. 2016 Aug;4(8):636-645.

doi: 10.1016/S2213-2600(16)30105-9. Epub 2016 Jun 10.

Pulmonary artery enlargement and cystic fibrosis pulmonary exacerbations: a cohort study

J Michael Wells¹, Roopan F Farris², Taylor A Gosdin³, Mark T Dransfield⁴, Michelle E Wood⁵, Scott C Bell⁵, Steven M Rowe⁶

Affiliations

¹ Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA; Division of Pulmonary, Allergy, and Critical Care, University of Alabama at Birmingham, Birmingham, AL, USA; UAB Lung Health Center, University of Alabama at Birmingham, Birmingham, AL, USA; Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, AL, USA; Birmingham VA Medical Center, Birmingham, AL, USA. Electronic address: jmwells@uabmc.edu.
² Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
³ Division of Pulmonary, Allergy, and Critical Care, University of Alabama at Birmingham, Birmingham, AL, USA.
⁴ Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA; Division of Pulmonary, Allergy, and Critical Care, University of Alabama at Birmingham, Birmingham, AL, USA; UAB Lung Health Center, University of Alabama at Birmingham, Birmingham, AL, USA; Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, AL, USA; Birmingham VA Medical Center, Birmingham, AL, USA.
⁵ Adult Cystic Fibrosis Centre, The Prince Charles Hospital Brisbane, Brisbane, QLD, Australia; QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia; School of Medicine, University of Queensland, Brisbane, QLD, Australia.
⁶ Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA; Division of Pulmonary, Allergy, and Critical Care, University of Alabama at Birmingham, Birmingham, AL, USA; UAB Lung Health Center, University of Alabama at Birmingham, Birmingham, AL, USA; Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, AL, USA.

PMID: 27298019
PMCID: PMC5672808
DOI: 10.1016/S2213-2600(16)30105-9

Pulmonary artery enlargement and cystic fibrosis pulmonary exacerbations: a cohort study

J Michael Wells et al. Lancet Respir Med. 2016 Aug.

. 2016 Aug;4(8):636-645.

doi: 10.1016/S2213-2600(16)30105-9. Epub 2016 Jun 10.

Authors

J Michael Wells¹, Roopan F Farris², Taylor A Gosdin³, Mark T Dransfield⁴, Michelle E Wood⁵, Scott C Bell⁵, Steven M Rowe⁶

Affiliations

¹ Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA; Division of Pulmonary, Allergy, and Critical Care, University of Alabama at Birmingham, Birmingham, AL, USA; UAB Lung Health Center, University of Alabama at Birmingham, Birmingham, AL, USA; Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, AL, USA; Birmingham VA Medical Center, Birmingham, AL, USA. Electronic address: jmwells@uabmc.edu.
² Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
³ Division of Pulmonary, Allergy, and Critical Care, University of Alabama at Birmingham, Birmingham, AL, USA.
⁴ Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA; Division of Pulmonary, Allergy, and Critical Care, University of Alabama at Birmingham, Birmingham, AL, USA; UAB Lung Health Center, University of Alabama at Birmingham, Birmingham, AL, USA; Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, AL, USA; Birmingham VA Medical Center, Birmingham, AL, USA.
⁵ Adult Cystic Fibrosis Centre, The Prince Charles Hospital Brisbane, Brisbane, QLD, Australia; QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia; School of Medicine, University of Queensland, Brisbane, QLD, Australia.
⁶ Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA; Division of Pulmonary, Allergy, and Critical Care, University of Alabama at Birmingham, Birmingham, AL, USA; UAB Lung Health Center, University of Alabama at Birmingham, Birmingham, AL, USA; Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, AL, USA.

PMID: 27298019
PMCID: PMC5672808
DOI: 10.1016/S2213-2600(16)30105-9

Abstract

Background: Acute pulmonary exacerbations are associated with progressive lung function decline and increased mortality in cystic fibrosis. The role of pulmonary vascular disease in pulmonary exacerbations is unknown. We aimed to assess the association between pulmonary artery enlargement (defined as pulmonary artery diameter to ascending aorta diameter [PA:A] ratio >1), a marker of pulmonary vascular disease, and exacerbations.

Methods: In this cohort study, we used clinical, CT imaging, and prospective exacerbation data from a previous prospective clinical trial (derivation cohort) and from The Prince Charles Hospital (TPCH; Brisbane, QLD, Australia) cystic fibrosis registry (validation cohort). In our derivation cohort, we included adults aged 18 years or older with cystic fibrosis and at least one CFTR nonsense mutation, who were enrolled in the trial between Sept 8, 2009, and Nov 30, 2010, randomly assigned to receive placebo, and had baseline CT imaging. Our validation cohort included adult patients with cystic fibrosis who had CT imaging performed between Jan 1, 2002, and Dec 31, 2014. We measured the PA:A ratio at the level of the pulmonary artery bifurcation on CT scans. Patients in each cohort were separated into two groups on the basis of PA:A ratio (>1 or ≤1) and were followed up for 1 year in the derivation cohort and 2 years in the validation cohort. The primary endpoint was the development of one or more acute pulmonary exacerbations during follow-up. We used linear and logistic regression models to determine associations between clinical factors, the PA:A ratio, and pulmonary exacerbations. We used Cox regression to determine the time to first exacerbation in the validation cohort.

Findings: 37 (50%) of 74 patients in the derivation cohort and 89 (47%) of 190 patients in the validation cohort had enlarged pulmonary arteries (PA:A>1). 50 (68%) patients in the derivation cohort had one or more exacerbations at 1 year and 133 (70%) patients in the validation cohort had one or more exacerbations at 2 years. At baseline, patients with pulmonary artery enlargement were younger than those without enlargement in both cohorts and had elevated sweat chloride concentrations in the derivation cohort (100·5 mmol/L [SD 10·9] vs 90·4 mmol/L [19·9]; difference 10·1 mmol/L [95% CI 2·5-17·7], p=0·017). Pulmonary artery enlargement was associated with exacerbations in the derivation cohort (odds ratio 3·49 [95% CI 1·18-10·3], p=0·023) when adjusted for sex, body-mass index (BMI), forced expiratory volume in 1 s (FEV1), and PA:A greater than 1, and in the validation cohort (2·41 [1·06-5·52], p=0·037) when adjusted for sex, BMI, chronic Pseudomonas aeruginosa infection, FEV1/FVC (forced vital capacity), PA:A greater than 1, and previous exacerbation. The time to first exacerbation was shorter in patients with enlarged pulmonary arteries than in those with normal-sized pulmonary arteries in the validation cohort (hazard ratio 1·66 [95% CI 1·18-2·34], p=0·0038) in unadjusted analysis, but not when adjusted for sex, BMI, exacerbations within 1 year before index CT scan, FEV1/FVC, and chronic P aeruginosa infection (1·14 [0·80-1·62], p=0·82).

Interpretation: Pulmonary artery enlargement is prevalent in adult patients with cystic fibrosis and was associated with acute pulmonary exacerbation risk in two well characterised cohorts. The PA:A ratio could be a predictive marker in cystic fibrosis.

Funding: US National Heart, Lung, and Blood Institute/National Institutes of Health, Cystic Fibrosis Foundation, the University of Alabama at Birmingham, and the Queensland Health Fellowship.

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Conflict of interest statement

Conflicts of Interest:

Dr. Wells reports grants from NIH/NHLBI, grants from Cystic Fibrosis Foundation, during the conduct of the study; other from AstraZeneca, other from GSK, other from AstraZeneca, other from Gilead, outside the submitted work.

Dr. Dransfield reports personal fees and other from AstraZeneca, personal fees and other from Boehringer Ingelheim, personal fees and other from Boston Scientific, personal fees and other from GlaxoSmithKline, personal fees from Ikaria, personal fees from Skyepharma, grants from NIH, grants from US Department of Defense, grants from American Heart Association, other from Aeris, other from Otsuka, other from Pearl, other from Pfizer, other from PneumRx, other from Pulmonx, other from Yungjin, outside the submitted work.

Ms. Wood reports non-financial support and other from Vertex Pharmaceuticals, non-financial support and other from PTC Pharmaceuticals, non-financial support and other from Galapagos NV, outside the submitted work.

Dr. Bell reports non-financial support and other from Vertex Pharmaceuticals, non-financial support and other from Gilead Pharmaceuticals, non-financial support and other from Novartis Pharmaceuticals, non-financial support and other from Raptor Pharmaceuticals, non-financial support and other from PTC Pharmaceuticals, outside the submitted work.

Dr. Rowe reports grants from NIH, grants from Cystic Fibrosis Foundation, during the conduct of the study; grants from Vertex Pharmaceuticals, grants from Novartis, grants from Nivalis Pharmaceuticals, grants from Bayer, grants from PTC Therapeutics, outside the submitted work.

All other authors declared no conflicts of interest.

Figures

**Figure 1. Disposition of subject data used in the study**
(A) The derivation cohort was developed using de-identified data from subjects enrolled in the placebo arm of a clinical trial. A total of 74 subjects were included. (B) The validation cohort consisted of de-identified data from patients enrolled at the Adult Cystic Fibrosis Centre, Prince Charles Hospital Brisbane, Queensland, Australia. A total of 190 subjects were included.

**Figure 2. Representative measurements of the pulmonary artery and aortic diameters by CT scan**
Non-contrast enhanced chest CT images depict the site of PA (blue) and A (red) diameters, measured at the level of the PA bifurcation. Aortic diameters were averaged values of two perpendicular measurements.

**Figure 3. Relationship between PA enlargement and acute pulmonary exacerbations in adults with cystic fibrosis**
We found an association between PA:A>1 and acute pulmonary exacerbations at (A) 12-months of follow-up in our derivation cohort. We recapitulated these findings in a validation cohort when followed for (B) 12-months and (C) 24-months. *P<0.05.

**Figure 4. Time to first acute pulmonary exacerbation in the validation cohort**
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 (B) 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].

See this image and copyright information in PMC

Comment in

Pulmonary artery hypertension: an underrated disease manifestation in cystic fibrosis?
Ratjen F. Ratjen F. Lancet Respir Med. 2016 Aug;4(8):596-598. doi: 10.1016/S2213-2600(16)30107-2. Epub 2016 Jun 10. Lancet Respir Med. 2016. PMID: 27298018 No abstract available.

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Pulmonary artery enlargement and cystic fibrosis pulmonary exacerbations: a cohort study

Affiliations

Pulmonary artery enlargement and cystic fibrosis pulmonary exacerbations: a cohort study

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

Comment in

References

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Grants and funding

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Medical

Research Materials