Role of high-resolution computed tomography in the detection of early cystic fibrosis lung disease

doi:10.1016/j.prrv.2008.05.009

Paediatric Respiratory Reviews

Volume 9, Issue 3, September 2008, Pages 168-175

https://doi.org/10.1016/j.prrv.2008.05.009 Get rights and content

Summary

High-resolution computed tomography (HRCT) has been demonstrated to be sensitive at detecting early lung disease in cystic fibrosis (CF), often before it is apparent clinically. There is emerging evidence that structural changes in the lung occur earlier in life than previously appreciated. Despite this, the role of HRCT in young children with CF has yet to be defined, principally because the repeated exposure of children to X-ray doses several multiples that of a standard chest X-ray raises the concern of the long-term risks of ionizing radiation. With the challenges of acquiring HRCT images in young children in mind, we review scanning protocols and settings specific to young children, and review the best available evidence that describes early structural lung disease in young children with CF. The role of CT scoring and quantitative measures of CF lung disease are reviewed. The challenge for the future is to develop techniques that provide clinically useful information at the lowest possible radiation risk.

Introduction

High-resolution computed tomography (HRCT) has become an indispensable tool for imaging the airways and lung parenchyma.¹ The cross-sectional perspective and high spatial resolution result in high quality images approaching gross histological detail. HRCT has the ability to delineate clearly the structural components of cystic fibrosis (CF) lung disease.2, 3 It has been demonstrated to be sensitive at detecting early disease, as well as detecting the extent and severity of more advanced disease, often before it is appreciated clinically.³ Despite this, the role of CT in young children with CF has yet to be defined.² CT may have its greatest utility in the component of the CF population in whom it is most difficult to perform, i.e. infants and young children.2, 3 Asymptomatic infants with CF have evidence of significant airway inflammation and infection,⁴ as well as diminished lung function.⁵ Emerging evidence suggests that structural changes occur earlier in life than previously appreciated.6, 7

Difficulties inherent in performing HRCT in young children include: their disinclination to lie still, a rapid respiratory rate, the inability to perform breath-holding manoeuvres and the structures of interest being small.⁸ These characteristics offer significant challenges to the standardization of scanning protocols, image acquisition and data analysis. The repeated exposure of young children to ionizing radiation raises the concern of long-term risks.⁹ Currently, there is no consensus regarding when HRCT scans are indicated in infants and preschool-aged children with CF, nor guidelines regarding scan acquisition. As such there is no standardized approach to important variables, including the lung volumes at which to scan, sedation guidelines, scanner settings or image analysis.

Section snippets

Early cystic fibrosis lung disease detected by HRCT

In established CF lung disease the most significant structural finding on HRCT is bronchiectasis. However, currently we have an incomplete understanding of which features of early structural lung disease predict the development of bronchiectasis, or how, and at what rate, this occurs. Indeed, some early radiological features may be reversible and amenable to treatment.

There are a limited number of studies describing the structural features of early CF lung disease in the infant and preschool

Scanner settings

HRCT is considered the gold standard technique to diagnose bronchiectasis.¹³ However, diagnostic ability may be affected by image quality. Image quality depends on several factors: thin beam collimation (slice thickness) typically 0.5–1.0 mm,14, 15 a high spatial frequency or edge enhancing reconstruction algorithm;¹⁶ the largest available matrix size, which is typically 512 × 512;¹ and a small field of view.1, 17 The optimal settings to delineate the airways is a window level of −450 and a window

HRCT Scoring

The ability of HRCT to demonstrate the structural features of CF lung disease with much greater detail and clarity than conventional chest X-ray has resulted in the development of an array of CT scoring systems.32, 33, 34, 35 The first CT score developed specifically for CF was that by Bhalla et al. in 1991 and it has formed the foundation for most subsequent scores.³² In 2004, Brody et al. published a substantial re-working of the Bhalla score, which focused on younger patients (6–10 years

Quantitative measures of CF lung disease

Quantitative measures of HRCT findings may be particularly relevant to the detection of early lung disease, as the features most amenable to quantitative scores are gas trapping and bronchial dimension measurements. Regions of gas trapping are best appreciated as low attenuation areas on expiratory scans which can be measured directly by recording the Hounsfield unit of each voxel on the image.19, 25 Areas below a threshold level, considered to be indicative of gas trapping, can then be

Radiation issues

Radiation exposure is measured in terms of the quantity of radiation energy ‘absorbed’ by body tissue. It is measured in joules per kilogram (J/kg) and is expressed in Sievert (Sv).³⁸ A radiation dose >1 Sv can result in massive cell death and organ failure.³⁹ Such large radiation doses are rarely encountered in medical radiation hence the mSv is more commonly used. The effect on the body of low dose radiation (<50 mSv) principally relates to damage to the genome, with a resultant increased

Conclusion

The role of CT in the CF population continues to be debated. It is important to distinguish between its roles as a research tool and as a clinical investigation. As a research tool CT is expanding our understanding of the early morphological changes that occur in the CF lung. It is providing new insights into the evolution and pathogenesis of airway and parenchymal changes. It may prove an invaluable tool to assess the efficacy of much needed interventions in treating early CF lung disease, and

Practice points

•
HRCT is a sensitive tool capable of detecting structural changes associated with early CF lung disease.
•
The acquisition of HRCT images in infants and young children requires some form of sedation or anaesthetic, along with augmented ventilation.
•
There is currently a lack of consensus regarding the role of HRCT in the routine clinical care of patients with CF.
•
Lifetime risk of fatal cancer secondary to repeated exposures to relatively low radiation doses is largely unknown but current evidence

Research directions

•
Development of scoring systems for early CF lung disease which incorporate quantitative measures of lung and airway morphology.
•
Development of low radiation CT scanning protocols.
•
Description of the evolution of structural changes from early (possibly reversible) CF lung disease to established disease.
•
Incorporation of CT findings into clinical trials as a surrogate outcome.
•
Correlation of structural changes detected by HRCT with measures of lung function, markers of airway inflammation and

CME Section

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Acknowledgements

B. Linnane is the recipient of a Medical Postgraduate Scholarship from the National Health and Medical Research Council, Australia. The authors are supported by a grant from the United States Cystic Fibrosis Fund.

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Citation Excerpt :
This silent period provides a window of opportunity where therapeutic interventions may be most effective [18,19]. Thus, a recent focus has been on the early detection [18,20–24] and treatment [25,26] of pre-symptomatic CF patients. However, these efforts are challenged by the fact that there is an incomplete understanding of the underlying pathobiology of lung function in early CF. As clinical strategies shift from treatment of symptoms to prevention of progressive lung disease, animal models are needed which manifest the pulmonary pathology characteristic of the early CF phenotype.
Altered pulmonary function is present early in the course of cystic fibrosis (CF), independent of documented infections or onset of pulmonary symptoms. New initiatives in clinical care are focusing on detection and characterization of preclinical disease. Thus, animal models are needed which recapitulate the pulmonary phenotype characteristic of early stage CF.
We investigated young CF mice to determine if they exhibit pulmonary pathophysiology consistent with the early CF lung phenotype. Lung histology and pulmonary mechanics were examined in 12- to 16-week-old congenic C57bl/6 F508del and R117H CF mice using a forced oscillation technique (flexiVent).
There were no significant differences in the resistance of the large airways. However, in both CF mouse models, prominent differences in the mechanical properties of the peripheral lung compartment were identified including decreased static lung compliance, increased elastance and increased tissue damping. CF mice also had distal airspace enlargement with significantly increased mean linear intercept distances.
An impaired ability to stretch and expand the peripheral lung compartment, as well as increased distances between gas exchange surfaces, were present in young CF mice carrying two independent Cftr mutations. This altered pulmonary histopathophysiology in the peripheral lung compartment, which develops in the absence of infection, is similar to the early lung phenotype of CF patients.
The evolution of cystic fibrosis care
2015, Chest
Citation Excerpt :
Although it is unusual for neonates to have respiratory symptoms, older infants can develop tachypnea, wheezing, and cough that is frequently associated with respiratory viral infections. Studies of infants and preschool children with CF have found abnormal pulmonary function, structural changes, and increased inflammatory markers in BAL fluid occurring as early as 6 months of age.30–32 Moreover, there is significant disease heterogeneity within the lungs of a single patient, particularly in the early stages of disease.
Cystic fibrosis (CF) is the most common life-limiting inherited illness of whites. Most of the morbidity and mortality in CF stems from impaired mucociliary clearance leading to chronic, progressive airways obstruction and damage. Significant progress has been made in the care of patients with CF, with advances focused on improving mucociliary clearance, minimizing inflammatory damage, and managing infections; these advances include new antimicrobial therapies, mucolytic and osmotic agents, and antiinflammatory treatments. More recently, researchers have targeted disease-causing mutations using therapies to promote gene transcription and improve channel function, which has led to impressive physiologic changes in some patients. As we develop more advanced, allele-directed therapies for the management of CF, it will become increasingly important to understand the specific genetic and environmental interactions that cause the significant heterogeneity of lung disease seen in the CF population. This understanding of CF endotypes will allow for more targeted, personalized therapies for future patients. This article reviews the genetic and molecular basis of CF lung disease, the treatments currently available, and novel therapies that are in development.
Spanish Consensus on the Prevention and Treatment of Pseudomonas aeruginosa Bronchial Infections in Cystic Fibrosis Patients
2015, Archivos de Bronconeumologia
Pseudomonas aeruginosa es el patógeno más importante en la infección broncopulmonar en fibrosis quística (FQ). Solo se erradica en la infección inicial, mientras que la reducción de su carga bacteriana es el objetivo terapéutico en la infección crónica y exacerbaciones. El cribado neonatal y la farmacocinética/farmacodinámica han cambiado el manejo del paciente con FQ. Se debe realizar un seguimiento microbiológico en los pacientes sin infección por P. aeruginosa. En la infección inicial se recomienda tratamiento inhalado (28 días) con colistina (0,5-2 MU/8 h), tobramicina (300 mg/12 h) o aztreonam (75 mg/8 h) con o sin ciprofloxacino oral (15-20 mg/kg/12 h, 2-3 semanas). En la infección crónica se recomienda solo vía inhalada en tratamiento continuo con colistina, o en ciclos on-off de 28 días con tobramicina o aztreonam. Durante las exacerbaciones leves-moderadas se recomienda tratamiento oral (ciprofloxacino, 2-3 semanas) y en las graves tratamiento intravenoso (β-lactámico asociado a un aminoglicósido o una fluoroquinolona). Estudios futuros sustentarán la rotación y nuevas combinaciones de antimicrobianos. Se deben establecer también medidas epidemiológicas que eviten nuevas infecciones y la transmisión cruzada de P. aeruginosa.
Pseudomonas aeruginosa is the main pathogen in bronchopulmonary infections in cystic fibrosis (CF) patients. It can only be eradicated at early infection stages while reduction of its bacterial load is the therapeutic goal during chronic infection or exacerbations. Neonatal screening and pharmacokinetic/pharmacodynamic knowledge has modified the management of CF-patients. A culture based microbiological follow-up should be performed in patients with no infection with P. aeruginosa. At initial infection, inhaled colistin (0,5-2 MU/tid), tobramycin (300 mg/bid) or aztreonam (75 mg/tid) with or without oral ciprofloxacin (15-20 mg/kg/bid, 2-3 weeks) are recommended. In chronic infections, treatment is based on continuous administration of colistin or with a 28-day on-off regimen with tobramycin or aztreonam. During mild-moderate exacerbations oral ciprofloxacin (2-3 weeks) can be administered while serious exacerbations must be treated with intravenous combination therapy (beta-lactam with an aminoglycoside or a fluoroquinolone). Future studies will support antibiotic rotation and/or new combination therapies. Epidemiological measures are also recommended to avoid new P. aeruginosa infections and “patient-to-patient transmission” of this pathogen.
Tracking Lung Clearance Index and chest CT in mild cystic fibrosis lung disease over a period of three years
2014, Respiratory Medicine
Citation Excerpt :
Thus, computed chest tomography (CT) is the reference method for detecting early and advanced bronchiectasis [6]. CT of the lungs has received increasing attention in recent years particularly for assessing early stages of CF lung disease that are not detectable by conventional spirometry [7–9]. However, there remains concern regarding repeated radiation exposure from routine CT, particularly with respect to the increasing life expectancy of patients with CF [10,11].
Lung disease remains the main cause of morbidity and mortality in patients with Cystic Fibrosis (CF). To detect lung disease before clinical symptoms become apparent, sensitive tools are essential. Spirometry is used for monitoring, but the FEV₁ remains frequently normal throughout childhood. The Lung Clearance Index (LCI) calculated from Multiple Breath Washout (MBW) was introduced at the CF centre Innsbruck in 2007 for assessing ventilation inhomogeneity in patients with mild lung disease.
We hypothesized that LCIs in 2007 are of prognostic value for the presence or absence of structural lung changes in later years.
Between 2007 and 2010 MBW, spirometry and ultra-low-dose HR-CT were prospectively tracked in 36 patients (6–53 years) with a mean FEV₁ ≥80% predicted in 2007.
At study start the majority of patients had abnormal CT scores and LCI results. While CT and spirometry remained largely stable throughout the study, LCI results slightly improved but still correlated with CT scores in 2010. LCI results in 2007 correlated with CT scores in 2010 while FEV₁ did not. In 86% the LCI value in 2007 was indicative for the presence or absence of structural lung changes in 2010.
The LCI is a sensitive tool for detecting and tracking pulmonary changes. Extended structural changes are unlikely if the LCI is normal. The LCI has the potential to be used for monitoring the progression of early CF lung disease and assessing the effect of treatment in both clinical care and research settings.
Differences in the pattern of structural abnormalities on CT scan in patients with cystic fibrosis and pancreatic sufficiency or insufficiency
2013, Chest
Cystic fibrosis (CF) genotypes characterized by pancreatic sufficiency (PS) are generally associated with milder disease vs genotypes characterized by pancreatic insufficiency (PI); however, the correlation between pancreatic status and type and severity of structural lung changes has not been studied. We aimed to evaluate differences in the severity and distribution of pulmonary manifestations of CF in patients with PS vs PI.
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In patients with CF-PI, structural lung changes are more severe with upper lobe predominance, prominent bronchiectasis, and bronchial wall thickening vs lower severity and more general distribution of changes in those with CF-PS.
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CME ArticleRole of high-resolution computed tomography in the detection of early cystic fibrosis lung disease

Summary

Introduction

Section snippets

Early cystic fibrosis lung disease detected by HRCT

Scanner settings

HRCT Scoring

Quantitative measures of CF lung disease

Radiation issues

Conclusion

Practice points

Research directions

CME Section

Acknowledgements

Lancet

J Pediatr

Chest

J Pediatr

CT Techniques and Anatomy. High-resolution Computed Tomography of the Lungs

Recent advances in imaging

Infant and preschool children: imaging the lungs

Lower respiratory infection and inflammation in infants with newly diagnosed cystic fibrosis

BMJ

High-resolution computed tomography imaging of airway disease in infants with cystic fibrosis

Am J Respir Crit Care Med

Techniques

Estimated risks of radiation-induced fatal cancer from pediatric CT

AJR Am J Roentgenol

Computed tomography reflects lower airway inflammation and tracks changes in early cystic fibrosis

Am J Respir Crit Care Med

Comparison of quiet breathing and controlled ventilation in the high-resolution CT assessment of airway disease in infants with cystic fibrosis

Pediatr Radiol

Endpoints for clinical trials in young children with cystic fibrosis

Proc Am Thorac Soc

Bronchiectasis: assessment by thin-section CT

Radiology

Bronchiectasis: comparison of preoperative thin-section CT and pathologic findings in resected specimens

Radiology

Measurement of the internal size of bronchi using high resolution computed tomography (HRCT)

Eur Respir J

High-resolution computed tomography of the lung in children with cystic fibrosis: technical factors

Proc Am Thorac Soc

Paediatric and adult computed tomography practice and patient dose in Australia

Australas Radiol

Quantitative air-trapping analysis in children with mild cystic fibrosis lung disease

Pediatr Pulmonol

Anesthesia-related cardiac arrest in children: update from the Pediatric Perioperative Cardiac Arrest Registry

Anesth Analg

Lungs in infants and young children: improved thin-section CT with a noninvasive controlled-ventilation technique – initial experience

Radiology

Technique and clinical applications of full-inflation and end-exhalation controlled-ventilation chest CT in infants and young children

Pediatr Radiol

Pentobarbital vs chloral hydrate for sedation of children undergoing MRI: efficacy and recovery characteristics

Paediatr Anaesth

CME Article
Role of high-resolution computed tomography in the detection of early cystic fibrosis lung disease