Clinical Radiology 69 (2014) e153ee162

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Pictorial Review

Pulmonary complications of cystic fibrosis M.Y. Ng a, *, W. Flight b, E. Smith a a b

Department of Radiology, University Hospital of South Manchester NHS Foundation Trust, Manchester, UK Manchester Adult Cystic Fibrosis Centre, University Hospital of South Manchester NHS Foundation Trust, UK

art icl e i nformat ion Article history: Received 31 July 2013 Received in revised form 29 October 2013 Accepted 30 October 2013

The life expectancy of patients with cystic fibrosis (CF) has steadily increased over recent decades with a corresponding increase in the frequency of complications of the disease. Radiologists are increasingly involved with managing and identifying the pulmonary complications of CF. This article reviews the common manifestations of CF lung disease as well as updating radiologists with a number of less well-known complications of the condition. Early and accurate detection of the pulmonary effects of CF are increasingly important to prevent irreversible lung damage and give patients the greatest possibility of benefiting from the new therapies becoming available, which correct the underlying defect causing CF. Ó 2013 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

Introduction Cystic fibrosis (CF) is an incurable autosomal recessive disease that affects approximately 1 in 2500 live births among caucasians.1 CF is caused by a mutation in the gene coding for the CF transmembrane conductance regulator (CFTR) protein, which is expressed in many different organs and acts primarily as a chloride channel.1 CFTR dysfunction in the lung leads to dehydration of the airway surface liquid, reduced mucociliary clearance, and a cycle of pulmonary infection and inflammation. In the majority of cases, CF leads to progressive respiratory failure and premature death. Improvements in CF care have led to an increase in median life expectancy to 37 years of age and children born with CF in this century are predicted to live beyond the age of 50 years.2 As a result, the CF population is increasing and the presence of pulmonary complications is likely to become more commonplace. Early recognition and

* Guarantor and correspondent: M.Y. Ng, Department of Radiology, University Hospital of South Manchester NHS Foundation Trust, Manchester, UK. E-mail address: [email protected] (M.Y. Ng).

appropriate management of these complications is essential for the continued improvement in survival of patients with CF. Additionally, new drugs targeting the underlying CFTR defect are becoming available, which raise the possibility of slowing disease progression.3,4 Radiologists have a vital role to play in the management of CF to help allow patients to benefit from these new personalized medicines. Imaging studies have the further benefit of allowing clinicians to target both diagnostic and therapeutic interventions most effectively. In this article, we review the full spectrum of pulmonary manifestations of CF from common features, such as bronchiectasis and pneumothorax, through to lesser-known conditions, such as the “Cepacia syndrome” and idiopathic progressive lung collapse. The role of computed tomography (CT) and chest radiography in management will also be discussed.

Bronchiectasis and small airway disease Bronchiectasis refers to abnormal, permanently dilated airways and is the hallmark of CF lung disease. A cycle of recurrent infection and inflammation complicates the development of bronchiectasis, which typically affects the upper lobes in CF, as shown in Fig 1. Recent data have

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Chronic endobronchial colonization The lungs of CF patients are frequently colonized with a variety of characteristic organisms such as Pseudomonas aeruginosa, Staphylococcus aureus, and Burkholderia cepacia complex.1 It is impossible to differentiate these organisms based on radiological studies. P. aeruginosa becomes the dominant respiratory pathogen by the age of 18 years old,9 and can be particularly difficult to eradicate once it has established biofilms within the lung. B. cepacia complex infection is often associated with accelerated lung function decline and has been responsible for devastating outbreaks within CF units.10 The combination of B. cepacia bacteraemia and necrotizing pneumonia is known as the “Cepacia syndrome”.11 This is a dreaded and poorly understood condition associated with very high mortality. The radiological appearances of the Cepacia syndrome have not been described in detail in the literature. In the authors’ experience, the chest radiograph in the Cepacia syndrome is characterized by progressive, bilateral, and diffuse nodular consolidation as shown in Fig 2. Figure 1 Typical chest radiograph of a patient with CF demonstrating bilateral generalized bronchial wall thickening, tram-lining indicating bronchiectasis, and the presence of a TIVAD in the right hemi-thorax.

shown a significant correlation between the extent of bronchiectasis and reduced survival amongst patients with CF.5 Bronchiectasis is often sub-divided into cylindrical, varicose, and cystic bronchiectasis based on the pathological or radiographic findings. Signs of bronchiectasis on the chest radiograph include tram-lining and cystic lesions containing airefluid levels. At CT, additional features of bronchiectasis include the “signet ring sign” where the internal bronchial diameter is larger than its corresponding artery; bronchial wall thickening; the presence of visible bronchi within 1 cm of the costal pleura or touching the mediastinal pleura6 and a lack of normal tapering of the bronchi.7 Fig 3 shows an example of the CT characteristics of severe bronchiectasis. Due to the near-universal presence of bronchiectasis in older CF patients, it can be difficult to differentiate coexisting pulmonary abnormalities. Mucus plugging and the tree-in-bud appearance are commonly associated with bronchiectasis but are also features of allergic bronchopulmonary aspergillosis (ABPA) and infection with nontuberculous mycobacteria (NTM). A high degree of suspicion for these conditions is required when reporting thoracic images from patients with CF. In addition to causing bronchiectasis, CF also affects the small airways. Obstruction of the small airways with mucus typically causes peripheral air-trapping within the lung. This is seen as mosaicism on CT images. Studies in infants diagnosed with CF through newborn screening have shown that small airways disease is frequently detectable by CT even in the absence of clinical evidence of lung disease.8

Aspergillus-related lung disease Aspergillus fumigatus is a fungus that is frequently isolated from the airways of patients with CF. The spectrum of Aspergillus-related lung disease includes allergic bronchopulmonary aspergillosis (ABPA), aspergilloma, and chronic necrotizing aspergillosis (also known as semi-invasive aspergillosis). Studies have indicated that 2e10% of patients with CF have ABPA.12,13 Despite this high prevalence, ABPA can be very difficult to diagnose radiologically due to considerable overlap with the typical bronchiectasis and mucous plugging seen in most CF patients. Fig 3 illustrates a characteristic thoracic CT image from a patient with CF and ABPA. The presence of central varicose bronchiectasis in CF may suggest a diagnosis of ABPA as an upper lobe predominance is more characteristic of CF itself.14 Another feature that may help identify ABPA is the presence of high-attenuation mucous plugging using the paraspinal muscles as a reference (i.e., the mucous is higher density than the paraspinal muscles).15 However, mimics of high-density mucous, such as haemorrhage and aspiration of radiodense material, should be considered in the differential. Aspergilloma is an uncommon complication of CF, which is more commonly seen in patients with cavitary lung disease, such as those with previous tuberculosis or sarcoidosis.16 Aspergillomas develop when Aspergillus spp. colonizes a pre-existing cavity. The initial radiological findings are of a cavity with thickened and irregular walls, which progresses into a fungal ball. The finding on CT of a solid lesion surrounded by air within a cavity, the aircrescent sign, is characteristic of an aspergilloma.17 Chronic necrotizing aspergillosis (also known as semiinvasive aspergillosis) is a further manifestation of Aspergillus-related lung disease, which usually affects patients with a mild degree of immunocompromise but can

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Figure 2 Cepacia syndrome: fatal necrotizing pneumonia associated with B. cenocepacia bacteraemia in an adult with CF. (a) Baseline check radiograph. (b) Radiograph taken close to admission shows early nodular consolidation in the left lung. (c) Nine days later, further progression of the nodular consolidation can be clearly seen in both lungs. These nodular areas over the next 6 days then become mass-like, and are seen in the lower zone bilaterally with the mass-like consolidation in the left lower zone showing possible cavitation. Unfortunately, the patient developed progressive respiratory failure and died despite maximal medical therapy.

complicate CF. Chronic necrotizing aspergillosis is characterized by consolidation, which becomes necrotic and may cavitate (see Fig 4). The appearance of this condition can be difficult to differentiate from angio-invasive aspergillosis, but it usually develops over months rather than days to weeks in the latter condition. In addition, angioinvasive aspergillosis normally occurs in heavily immunocompromised patients and, in the context of CF, would be most likely in the patient who had undergone lung transplantation.17

NTM infection Pulmonary tuberculosis is rare in CF. NTM, however, are common and are found in the lungs of up to 23% of patients

with CF.18,19 Mycobacterium avium intracellulare and Mycobacterium abscessus are the most prevalent species of NTM in CF. NTM may lead to simple saprophagous colonization, but equally they may cause severe, progressive pulmonary infection. Treatment of NTM typically requires a prolonged course of multiple anti-mycobacterial drugs and certain species, such as M. abscessus, are considered a relative contraindication to lung transplantation.20,21 The radiological appearances of NTM disease have been classified into two main forms: classical (also known as cavitary) and non-classical (bronchiectatic).22 In the classical form, cavities are typically seen in the upper lobes with adjacent nodules. The bronchiectatic form typically involves cylindrical bronchiectasis with centrilobular nodule formation, which can range from small to large nodules. An

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Figure 3 CF patient with ABPA. Extensive bronchiectasis with large mucous plugs in the middle lobe and right lower lobe. However, this appearance is not infrequently seen in CF patients.

example of NTM-related lung disease in CF is shown in Fig 5. It is important to note, however, that it is frequently difficult to differentiate the features of NTM infection from underlying CF lung disease. The decision on when to initiate antimycobacterial therapy must be guided by the combination of clinical, radiological, and microbiological features.20

Pneumothorax Pneumothorax has an incidence of 0.64% per year among patients with CF.23 Fig 6 shows an example of a left-sided pneumothorax in a patient with end-stage CF lung disease. Pneumothorax is thought to develop when mucous plugging of the airways leads to increased pressure in the alveoli. If the pressure reaches a critical level exceeding the interstitial pressure, air ruptures out of the alveoli and perforates through to the pleural space resulting in a pneumothorax.23 Risk factors for pneumothorax in CF

Figure 5 Chronic M. abscessus infection in a 25-year-old patient with CF. The patient presented with declining lung function and pyrexia. This thoracic high-resolution CT image shows evidence of bronchiectasis (white arrowheads) and widespread bilateral nodules (white arrows), which would be in keeping with the non-classical/ bronchiectatic form of NTM. Long-term therapy with a combination of oral and nebulized anti-mycobacterial drugs was commenced.

include P. aeruginosa or B. cepacia complex infection, ABPA, previous massive haemoptysis, and a forced expiratory volume in 1 s (FEV1) of 15 mm for females and 16 mm for males), or pruning of the peripheral arteries.28 At thoracic CT, the signs most likely to indicate pulmonary hypertension are enlargement of the pulmonary artery by >31.5 mm or a mean pulmonary artery diameter/ascending aorta diameter (mPAD/AAD) ratio >1 (Fig 10).31e33 Other signs suggesting pulmonary hypertension are right midventricular diameter larger than the left, bowing or straightening of the interventricular septum, right ventricular wall thickness greater than 4 mm, reflux of contrast medium into the inferior vena cava (IVC) and/or hepatic veins, and a 1. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

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Figure 11 Bronchial artery embolization for massive haemoptysis in CF. Image on the left is the pre-embolization image, which shows abnormal, dilated vessels. These were embolized with gelfoam and the image on the right shows the post-embolization result with a reduction in flow through the abnormal vessels. The patient experienced complete resolution of the haemoptysis.

Figure 12 Venous stenosis due to a TIVAD. (a) A SVC venogram demonstrating mid-SVC occlusion. (b) A wire is passed through the occlusion and the tip of the TIVAD has been snared into the right brachiocephalic vein in order that the stent can be deployed. (c) The stent is deployed across the SVC with its superior edge below the confluence of the brachiocephalic veins. There is a significant waist to the SVC stent, which is subsequently dilated with a 15 mm balloon. (d) The stent with no significant waist and the tip of the TIVAD is now back in the SVC having been snared and re-sited to its original position. A repeat venogram shows successful opening of the occlusion.

through the obstructed line is frequently effective in this situation. TIVAD-associated venous stenosis, as shown in Fig 12, may present with overt superior vena cava (SVC) obstruction and can be confirmed with venography. Venous stenosis may be treated with removal of the device, angioplasty, or stent placement. The role of anticoagulation to prevent re-stenosis is unclear.

Role of CT and chest radiography Chest CT allows earlier detection of lung disease compared to chest radiography and in a CF patient showing signs of deteriorating lung function, chest radiography findings not infrequently show poor correlation with the clinical picture.39 However, the debate about how often and when to use CT remains unresolved.40 Several papers have recommended increasing the frequency of chest CT as there have been several small studies showing an improvement in quality of life and a reduction in respiratory tract

exacerbation rates as a result of increased CT examinations.40,41 This has gone as far as yearly CT examinations in some institutions, despite the known radiation risks especially in this of group of patients.41 To minimize radiation exposure, low-dose CT techniques have been advocated, and in one report investigating chest CT to monitor CF patients, average radiation doses of 0.35 mSv and 0.69 mSv for expiratory and inspiratory imaging, respectively, was achieved.42 A radiation risk model put the estimated risk of radiation-induced cancer for an annual CT examination starting when the patient is 2 years old at 0.08% for males and 0.46% for females assuming median survival increases to 50 years of age.43 Alternative recommendations include magnetic resonance imaging (MRI) of the chest or lung clearance index (LCI). The LCI has been shown to be overcome the limitations of spirometry in detecting early disease and is comparable to CT.40,41 In our institution (University Hospital of South Manchester), CT is normally reserved for difficult cases, such as lung transplant

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assessment, atypical infection, co-existing Aspergillus disease, and late presentation of CF.

Conclusion The pulmonary complications of CF are highly variable and present a considerable challenge to both the radiologist and the respiratory physician. The prevalence of these complications is likely to increase as the life expectancy of patients with CF continues to rise. It is vital for radiologists who deal with CF patients to have a thorough knowledge of the spectrum of pulmonary disease seen in this population with the aim of allowing the early recognition and treatment of the complications of CF. The radiologist has a key role to play in maintaining lung health in CF so that patients may gain maximum benefit from future disease-modifying therapies.

Acknowledgement The authors would like to thank Dr Steve Butterfield for assistance with vascular imaging and advice on the manuscript.

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Pulmonary complications of cystic fibrosis.

The life expectancy of patients with cystic fibrosis (CF) has steadily increased over recent decades with a corresponding increase in the frequency of...
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