidence). Intravenous versus oral antibiotics Three studies (172 participants) reported no difference in different measures of lung function. We found no difference in analysable data between IV and oral antibiotic regimens in either FEV1 % predicted or FVC % predicted (1 study, 24 participants; low-certainty evidence) or in the time to the next exacerbation (1 study, 108 participants; very low-certainty evidence). No study measured quality of life. Intravenous antibiotic regimens compared One study (analysed as two data sets) compared the duration of IV antibiotic regimens between two groups (split according to initial antibiotic response). The first part was a non-inferiority study in 214 early treatment responders to establish whether 10 days of IV antibiotic treatment was as effective as 14 days. Second, investigators looked at whether 14 or 21 days of IV antibiotics were more effective in 705 participants who did not respond early to treatment. We found no difference in FEV1 % predicted with any duration of treatment (919 participants; high-certainty evidence) or the time to next exacerbation (information later taken from registry data). Investigators did not report FVC or quality of life. Other comparisons We also found little or no difference in lung function when comparing single IV antibiotic regimens to placebo (2 studies, 70 participants), or in lung function and time to next exacerbation when comparing different single antibiotic regimens (2 studies, 95 participants). There may be a greater improvement in lung function in participants receiving combined IV antibiotics compared to single IV antibiotics (6 studies, 265 participants; low- to very low-certainty evidence), but probably no difference in the time to next exacerbation (1 study, 34 participants; low-certainty evidence). Four studies compared a single IV antibiotic plus placebo to a combined IV antibiotic regimen with high levels of heterogeneity in the results. We are very uncertain if there is any difference between groups in lung function (4 studies, 214 participants) and there may be little or no difference to being re-admitted to hospital for an exacerbation (2 studies, 104 participants). Nine studies (417 participants) compared combined IV antibiotic regimens with a great variation in drugs. We identified no differences in any measure of lung function or the time to next exacerbation between different regimens (low- to very low-certainty evidence). There were mixed results for adverse events across all comparisons; common adverse effects included elevated liver function tests, gastrointestinal events and haematological abnormalities. There were limited data for other secondary outcomes, such as weight, and there was no evidence of treatment effect. AUTHORS' CONCLUSIONS The evidence of benefit from administering IV antibiotics for pulmonary exacerbations in cystic fibrosis is often poor, especially in terms of size of studies and risk of bias, particularly in older studies. We are not certain whether there is any difference between specific antibiotic combinations, and neither is there evidence of a difference between the IV route and the inhaled or oral routes. There is limited evidence that shorter antibiotic duration in adults who respond early to treatment is not different to a longer period of treatment. There remain several unanswered questions regarding optimal IV antibiotic treatment regimens.
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Affiliation(s)
- Matthew N Hurley
- Paediatric Respiratory Medicine, Nottingham Children's Hospital, Nottingham University Hospitals NHS Trust, Nottingham, UK
| | - Sherie Smith
- Lifespan and Population Health, School of Medicine, University of Nottingham, Nottingham, UK
| | - Patrick Flume
- Department of Medicine, Division of Pulmonary and Critical Care, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Nikki Jahnke
- Lifespan and Population Health, School of Medicine, University of Nottingham, Nottingham, UK
| | - Andrew P Prayle
- Lifespan and Population Health, School of Medicine, University of Nottingham, Nottingham, UK
- NIHR Biomedical Research Centre, University of Nottingham, Nottingham, UK
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Wielpütz MO, Mall MA. Therapeutic improvement of CFTR function and reversibility of bronchiectasis in cystic fibrosis. Eur Respir J 2024; 63:2400234. [PMID: 38548272 DOI: 10.1183/13993003.00234-2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Accepted: 02/14/2024] [Indexed: 04/02/2024]
Affiliation(s)
- Mark O Wielpütz
- Department of Diagnostic and Interventional Radiology, University Hospital Heidelberg, Heidelberg, Germany
- Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Heidelberg, Germany
- Department of Diagnostic and Interventional Radiology with Nuclear Medicine, Thoraxklinik at University Hospital Heidelberg, Heidelberg, Germany
| | - Marcus A Mall
- Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine, Charité-Universitätsmedizin Berlin, Berlin, Germany
- German Center for Lung Research (DZL), associated partner site, Berlin, Germany
- Berlin Institute of Health (BIH) at Charité-Universitätsmedizin Berlin, Berlin, Germany
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Kim SO, Shapiro JP, Cottrill KA, Collins GL, Shanthikumar S, Rao P, Ranganathan S, Stick SM, Orr ML, Fitzpatrick AM, Go YM, Jones DP, Tirouvanziam RM, Chandler JD. Substrate-dependent metabolomic signatures of myeloperoxidase activity in airway epithelial cells: Implications for early cystic fibrosis lung disease. Free Radic Biol Med 2023; 206:180-190. [PMID: 37356776 PMCID: PMC10513041 DOI: 10.1016/j.freeradbiomed.2023.06.021] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2023] [Revised: 06/14/2023] [Accepted: 06/23/2023] [Indexed: 06/27/2023]
Abstract
Myeloperoxidase (MPO) is released by neutrophils in inflamed tissues. MPO oxidizes chloride, bromide, and thiocyanate to produce hypochlorous acid (HOCl), hypobromous acid (HOBr), and hypothiocyanous acid (HOSCN), respectively. These oxidants are toxic to pathogens, but may also react with host cells to elicit biological activity and potential toxicity. In cystic fibrosis (CF) and related diseases, increased neutrophil inflammation leads to increased airway MPO and airway epithelial cell (AEC) exposure to its oxidants. In this study, we investigated how equal dose-rate exposures of MPO-derived oxidants differentially impact the metabolome of human AECs (BEAS-2B cells). We utilized enzymatic oxidant production with rate-limiting glucose oxidase (GOX) coupled to MPO, and chloride, bromide (Br-), or thiocyanate (SCN-) as substrates. AECs exposed to GOX/MPO/SCN- (favoring HOSCN) were viable after 24 h, while exposure to GOX/MPO (favoring HOCl) or GOX/MPO/Br- (favoring HOBr) developed cytotoxicity after 6 h. Cell glutathione and peroxiredoxin-3 oxidation were insufficient to explain these differences. However, untargeted metabolomics revealed GOX/MPO and GOX/MPO/Br- diverged significantly from GOX/MPO/SCN- for dozens of metabolites. We noted methionine sulfoxide and dehydromethionine were significantly increased in GOX/MPO- or GOX/MPO/Br--treated cells, and analyzed them as potential biomarkers of lung damage in bronchoalveolar lavage fluid from 5-year-olds with CF (n = 27). Both metabolites were associated with increasing bronchiectasis, neutrophils, and MPO activity. This suggests MPO production of HOCl and/or HOBr may contribute to inflammatory lung damage in early CF. In summary, our in vitro model enabled unbiased identification of exposure-specific metabolite products which may serve as biomarkers of lung damage in vivo. Continued research with this exposure model may yield additional oxidant-specific biomarkers and reveal explicit mechanisms of oxidant byproduct formation and cellular redox signaling.
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Affiliation(s)
- Susan O Kim
- Department of Pediatrics, Division of Pulmonary, Asthma, Cystic Fibrosis, and Sleep, Emory University, Atlanta, GA, USA
| | - Joseph P Shapiro
- Department of Pediatrics, Division of Pulmonary, Asthma, Cystic Fibrosis, and Sleep, Emory University, Atlanta, GA, USA
| | - Kirsten A Cottrill
- Department of Pediatrics, Division of Pulmonary, Asthma, Cystic Fibrosis, and Sleep, Emory University, Atlanta, GA, USA
| | - Genoah L Collins
- Department of Pediatrics, Division of Pulmonary, Asthma, Cystic Fibrosis, and Sleep, Emory University, Atlanta, GA, USA
| | - Shivanthan Shanthikumar
- Respiratory and Sleep Medicine, Royal Children's Hospital, Parkville, VIC, Australia; Respiratory Diseases, Murdoch Children's Research Institute, Parkville, VIC, Australia; Department of Paediatrics, University of Melbourne, Parkville, VIC, Australia
| | - Padma Rao
- Medical Imaging, Royal Children's Hospital, Parkville, VIC, Australia
| | - Sarath Ranganathan
- Respiratory and Sleep Medicine, Royal Children's Hospital, Parkville, VIC, Australia; Respiratory Diseases, Murdoch Children's Research Institute, Parkville, VIC, Australia; Department of Paediatrics, University of Melbourne, Parkville, VIC, Australia
| | - Stephen M Stick
- Telethon Kids Institute, Perth, Western Australia, Australia
| | - Michael L Orr
- Department of Medicine, Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Emory University, Atlanta, GA, USA
| | - Anne M Fitzpatrick
- Department of Pediatrics, Division of Pulmonary, Asthma, Cystic Fibrosis, and Sleep, Emory University, Atlanta, GA, USA; Children's Healthcare of Atlanta, Atlanta, GA, USA
| | - Young-Mi Go
- Department of Medicine, Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Emory University, Atlanta, GA, USA
| | - Dean P Jones
- Department of Medicine, Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Emory University, Atlanta, GA, USA
| | - Rabindra M Tirouvanziam
- Department of Pediatrics, Division of Pulmonary, Asthma, Cystic Fibrosis, and Sleep, Emory University, Atlanta, GA, USA; Children's Healthcare of Atlanta, Atlanta, GA, USA
| | - Joshua D Chandler
- Department of Pediatrics, Division of Pulmonary, Asthma, Cystic Fibrosis, and Sleep, Emory University, Atlanta, GA, USA; Department of Medicine, Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Emory University, Atlanta, GA, USA; Children's Healthcare of Atlanta, Atlanta, GA, USA.
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Milinic T, McElvaney OJ, Goss CH. Diagnosis and Management of Cystic Fibrosis Exacerbations. Semin Respir Crit Care Med 2023; 44:225-241. [PMID: 36746183 PMCID: PMC10131792 DOI: 10.1055/s-0042-1760250] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
With the improving survival of cystic fibrosis (CF) patients and the advent of highly effective cystic fibrosis transmembrane conductance regulator (CFTR) therapy, the clinical spectrum of this complex multisystem disease continues to evolve. One of the most important clinical events for patients with CF in the course of this disease is acute pulmonary exacerbation (PEx). Clinical and microbial epidemiology studies of CF PEx continue to provide important insight into the disease course, prognosis, and complications. This work has now led to several large-scale clinical trials designed to clarify the treatment paradigm for CF PEx. The primary goal of this review is to provide a summary and update of the pathophysiology, clinical and microbial epidemiology, outcome and treatment of CF PEx, biomarkers for exacerbation, and the impact of highly effective modulator therapy on these events moving forward.
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Affiliation(s)
- Tijana Milinic
- Department of Medicine, University of Washington School of Medicine, Seattle, Washington
| | - Oliver J McElvaney
- Cysic Fibrosis Therapeutics Development Network Coordinating Center, Seattle Children's Research Institute, Seattle, Washington
| | - Christopher H Goss
- Department of Medicine, University of Washington School of Medicine, Seattle, Washington
- Cysic Fibrosis Therapeutics Development Network Coordinating Center, Seattle Children's Research Institute, Seattle, Washington
- Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington
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Caverly LJ, Riquelme SA, Hisert KB. The Impact of Highly Effective Modulator Therapy on Cystic Fibrosis Microbiology and Inflammation. Clin Chest Med 2022; 43:647-665. [PMID: 36344072 PMCID: PMC10224747 DOI: 10.1016/j.ccm.2022.06.007] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Highly effective cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulator therapy (HEMT) corrects the underlying molecular defect causing CF disease. HEMT decreases symptom burden and improves clinical metrics and quality of life for most people with CF (PwCF) and eligible cftr mutations. Improvements in measures of pulmonary health suggest that restoration of function of defective CFTR anion channels by HEMT not only enhances airway mucociliary clearance, but also reduces chronic pulmonary infection and inflammation. This article reviews the evidence for how HEMT influences the dynamic and interdependent processes of infection and inflammation in the CF airway, and what questions remain unanswered.
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Affiliation(s)
- Lindsay J Caverly
- Department of Pediatrics, University of Michigan Medical School, L2221 UH South, 1500 East Medical Center Drive, Ann Arbor, MI 48109-5212, USA
| | - Sebastián A Riquelme
- Department of Pediatrics, College of Physicians and Surgeons, Columbia University, Columbia University Medical Center, 650West 168th Street, New York, NY 10032, USA
| | - Katherine B Hisert
- Department of Medicine, National Jewish Health, Smith A550, 1400 Jackson Street, Denver, CO 80205, USA.
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Zorzo C, Girón RM, Hernández S, Gómez-Punter RM, Caballero P. Association Between Evolution of Mucus Plugging, Parenchymal Alterations and Air Trapping on Computed Tomography and Risk of Exacerbations in Adults With Cystic Fibrosis. Arch Bronconeumol 2022; 58:575-577. [PMID: 35312590 DOI: 10.1016/j.arbres.2021.08.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Revised: 08/13/2021] [Accepted: 08/16/2021] [Indexed: 11/02/2022]
Affiliation(s)
- Cristina Zorzo
- Department of Radiology, Hospital Universitario La Princesa, Calle Diego de León, 52, 28006 Madrid, Spain; Universidad Autónoma de Madrid, Spain.
| | - Rosa María Girón
- Department of Respiratory Medicine, Hospital Universitario La Princesa, Calle Diego de León, 52, 28006 Madrid, Spain; Universidad Autónoma de Madrid, Spain
| | - Susana Hernández
- Department of Radiology, Hospital Universitario La Princesa, Calle Diego de León, 52, 28006 Madrid, Spain; Universidad Autónoma de Madrid, Spain
| | - Rosa Mar Gómez-Punter
- Department of Respiratory Medicine, Hospital Universitario La Princesa, Calle Diego de León, 52, 28006 Madrid, Spain; Universidad Autónoma de Madrid, Spain
| | - Paloma Caballero
- Department of Radiology, Hospital Universitario La Princesa, Calle Diego de León, 52, 28006 Madrid, Spain; Universidad Autónoma de Madrid, Spain
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Volpi S, Carnovale V, Colombo C, Raia V, Blasi F, Pappagallo G. Use of mucoactive agents in cystic fibrosis: A consensus survey of Italian specialists. Health Sci Rep 2022; 5:e604. [PMID: 35677472 PMCID: PMC9169509 DOI: 10.1002/hsr2.604] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 01/27/2022] [Accepted: 02/06/2022] [Indexed: 11/12/2022] Open
Abstract
Background The goal of mucoactive therapies in cystic fibrosis (CF) is to enhance sputum clearance and to reduce a progressive decline in lung function over the patient's lifetime. We aimed to investigate the level of consensus among specialists from Italian CF Centers on appropriateness of therapeutic use of dornase alfa (rhDNase) for CF patients. Method A consensus on appropriate prescribing in CF mucoactive agents was appraised by an online Delphi method, based on a panel of 27 pulmonologists, coordinated by a Scientific Committee of six experts in medical care of patients with CF. Results Full or very high consensus was reached on several issues related to therapeutic use of dornase alfa for CF patients in clinical practice. Conclusions The consensus reached on a number of topics regarding use of mucoactive agents in patients with CF can help guide clinicians in daily practice based on expert experience and define the most appropriate therapeutic strategy for the individual patient.
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Affiliation(s)
- Sonia Volpi
- Cystic Fibrosis Center Azienda Ospedialiera Universitaria Integrata Verona Italy
| | - Vincenzo Carnovale
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Cystic Fibrosis Center Milan Italy
| | - Carla Colombo
- Department of Translational Medical Science, Cystic Fibrosis Centre, Adult Unit University “Federico II” Naples Italy
| | - Valeria Raia
- Section of Pediatrics, Department of Translational Medical Sciences “University Federico II” Naples Italy
| | - Francesco Blasi
- Department of Internal Medicine Respiratory Unit and Adult Cystic Fibrosis Center Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico Milano Milan Italy
- Department of Pathophysiology and Transplantation Università degli Studi di Milano Milan Italy
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Wojsyk-Banaszak I, Więckowska B, Stachowiak Z, Kycler M, Szczepankiewicz A. Predictive value of impulse oscillometry and multiple breath washout parameters in pediatric patients with cystic fibrosis pulmonary exacerbation. Pediatr Pulmonol 2022; 57:1466-1474. [PMID: 35293155 DOI: 10.1002/ppul.25891] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 03/09/2022] [Accepted: 03/12/2022] [Indexed: 11/11/2022]
Abstract
BACKGROUND Pulmonary exacerbations (PE) tend to complicate the course of cystic fibrosis (CF) and worsen the disease prognosis. One of the diagnostic criteria for an exacerbation is the forced expiratory volume in the first second (FEV1 ) decline. Not all children, however, are able to perform spirometry. Therefore, the aim of this study was to evaluate alternative lung function tests in the diagnosis of PE. METHODS We assessed retrospectively the results of impulse oscillometry (IOS) and lung clearance index in multiple breath washout (MBW) during 259 visits in 47 CF paediatric patients. The differences in the results were compared between patients diagnosed with PE (ΔPE) and those in stable condition (ΔS). RESULTS Among the whole group of patients, we found significant differences between the changes during exacerbation (ΔPEs) and stable condition (ΔSs) values for lung clearance index (LCI), Sacin , R5Hz, R5-20Hz, X10Hz, AX, and Fres. The predictive values of Fres and X10Hz in IOS (AUCROC 0.71 both parameters) were higher than those of LCI (AUCROC 0.67). There was no difference in the predictive values (AUCROC ) of Δ LCI and IOS parameters in the subgroups of patients stratified based on FEV1 z-score cut-off value of -1.64. In both groups of patients, predictive values of LCI were slightly lower than of IOS parameters (AUC 0.66 for LCI vs. 0.69 for both ΔX10Hz z-score and Δ Fres z-score in patients with FEV1 z-score ≥-1.64 and AUC 0.67 for LCI vs 0.69 for both ΔX10Hz zscore and Δ Fres zscore in patients with FEV1 <1.64. CONCLUSIONS Both IOS and MBW measurements are useful in the assessment of pediatric CF patients with PE. LCI has a similar predictive value to IOS in children with CF independently of their FEV1 value.
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Affiliation(s)
- Irena Wojsyk-Banaszak
- Department of Paediatric Pulmonology, Allergy, and Clinical Immunology, Poznan University of Medical Sciences, Poznan, Poland
| | - Barbara Więckowska
- Department of Computer Science and Statistics, Poznan University of Medical Sciences, Poznan, Poland
| | - Zuzanna Stachowiak
- Unit of Molecular and Cell Biology, Department of Paediatric Pulmonology, Allergy, and Clinical Immunology, Poznan University of Medical Sciences, Poznan, Poland
| | - Maciej Kycler
- Department of Paediatric Pulmonology, Allergy, and Clinical Immunology, Poznan University of Medical Sciences, Poznan, Poland
| | - Aleksandra Szczepankiewicz
- Unit of Molecular and Cell Biology, Department of Paediatric Pulmonology, Allergy, and Clinical Immunology, Poznan University of Medical Sciences, Poznan, Poland
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Cai Q, Triphuridet N, Zhu Y, You N, Yip R, Yankelevitz DF, Henschke CI. Bronchiectasis in Low-Dose CT Screening for Lung Cancer. Radiology 2022; 304:437-447. [PMID: 35438565 DOI: 10.1148/radiol.212547] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Background Bronchiectasis is associated with loss of lung function, substantial use of health care resources, and increased morbidity and mortality in people with cardiopulmonary diseases. Purpose To assess the frequency and severity of bronchiectasis and related clinical findings of participants in a low-dose CT (LDCT) screening program. Materials and Methods The Early Lung and Cardiac Action Program (ELCAP) bronchiectasis score (range, 0-42; higher values indicate more severe bronchiectasis) was developed to facilitate bronchiectasis assessment. This quantitative scoring system screened participants based on accumulated knowledge and improved CT imaging capabilities. Secondary review of LDCT studies from smokers aged 40-90 years was performed when they were initially enrolled in the prospective Mount Sinai ELCAP screening study between 2010 and 2019. Medical records were reviewed to identify associated respiratory symptoms and acute respiratory events during the 2 years after LDCT. Logistic regression analysis was performed to examine factors associated with bronchiectasis. Results LDCT studies of 2191 screening participants (mean age, 65 years ± 9; 1140 [52%] women) were obtained, and bronchiectasis was identified in 504 (23%) participants. Median ELCAP bronchiectasis score was 12 (interquartile range, 9-16). Bronchiectasis was most common in the lower lobes for all participants, and lower lobe prevalence was greater with higher ELCAP score (eg, 91% prevalence with an ELCAP score of 16-42). In the fourth quartile, however, midlung involvement was higher compared with lower lung involvement (128 of 131 participants [98%] vs 122 of 131 participants [93%]). Bronchiectasis was more frequent with greater age (odds ratio [OR] = 2.0 per decade; 95% CI: 1.7, 2.4); being a former smoker (OR = 1.33; 95% CI: 1.01, 1.73); and having self-reported chronic obstructive pulmonary disease (OR = 1.38; 95% CI: 1.02, 1.88), an elevated hemidiaphragm (OR = 4; 95% CI: 2, 11), or consolidation (OR = 5; 95% CI: 3, 11). It was less frequent in overweight (OR = 0.7; 95% CI: 0.5, 0.9) or obese (OR = 0.6; 95% CI: 0.4, 0.8) participants. Two years after baseline LDCT, respiratory symptoms, acute respiratory events, and respiratory events that required hospitalization were more frequent with increasing severity of the ELCAP bronchiectasis score (P < .005 for all trends). Conclusion Prevalence of bronchiectasis in smokers undergoing low-dose CT screening was high, and respiratory symptoms and acute events were more frequent with increasing severity of the Early Lung and Cardiac Action Program Bronchiectasis score. © RSNA, 2022 See also the editorial by Verschakelen in this issue.
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Affiliation(s)
- Qiang Cai
- From the Department of Radiology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1234, New York, NY 10029
| | - Natthaya Triphuridet
- From the Department of Radiology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1234, New York, NY 10029
| | - Yeqing Zhu
- From the Department of Radiology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1234, New York, NY 10029
| | - Nan You
- From the Department of Radiology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1234, New York, NY 10029
| | - Rowena Yip
- From the Department of Radiology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1234, New York, NY 10029
| | - David F Yankelevitz
- From the Department of Radiology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1234, New York, NY 10029
| | - Claudia I Henschke
- From the Department of Radiology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1234, New York, NY 10029
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Ciet P, Bertolo S, Ros M, Casciaro R, Cipolli M, Colagrande S, Costa S, Galici V, Gramegna A, Lanza C, Lucca F, Macconi L, Majo F, Paciaroni A, Parisi GF, Rizzo F, Salamone I, Santangelo T, Scudeller L, Saba L, Tomà P, Morana G. State-of-the-art review of lung imaging in cystic fibrosis with recommendations for pulmonologists and radiologists from the "iMAging managEment of cySTic fibROsis" (MAESTRO) consortium. Eur Respir Rev 2022; 31:210173. [PMID: 35321929 PMCID: PMC9489084 DOI: 10.1183/16000617.0173-2021] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Accepted: 12/20/2021] [Indexed: 12/15/2022] Open
Abstract
OBJECTIVE Imaging represents an important noninvasive means to assess cystic fibrosis (CF) lung disease, which remains the main cause of morbidity and mortality in CF patients. While the development of new imaging techniques has revolutionised clinical practice, advances have posed diagnostic and monitoring challenges. The authors aim to summarise these challenges and make evidence-based recommendations regarding imaging assessment for both clinicians and radiologists. STUDY DESIGN A committee of 21 experts in CF from the 10 largest specialist centres in Italy was convened, including a radiologist and a pulmonologist from each centre, with the overall aim of developing clear and actionable recommendations for lung imaging in CF. An a priori threshold of at least 80% of the votes was required for acceptance of each statement of recommendation. RESULTS After a systematic review of the relevant literature, the committee convened to evaluate 167 articles. Following five RAND conferences, consensus statements were developed by an executive subcommittee. The entire consensus committee voted and approved 28 main statements. CONCLUSIONS There is a need for international guidelines regarding the appropriate timing and selection of imaging modality for patients with CF lung disease; timing and selection depends upon the clinical scenario, the patient's age, lung function and type of treatment. Despite its ubiquity, the use of the chest radiograph remains controversial. Both computed tomography and magnetic resonance imaging should be routinely used to monitor CF lung disease. Future studies should focus on imaging protocol harmonisation both for computed tomography and for magnetic resonance imaging. The introduction of artificial intelligence imaging analysis may further revolutionise clinical practice by providing fast and reliable quantitative outcomes to assess disease status. To date, there is no evidence supporting the use of lung ultrasound to monitor CF lung disease.
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Affiliation(s)
- Pierluigi Ciet
- Radiology and Nuclear Medicine Dept, Erasmus MC, Rotterdam, The Netherlands
- Pediatric Pulmonology and Allergology Dept, Erasmus MC, Sophia Children's Hospital, Rotterdam, The Netherlands
- Depts of Radiology and Medical Science, University of Cagliari, Cagliari, Italy
| | - Silvia Bertolo
- Radiology Dept, Ca'Foncello S. Maria Hospital, Treviso, Italy
| | - Mirco Ros
- Dept of Pediatrics, Ca'Foncello S. Maria Hospital, Treviso, Italy
| | - Rosaria Casciaro
- Dept of Pediatrics, IRCCS Institute "Giannina Gaslini", Cystic Fibrosis Centre, Genoa, Italy
| | - Marco Cipolli
- Regional Reference Cystic Fibrosis center, University hospital of Verona, Verona, Italy
| | - Stefano Colagrande
- Dept of Experimental and Clinical Biomedical Sciences, Radiodiagnostic Unit n. 2, University of Florence- Careggi Hospital, Florence, Italy
| | - Stefano Costa
- Dept of Pediatrics, Gaetano Martino Hospital, Messina, Italy
| | - Valeria Galici
- Cystic Fibrosis Centre, Dept of Paediatric Medicine, Anna Meyer Children's University Hospital, Florence, Italy
| | - Andrea Gramegna
- Respiratory Disease and Adult Cystic Fibrosis Centre, Internal Medicine Dept, IRCCS Ca' Granda, Milan, Italy
- Dept of Pathophysiology and Transplantation, University of Milan, Milan, Italy
| | - Cecilia Lanza
- Radiology Dept, University Hospital Ospedali Riuniti, Ancona, Italy
| | - Francesca Lucca
- Regional Reference Cystic Fibrosis center, University hospital of Verona, Verona, Italy
| | - Letizia Macconi
- Radiology Dept, Tuscany Reference Cystic Fibrosis Centre, Meyer Children's Hospital, Florence, Italy
| | - Fabio Majo
- Dept of Pediatrics, IRCCS Bambino Gesù Children's Hospital, Rome, Italy
| | | | - Giuseppe Fabio Parisi
- Pediatric Pulmonology Unit, Dept of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - Francesca Rizzo
- Radiology Dept, IRCCS Institute "Giannina Gaslini", Cystic Fibrosis Center, Genoa, Italy
| | | | - Teresa Santangelo
- Dept of Radiology, IRCCS Bambino Gesù Children's Hospital, Rome, Italy
| | - Luigia Scudeller
- Clinical Epidemiology, IRCCS Azienda Ospedaliera Universitaria di Bologna, Bologna, Italy
| | - Luca Saba
- Depts of Radiology and Medical Science, University of Cagliari, Cagliari, Italy
| | - Paolo Tomà
- Dept of Radiology, IRCCS Bambino Gesù Children's Hospital, Rome, Italy
| | - Giovanni Morana
- Radiology Dept, Ca'Foncello S. Maria Hospital, Treviso, Italy
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12
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Ciuca IM, Pop LL, Dediu M, Stoicescu ER, Marc MS, Manea AM, Manolescu DL. Lung Ultrasound in Children with Cystic Fibrosis in Comparison with Chest Computed Tomography: A Feasibility Study. Diagnostics (Basel) 2022; 12:diagnostics12020376. [PMID: 35204467 PMCID: PMC8871437 DOI: 10.3390/diagnostics12020376] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 01/28/2022] [Accepted: 01/30/2022] [Indexed: 01/15/2023] Open
Abstract
Background: Cystic fibrosis (CF) lung disease determines the outcome of this condition. For lung evaluation processes, computed tomography (CT) is the gold standard, but also causes irradiation. Lately, lung ultrasound (LUS) has proven to be reliable for the diagnosis of consolidations, atelectasis, and/or bronchiectasis. The aim of our study was to evaluate the value of a newly conceived LUS score by comparing it to the modified Bhalla CT score. A further aim was to evaluate the correlation between the score and the lung clearance index (LCI). Methods: Patients with CF were screened by LUS, followed by a CT scan. Spearman’s test was used for correlations. Results: A total of 98 patients with CF were screened, and 57 were included in the study; their mean age was 11.8 ± 5.5 (mean ± SD) years. The mean LUS score was 5.88 ± 5.4 SD. The LUS CF score had a very strong correlation with the CT score of rs = 0.87 (p = 0.000). LUS showed a good sensibility for detecting atelectasis (Se = 83.7%) and consolidations (Se = 94.4%). A lower Se (77.7%) and Sp (9%) were found for cylindrical bronchiectasis. Conclusion: Our study shows that LUS and the lung CF score are parameters that can be used with a complementary role in the diagnosis and monitoring of CF lung disease in children.
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Affiliation(s)
- Ioana Mihaiela Ciuca
- Pediatric Department, “Victor Babes” University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square No. 2, 300041 Timisoara, Romania; (I.M.C.); (L.L.P.); (M.D.)
| | - Liviu Laurentiu Pop
- Pediatric Department, “Victor Babes” University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square No. 2, 300041 Timisoara, Romania; (I.M.C.); (L.L.P.); (M.D.)
| | - Mihaela Dediu
- Pediatric Department, “Victor Babes” University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square No. 2, 300041 Timisoara, Romania; (I.M.C.); (L.L.P.); (M.D.)
| | - Emil Robert Stoicescu
- Radiology Department, “Victor Babes” University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square No. 2, 300041 Timisoara, Romania; (E.R.S.); (D.L.M.)
- Research Center for Pharmaco-Toxicological Evaluations, “Victor Babes” University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square No. 2, 300041 Timisoara, Romania
| | - Monica Steluta Marc
- Pulmonology Department, “Victor Babes” University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square No. 2, 300041 Timisoara, Romania
- Correspondence: ; Tel.: +40-721434044
| | - Aniko Maria Manea
- Neonatology and Puericulture Department, “Victor Babes” University of Medicine and Pharmacy, Eftimie Murgu Square No. 2, 300041 Timisoara, Romania;
| | - Diana Luminita Manolescu
- Radiology Department, “Victor Babes” University of Medicine and Pharmacy Timisoara, Eftimie Murgu Square No. 2, 300041 Timisoara, Romania; (E.R.S.); (D.L.M.)
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13
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Caudri D, Turkovic L, de Klerk NH, Rosenow T, Murray CP, Steyerberg EW, Ranganathan SC, Sly P, Stick SM, Breuer O. A screening tool to identify risk for bronchiectasis progression in children with cystic fibrosis. Pediatr Pulmonol 2022; 57:122-131. [PMID: 34596357 PMCID: PMC9292934 DOI: 10.1002/ppul.25712] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 08/26/2021] [Accepted: 09/23/2021] [Indexed: 12/03/2022]
Abstract
BACKGROUND The marked heterogeneity in cystic fibrosis (CF) disease complicates the selection of those most likely to benefit from existing or emergent treatments. OBJECTIVE We aimed to predict the progression of bronchiectasis in preschool children with CF. METHODS Using data collected up to 3 years of age, in the Australian Respiratory Early Surveillance Team for CF cohort study, clinical information, chest computed tomography (CT) scores, and biomarkers from bronchoalveolar lavage were assessed in a multivariable linear regression model as predictors for CT bronchiectasis at age 5-6. RESULTS Follow-up at 5-6 years was available in 171 children. Bronchiectasis prevalence at 5-6 was 134/171 (78%) and median bronchiectasis score was 3 (range 0-12). The internally validated multivariate model retained eight independent predictors accounting for 37% (adjusted R2 ) of the variance in bronchiectasis score. The strongest predictors of future bronchiectasis were: pancreatic insufficiency, repeated intravenous treatment courses, recurrent lower respiratory infections in the first 3 years of life, and lower airway inflammation. Dichotomizing the resulting prediction score at a bronchiectasis score of above the median resulted in a diagnostic odds ratio of 13 (95% confidence interval [CI], 6.3-27) with positive and negative predictive values of 80% (95% CI, 72%-86%) and 77% (95% CI, 69%-83%), respectively. CONCLUSION Early assessment of bronchiectasis risk in children with CF is feasible with reasonable precision at a group level, which can assist in high-risk patient selection for interventional trials. The unexplained variability in disease progression at individual patient levels remains high, limiting the use of this model as a clinical prediction tool.
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Affiliation(s)
- Daan Caudri
- Telethon Kids Institute, The University of Western Australia, Perth, Australia.,Department of Respiratory Medicine, Princess Margaret Hospital, Perth, Australia.,Department of Pediatrics/Respiratory Medicine, Erasmus MC, Rotterdam, The Netherlands
| | - Lidija Turkovic
- Telethon Kids Institute, The University of Western Australia, Perth, Australia
| | - Nicholas H de Klerk
- Telethon Kids Institute, The University of Western Australia, Perth, Australia
| | - Tim Rosenow
- Telethon Kids Institute, The University of Western Australia, Perth, Australia
| | - Conor P Murray
- Department of Diagnostic Imaging, Princess Margaret Hospital for Children, Perth, Western Australia, Australia
| | - Ewout W Steyerberg
- Department of Public Health, Erasmus MC, Rotterdam, The Netherlands.,Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, The Netherlands
| | - Sarath C Ranganathan
- Murdoch Children's Research Institute, Parkville, Australia.,Department of Respiratory Medicine, Royal Children's Hospital, Parkville, Australia.,Department of Paediatrics, University of Melbourne, Parkville, Australia
| | - Peter Sly
- Child Health Research Centre, The University of Queensland, Brisbane, Australia
| | - Stephen M Stick
- Telethon Kids Institute, The University of Western Australia, Perth, Australia.,Department of Respiratory Medicine, Princess Margaret Hospital, Perth, Australia
| | - Oded Breuer
- Telethon Kids Institute, The University of Western Australia, Perth, Australia.,Department of Respiratory Medicine, Princess Margaret Hospital, Perth, Australia.,Pediatric Pulmonology and CF Unit, Department of Pediatrics, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
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14
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Terpstra LC, Altenburg J, Mohamed Hoesein FA, Bronsveld I, Go S, van Rijn PAC, De Jong PA, Heijerman HGM, Boersma WG. The effect of maintenance azithromycin on radiological features in patients with bronchiectasis - Analysis from the BAT randomized controlled trial. Respir Med 2021; 192:106718. [PMID: 34974413 DOI: 10.1016/j.rmed.2021.106718] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Revised: 11/25/2021] [Accepted: 12/12/2021] [Indexed: 10/19/2022]
Abstract
RATIONALE Bronchiectasis (abnormal dilatation of bronchi) is usually diagnosed by high resolution computed tomography (HRCT) and radiological severity has been found to correspond with clinical outcome. A beneficial effect of macrolides maintenance treatment in frequent exacerbating bronchiectasis patients has been established in randomized trials. This study was undertaken to prospectively evaluate the effect of long-term azithromycin (AZM) on radiological features in patients with bronchiectasis. METHODS The BAT randomized controlled trial (2008-2010) investigated the effect of 1 year of AZM (250 mg OD) in bronchiectasis with frequent exacerbations. Chest (HR)CT-scans at baseline and after one year of study treatment were obtained and scored by two radiologists according to the Brody - and the Bhalla scoring system. RESULTS 77 (93%) patients conducted the BAT trial were evaluated in this post-hoc analysis. A significant improvement of the radiological features based on the Brody score was found after one year of AZM therapy as compared to placebo (p = 0.024), with a not significant improvement of the Bhalla score (p=0.071). Especially the consolidation (Bhalla) and parenchymal changes (Brody) sub scores significantly improved (both p=0.030), and even a radiological deterioration was seen on the Brody bronchiectasis sub score for the placebo treated patients (mean 14.5 (11.7) vs.15.7 (11.9)). CONCLUSIONS The beneficial effect of long-term AZM treatment on radiological features was demonstrated in this randomized controlled trial. (HR)CT's can be used as an objective measure of treatment response in bronchiectasis. CLINICAL TRIAL REGISTRATION NUMBER NCT00415350.
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Affiliation(s)
- Lotte C Terpstra
- Department of Pulmonary Diseases, Northwest Clinics, Alkmaar, the Netherlands.
| | - Josje Altenburg
- Department of Pulmonary Diseases, Academic Medical Center, Amsterdam, the Netherlands
| | - Firdaus A Mohamed Hoesein
- Department of Radiology, University Medical Center Utrecht and Utrecht University, Utrecht, the Netherlands
| | - Inez Bronsveld
- Department of Pulmonary Diseases, University Medical Center Utrecht and Utrecht University, Utrecht, the Netherlands
| | - Shirley Go
- Department of Radiology, Northwest Clinics, Alkmaar, the Netherlands
| | - Philip A C van Rijn
- Department of Radiology, Department of Radiology, Slingeland Hospital, Doetinchem, the Netherlands
| | - Pim A De Jong
- Department of Radiology, University Medical Center Utrecht and Utrecht University, Utrecht, the Netherlands
| | - Harry G M Heijerman
- Department of Pulmonary Diseases, University Medical Center Utrecht and Utrecht University, Utrecht, the Netherlands
| | - Wim G Boersma
- Department of Pulmonary Diseases, Northwest Clinics, Alkmaar, the Netherlands
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15
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Brody AS, Huang R, Zhang B, Long FR, Powers SW. Structural lung disease in preschool children with cystic fibrosis: An 18 month natural history study. J Cyst Fibros 2021; 21:e165-e171. [PMID: 34961706 DOI: 10.1016/j.jcf.2021.12.009] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 11/28/2021] [Accepted: 12/08/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND This study was performed to describe the natural history of CF lung disease in young children over an 18 month period to assess the use of CT scanning as an outcome measure for intervention trials. METHODS Chest CT scans were obtained at baseline and after 18 months in 42 two- to six-year-old children with CF. CT scans were scored by 2 experienced radiologists for the presence and severity of bronchiectasis, mucous plugging, and air trapping. RESULTS Mean age at baseline 3.5 (1.3) (mean, sd) years. One or more findings of CF lung disease was seen on the first CT in 27 (64%) and at 18 months in 30 (75%). From baseline to 18 months bronchiectasis, mucous plugging, and air trapping increased from 50% to 53%, 14% to 28%, and 48% to 58% respectively. There was marked variability in the rate of progression, with subjects commonly showing improvement in lung disease. Bronchiectasis worsened in 14 (33%) and improved in 13 (31%). Single subjects with F508del/class III and F508del/class V demonstrated greater worsening and improvement respectively than F508del homozygous and class I genotypes. CONCLUSIONS The natural history of CF lung disease over 18 months varies widely between subjects. Factors including genotype may affect natural history as well as the effectiveness of mediators and could be an important confounder if not recognized. These findings suggest that the use of CT scanning as an outcome surrogate for CF lung disease in young children may be more challenging than has been previously recognized.
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Affiliation(s)
- Alan S Brody
- Department of Radiology, Cincinnati Children's Hospital and Medical Center, and the University of Cincinnati College of Medicine, Cincinnati, OH, USA.
| | - Rui Huang
- Division of Biostatistics and Bioinformatics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Bin Zhang
- Division of Biostatistics and Epidemiology, Cincinnati Children's Hospital and Medical Center, Cincinnati, OH, USA
| | - Frederick R Long
- Department of Radiology, Nationwide Children's Hospital and the College of Medicine, Ohio State University, Columbus, OH, USA
| | - Scott W Powers
- Division of Behavioral Medicine and Clinical Psychology, Cincinnati Children's Hospital and Medical Center, Cincinnati, OH, USA
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16
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Best Practices: Imaging Strategies for Reduced-Dose Chest CT in the Management of Cystic Fibrosis-Related Lung Disease. AJR Am J Roentgenol 2021; 217:304-313. [PMID: 34076456 DOI: 10.2214/ajr.19.22694] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
OBJECTIVE. Cystic fibrosis (CF) is a multisystemic life-limiting disorder. The leading cause of morbidity in CF is chronic pulmonary disease. Chest CT is the reference standard for detection of bronchiectasis. Cumulative ionizing radiation limits the use of CT, particularly as treatments improve and life expectancy increases. The purpose of this article is to summarize the evidence on low-dose chest CT and its effect on image quality to determine best practices for imaging in CF. CONCLUSION. Low-dose chest CT is technically feasible, reduces dose, and renders satisfactory image quality. There are few comparison studies of low-dose chest CT and standard chest CT in CF; however, evidence suggests equivalent diagnostic capability. Low-dose chest CT with iterative reconstructive algorithms appears superior to chest radiography and equivalent to standard CT and has potential for early detection of bronchiectasis and infective exacerbations, because clinically significant abnormalities can develop in patients who do not have symptoms. Infection and inflammation remain the primary causes of morbidity requiring early intervention. Research gaps include the benefits of replacing chest radiography with low-dose chest CT in terms of improved diagnostic yield, clinical decision making, and patient outcomes. Longitudinal clinical studies comparing CT with MRI for the monitoring of CF lung disease may better establish the complementary strengths of these imaging modalities.
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17
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Chassagnon G, Zacharaki EI, Bommart S, Burgel PR, Chiron R, Dangeard S, Paragios N, Martin C, Revel MP. Quantification of Cystic Fibrosis Lung Disease with Radiomics-based CT Scores. Radiol Cardiothorac Imaging 2020; 2:e200022. [PMID: 33778637 DOI: 10.1148/ryct.2020200022] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Revised: 09/10/2020] [Accepted: 10/30/2020] [Indexed: 11/11/2022]
Abstract
Purpose To develop radiomics-based CT scores for assessing lung disease severity and exacerbation risk in adult patients with cystic fibrosis (CF). Materials and Methods This two-center retrospective observational study was approved by an institutional ethics committee, and the need for patient consent was waived. A total of 215 outpatients with CF referred for unenhanced follow-up chest CT were evaluated in two different centers between January 2013 and December 2016. After lung segmentation, chest CT scans from center 1 (training cohort, 162 patients [median age, 29 years; interquartile range {IQR}, 24-36 years; 84 men]) were used to build CT scores from 38 extracted CT features, using five different machine learning techniques trained to predict a clinical prognostic score, the Nkam score. The correlations between the developed CT scores, two different clinical prognostic scores (Liou and CF-ABLE), forced expiratory volume in 1 second (FEV1), and risk of respiratory exacerbations were evaluated in the test cohort (center 2, 53 patients [median age, 27 years; IQR, 22-35 years; 34 men]) using the Spearman rank coefficient. Results In the test cohort, all radiomics-based CT scores showed moderate to strong correlation with the Nkam score (R = 0.57 to 0.63, P < .001) and Liou scores (R = -0.55 to -0.65, P < .001), whereas the correlation with CF-ABLE score was weaker (R = 0.28 to 0.38, P = .005 to .048). The developed CT scores showed strong correlation with predicted FEV1 (R = -0.62 to -0.66, P < .001) and weak to moderate correlation with the number of pulmonary exacerbations to occur in the 12 months after the CT examination (R = 0.38 to 0.55, P < .001 to P = .006). Conclusion Radiomics can be used to build automated CT scores that correlate to clinical severity and exacerbation risk in adult patients with CF.Supplemental material is available for this article.See also the commentary by Elicker and Sohn in this issue.© RSNA, 2020.
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Affiliation(s)
- Guillaume Chassagnon
- Department of Radiology (G.C., S.D., M.P.R.) and Respiratory Medicine and National Cystic Reference Center (P.R.B.), Groupe Hospitalier Cochin-Hotel Dieu, AP-HP, Université Paris Descartes, 27 Rue du Faubourg Saint-Jacques, 75014 Paris, France; Center for Visual Computing, Ecole CentraleSupelec, Grande Voie des Vignes, Chatenay Malabry, France (G.C., E.I.Z., N.P.); U1016 Inserm, Institut Cochin, Paris, France (G.C., P.R.B., C.M., M.P.R.); Radiology Department (S.B.) and Pulmonary Department (R.C.), Hôpital Arnaud de Villeneuve, CHU de Montpellier, Université de Montpellier, Montpellier, France; ERN-Lung CF Network, France (P.R.B., C.M.); and TheraPanacea, Paris-Biotech-Santé, Paris, France (N.P.)
| | - Evangelia I Zacharaki
- Department of Radiology (G.C., S.D., M.P.R.) and Respiratory Medicine and National Cystic Reference Center (P.R.B.), Groupe Hospitalier Cochin-Hotel Dieu, AP-HP, Université Paris Descartes, 27 Rue du Faubourg Saint-Jacques, 75014 Paris, France; Center for Visual Computing, Ecole CentraleSupelec, Grande Voie des Vignes, Chatenay Malabry, France (G.C., E.I.Z., N.P.); U1016 Inserm, Institut Cochin, Paris, France (G.C., P.R.B., C.M., M.P.R.); Radiology Department (S.B.) and Pulmonary Department (R.C.), Hôpital Arnaud de Villeneuve, CHU de Montpellier, Université de Montpellier, Montpellier, France; ERN-Lung CF Network, France (P.R.B., C.M.); and TheraPanacea, Paris-Biotech-Santé, Paris, France (N.P.)
| | - Sébastien Bommart
- Department of Radiology (G.C., S.D., M.P.R.) and Respiratory Medicine and National Cystic Reference Center (P.R.B.), Groupe Hospitalier Cochin-Hotel Dieu, AP-HP, Université Paris Descartes, 27 Rue du Faubourg Saint-Jacques, 75014 Paris, France; Center for Visual Computing, Ecole CentraleSupelec, Grande Voie des Vignes, Chatenay Malabry, France (G.C., E.I.Z., N.P.); U1016 Inserm, Institut Cochin, Paris, France (G.C., P.R.B., C.M., M.P.R.); Radiology Department (S.B.) and Pulmonary Department (R.C.), Hôpital Arnaud de Villeneuve, CHU de Montpellier, Université de Montpellier, Montpellier, France; ERN-Lung CF Network, France (P.R.B., C.M.); and TheraPanacea, Paris-Biotech-Santé, Paris, France (N.P.)
| | - Pierre-Régis Burgel
- Department of Radiology (G.C., S.D., M.P.R.) and Respiratory Medicine and National Cystic Reference Center (P.R.B.), Groupe Hospitalier Cochin-Hotel Dieu, AP-HP, Université Paris Descartes, 27 Rue du Faubourg Saint-Jacques, 75014 Paris, France; Center for Visual Computing, Ecole CentraleSupelec, Grande Voie des Vignes, Chatenay Malabry, France (G.C., E.I.Z., N.P.); U1016 Inserm, Institut Cochin, Paris, France (G.C., P.R.B., C.M., M.P.R.); Radiology Department (S.B.) and Pulmonary Department (R.C.), Hôpital Arnaud de Villeneuve, CHU de Montpellier, Université de Montpellier, Montpellier, France; ERN-Lung CF Network, France (P.R.B., C.M.); and TheraPanacea, Paris-Biotech-Santé, Paris, France (N.P.)
| | - Raphael Chiron
- Department of Radiology (G.C., S.D., M.P.R.) and Respiratory Medicine and National Cystic Reference Center (P.R.B.), Groupe Hospitalier Cochin-Hotel Dieu, AP-HP, Université Paris Descartes, 27 Rue du Faubourg Saint-Jacques, 75014 Paris, France; Center for Visual Computing, Ecole CentraleSupelec, Grande Voie des Vignes, Chatenay Malabry, France (G.C., E.I.Z., N.P.); U1016 Inserm, Institut Cochin, Paris, France (G.C., P.R.B., C.M., M.P.R.); Radiology Department (S.B.) and Pulmonary Department (R.C.), Hôpital Arnaud de Villeneuve, CHU de Montpellier, Université de Montpellier, Montpellier, France; ERN-Lung CF Network, France (P.R.B., C.M.); and TheraPanacea, Paris-Biotech-Santé, Paris, France (N.P.)
| | - Séverine Dangeard
- Department of Radiology (G.C., S.D., M.P.R.) and Respiratory Medicine and National Cystic Reference Center (P.R.B.), Groupe Hospitalier Cochin-Hotel Dieu, AP-HP, Université Paris Descartes, 27 Rue du Faubourg Saint-Jacques, 75014 Paris, France; Center for Visual Computing, Ecole CentraleSupelec, Grande Voie des Vignes, Chatenay Malabry, France (G.C., E.I.Z., N.P.); U1016 Inserm, Institut Cochin, Paris, France (G.C., P.R.B., C.M., M.P.R.); Radiology Department (S.B.) and Pulmonary Department (R.C.), Hôpital Arnaud de Villeneuve, CHU de Montpellier, Université de Montpellier, Montpellier, France; ERN-Lung CF Network, France (P.R.B., C.M.); and TheraPanacea, Paris-Biotech-Santé, Paris, France (N.P.)
| | - Nikos Paragios
- Department of Radiology (G.C., S.D., M.P.R.) and Respiratory Medicine and National Cystic Reference Center (P.R.B.), Groupe Hospitalier Cochin-Hotel Dieu, AP-HP, Université Paris Descartes, 27 Rue du Faubourg Saint-Jacques, 75014 Paris, France; Center for Visual Computing, Ecole CentraleSupelec, Grande Voie des Vignes, Chatenay Malabry, France (G.C., E.I.Z., N.P.); U1016 Inserm, Institut Cochin, Paris, France (G.C., P.R.B., C.M., M.P.R.); Radiology Department (S.B.) and Pulmonary Department (R.C.), Hôpital Arnaud de Villeneuve, CHU de Montpellier, Université de Montpellier, Montpellier, France; ERN-Lung CF Network, France (P.R.B., C.M.); and TheraPanacea, Paris-Biotech-Santé, Paris, France (N.P.)
| | - Clémence Martin
- Department of Radiology (G.C., S.D., M.P.R.) and Respiratory Medicine and National Cystic Reference Center (P.R.B.), Groupe Hospitalier Cochin-Hotel Dieu, AP-HP, Université Paris Descartes, 27 Rue du Faubourg Saint-Jacques, 75014 Paris, France; Center for Visual Computing, Ecole CentraleSupelec, Grande Voie des Vignes, Chatenay Malabry, France (G.C., E.I.Z., N.P.); U1016 Inserm, Institut Cochin, Paris, France (G.C., P.R.B., C.M., M.P.R.); Radiology Department (S.B.) and Pulmonary Department (R.C.), Hôpital Arnaud de Villeneuve, CHU de Montpellier, Université de Montpellier, Montpellier, France; ERN-Lung CF Network, France (P.R.B., C.M.); and TheraPanacea, Paris-Biotech-Santé, Paris, France (N.P.)
| | - Marie-Pierre Revel
- Department of Radiology (G.C., S.D., M.P.R.) and Respiratory Medicine and National Cystic Reference Center (P.R.B.), Groupe Hospitalier Cochin-Hotel Dieu, AP-HP, Université Paris Descartes, 27 Rue du Faubourg Saint-Jacques, 75014 Paris, France; Center for Visual Computing, Ecole CentraleSupelec, Grande Voie des Vignes, Chatenay Malabry, France (G.C., E.I.Z., N.P.); U1016 Inserm, Institut Cochin, Paris, France (G.C., P.R.B., C.M., M.P.R.); Radiology Department (S.B.) and Pulmonary Department (R.C.), Hôpital Arnaud de Villeneuve, CHU de Montpellier, Université de Montpellier, Montpellier, France; ERN-Lung CF Network, France (P.R.B., C.M.); and TheraPanacea, Paris-Biotech-Santé, Paris, France (N.P.)
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18
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Willmering MM, Roach DJ, Kramer EL, Walkup LL, Cleveland ZI, Woods JC. Sensitive structural and functional measurements and 1-year pulmonary outcomes in pediatric cystic fibrosis. J Cyst Fibros 2020; 20:533-539. [PMID: 33288474 DOI: 10.1016/j.jcf.2020.11.019] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 09/17/2020] [Accepted: 11/25/2020] [Indexed: 12/21/2022]
Abstract
BACKGROUND Two functional measurements (multiple breath washout [MBW] and hyperpolarized 129Xe ventilation magnetic resonance imaging [129Xe MRI]) have been shown to be more sensitive to cystic fibrosis (CF) lung obstruction than traditional spirometry. However, functional techniques may be sensitive to different underlying structural abnormalities. The purpose of this study was to determine relationships between these functional markers, their pathophysiology, and 1-year clinical outcomes. METHODS Spirometry, MBW, 129Xe MRI, and ultrashort echo-time (UTE) MRI were obtained in a same-day assessment of 27 pediatric CF patients (ages 11.5±5.0) who had not begun CFTR modulator therapies. UTE MRI was scored for structural abnormalities and functional metrics obtained via spirometry, MBW and 129Xe MRI. 1-year outcomes (ΔFEV1 and pulmonary exacerbations), during which ≈50% initiated modulator therapy, were obtained from the electronic medical record. RESULTS MBW, 129Xe MRI, and UTE MRI detected clinically significant disease in more subjects (>78%) compared to spirometry (<30%). UTE MRI suggests increased odds of bronchial changes when mucus plugging is present in the same lobe. MBW and 129Xe MRI correlated best with mucus plugging, while spirometry correlated best with consolidations. Bronchial abnormalities were associated with future pulmonary exacerbations. CONCLUSIONS MBW, 129Xe MRI, and UTE MRI are more sensitive for detection of pediatric CF lung disease when compared to spirometry. MBW and 129Xe MRI correlated with structural abnormalities which occur in early CF disease, suggesting MBW and 129Xe MRI are valuable tools in mild CF lung disease that can guide clinical decision making.
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Affiliation(s)
- Matthew M Willmering
- Center for Pulmonary Imaging Research, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, United States; Division of Pulmonary Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, United States
| | - David J Roach
- Center for Pulmonary Imaging Research, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, United States; Division of Pulmonary Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, United States
| | - Elizabeth L Kramer
- Division of Pulmonary Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, United States; Department of Pediatrics, University of Cincinnati Medical Center, Cincinnati, OH 45229, United States
| | - Laura L Walkup
- Center for Pulmonary Imaging Research, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, United States; Division of Pulmonary Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, United States; Department of Pediatrics, University of Cincinnati Medical Center, Cincinnati, OH 45229, United States; Department of Biomedical Engineering, University of Cincinnati, Cincinnati, OH 45229, United States
| | - Zackary I Cleveland
- Center for Pulmonary Imaging Research, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, United States; Division of Pulmonary Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, United States; Department of Pediatrics, University of Cincinnati Medical Center, Cincinnati, OH 45229, United States; Department of Biomedical Engineering, University of Cincinnati, Cincinnati, OH 45229, United States
| | - Jason C Woods
- Center for Pulmonary Imaging Research, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, United States; Division of Pulmonary Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, United States; Department of Pediatrics, University of Cincinnati Medical Center, Cincinnati, OH 45229, United States; Department of Radiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, United States; Department of Physics, University of Cincinnati, Cincinnati, OH 45229, United States.
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19
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Tiddens HAWM, Andrinopoulou ER, McIntosh J, Elborn JS, Kerem E, Bouma N, Bosch J, Kemner-van de Corput M. Chest computed tomography outcomes in a randomized clinical trial in cystic fibrosis: Lessons learned from the first ataluren phase 3 study. PLoS One 2020; 15:e0240898. [PMID: 33141825 PMCID: PMC7608929 DOI: 10.1371/journal.pone.0240898] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Accepted: 10/05/2020] [Indexed: 12/04/2022] Open
Abstract
A phase 3 randomized double blind controlled, trial in 238 people with cystic fibrosis (CF) and at least one nonsense mutation (nmCF) investigated the effect of ataluren on FEV1. The study was of 48 weeks duration and failed to meet its primary endpoint. Unexpectedly, while FEV1 declined, chest computed tomography (CT) scores using the Brody-II score as secondary outcome measures did not show progression in the placebo group. Based on this observation it was concluded that the role of CT scans in CF randomized clinical trials was limited. However, more sensitive scoring systems were developed over the last decade warranting a reanalysis of this unique dataset. The aim of our study was to reanalyse all chest CT scans, obtained in the ataluren phase 3 study, using 2 independent scoring systems to characterize structural lung disease in this cohort and to compare progression of structural lung disease over the 48 weeks between treatment arms. 391 study CT scans from 210 patients were reanalysed in random order by 2 independent observers using the CF-CT and Perth-Rotterdam Annotated Grid Morphometric Analysis for CF (PRAGMA-CF) scoring systems. CF-CT and PRAGMA-CF subscores were expressed as %maximal score and %total lung volume, respectively. PRAGMA-CF subscores %Disease (p = 0.008) and %Mucus Plugging (p = 0.029) progressed over 48 weeks. CF-CT subscores did not show progression. There was no difference in progression of structural lung disease between treatment arm and placebo independent of tobramycin use. PRAGMA-CF Chest CT scores can be used as an outcome measure to study the effect of potential disease modifying drugs in CF on lung structure.
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Affiliation(s)
- Harm A. W. M. Tiddens
- Department of Pediatric Pulmonology and Allergology, Erasmus Medical Center Sophia Children’s Hospital, Rotterdam, The Netherlands
- Department and Radiology and Nuclear Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
| | | | - Joe McIntosh
- Aruvant Biotech, New York, NY, United States of America
| | - J. Stuart Elborn
- Centre for Experimental Medicine, Queen's University Belfast, Belfast, United Kingdom
| | - Eitan Kerem
- Department of Pediatrics and CF Center, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Nynke Bouma
- Department of Pediatric Pulmonology and Allergology, Erasmus Medical Center Sophia Children’s Hospital, Rotterdam, The Netherlands
| | - Jochem Bosch
- Department of Pediatric Pulmonology and Allergology, Erasmus Medical Center Sophia Children’s Hospital, Rotterdam, The Netherlands
| | - Mariette Kemner-van de Corput
- Department of Pediatric Pulmonology and Allergology, Erasmus Medical Center Sophia Children’s Hospital, Rotterdam, The Netherlands
- Department and Radiology and Nuclear Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
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20
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Somayaji R, Nichols DP, Bell SC. Cystic fibrosis - Ten promising therapeutic approaches in the current era of care. Expert Opin Investig Drugs 2020; 29:1107-1124. [PMID: 32744089 DOI: 10.1080/13543784.2020.1805733] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
INTRODUCTION Cystic fibrosis (CF) is a genetic disease affecting multiple organ systems. Research and innovations in novel therapeutic agents and health care delivery have resulted in dramatic improvements in quality of life and survival for people with CF. Despite this, significant disease burden persists for many and this is compounded by disparities in treatment access and care which globally necessitates further work to improve outcomes. Because of the advent of numerous therapies which include gene-targeted modulators in parallel with specialized care delivery models, innovative efforts continue. AREAS COVERED In this review, we discuss the available data on investigational agents in clinical development and currently available treatments for CF. We also evaluate approaches to care delivery, consider treatment gaps, and propose future directions for advancement. EXPERT OPINION Since the discovery of the CF gene, CFTR modulators have provided a hallmark of success, even though it was thought not previously possible. This has led to reinvigorated efforts and innovations in treatment approaches and care delivery. Numerous challenges remain because of genetic and phenotypic heterogeneity, access issues, and therapeutic costs, but the collaborative approach between stakeholders for continued innovation fuels optimism. Abbreviations: CF cystic fibrosis; CFF Cystic Fibrosis Foundation (USA); CFTR cystic fibrosis transmembrane regulator; CRISPR clustered regularly interspaced short palindromic repeats; COX cyclo oxygenase; FDA US Food and Drug Administration; FEV1% forced expiratory volume in one second % predicted; F508del deletion of phenylalanine (F) in the 508th position (most common mutation); G551D substitution of the amino acid glycine by aspartate at position 551 in the nucleotide binding domain-1 of the CFTR gene; LMIC low- and middle-income country; LTB4 leukotriene B4; MDT multi-disciplinary care team; NO nitric oxide; NSAIDs non-steroidal anti-inflammatory drugs; SLPI secretory leukocyte protease inhibitor.
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Affiliation(s)
- Ranjani Somayaji
- Departments of Medicine; Microbiology, Immunology & Infectious Disease; Community Health Sciences, University of Calgary , Calgary, AB, Canada.,Snyder Institute for Chronic Diseases , Calgary, AB, Canada.,O'Brien Institute for Public Health , Calgary, AB, Canada
| | - Dave P Nichols
- Department of Pediatrics, Seattle Children's Hospital , Seattle, WA, USA.,Department of Pediatrics, University of Washington , Seattle, WA, USA.,Seattle Children's Research Institute , Seattle, WA, USA
| | - Scott C Bell
- Department of Thoracic Medicine, The Prince Charles Hospital , Brisbane, QLD, Australia.,Children's Health Research Centre, Faculty of Medicine, The University of Queensland , Brisbane, QLD, Australia.,Translational Research Institute , Brisbane, QLD, Australia
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21
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Perrem L, Ratjen F. Designing Clinical Trials for Anti-Inflammatory Therapies in Cystic Fibrosis. Front Pharmacol 2020; 11:576293. [PMID: 33013419 PMCID: PMC7516261 DOI: 10.3389/fphar.2020.576293] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Accepted: 08/24/2020] [Indexed: 01/15/2023] Open
Abstract
The inflammatory response in the CF airway begins early in the disease process and becomes persistent through life in most patients. Inflammation, which is predominantly neutrophilic, worsens airway obstruction and plays a critical role in the development of structural lung damage. While cystic fibrosis transmembrane regulator modulators will likely have a dramatic impact on the trajectory of CF lung disease over the coming years, addressing other important aspects of lung disease such as inflammation will nevertheless remain a priority. Considering the central role of neutrophils and their products in the inflammatory response, potential therapies should ultimately affect neutrophils and their products. The ideal anti-inflammatory therapy would exert a dual effect on the pro-inflammatory and pro-resolution arms of the inflammatory cascade, both of which contribute to dysregulated inflammation in CF. This review outlines the key factors to be considered in the design of clinical trials evaluating anti-inflammatory therapies in CF. Important lessons have been learned from previous clinical trials in this area and choosing the right efficacy endpoints is key to the success of any anti-inflammatory drug development program. Identifying and validating non-invasive biomarkers, novel imaging techniques and sensitive lung function tests capable of monitoring disease activity and therapeutic response are important areas of research and will be useful for the design of future anti-inflammatory drug trials.
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Affiliation(s)
- Lucy Perrem
- Division of Respiratory Medicine, The Hospital for Sick Children, Toronto, ON, Canada.,Department of Paediatrics, University of Toronto, Toronto, ON, Canada.,Translational Medicine Program, SickKids Research Institute, Toronto, ON, Canada
| | - Felix Ratjen
- Division of Respiratory Medicine, The Hospital for Sick Children, Toronto, ON, Canada.,Department of Paediatrics, University of Toronto, Toronto, ON, Canada.,Translational Medicine Program, SickKids Research Institute, Toronto, ON, Canada
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22
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Diab-Cáceres L, Girón-Moreno RM, García-Castillo E, Pastor-Sanz MT, Olveira C, García-Clemente MM, Nieto-Royo R, Prados-Sánchez C, Caballero-Sánchez P, Olivera-Serrano MJ, Padilla-Galo A, Nava-Tomas E, Esteban-Peris A, Fernández-Velilla M, Torres M, Gómez-Punter RM, Ancochea J. Predictive value of the modified Bhalla score for assessment of pulmonary exacerbations in adults with cystic fibrosis. Eur Radiol 2020; 31:112-120. [PMID: 32740815 DOI: 10.1007/s00330-020-07095-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2019] [Revised: 04/19/2020] [Accepted: 07/21/2020] [Indexed: 12/16/2022]
Abstract
OBJECTIVES The objective of this study was to analyze the predictive value of the modified Bhalla score in high-resolution computed tomography (HRCT) for assessment of pulmonary exacerbations (PEx) in cystic fibrosis (CF) patients. We also describe the relationship between this score and pulmonary function test results. METHODS We performed a multicenter and prospective study where adult patients with CF were included consecutively over 18 months. All patients underwent HRCT with acquisition in inspiration and expiration. The results were analyzed by an expert radiologist who assigned a modified Bhalla score value. Lung function was also assessed, and clinical variables were collected. Follow-up lasted approximately 1 year, and PEx were registered. RESULTS The study population comprised 160 subjects selected from 360 CF patients monitored in the participating CF units. The mean age was 28 years, 47.5% were women, and mean forced expiratory volume in 1 s (FEV1) was 67.5%. The mean global modified Bhalla score was 14.5 ± 0.31 points. Pulmonary function test (PFT) results and the modified Bhalla score correlated well, mainly forced vital capacity (FVC) and FEV1. We constructed a statistical model based on the overall Bhalla score to predict the number of PEx. CONCLUSIONS The overall modified Bhalla score can predict future PEx in CF patients. This useful tool can help to prevent PEx in higher risk patients. KEY POINTS • Pulmonary function test results and the modified Bhalla score correlated well with FVC and FEV1. • The total modified Bhalla score can predict the number of exacerbations in adult CF patients. • Our findings highlight the need to establish a unified protocol for chest HRCT during the follow-up of adult patients with CF in order to anticipate possible complications and determine their impact on pulmonary function.
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Affiliation(s)
| | | | | | | | - Casilda Olveira
- Respirology Service, Hospital Regional Universitario de Málaga, Málaga, Spain
| | | | - Rosa Nieto-Royo
- Respirology Service, Hospital Universitario Ramón y Cajal, Madrid, Spain
| | | | | | | | - Alicia Padilla-Galo
- Radiodiagnostic Service, Hospital Regional Universitario de Málaga, Málaga, Spain
| | | | | | | | - Maribel Torres
- Radiodiagnostic Service, Hospital Universitario La Paz, Madrid, Spain
| | | | - Julio Ancochea
- Respirology Service, Hospital Universitario La Princesa, Madrid, Spain
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23
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Oudraad MCJ, Kuo W, Rosenow T, Andrinopoulou ER, Stick SM, Tiddens HAWM. Assessment of early lung disease in young children with CF: A comparison between pressure-controlled and free-breathing chest computed tomography. Pediatr Pulmonol 2020; 55:1161-1168. [PMID: 32119198 PMCID: PMC7187326 DOI: 10.1002/ppul.24702] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2019] [Accepted: 02/11/2020] [Indexed: 12/15/2022]
Abstract
BACKGROUND Chest computed tomography (CT) in children with cystic fibrosis (CF) is sensitive in detecting early airways disease. The pressure-controlled CT-protocol combines a total lung capacity scan (TLC PC-CT) with a near functional residual capacity scan (FRC PC-CT) under general anesthesia, while another CT-protocol is acquired during free breathing (FB-CT) near functional residual capacity. The aim of this study was to evaluate the sensitivity in detecting airways disease of both protocols in two cohorts. METHODS Routine PC-CTs (Princess Margaret Children's Hospital) and FB-CTs (Erasmus MC-Sophia Children's Hospital) were retrospectively collected from CF children aged 2 to 6 years. Total airways disease (%disease), bronchiectasis (%Bx), and low attenuation regions (%LAR) were scored on CTs using the Perth-Rotterdam annotated grid morphometric analysis-CF method. The Wilcoxon signed-rank test was used for differences between TLC and FRC PC-CTs and the Wilcoxon rank-sum test for differences between FRC PC-CTs and FB-CTs. RESULTS Fifty patients with PC-CTs (21 male, aged 2.5-5.5 years) and 42 patients with FB-CTs (26 male, aged 2.3-6.8 years) were included. %Disease was higher on TLC PC-CTs compared with FRC PC-CTs (median 4.51 vs 2.49; P < .001). %Disease and %Bx were not significantly different between TLC PC-CTs and FB-CTs (median 4.51% vs 3.75%; P = .143 and 0.52% vs 0.57%; P = .849). %Disease, %Bx, and %LAR were not significantly different between FRC PC-CTs and FB-CTs (median 2.49% vs 3.75%; P = .055, 0.54% vs 0.57%; P = .797, and 2.49% vs 1.53%; P = .448). CONCLUSIONS Our data suggest that FRC PC-CTs are less sensitive than TLC PC-CTs and that FB-CTs have similar sensitivity to PC-CTs in detecting lung disease. FB-CTs seem to be a viable alternative for PC-CTs to track CF lung disease in young patients with CF.
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Affiliation(s)
- Merel C J Oudraad
- Faculty of Medicine, University of Utrecht, Utrecht, The Netherlands
| | - Wieying Kuo
- Department of Pediatric Pulmonology and Allergology, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands.,Department of Radiology and Nuclear Medicine, Erasmus MC, Rotterdam, The Netherlands
| | - Tim Rosenow
- School of Paediatrics and Child Health, The University of Western Australia, Perth, Australia.,Telethon Kids Institute, The University of Western Australia, Perth, Australia
| | | | - Stephen M Stick
- Department of Respiratory and Sleep Medicine, Princess Margaret Hospital for Children, Perth, Australia
| | - Harm A W M Tiddens
- Department of Pediatric Pulmonology and Allergology, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands.,Department of Radiology and Nuclear Medicine, Erasmus MC, Rotterdam, The Netherlands
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24
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25
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Predictive value of computed tomography scoring systems evolution in adults with cystic fibrosis. Eur Radiol 2020; 30:3634-3640. [PMID: 32128619 DOI: 10.1007/s00330-020-06759-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Revised: 02/04/2020] [Accepted: 02/18/2020] [Indexed: 01/27/2023]
Abstract
OBJECTIVES To assess whether the evolution of two consecutive high-resolution computed tomography (HRCT) scores in patients with cystic fibrosis (CF) has prognostic value. METHODS A longitudinal retrospective study was performed to research adult patients with CF. Two consecutive HRCT studies were scored using Bhalla and Brody II scoring scales by two senior radiologists. Annual scoring changes for each scale were calculated and correlated with annual FEV1% decline, with pulmonary exacerbations and number of antibiotic treatments. RESULTS We selected sixty-four adult patients. The median interval between the two HRCTs was 3.88 ± 1.59 years. The mean spirometric values showed dynamic lung volumes lower than the general population; globally, there was a worsening of respiratory function over time. The change in the annual HRCT scores was positive on both scales, indicating a worse structural situation over time. The Brody II scale annual change showed a significant statistical correlation with a decline in the annual FEV1%, exacerbations and number of oral antibiotic treatments. In contrast, for the Bhalla scale, the relationship was moderately inverse with exacerbations and with the number of oral treatments. No statistically significant relationships were found for the change in the annual FEV1% and exacerbations or number of antibiotic treatments. The interobservational and intraobservational agreements were very strong in both scales. CONCLUSIONS The annual evolution of the Brody II HRCT scoring system demonstrated a predictive value and correlated with FEV1% decline, pulmonary exacerbations and oral antibiotic treatments. KEY POINTS • HRCT evolution has prognostic value in cystic fibrosis. • Temporal evolution for the Brody II score is useful for clinical follow-up. • Brody II score changes correlate with FEV1% decline, pulmonary exacerbations and number of antibiotic treatments.
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26
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Bouma NR, Janssens HM, Andrinopoulou E, Tiddens HAWM. Airway disease on chest computed tomography of preschool children with cystic fibrosis is associated with school-age bronchiectasis. Pediatr Pulmonol 2020; 55:141-148. [PMID: 31496137 PMCID: PMC6972540 DOI: 10.1002/ppul.24498] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2019] [Accepted: 08/07/2019] [Indexed: 12/17/2022]
Abstract
Airway wall thickening and mucus plugging are important characteristics of cystic fibrosis (CF) lung disease in the first 5 years of life.The aim of this study is to investigate the association of lung disease in preschool children (age, 2-6) with bronchiectasis and other clinical outcome measures in the school age (age >7). Deidentified computed tomography-scans were annotated using Perth-Rotterdam annotated grid morphometric analysis for CF. Preschool %disease (a composite score of %airway wall thickening, %mucus plugging, and %bronchiectasis) and %MUPAT (a composite score of %airway wall thickening and %mucus plugging) were used as predictors for %bronchiectasis and several other school-age clinical outcomes. For statistical analysis, we used regression analysis, linear mixed-effects models and two-way mixed models. Sixty-one patients were included. %Disease increased significantly with age (P < .01). Preschool %disease and %MUPAT were significantly associated with school-age %bronchiectasis (P < .01 and P < .01, respectively). No significant association was found between preschool %disease and %MUPAT and school-age forced expiratory volume 1 (FEV1%) predicted and quality of life (P > .05). Cross-sectional, %disease in school-age was associated with a low FEV1% predicted and low quality of life (P = .01 and P = .007, respectively). %Disease can be considered an early marker of diffuse airways disease and is a risk factor for school-age bronchiectasis.
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Affiliation(s)
- Nynke R. Bouma
- Pediatric Pulmonology and AllergologySophia Children's HospitalRotterdamThe Netherlands
| | - Hettie M. Janssens
- Pediatric Pulmonology and AllergologySophia Children's HospitalRotterdamThe Netherlands
| | | | - Harm A. W. M. Tiddens
- Pediatric Pulmonology and AllergologySophia Children's HospitalRotterdamThe Netherlands
- Radiology and Nuclear MedicineErasmus Medical CenterRotterdamThe Netherlands
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27
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Abstract
With the improving survival of cystic fibrosis (CF) patients and the advent of highly effective cystic fibrosis transmembrane conductance regulator therapy, the clinical spectrum of this complex multisystem disease continues to evolve. One of the most important clinical events for patients with CF in the course of this disease is an acute pulmonary exacerbation. Clinical and microbial epidemiology studies of CF pulmonary exacerbations continue to provide important insight into the disease course, prognosis, and complications. This work has now led to a number of large scale clinical trials with the goal of improving the treatment paradigm for CF pulmonary exacerbation. The primary goal of this review is to provide a summary of the pathophysiology, the clinical epidemiology, microbial epidemiology, outcome and the treatment of CF pulmonary exacerbation.
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Affiliation(s)
- Christopher H Goss
- CFF Therapeutics Development Network Coordinating Center, Department of Pediatrics, Seattle Children's Research Institute, Seattle, Washington.,Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine and Pediatrics, University of Washington School of Medicine, Seattle, Washington
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28
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Strzelczuk–Judka L, Wojsyk–Banaszak I, Zakrzewska A, Jończyk–Potoczna K. Diagnostic value of chest ultrasound in children with cystic fibrosis - Pilot study. PLoS One 2019; 14:e0215786. [PMID: 31291258 PMCID: PMC6619605 DOI: 10.1371/journal.pone.0215786] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2019] [Accepted: 06/22/2019] [Indexed: 01/08/2023] Open
Abstract
Cystic fibrosis (CF) is one of the most common genetic disorders among the White population. The disease has a progressive course and leads to a reduction in the quality of life and of life expectancy. Standard diagnostic procedures used in the monitoring of CF patients include methods which expose patients to ionizing radiation. With increasing life expectancy in CF the cumulative dose of ionising radiation increases, prompting clinicians’ search for safer imaging studies. Despite its safety and availability lung ultrasound (LUS) is not routinely used in the diagnostic evaluation of CF patients. The aim of the study was to evaluate the diagnostic value of LUS in children with CF compared to a chest X-ray, and to assess the diagnostic value of the recently developed LUS score—CF-USS (Cystic Fibrosis Ultrasound Score). LUS was performed in 48 CF children and adolescents aged from 5 to 18 years (24 girls and 24 boys). LUS consisted of the assessment of the pleura, lung sliding, A-line and B-line artefacts, "lung rockets", alveolar consolidations, air bronchogram and pleural effusion. Chest radiography was performed in all patients and analyzed according to the modified Chrispin-Norman score. LUS was analyzed according to CF-USS. The correlation between the CF-USS and the modified Chrispin-Norman scores was moderate (R = 0.52, p = 0.0002) and strong in control studies. In 75% of patients undergoing LUS, small areas of subpleural consolidations were observed, which were not visible on x-rays. At the same time, LUS was not sensitive enough to visualize bronchial pathology, which plays an important role in assessing the progression of the disease. Conclusions: LUS constitutes an invaluable tool for the diagnosis of subpleural consolidations. CF-USS results correlate with the conventional x-ray modified Chrispin–Norman score. LUS should be considered a supplementary radiographic examination in the monitoring of CF patients, and CF-USS may provide clinicians with valuable information concerning the progression of the disease.
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Affiliation(s)
- Lidia Strzelczuk–Judka
- Department of Pediatric Radiology, Chair of General and Invasive Radiology, Poznan University of Medical Sciences, Poznań, Poland
| | - Irena Wojsyk–Banaszak
- Department of Pulmonology, Pediatric Allergy and Clinical Immunology, Poznan University of Medical Sciences, Poznań, Poland
- * E-mail:
| | - Aleksandra Zakrzewska
- Department of Pediatric Radiology, Chair of General and Invasive Radiology, Poznan University of Medical Sciences, Poznań, Poland
| | - Katarzyna Jończyk–Potoczna
- Department of Pediatric Radiology, Chair of General and Invasive Radiology, Poznan University of Medical Sciences, Poznań, Poland
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Lin S, Lin M, Lau K. Efficacy of model-based iterative reconstruction in cystic fibrosis assessment using CT. Clin Radiol 2019; 74:569.e19-569.e27. [DOI: 10.1016/j.crad.2019.03.009] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2018] [Accepted: 03/11/2019] [Indexed: 02/03/2023]
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Refait J, Macey J, Bui S, Fayon M, Berger P, Delhaes L, Laurent F, Dournes G. CT evaluation of hyperattenuating mucus to diagnose allergic bronchopulmonary aspergillosis in the special condition of cystic fibrosis. J Cyst Fibros 2019; 18:e31-e36. [PMID: 30765182 DOI: 10.1016/j.jcf.2019.02.002] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2018] [Revised: 01/27/2019] [Accepted: 02/05/2019] [Indexed: 11/30/2022]
Abstract
BACKGROUND Mucus plugging (MP), central bronchiectasis (CB), and consolidation/atelectasia (CA) are conventional CT signs to diagnose allergic bronchopulmonary aspergillosis (ABPA) in cystic fibrosis (CF). Hyperattenuating mucus (HAM) has recently been described and may improve diagnostic accuracy. The goal of our study was to compare HAM versus conventional CT signs to diagnose ABPA in CF. Secondary objectives were to determine the optimal threshold of HAM quantitatively and to assess the diagnostic value of HAM using chest radiograph (CXR). METHODS The study was retrospective and included 137 patients with CF, aged >6-year-old. The presence of HAM, CB, MP and CA were determined by two radiologists in consensus. HAM was quantified using an absolute mean density value (AMD) and a ratio between mucus and paraspinal muscle (DRM). Sensitivity (Se), Specificity (Sp) and Youden's J-index were calculated. The Cystic Fibrosis Conference Consensus criteria were chosen as Gold Standard. RESULTS 23 out of 137 CF patients had ABPA. Using CT, the most sensitive structural alteration was MP (Se = 91%), followed by CB (Se = 87%) and CA (Se = 70%) whereas specificities were 28%, 19% and 58%, respectively. Conversely, HAM had the highest specificity (Sp = 100%) whereas Se was 69%. HAM had the highest Youden's J-index (p < 0.001) Quantitative optimal thresholds were AMD > 78 HU (Se/Sp = 71%/98%) and DRM > 1.3 (Se/Sp = 82%/97%). HAM was unseen using CXR (Se = 0%). CONCLUSION HAM is the most specific CT biomarker of ABPA in CF, with good sensitivity. Our study suggests that characterization of mucus density may improve the accuracy of imaging criteria to diagnose ABPA early.
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Affiliation(s)
- John Refait
- CHU de Bordeaux, Service d'Imagerie Thoracique et Cardiovasculaire, Service des Maladies Respiratoires, Service d'Exploration Fonctionnelle Respiratoire, Unité de Pneumologie pédiatrique, Service de Parasitologie-Mycologie, CIC 1401, F-33600 Pessac, France
| | - Julie Macey
- CHU de Bordeaux, Service d'Imagerie Thoracique et Cardiovasculaire, Service des Maladies Respiratoires, Service d'Exploration Fonctionnelle Respiratoire, Unité de Pneumologie pédiatrique, Service de Parasitologie-Mycologie, CIC 1401, F-33600 Pessac, France; Univ. Bordeaux, Centre de Recherche Cardio-Thoracique de Bordeaux, U1045, CIC 1401, F-33000 Bordeaux, France; Inserm, Centre de Recherche Cardio-Thoracique de Bordeaux, U1045, CIC 1401, F-33000 Bordeaux, France
| | - Stephanie Bui
- CHU de Bordeaux, Service d'Imagerie Thoracique et Cardiovasculaire, Service des Maladies Respiratoires, Service d'Exploration Fonctionnelle Respiratoire, Unité de Pneumologie pédiatrique, Service de Parasitologie-Mycologie, CIC 1401, F-33600 Pessac, France
| | - Michaël Fayon
- CHU de Bordeaux, Service d'Imagerie Thoracique et Cardiovasculaire, Service des Maladies Respiratoires, Service d'Exploration Fonctionnelle Respiratoire, Unité de Pneumologie pédiatrique, Service de Parasitologie-Mycologie, CIC 1401, F-33600 Pessac, France; Univ. Bordeaux, Centre de Recherche Cardio-Thoracique de Bordeaux, U1045, CIC 1401, F-33000 Bordeaux, France; Inserm, Centre de Recherche Cardio-Thoracique de Bordeaux, U1045, CIC 1401, F-33000 Bordeaux, France
| | - Patrick Berger
- CHU de Bordeaux, Service d'Imagerie Thoracique et Cardiovasculaire, Service des Maladies Respiratoires, Service d'Exploration Fonctionnelle Respiratoire, Unité de Pneumologie pédiatrique, Service de Parasitologie-Mycologie, CIC 1401, F-33600 Pessac, France; Univ. Bordeaux, Centre de Recherche Cardio-Thoracique de Bordeaux, U1045, CIC 1401, F-33000 Bordeaux, France; Inserm, Centre de Recherche Cardio-Thoracique de Bordeaux, U1045, CIC 1401, F-33000 Bordeaux, France
| | - Laurence Delhaes
- CHU de Bordeaux, Service d'Imagerie Thoracique et Cardiovasculaire, Service des Maladies Respiratoires, Service d'Exploration Fonctionnelle Respiratoire, Unité de Pneumologie pédiatrique, Service de Parasitologie-Mycologie, CIC 1401, F-33600 Pessac, France; Univ. Bordeaux, Centre de Recherche Cardio-Thoracique de Bordeaux, U1045, CIC 1401, F-33000 Bordeaux, France; Inserm, Centre de Recherche Cardio-Thoracique de Bordeaux, U1045, CIC 1401, F-33000 Bordeaux, France
| | - François Laurent
- CHU de Bordeaux, Service d'Imagerie Thoracique et Cardiovasculaire, Service des Maladies Respiratoires, Service d'Exploration Fonctionnelle Respiratoire, Unité de Pneumologie pédiatrique, Service de Parasitologie-Mycologie, CIC 1401, F-33600 Pessac, France; Univ. Bordeaux, Centre de Recherche Cardio-Thoracique de Bordeaux, U1045, CIC 1401, F-33000 Bordeaux, France; Inserm, Centre de Recherche Cardio-Thoracique de Bordeaux, U1045, CIC 1401, F-33000 Bordeaux, France
| | - Gaël Dournes
- CHU de Bordeaux, Service d'Imagerie Thoracique et Cardiovasculaire, Service des Maladies Respiratoires, Service d'Exploration Fonctionnelle Respiratoire, Unité de Pneumologie pédiatrique, Service de Parasitologie-Mycologie, CIC 1401, F-33600 Pessac, France; Univ. Bordeaux, Centre de Recherche Cardio-Thoracique de Bordeaux, U1045, CIC 1401, F-33000 Bordeaux, France; Inserm, Centre de Recherche Cardio-Thoracique de Bordeaux, U1045, CIC 1401, F-33000 Bordeaux, France.
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Kopp BT, Thompson R, Kim J, Konstan R, Diaz A, Smith B, Shrestha C, Rogers LK, Hayes D, Tumin D, Woodley FW, Ramilo O, Sanders DB, Groner JA, Mejias A. Secondhand smoke alters arachidonic acid metabolism and inflammation in infants and children with cystic fibrosis. Thorax 2019; 74:237-246. [PMID: 30661024 DOI: 10.1136/thoraxjnl-2018-211845] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2018] [Revised: 11/09/2018] [Accepted: 12/24/2018] [Indexed: 11/04/2022]
Abstract
BACKGROUND Mechanisms that facilitate early infection and inflammation in cystic fibrosis (CF) are unclear. We previously demonstrated that children with CF and parental-reported secondhand smoke exposure (SHSe) have increased susceptibility to bacterial infections. SHSe hinders arachidonic acid (AA) metabolites that mediate immune function in patients without CF, and may influence CF immune dysfunction. We aimed to define SHSe's impact on inflammation mediators and infection in children with CF. METHODS Seventy-seven children with CF <10 years of age (35 infants <1 year; 42 children 1-10 years) were enrolled and hair nicotine concentrations measured as an objective surrogate of SHSe. AA signalling by serum and macrophage lipidomics, inflammation using blood transcriptional profiles and in vitro macrophage responses to bacterial infection after SHSe were assessed. RESULTS Hair nicotine concentrations were elevated in 63% of patients. Of the AA metabolites measured by plasma lipidomics, prostaglandin D2 (PGD2) concentrations were decreased in children with CF exposed to SHSe, and associated with more frequent hospitalisations (p=0.007) and worsened weight z scores (p=0.008). Children with CF exposed to SHSe demonstrated decreased expression of the prostaglandin genes PTGES3 and PTGR2 and overexpression of inflammatory pathways. These findings were confirmed using an in vitro model, where SHSe was associated with a dose-dependent decrease in PGD2 and increased methicillin-resistant Staphylococcus aureus survival in human CF macrophages. CONCLUSIONS Infants and young children with CF and SHSe have altered AA metabolism and dysregulated inflammatory gene expression resulting in impaired bacterial clearance. Our findings identified potential therapeutic targets to halt early disease progression associated with SHSe in the young population with CF.
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Affiliation(s)
- Benjamin T Kopp
- Division of Pulmonary Medicine, Nationwide Children's Hospital, Columbus, Ohio, USA.,Center for Microbial Pathogenesis, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Rohan Thompson
- Division of Pulmonary Medicine, Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Jeeho Kim
- Center for Microbial Pathogenesis, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Robert Konstan
- Center for Microbial Pathogenesis, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Alejandro Diaz
- Center for Vaccines and Immunity, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Bennett Smith
- Center for Vaccines and Immunity, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Chandra Shrestha
- Center for Microbial Pathogenesis, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Lynette K Rogers
- Center for Perinatal Research, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Don Hayes
- Division of Pulmonary Medicine, Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Dmitry Tumin
- Department of Anesthesiology and Pain Medicine, Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Frederick W Woodley
- Division of Gastroenterology, Hepatology and Nutrition, Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Octavio Ramilo
- Center for Vaccines and Immunity, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Don B Sanders
- Riley Children's Hospital, Indianapolis, Indiana, USA
| | - Judith A Groner
- Section of Ambulatory Pediatrics, Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Asuncion Mejias
- Center for Vaccines and Immunity, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA
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Zha W, Nagle SK, Cadman RV, Schiebler ML, Fain SB. Three-dimensional Isotropic Functional Imaging of Cystic Fibrosis Using Oxygen-enhanced MRI: Comparison with Hyperpolarized 3He MRI. Radiology 2018; 290:229-237. [PMID: 30351258 DOI: 10.1148/radiol.2018181148] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Purpose To compare the performance of three-dimensional radial ultrashort echo time (UTE) oxygen-enhanced (OE) MRI with that of hyperpolarized helium 3 (3He) MRI with respect to quantitative ventilation measurements in patients with cystic fibrosis (CF). Materials and Methods In this prospective study conducted from June 2013 to May 2015, 25 participants with CF aged 10-55 years (14 male; age range, 13-55 years; 11 female; age range, 10-37 years) successfully underwent pulmonary function tests, hyperpolarized 3He MRI, and OE MRI. OE MRI used two sequential 3.5-minute normoxic and hyperoxic steady-state free-breathing UTE acquisitions. Seven participants underwent imaging at two separate examinations 1-2 weeks apart to assess repeatability. Regional ventilation was quantified as ventilation defect percentage (VDP) individually from OE MRI and hyperpolarized 3He MRI by using the same automated quantification tool. Bland-Altman analysis, intraclass correlation coefficient (ICC), Spearman correlation coefficient, and Wilcoxon signed-rank test were used to evaluate repeatability. Results In all 24 participants, the global VDP measurements from either OE MRI (ρ = -0.66, P < .001) or hyperpolarized 3He MRI (ρ = -0.75, P < .001) were significantly correlated with the percentage predicted forced expiratory volume in 1 second. VDP reported at OE MRI was 5.0% smaller than (P = .014) but highly correlated with (ρ = 0.78, P < .001) VDP reported at hyperpolarized 3He MRI. Both OE MRI-based VDP and hyperpolarized 3He MRI-based VDP demonstrated good repeatability (ICC = 0.91 and 0.95, respectively; P ≤ .001). Conclusion In lungs with cystic fibrosis, ultrashort echo time oxygen-enhanced MRI showed similar performance compared with hyperpolarized 3He MRI for quantitative measures of ventilation defects and their repeatability. © RSNA, 2018 Online supplemental material is available for this article.
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Affiliation(s)
- Wei Zha
- From the Departments of Medical Physics (W.Z., S.K.N., R.V.C., S.B.F.), Radiology (S.K.N., M.L.S., S.B.F.), Pediatrics (S.K.N.), and Biomedical Engineering (S.B.F.), University of Wisconsin-Madison, Wisconsin Institutes for Medical Research, 1111 Highland Ave, Room 2492, Madison, WI 53792
| | - Scott K Nagle
- From the Departments of Medical Physics (W.Z., S.K.N., R.V.C., S.B.F.), Radiology (S.K.N., M.L.S., S.B.F.), Pediatrics (S.K.N.), and Biomedical Engineering (S.B.F.), University of Wisconsin-Madison, Wisconsin Institutes for Medical Research, 1111 Highland Ave, Room 2492, Madison, WI 53792
| | - Robert V Cadman
- From the Departments of Medical Physics (W.Z., S.K.N., R.V.C., S.B.F.), Radiology (S.K.N., M.L.S., S.B.F.), Pediatrics (S.K.N.), and Biomedical Engineering (S.B.F.), University of Wisconsin-Madison, Wisconsin Institutes for Medical Research, 1111 Highland Ave, Room 2492, Madison, WI 53792
| | - Mark L Schiebler
- From the Departments of Medical Physics (W.Z., S.K.N., R.V.C., S.B.F.), Radiology (S.K.N., M.L.S., S.B.F.), Pediatrics (S.K.N.), and Biomedical Engineering (S.B.F.), University of Wisconsin-Madison, Wisconsin Institutes for Medical Research, 1111 Highland Ave, Room 2492, Madison, WI 53792
| | - Sean B Fain
- From the Departments of Medical Physics (W.Z., S.K.N., R.V.C., S.B.F.), Radiology (S.K.N., M.L.S., S.B.F.), Pediatrics (S.K.N.), and Biomedical Engineering (S.B.F.), University of Wisconsin-Madison, Wisconsin Institutes for Medical Research, 1111 Highland Ave, Room 2492, Madison, WI 53792
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Sanders DB, Li Z, Parker-McGill K, Farrell P, Brody AS. Quantitative chest computerized tomography and FEV 1 equally identify pulmonary exacerbation risk in children with cystic fibrosis. Pediatr Pulmonol 2018; 53:1369-1377. [PMID: 30160050 PMCID: PMC7059197 DOI: 10.1002/ppul.24144] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2017] [Accepted: 07/16/2018] [Indexed: 01/08/2023]
Abstract
BACKGROUND Chest computerized tomography (CT) scores are associated with the frequency of future pulmonary exacerbations in people with cystic fibrosis (CF). However, cut-off values to identify children with mild lung disease with different risks for frequent future pulmonary exacerbations have not been identified. METHODS Chest CT scans were assessed using the Brody score for participants of the Pulmozyme Early Intervention Trial (PEIT) and Wisconsin Randomized Clinical Trial of CF Newborn Screening (WI RCT). We determined the area under the receiver operating characteristic (ROC) curve for Brody scores and forced expiratory volume in 1 s (FEV1 ) to compare with the frequency of pulmonary exacerbations up to 10 years later. RESULTS There were 60 participants in the PEIT with mean (SD) age 10.6 (1.7) years at the time of the CT and 81 participants in the WI RCT with mean age 11.5 (3.0) years. The Brody score cut-off that best identified children at-risk for ≥0.3 annual pulmonary exacerbations was 3.6 in the PEIT and 2.1 in the WI RCT. There were no statistical differences between ROC curves for the Brody CT score and FEV1 % predicted in either study (P ≥ 0.4). CONCLUSIONS CT score cut-off values that identify children with CF with mild lung disease at different risks for frequent pulmonary exacerbations over an extended follow up period are similar in separate cohorts. Brody scores and FEV1 % predicted have similar abilities to identify these children, suggesting that FEV1 % predicted alone may be adequate for predicting future frequency of pulmonary exacerbations.
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Affiliation(s)
- Don B Sanders
- Department of Pediatrics, Riley Hospital for Children, School of Medicine, Indiana University, Indianapolis, Indiana
| | - Zhanhai Li
- Department of Biostatistics and Medical Informatics, University of Wisconsin, Madison, Wisconsin
| | | | - Philip Farrell
- Departments of Pediatrics and Population Health Sciences, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Alan S Brody
- Department of Radiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
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Breuer O, Caudri D, Stick S, Turkovic L. Predicting disease progression in cystic fibrosis. Expert Rev Respir Med 2018; 12:905-917. [PMID: 30173593 DOI: 10.1080/17476348.2018.1519400] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
INTRODUCTION Progressive lung disease is the major cause of morbidity and mortality in patients with cystic fibrosis (CF). Methods of correctly predicting the future progression of lung disease in patients with CF are essential for directing aggressive treatment to prevent loss of lung function and end stage respiratory failure. Areas covered: This review addresses predictors of respiratory disease progression in patients with CF. We searched Web of Science and Medline, with no restriction on publication date, with the search terms 'cystic fibrosis' and 'disease progression', 'lung function decline', 'prognosis', 'prediction/predictive', 'prediction/prognostic scores', 'risk factors', 'outcome measures/endpoints/disease surrogate', 'longitudinal/long term', 'statistical model', and 'survival'. Expert commentary: Forced expiratory volume in 1 sec (FEV1) and rate of FEV1 decline, remain the most significant predictors of mortality in patients with CF while CT scores and airway secretion biomarkers are the main predictors of early CF lung disease. Comprehensive scores incorporating clinical, lung function, imaging and laboratory data will become essential in the future for predicting disease progression and for use in clinical trials. Early interventions may delay the progression of structural lung disease.
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Affiliation(s)
- Oded Breuer
- a Telethon Kids Institute , University of Western Australia , Perth , Australia.,b Department of Respiratory and Sleep Medicine , Princess Margaret Hospital for Children , Perth , Australia
| | - Daan Caudri
- a Telethon Kids Institute , University of Western Australia , Perth , Australia.,b Department of Respiratory and Sleep Medicine , Princess Margaret Hospital for Children , Perth , Australia.,c Department of Pediatrics/Respiratory Medicine , Erasmus MC , Rotterdam , The Netherlands
| | - Stephen Stick
- a Telethon Kids Institute , University of Western Australia , Perth , Australia.,b Department of Respiratory and Sleep Medicine , Princess Margaret Hospital for Children , Perth , Australia
| | - Lidija Turkovic
- a Telethon Kids Institute , University of Western Australia , Perth , Australia
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Chassagnon G, Martin C, Burgel PR, Hubert D, Fajac I, Paragios N, Zacharaki EI, Legmann P, Coste J, Revel MP. An automated computed tomography score for the cystic fibrosis lung. Eur Radiol 2018; 28:5111-5120. [PMID: 29869171 DOI: 10.1007/s00330-018-5516-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2017] [Revised: 04/16/2018] [Accepted: 04/26/2018] [Indexed: 01/25/2023]
Abstract
OBJECTIVES To develop an automated density-based computed tomography (CT) score evaluating high-attenuating lung structural abnormalities in patients with cystic fibrosis (CF). METHODS Seventy adult CF patients were evaluated. The development cohort comprised 17 patients treated with ivacaftor, with 45 pre-therapeutic and follow-up chest CT scans. Another cohort of 53 patients not treated with ivacaftor was used for validation. CT-density scores were calculated using fixed and adapted thresholds based on histogram characteristics, such as the mode and standard deviation. Visual CF-CT score was also calculated. Correlations between the CT scores and forced expiratory volume in 1 s (FEV1% pred), and between their changes over time were assessed. RESULTS On cross-sectional evaluation, the correlation coefficients between FEV1%pred and the automated scores were slightly lower to that of the visual score in the development and validation cohorts (R = up to -0.68 and -0.61, versus R = -0.72 and R = -0.64, respectively). Conversely, the correlation to FEV1%pred tended to be higher for automated scores (R = up to -0.61) than for visual score (R = -0.49) on longitudinal follow-up. Automated scores based on Mode + 3 SD and Mode +300 HU showed the highest cross-sectional (R = -0.59 to -0.68) and longitudinal (R = -0.51 to -0.61) correlation coefficients to FEV1%pred. CONCLUSIONS The developed CT-density score reliably quantifies high-attenuating lung structural abnormalities in CF. KEY POINTS • Automated CT score shows moderate to good cross-sectional correlations with FEV 1 %pred . • CT score has potential to be integrated into the standard reporting workflow.
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Affiliation(s)
- Guillaume Chassagnon
- Radiology Department, Groupe Hospitalier Cochin-Hotel Dieu, Université Paris Descartes, 27 Rue du Faubourg Saint-Jacques, 75014, Paris, France.
- Centre for Visual Computing, Ecole Centrale Paris, Grande Voie des Vignes, 92290, Chatenay Malabry, France.
| | - Clémence Martin
- Pulmonary Department and Adult CF Centre, Groupe Hospitalier Cochin-Hotel Dieu, Université Paris Descartes, 27 Rue du Faubourg Saint-Jacques, 75014, Paris, France
| | - Pierre-Régis Burgel
- Pulmonary Department and Adult CF Centre, Groupe Hospitalier Cochin-Hotel Dieu, Université Paris Descartes, 27 Rue du Faubourg Saint-Jacques, 75014, Paris, France
| | - Dominique Hubert
- Pulmonary Department and Adult CF Centre, Groupe Hospitalier Cochin-Hotel Dieu, Université Paris Descartes, 27 Rue du Faubourg Saint-Jacques, 75014, Paris, France
| | - Isabelle Fajac
- Physiology Department, Groupe Hospitalier Cochin-Hotel Dieu, Université Paris Descartes, 27 Rue du Faubourg Saint-Jacques, 75014, Paris, France
| | - Nikos Paragios
- Centre for Visual Computing, Ecole Centrale Paris, Grande Voie des Vignes, 92290, Chatenay Malabry, France
| | - Evangelia I Zacharaki
- Centre for Visual Computing, Ecole Centrale Paris, Grande Voie des Vignes, 92290, Chatenay Malabry, France
| | - Paul Legmann
- Radiology Department, Groupe Hospitalier Cochin-Hotel Dieu, Université Paris Descartes, 27 Rue du Faubourg Saint-Jacques, 75014, Paris, France
| | - Joel Coste
- Biostatistics and Epidemiology Department, Groupe Hospitalier Cochin-Hotel Dieu, Université Paris Descartes, 27 Rue du Faubourg Saint-Jacques, 75014, Paris, France
| | - Marie-Pierre Revel
- Radiology Department, Groupe Hospitalier Cochin-Hotel Dieu, Université Paris Descartes, 27 Rue du Faubourg Saint-Jacques, 75014, Paris, France
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Schäfer J, Griese M, Chandrasekaran R, Chotirmall SH, Hartl D. Pathogenesis, imaging and clinical characteristics of CF and non-CF bronchiectasis. BMC Pulm Med 2018; 18:79. [PMID: 29788954 PMCID: PMC5964733 DOI: 10.1186/s12890-018-0630-8] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2017] [Accepted: 04/25/2018] [Indexed: 12/26/2022] Open
Abstract
Bronchiectasis is a common feature of severe inherited and acquired pulmonary disease conditions. Among inherited diseases, cystic fibrosis (CF) is the major disorder associated with bronchiectasis, while acquired conditions frequently featuring bronchiectasis include post-infective bronchiectasis and chronic obstructive pulmonary disease (COPD). Mechanistically, bronchiectasis is driven by a complex interplay of inflammation and infection with neutrophilic inflammation playing a predominant role. The clinical characterization and management of bronchiectasis should involve a precise diagnostic workup, tailored therapeutic strategies and pulmonary imaging that has become an essential tool for the diagnosis and follow-up of bronchiectasis. Prospective future studies are required to optimize the diagnostic and therapeutic management of bronchiectasis, particularly in heterogeneous non-CF bronchiectasis populations.
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Affiliation(s)
- Jürgen Schäfer
- Department of Radiology, Division of Pediatric Radiology, University of Tübingen, Tübingen, Germany.
| | | | | | - Sanjay H Chotirmall
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
| | - Dominik Hartl
- Department of Pediatrics I, University of Tübingen, Tübingen, Germany.,Roche Pharma Research & Early Development (pRED), Immunology, Inflammation and Infectious Diseases (I3) Discovery and Translational Area, Roche Innovation Center, Basel, Switzerland
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HRCT findings of childhood follicular bronchiolitis. Pediatr Radiol 2017; 47:1759-1765. [PMID: 28844075 DOI: 10.1007/s00247-017-3951-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2017] [Revised: 06/04/2017] [Accepted: 07/12/2017] [Indexed: 10/19/2022]
Abstract
BACKGROUND Follicular bronchiolitis is a lymphoproliferative form of interstitial lung disease (ILD) defined by the presence of peribronchial lymphoid follicles. Follicular bronchiolitis has been associated with viral infection, autoimmune disease and immunodeficiency. The most common clinical manifestation is respiratory distress in infancy followed by a prolonged course with gradual improvement. We found no reports of systematic review of high-resolution computed tomography (HRCT) findings in pediatric follicular bronchiolitis. OBJECTIVE The purpose of this study was to describe the HRCT findings of follicular bronchiolitis in children and correlate these imaging findings with histopathology. MATERIALS AND METHODS A 5-year retrospective review of all pathology-proven cases of follicular bronchiolitis was performed. Inclusion criteria were age <18 years and an HRCT within 6 months of lung biopsy. HRCTs were reviewed by three observers and scored using the system previously described by Brody et al. RESULTS Six patients met the inclusion criteria with age range at HRCT of 7-82 months (median: 39.5 months). Pulmonary nodules (n=6) were the most common HRCT finding followed by focal consolidation (n=5), bronchiectasis (n=4) and lymphadenopathy (n=3). Tree and bud opacities and nodules on CT correlated with interstitial lymphocytic infiltrates and discrete lymphoid follicles on pathology. CONCLUSION The salient HRCT findings of childhood follicular bronchiolitis are bilateral, lower lung zone predominant pulmonary nodules and bronchiectasis with infantile onset of symptoms. These characteristic HRCT findings help differentiate follicular bronchiolitis from other forms of infantile onset ILD.
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Hisert KB, Heltshe SL, Pope C, Jorth P, Wu X, Edwards RM, Radey M, Accurso FJ, Wolter DJ, Cooke G, Adam RJ, Carter S, Grogan B, Launspach JL, Donnelly SC, Gallagher CG, Bruce JE, Stoltz DA, Welsh MJ, Hoffman LR, McKone EF, Singh PK. Restoring Cystic Fibrosis Transmembrane Conductance Regulator Function Reduces Airway Bacteria and Inflammation in People with Cystic Fibrosis and Chronic Lung Infections. Am J Respir Crit Care Med 2017; 195:1617-1628. [PMID: 28222269 DOI: 10.1164/rccm.201609-1954oc] [Citation(s) in RCA: 315] [Impact Index Per Article: 39.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
RATIONALE Previous work indicates that ivacaftor improves cystic fibrosis transmembrane conductance regulator (CFTR) activity and lung function in people with cystic fibrosis and G551D-CFTR mutations but does not reduce density of bacteria or markers of inflammation in the airway. These findings raise the possibility that infection and inflammation may progress independently of CFTR activity once cystic fibrosis lung disease is established. OBJECTIVES To better understand the relationship between CFTR activity, airway microbiology and inflammation, and lung function in subjects with cystic fibrosis and chronic airway infections. METHODS We studied 12 subjects with G551D-CFTR mutations and chronic airway infections before and after ivacaftor. We measured lung function, sputum bacterial content, and inflammation, and obtained chest computed tomography scans. MEASUREMENTS AND MAIN RESULTS Ivacaftor produced rapid decreases in sputum Pseudomonas aeruginosa density that began within 48 hours and continued in the first year of treatment. However, no subject eradicated their infecting P. aeruginosa strain, and after the first year P. aeruginosa densities rebounded. Sputum total bacterial concentrations also decreased, but less than P. aeruginosa. Sputum inflammatory measures decreased significantly in the first week of treatment and continued to decline over 2 years. Computed tomography scans obtained before and 1 year after ivacaftor treatment revealed that ivacaftor decreased airway mucous plugging. CONCLUSIONS Ivacaftor caused marked reductions in sputum P. aeruginosa density and airway inflammation and produced modest improvements in radiographic lung disease in subjects with G551D-CFTR mutations. However, P. aeruginosa airway infection persisted. Thus, measures that control infection may be required to realize the full benefits of CFTR-targeting treatments.
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Affiliation(s)
| | | | | | - Peter Jorth
- 3 Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California
| | - Xia Wu
- 4 Department of Genome Sciences
| | | | - Matthew Radey
- 6 Department of Microbiology, University of Washington School of Medicine, Seattle, Washington
| | - Frank J Accurso
- 7 Department of Pediatrics, University of Colorado, Aurora, Colorado
| | | | - Gordon Cooke
- 8 St. Vincent's University Hospital, Dublin, Ireland
| | - Ryan J Adam
- 9 Department of Internal Medicine, University of Iowa, Iowa City, Iowa; and
| | | | - Brenda Grogan
- 8 St. Vincent's University Hospital, Dublin, Ireland
| | - Janice L Launspach
- 9 Department of Internal Medicine, University of Iowa, Iowa City, Iowa; and
| | | | | | | | - David A Stoltz
- 9 Department of Internal Medicine, University of Iowa, Iowa City, Iowa; and
| | - Michael J Welsh
- 9 Department of Internal Medicine, University of Iowa, Iowa City, Iowa; and
| | - Lucas R Hoffman
- 2 Department of Pediatrics.,6 Department of Microbiology, University of Washington School of Medicine, Seattle, Washington
| | | | - Pradeep K Singh
- 1 Department of Medicine.,6 Department of Microbiology, University of Washington School of Medicine, Seattle, Washington
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Somayaji R, Ramos KJ, Kapnadak SG, Aitken ML, Goss CH. Common clinical features of CF (respiratory disease and exocrine pancreatic insufficiency). Presse Med 2017; 46:e109-e124. [PMID: 28554722 DOI: 10.1016/j.lpm.2017.03.021] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2016] [Revised: 03/06/2017] [Accepted: 03/29/2017] [Indexed: 12/17/2022] Open
Abstract
First described as a disease of the pancreas, cystic fibrosis is a genetically inherited progressive disease affecting multiple organ systems. Pulmonary and pancreatic involvement is common in individuals with cystic fibrosis, and the former is attributable to most of the mortality that occurs with the condition. This chapter provides an overview of a clinical approach to the pulmonary and pancreatic manifestations of cystic fibrosis.
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Affiliation(s)
- Ranjani Somayaji
- University of Calgary, Department of Medicine, Calgary, AB, Canada
| | - Kathleen J Ramos
- University of Washington, Department of Medicine, Division of Pulmonary and Critical Care Medicine, Seattle, WA, USA
| | - Siddhartha G Kapnadak
- University of Washington, Department of Medicine, Division of Pulmonary and Critical Care Medicine, Seattle, WA, USA
| | - Moira L Aitken
- University of Washington, Department of Medicine, Division of Pulmonary and Critical Care Medicine, Seattle, WA, USA
| | - Christopher H Goss
- University of Washington, Department of Medicine, Division of Pulmonary and Critical Care Medicine, Seattle, WA, USA; University of Washington, Department of Pediatrics, Division of Pediatric Pulmonology, Seattle, WA, USA; Seattle Children's Research Institute, Cystic Fibrosis Foundation Therapeutics Development Network Coordinating Center, Seattle, WA, USA.
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Scholz O, Denecke T, Böttcher J, Schwarz C, Mentzel HJ, Streitparth F, Maurer MH, Pfeil A, Huppertz A, Mehl A, Staab D, Hamm B, Renz DM. MRI of cystic fibrosis lung manifestations: sequence evaluation and clinical outcome analysis. Clin Radiol 2017; 72:754-763. [PMID: 28545684 DOI: 10.1016/j.crad.2017.03.017] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2016] [Revised: 01/19/2017] [Accepted: 03/20/2017] [Indexed: 11/17/2022]
Abstract
AIM To evaluate different magnetic resonance imaging (MRI) sequences for diagnosis of pulmonary manifestations of cystic fibrosis (CF) in comparison to chest computed tomography (CT), including an extended outcome analysis. MATERIALS AND METHODS Twenty-eight patients with CF (15 male, 13 female, mean age 30.5±9.4 years) underwent CT and MRI of the lung. MRI (1.5 T) included different T2- and T1-weighted sequences: breath-hold HASTE (half Fourier acquisition single shot turbo spin echo) and VIBE (volumetric interpolated breath-hold examination, before and after contrast medium administration) sequences and respiratory-triggered PROPELLER (periodically rotated overlapping parallel lines with enhanced reconstruction) sequences with and without fat signal suppression, and perfusion imaging. CT and MRI images were evaluated by the modified Helbich and the Eichinger scoring systems. The clinical follow-up analysis assessed pulmonary exacerbations within 24 months. RESULTS The highest concordance to CT was achieved for the PROPELLER sequences without fat signal suppression (concordance correlation coefficient CCC of the overall modified Helbich score 0.93 and of the overall Eichinger score 0.93). The other sequences had the following concordance: PROPELLER with fat signal suppression (CCCs 0.91 and 0.92), HASTE (CCCs 0.87 and 0.89), VIBE (CCCs 0.84 and 0.85) sequences. In the outcome analysis, the combined MRI analysis of all five sequences and a specific MRI protocol (PROPELLER without fast signal suppression, VIBE sequences, perfusion imaging) reached similar correlations to the number of pulmonary exacerbations as the CT examinations. CONCLUSION An optimum lung MRI protocol in patients with CF consists of PROPELLER sequences without fat signal suppression, VIBE sequences, and lung perfusion analysis to enable high diagnostic efficacy and outcome prediction.
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Affiliation(s)
- O Scholz
- Department of Radiology, Charité University Medicine Berlin, Campus Virchow Clinic, Augustenburger Platz 1, 13353 Berlin, Germany
| | - T Denecke
- Department of Radiology, Charité University Medicine Berlin, Campus Virchow Clinic, Augustenburger Platz 1, 13353 Berlin, Germany
| | - J Böttcher
- Institute of Diagnostic and Interventional Radiology, SRH Clinic Gera, Str. des Friedens 122, 07548 Gera, Germany
| | - C Schwarz
- Division of Pulmonology and Immunology, Department of Pediatrics, Charité University Medicine Berlin, Campus Virchow Clinic, Augustenburger Platz 1, 13353 Berlin, Germany
| | - H-J Mentzel
- Institute of Diagnostic and Interventional Radiology, Department of Pediatric Radiology, Friedrich-Schiller-University, Jena University Hospital, Am Klinikum 1, 07740 Jena, Germany
| | - F Streitparth
- Department of Radiology, Charité University Medicine Berlin, Campus Virchow Clinic, Augustenburger Platz 1, 13353 Berlin, Germany
| | - M H Maurer
- Department of Radiology, Charité University Medicine Berlin, Campus Virchow Clinic, Augustenburger Platz 1, 13353 Berlin, Germany
| | - A Pfeil
- Department of Internal Medicine III, Friedrich-Schiller-University, Jena University Hospital, Am Klinikum 1, 07740 Jena, Germany
| | - A Huppertz
- Department of Radiology, Charité University Medicine Berlin, Campus Virchow Clinic, Augustenburger Platz 1, 13353 Berlin, Germany
| | - A Mehl
- Division of Pulmonology and Immunology, Department of Pediatrics, Charité University Medicine Berlin, Campus Virchow Clinic, Augustenburger Platz 1, 13353 Berlin, Germany
| | - D Staab
- Division of Pulmonology and Immunology, Department of Pediatrics, Charité University Medicine Berlin, Campus Virchow Clinic, Augustenburger Platz 1, 13353 Berlin, Germany
| | - B Hamm
- Department of Radiology, Charité University Medicine Berlin, Campus Virchow Clinic, Augustenburger Platz 1, 13353 Berlin, Germany
| | - D M Renz
- Department of Radiology, Charité University Medicine Berlin, Campus Virchow Clinic, Augustenburger Platz 1, 13353 Berlin, Germany; Institute of Diagnostic and Interventional Radiology, Department of Pediatric Radiology, Friedrich-Schiller-University, Jena University Hospital, Am Klinikum 1, 07740 Jena, Germany.
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Pulmonary artery enlargement and cystic fibrosis pulmonary exacerbations: a cohort study. THE LANCET RESPIRATORY MEDICINE 2016; 4:636-645. [PMID: 27298019 PMCID: PMC5672808 DOI: 10.1016/s2213-2600(16)30105-9] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/11/2016] [Revised: 04/28/2016] [Accepted: 04/28/2016] [Indexed: 01/04/2023]
Abstract
Background Acute pulmonary exacerbations are associated with progressive lung function decline and increased mortality in cystic fibrosis (CF). The role of pulmonary vascular disease in pulmonary exacerbations is unknown. We investigated the association between pulmonary artery enlargement (PA:A>1), a marker of pulmonary vascular disease, and exacerbations. Methods We analyzed clinical, computed tomography (CT), and prospective exacerbation data in a derivation cohort of 74 adult CF patients, measuring the PA:A at the level of the PA bifurcation. We then replicated our findings in a validation cohort of 190 adult CF patients. Patients were separated into groups based on the presence or absence of a PA:A>1 and were followed for 1-year in the derivation cohort and 2-years in the validation cohort. The primary endpoint was developing ≥1 acute pulmonary exacerbation during follow-up. Linear and logistic regression models were used to determine associations between clinical factors, the PA:A ratio, and pulmonary exacerbations. We used Cox regression to determine time to first exacerbation in the validation cohort. Findings We found that PA:A>1 was present in n=37/74 (50%) of the derivation and n=89/190 (47%) of the validation cohort. In the derivation cohort, n=50/74 (68%) had ≥1 exacerbation at 1 year and n=133/190 (70%) in the validation cohort had ≥1 exacerbation after 2 years. PA:A>1 was associated with younger age in both cohorts and with elevated sweat chloride (100.5±10.9 versus 90.4±19.9mmol/L, difference between groups 10.1mmol/L [95%CI 2.5–17.7], P=0.017) in the derivation group. PA:A>1 was associated with exacerbations in the derivation (OR 3.49, 95%CI 1.18–10.3, P=0.023) and validation (OR 2.41, 95%CI 1.06–5.52, P=0.037) cohorts when adjusted for confounders. Time to first exacerbation was shorter in PA:A>1 versus PA:A<1 [HR 1.66 (95%CI 1.18–2.34), P=0.004] in unadjusted analysis, but not when adjusted for sex, BMI, prior exacerbation, positive Pseudomonas status, and FEV1/FVC [HR 1.14 (95%CI 0.80–1.62), P=0.82]). Interpretation PA enlargement is prevalent in adult CF patients and is associated with acute pulmonary exacerbation risk in two well-characterized cohorts. PA:A may be a predictive marker in CF.
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Ferris H, Twomey M, Moloney F, O’Neill SB, Murphy K, O’Connor OJ, Maher M. Computed tomography dose optimisation in cystic fibrosis: A review. World J Radiol 2016; 8:331-341. [PMID: 27158420 PMCID: PMC4840191 DOI: 10.4329/wjr.v8.i4.331] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2015] [Revised: 10/15/2015] [Accepted: 01/19/2016] [Indexed: 02/06/2023] Open
Abstract
Cystic fibrosis (CF) is the most common autosomal recessive disease of the Caucasian population worldwide, with respiratory disease remaining the most relevant source of morbidity and mortality. Computed tomography (CT) is frequently used for monitoring disease complications and progression. Over the last fifteen years there has been a six-fold increase in the use of CT, which has lead to a growing concern in relation to cumulative radiation exposure. The challenge to the medical profession is to identify dose reduction strategies that meet acceptable image quality, but fulfil the requirements of a diagnostic quality CT. Dose-optimisation, particularly in CT, is essential as it reduces the chances of patients receiving cumulative radiation doses in excess of 100 mSv, a dose deemed significant by the United Nations Scientific Committee on the Effects of Atomic Radiation. This review article explores the current trends in imaging in CF with particular emphasis on new developments in dose optimisation.
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Rybacka A, Karmelita-Katulska K. The Role of Computed Tomography in Monitoring Patients with Cystic Fibrosis. Pol J Radiol 2016; 81:141-5. [PMID: 27103945 PMCID: PMC4821342 DOI: 10.12659/pjr.896051] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2015] [Accepted: 10/13/2015] [Indexed: 11/09/2022] Open
Abstract
Cystic fibrosis is the most common lethal autosomal recessive disorder in the Caucasian population. Although the survival rate in patients constantly improves, lung damage is still the major cause of morbidity and mortality in patients with cystic fibrosis. In clinical practice, evaluation of patients' pulmonary state is made by combination of monitoring of lung function and more directly by assessing the lung structure in imaging studies. Studies showed that computed tomography findings are more sensitive as compared to the pulmonary function tests. Computed tomography can identify a wide range of morphological abnormalities in patients with cystic fibrosis, such as bronchiectasis (which is progressive, irreversible and probably the most relevant structural change in cystic fibrosis) peribronchial thickening, mucous plugging and many other disorders that occur in the course of the disease. Computed tomography has a crucial role in the assessment of pulmonary damage over time, detecting complications and monitoring treatment effects in patients with cystic fibrosis.
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Affiliation(s)
- Anna Rybacka
- Department of Diagnostic Imaging, Poznań University of Medical Sciences, Poznań, Poland
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45
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Wielpütz MO, Kauczor HU. Imaging cystic fibrosis lung disease with MRI. IMAGING 2016. [DOI: 10.1183/2312508x.10002415] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
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Tepper LA, Ciet P, Caudri D, Quittner AL, Utens EMWJ, Tiddens HAWM. Validating chest MRI to detect and monitor cystic fibrosis lung disease in a pediatric cohort. Pediatr Pulmonol 2016; 51:34-41. [PMID: 26436668 DOI: 10.1002/ppul.23328] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2014] [Revised: 08/20/2015] [Accepted: 09/18/2015] [Indexed: 11/09/2022]
Abstract
BACKGROUND Computed Tomography (CT) is the gold standard to assess bronchiectasis and trapped air in cystic fibrosis (CF) lung disease, but has the disadvantage of radiation exposure. Magnetic Resonance Imaging (MRI) is a radiation free alternative. OBJECTIVE To validate MRI as outcome measure by: correlating MRI scores for bronchiectasis and trapped air with clinical parameters, and by comparing those MRI scores with CT scores. METHODS In patients with CF (aged 5.6-17.4 years), MRI and CT were alternated annually during routine annual check-ups between July 2007 and January 2010. Twenty-three children had an MRI performed 1 year prior to CT, 34 children had a CT 1 year prior to MRI. Bronchiectasis and trapped air were scored using the CF-MRI and CF-CT scoring system. CF-MRI scores were correlated with clinical parameters: FEV1 , Pseudomonas aeruginosa, pulmonary exacerbations and patient-reported respiratory symptoms measured on the Cystic Fibrosis Questionnaire-Revised (CFQ-R), using Spearman's correlation coefficient. MRI and CT scores were compared using intra-class correlation coefficients (ICC) and Bland-Altman plots. RESULTS Fifty-seven patients who had an MRI, CT and CFQ-R during the study period were included. CF-MRI bronchiectasis correlated with FEV1 , Pseudomonas aeruginosa, pulmonary exacerbations and patient-reported respiratory symptoms. CF-MRI trapped air only correlated with FEV1 and Pseudomonas aeruginosa. ICCs between MRI and CT bronchiectasis and trapped air were 0.41 and 0.35 respectively. MRI tended to overestimate bronchiectasis compared to CT. CONCLUSION The associations between CF-MRI scores and several important clinical parameters further contributes to the validation of MRI. MRI provides different information than CT.
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Affiliation(s)
- Leonie A Tepper
- Department of Pediatric Pulmonology, Erasmus Medical Centre (MC)/Sophia Children's Hospital, Rotterdam, The Netherlands.,Department of Radiology, Erasmus MC/Sophia Children's Hospital, Rotterdam, The Netherlands
| | - Pierluigi Ciet
- Department of Pediatric Pulmonology, Erasmus Medical Centre (MC)/Sophia Children's Hospital, Rotterdam, The Netherlands.,Department of Radiology, Erasmus MC/Sophia Children's Hospital, Rotterdam, The Netherlands
| | - Daan Caudri
- Department of Pediatric Pulmonology, Erasmus Medical Centre (MC)/Sophia Children's Hospital, Rotterdam, The Netherlands
| | - Alexandra L Quittner
- Departments of Psychology and Pediatrics, University of Miami, Coral Gables, Florida
| | - Elisabeth M W J Utens
- Department of Child and Adolescent Psychiatry and Psychology, Erasmus MC/ Sophia Children's Hospital, Rotterdam, The Netherlands
| | - Harm A W M Tiddens
- Department of Pediatric Pulmonology, Erasmus Medical Centre (MC)/Sophia Children's Hospital, Rotterdam, The Netherlands.,Department of Radiology, Erasmus MC/Sophia Children's Hospital, Rotterdam, The Netherlands
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Scaglione M, Linsenmaier U, Schueller G, Berger F, Wirth S. Airway Disease. EMERGENCY RADIOLOGY OF THE CHEST AND CARDIOVASCULAR SYSTEM 2016. [PMCID: PMC7119984 DOI: 10.1007/174_2016_39] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Affiliation(s)
- Mariano Scaglione
- Dept of Radiology, Pineta Grande Medical Center, Castel Volturno, Caserta, Italy
| | | | | | - Ferco Berger
- VU University Medical Center, Amsterdam, The Netherlands
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Walkup LL, Woods JC. Advances in Imaging Cystic Fibrosis Lung Disease. PEDIATRIC ALLERGY IMMUNOLOGY AND PULMONOLOGY 2015; 28:220-229. [DOI: 10.1089/ped.2015.0588] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Affiliation(s)
- Laura L. Walkup
- Center for Pulmonary Imaging Research, Division of Pulmonary Medicine and Department of Radiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Jason C. Woods
- Center for Pulmonary Imaging Research, Division of Pulmonary Medicine and Department of Radiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
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Pittman JE. Assessment and Detection of Early Lung Disease in Cystic Fibrosis. PEDIATRIC ALLERGY IMMUNOLOGY AND PULMONOLOGY 2015; 28:212-219. [DOI: 10.1089/ped.2015.0568] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Affiliation(s)
- Jessica E. Pittman
- Division of Pediatric Allergy, Immunology, and Pulmonary Medicine, Washington University School of Medicine, Saint Louis, Missouri
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Chest computed tomography predicts the frequency of pulmonary exacerbations in children with cystic fibrosis. Ann Am Thorac Soc 2015; 12:64-9. [PMID: 25474182 DOI: 10.1513/annalsats.201407-338oc] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
RATIONALE Abnormalities on chest computed tomography (CT) in children with cystic fibrosis (CF) have been shown to correlate with short-term measures of lung disease. Chest CT scores offer promise as a potential surrogate end point in CF; however, there is limited information available on the ability of chest CT scores to predict future morbidity. OBJECTIVES Determine whether chest CT scores are associated with the rate of pulmonary exacerbations over the next 10 years. METHODS Ten years of follow-up data were obtained from the CF Foundation Patient Registry for 60 children enrolled in the Pulmozyme Early Intervention Trial and who had chest CT scans at baseline. MEASUREMENTS AND MAIN RESULTS Multivariable Poisson regression was used to compare Brody CT scores and the number of pulmonary exacerbations in the following 10 years. At the time of the chest CT, the mean (SD) age was 10.6 (1.7) years. A 1-point increase in the Brody CT score was associated with an increase in the mean (95% confidence interval) rate of pulmonary exacerbations of 1.39 (1.15, 1.67) (P < 0.001). Brody CT scores were more strongly associated with the number of pulmonary exacerbations than FEV1 % predicted at the time of the chest CT (P = 0.037 by chi-square test). CONCLUSIONS There is a significant association between Brody CT scores and the rate of pulmonary exacerbations up to 10 years later. This association is stronger than for FEV1 obtained at the time of the CT, suggesting that chest CT scores offer improved ability to predict future outcomes.
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