This article appears in the following Rheumatology issue: Update in systemic sclerosis [View the issue table of contents]
High-resolution computed tomography and scleroderma lung disease
1Interstitial Lung Disease Unit, Royal Brompton Hospital, London, UK.
Correspondence to: A. U. Wells, Interstitial Lung Disease Unit, Royal Brompton Hospital, Emmanuel Kaye Building, Manresa Rd, Chelsea, London SW3 6LR, UK. E-mail: A.Wells{at}rbht.nhs.uk
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Abstract |
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 Top Abstract IntroductionThe identification of...The detection of reversible...The staging of disease...The detection of change...AcknowledgementsReferences |
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High-resolution CT has now become an important part of the routine detection and evaluation of interstitial lung disease in SSc. CT now has a central role in the detection of interstitial disease, largely because other modalities have been unsatisfactory in this regard. Historically, CT has also been used to identify a high likelihood of reversible inflammatory disease in SSc, based upon studies in other diffuse lung diseases. However, accumulated evidence indicates that ground-glass attenuation on CT is not a reliable indicator of underlying alveolitis. Ground-glass attenuation on CT is common in SSc but reversible disease is found at surgical biopsy in a minority of cases, and is rare when ground glass is associated with reticular abnormalities or traction bronchiectasis. Furthermore, ground glass regresses inconsistently on serial CT evaluation, with or without treatment. CT is more useful in the staging of disease extent. Although formal CT scoring is not realistic in routine practice, rapid semi-quantitative estimation of disease extent on CT in combination with a forced vital capacity threshold has been used to stage disease as limited or extensive. The distinction between a higher and lower risk of progression of lung disease, made using this system, has important implications for both routine practice and the enrolment of higher risk patients in therapeutic studies.
KEY WORDS: High-resolution computed tomography, Scleroderma, Pulmonary fibrosis, Outcome, Mortality, Ground glass
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Introduction |
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The advent of high-resolution CT has transformed the routine detection and management of interstitial lung disease in SSc. In this article, the use of CT to detect lung disease, identify reversible disease, stage disease and identify changes in disease extent at follow-up evaluation are reviewed.
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The identification of interstitial lung disease |
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Prior to CT, the identification of lung disease was often difficult. Exertional dyspnoea is highly non-specific, as it may represent interstitial disease, pulmonary vascular disease, other cardiac limitation or, merely, the increased work of locomotion of musculoskeletal involvement or general debility. Chest radiography was found to be highly insensitive in the detection of lung involvement, when compared with CT [1], and also very imprecise in the evaluation of the extent of interstitial disease. Pulmonary function tests are seriously limited by the wide range (80–120%) of normal values, calculated from the age, gender and height of the patient. Thus, in an individual patient, a forced vital capacity (FVC) of 80% of predicted value may not have changed from pre-morbid levels but may, equally, represent a fall of up to 40%. Bronchoalveolar lavage (BAL) is not suitable for use as a routine screening test but, in any case, a BAL neutrophilia is more often present in SSc when disease on CT is more extensive [2]. In any case, the significance of BAL abnormalities not associated with clinically significant lung disease is wholly uncertain. Thus, symptoms, chest radiography, pulmonary function tests and BAL findings may be striking in severe lung disease but are sometimes unsatisfactory when lung disease is less advanced.
It should be stressed that the use of CT in the detection of interstitial lung disease is not based on definitive validation, but reflects widespread clinician recognition of the inadequacy of other modalities. Simply put, CT has been widely found, over two decades, to be clinically useful in this regard, and has assumed a central role by default, exactly as it has in other interstitial lung diseases. There is currently no consensus on whether CT should be used routinely as a screening test, or whether it should instead be performed when there are unexplained symptoms, equivocal chest radiographic abnormalities or marginal reductions in pulmonary function indices. There are recent data to support a strategy of routine CT in all SSc patients. In a study of 90 SSc patients, 40 had no disease on CT and in these cases, 85% has no disease at repeat CT at an average time interval of 5 yrs [3]. Interstitial lung disease is now a major source of mortality in SSc and, thus, the routine use of a test can be justified if it establishes a low intermediate term probability of this complication and allows less frequent pulmonary function monitoring. However, a recommendation that routine baseline thoracic CT should be performed in SSc has yet to be made by expert groups.
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The detection of reversible disease |
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In idiopathic disease, extensive ground-glass attenuation on CT identifies a higher likelihood of reversible inflammatory cell infiltration and, thus, a greater probability of significant responsiveness to therapy. However, ground-glass on CT is also a recognized feature of fine intra-lobular fibrosis. This apparent paradox reflects the resolution limitations of CT. Anatomical structures are disclosed by variations in density, measured in spatial units (‘voxels’). When intra-lobular fibrosis is finer than the width of individual voxels, it manifests, not as a reticular abnormality, but as a diffuse increase in average density, indistinguishable from inflammatory ground glass. The likelihood of irreversible disease increases when there is an admixed reticular pattern, as first described in a study of lung disease in SSc [4], and when there is traction bronchiectasis [5]. However, even in the absence of these two ancillary signs, prominent ground-glass attenuation cannot be confidently equated with inflammatory disease. In SSc, fibrotic non-specific interstitial pneumonia (NSIP) was the underlying histological pattern in most patients with overt lung involvement in the largest histological series, with reversible cellular NSIP present in only 20% of the cases [6]. In contrast, in an high resolution computed tomography (HRCT) series of 216 patients, ground glass made up
50% of the observed abnormalities and was generally prominent, even when reticular change was more extensive [7]. Thus, in SSc, ground glass may represent fine fibrosis in many cases, in keeping with the observation in several series that it is also prominent on HRCT in idiopathic fibrotic NSIP. For this reason, the widespread use of the phrase ‘an alveolitis on CT’, denoting likely reversibility, is seriously problematic. The limitations of CT in this regard have been underlined by longitudinal studies of CT change with and without treatment. When there are associated reticular abnormalities, present in most SSc cases, regression of disease is seen in only a minority of patients in the shorter term [8] and in the longer term, ground glass usually progresses to overt fibrotic change [3]. Recently, in a serial study of 41 SSc patients, ground glass (seen in two-thirds of the cases) was found to regress in only 5% in the next 2 yrs and was often resistant to treatment [9].
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The staging of disease extent |
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Although CT is highly sensitive in SSc and is able to detect interstitial abnormalities in up to 60% of the patients, disease is often limited in extent, involving 10% of the lung parenchyma or less in almost half of the cases in a large recent series [10]. In some respects, the high sensitivity of CT creates its own difficulties. Although it may be useful to identify limited interstitial involvement, with a view to close monitoring, the immediate clinical significance of trivial lung disease in SSc is often uncertain. It is unrealistic to expect CT radiologists to make definitive statements that trivial disease is not clinically significant and does not require to be monitored. In individual patients, there may be more extensive histological abnormalities than are visible on CT, and thus the clinical significance of trivial disease should be further appraised using pulmonary function tests. However, even if all interstitial disease is regarded as potentially clinically significant, CT can play a useful prognostic role in distinguishing between limited and extensive abnormalities.
Clinicians need to distinguish between patients at higher and lower risk of disease progression, with a view to earlier treatment. In treatment trials, it is important to enrol patients at higher risk in order to ensure that studies are adequately powered. It is widely recognized that baseline disease severity is an important determinant of the likelihood of progression but, until recently, there has been no means of separating patients into discrete high- and low-risk groups. In a recent study of 216 SSc patients, the risk of death and, separately, progression of disease (as judged by disease-free survival) rose strikingly when the overall percentage of lung involved on CT exceeded 20% [10]. This threshold value was defined using formal CT scoring, which is seldom practicable in routine practice. However, the authors proposed a simple and reproducible staging system (Fig. 1), in which rapid semi-quantitative CT evaluation was integrated with FVC levels. Essentially, patients were staged as having mild or extensive disease when the extent of disease on CT was clearly <20% or >20%, respectively. When this distinction could not be made easily on CT, an FVC threshold of 70% was substituted for CT scoring. The proposed limited/extensive staging system was more accurate, prognostically, than either CT or FVC in isolation. Total disease extent on CT was as accurate, prognostically, as the extent of overt fibrotic change. More extensive fibrosis on CT was found, in the US oral cyclophosphamide study, to identify patients who benefited from treatment [11] but, it can be argued, may be less amenable than total disease extent to rapid semi-quantitative evaluation. It is likely that the mild/extensive staging system will require further refinement in follow-up studies, but it is clear that CT evaluation is likely to play a major future role in separating SSc patients into those at higher and lower risk of progression of lung disease.
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The detection of change in disease at follow-up |
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Although serial CT is widely performed during follow-up in established interstitial lung disease, this use of CT has been remarkably under-studied in SSc, to the extent that it is not possible to cite an authoritative study of serial CT in this review. In part, this reflects the difficulty of achieving exact anatomical comparability between initial and follow-up CT evaluation, due to the interspaced nature of high-resolution CT evaluation. Volume acquisition techniques overcome this problem but at the cost of a major increase in the radiation burden. In contrast, when anatomical comparability is achieved, it is sometimes difficult to ascertain the clinical significance of minor CT change, confined to limited lung regions. The recent serial study of Launay et al. [3] was limited by the fact that change was defined by an increase in disease extent from <50% to >50% of the involvement of the lungs. This system fails to identify major change in many cases, in which the arbitrary threshold of 50% is not crossed.
Based upon anecdotal experience, repetition of CT is probably most useful when there are serial reductions in gas transfer levels, but serial FVC levels are stable or exhibit marginal reduction. CT may confirm progression of interstitial disease and when it does not, the clinician receives a useful prompt to re-evaluate pulmonary vascular involvement.
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Supplement: This paper forms part of the supplement entitled ‘Update in systemic sclerosis’. This supplement was supported by an unrestricted grant from Encysive.
Disclosure statement: The author has declared no conflicts of interest.
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