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doi:10.1378/chest.06-1401
(Chest. 2007; 131:672-681)
© 2007 American College of Chest Physicians
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Lung CT Densitometry in Systemic Sclerosis*

Correlation With Lung Function, Exercise Testing, and Quality of Life

Gianna Camiciottoli, MD; Ilaria Orlandi, MD; Maurizio Bartolucci, MD; Eleonora Meoni, MD; Francesca Nacci, MD; Stefano Diciotti, PhD; Chiara Barcaroli, MD; Maria Letizia Conforti, MD; Massimo Pistolesi, MD; Marco Matucci-Cerinic, MD and Mario Mascalchi, MD, PhD

* From the Respiratory Medicine Unit, Department of Critical Care (Drs. Camiciottoli, Meoni, and Pistolesi); Radiodiagnostic Section, Department of Clinical Physiopathology (Drs. Orlandi, Bartolucci, Barcaroli, and Mascalchi); Rheumatology Unit, Department of Internal Medicine (Drs. Conforti and Matucci-Cerinic); and Department of Electronics and Telecommunications (Dr. Diciotti), University of Florence, Florence, Italy.

Correspondence to: Gianna Camiciottoli, MD, Respiratory Medicine Unit, Department of Critical Care, Università degli Studi di Firenze, Viale Morgagni 85, Firenze, Italy; e-mail: g.camiciottoli{at}dac.unifi.it

Abstract

Background: To ascertain if analysis of lung density histograms in thin-section CT was more reproducible than visual assessment of lung changes in systemic sclerosis (SSc), and if such density histogram parameters as mean lung attenuation (MLA), skewness, and kurtosis could more closely reflect pulmonary function as well as exercise and quality of life impairment.

Methods: The intraoperator and interoperator reproducibility of visual and densitometric lung CT analysis in 48 SSc patients examined with CT were evaluated by means of weighted {kappa} statistics. Univariate and multivariate regression analyses were applied to evaluate the relationship of visual and densitometric CT measurements with functional parameters including functional residual capacity (FRC), FVC, FEV1, diffusion capacity of the lung for carbon monoxide (DLCO), 6-min walking testing (6MWT), and health-related quality of life questionnaire (QLQ) parameters.

Results: The intraoperator and interoperator reproducibility of MLA (intraobserver weighted {kappa} = 0.97; interobserver weighted {kappa} = 0.96), skewness (intraobserver weighted {kappa} = 0.89; interobserver weighted {kappa} = 0.88), and kurtosis (intraobserver weighted {kappa} = 0.89; interobserver weighted {kappa} = 0.88) were higher than those of visual assessment (intraobserver weighted {kappa} = 0.71; interobserver weighted {kappa} = 0.69). In univariate analysis, only densitometric measurements were correlated with some exercise and QLQ parameters. In multivariate analysis, MLA (square regression coefficient corrected [R2c] = 0.70), skewness (R2c = 0.78), and kurtosis (R2c = 0.77) were predicted by FRC, FVC, DLCO, 6MWT, and QLQ parameters, while visual assessment was associated only with FRC and FVC (R2c = 0.40).

Conclusions: In SSc, densitometric analysis is more reproducible than visual assessment of lung changes in thin-section CT and more closely correlated to pulmonary function testing, 6MWT, and QLQ. Density histogram parameters may be useful for cross-sectional and longitudinal studies of lung involvement in SSc.

Key Words: CT • densitometry • histogram analysis • pulmonary function tests • systemic sclerosis

Lung involvement is found at autopsy in 70 to 100% of patients with systemic sclerosis (SSc) and represents the first cause of death for this disease.123 Two types of lung involvement in SSc are observed: fibrosing interstitial pneumonia, with the histologic feature of nonspecific interstitial pneumonia or less frequently usual interstitial pneumonia456; and pulmonary arterial hypertension (PAH) due to obliterative pulmonary arteriopathy and/or to advanced lung fibrosis.789 Fibrosing interstitial pneumonia is characteristic of diffuse SSc, whereas PAH is typically observed in limited SSc.10

Early detection of lung changes in SSc may help to establish need of treatment5 and to monitor disease progression. For such purposes, high-resolution CT (HRCT) of the lung has a relevant role along with pulmonary function testing (PFT), BAL, Doppler echocardiography (DE), and right-heart catheterization.8911 In particular, CT can substitute thoracoscopic biopsy for demonstration of severity and extent of fibrosing interstitial pneumonia.412 In fact, CT has the advantage of evaluating panoramically both lungs, whereas thoracoscopic biopsies are usually performed on peripheral parenchyma and tend to reflect the most advanced stages of subpleural fibrosing interstitial pneumonia.13

Visual scales of varying complexity have been developed to assess the pattern and extent of lung changes in SSc.111314 Moreover, lung CT densitometric parameter such as mean lung attenuation (MLA), skewness, and kurtosis, which have been recently used in idiopathic pulmonary fibrosis (IPF), could provide quantitative and objective assessment of lung disease also in SSc.

Exercise capacity and quality of life are important parameters in the evaluation and monitoring of SSc. Six-minute walking testing (6MWT) has been validated in interstitial lung disease15 as a reproducible and useful tool to stage the disease and its progression. Health-related quality of life questionnaires (QLQs) can be used to quantify functional impairment in daily activities, dyspnea perception, and decreased lung function.16

To ascertain whether analysis of lung density histograms in thin-section CT could be more reproducible than visual scoring of lung changes in SSc, and whether MLA, skewness, and kurtosis could more closely reflect pulmonary function as well as exercise and quality of life impairment, we compared visual and densitometric assessment of lung CT in patients with SSc and correlated CT findings with PFT, 6MWT, and QLQ parameters.

Materials and Methods

Selection of Patients
We enrolled 48 consecutive SSc patients from May 2004 to December 2004 (42 women; mean age, 57 ± 13 years [± SD]; range, 18 to 80 years; disease duration, 146 ± 119 months; range, 1 to 524 months). Thirty-three patients were classified as having limited SSc (mean age, 60 ± 12 years; range, 29 to 80 years; disease duration, 166 ± 131 months; range, 1 to 524 months), and 15 patients were classified as having diffuse SSc (mean age, 51 ± 14 years; range, 18 to 66 years; disease duration, 104 ± 78 months; range, 32 to 308 months).10 All patients underwent clinical and laboratory evaluations as recommended by international guidelines.17 Ten patients (7 patients with limited disease, and 3 patients with diffuse disease) had suspected mild PAH based on the results of DE.9181920 The ethical committee approved the study, and written informed consent was obtained from all patients. On the same day, each patient answered QLQs, performed 6MWT, and underwent PFT and chest CT.

QLQ
The Systemic Sclerosis Health Assessment Questionnaire (SHAQ) and the baseline dyspnea index (BDI)2122 were administered before any instrumental evaluation. The SHAQ is a 20-item questionnaire related to daily activities of the last week, grouped in eight domains: dressing, arising, eating, walking, hygiene, reach, grip, and activities. For each item, the response is scored as 0 (without any difficulty), 1 (with some difficulty), 2 (with much difficulty), or 3 (unable to do). For each domain, the highest score is recorded; the average of the eight domain scores is the disability index (range, 0 to 3). The SHAQ includes six visual analog scales (VASs), standardized in length, marked with 0 (no limitation) at the left side and with 100 (maximum limitation) at the right side. The VAS investigated six domains: pain (pain scale), GI function (gastric scale), breathing problems (lung scale), Raynaud (Raynaud scale), finger ulcers (ulcer scale), and severity of disease (disease scale). For each scale, the distance (in millimeters) between 0 and the patient’s mark has been measured.

The BDI is devised such as grading breathlessness and includes five grades of impairment: 0 (very severe), 1 (severe), 2 (moderate), 3 (slight), and 4 (no impairment) for three different activities: functional impairment, magnitude of task, and magnitude of effort. The scores are summed to obtain a focal score (range, 0 to 12).

6MWT
6MWT was performed according to the American Thoracic Society statement.23 Pulse oxygen saturation (SpO2) was measured by means of a forehead probe connected to an oximeter (Nellcor N-595; Puritan Bennett; Pleasanton CA). Dyspnea was evaluated by means of Borg scale23 that rates dyspnea perception and overall fatigue of breathing from 0 (nothing at all) to 10 (very severe) at the beginning and at the end of 6MWT.

PFT
Static (functional residual capacity [FRC]) and dynamic (FEV1 and FVC) lung volumes were measured using a constant-volume body plethysmograph (V6200 Autobox DL; SensorMedics; Yorba Linda, CA) equipped with a spirometer (Vmax 22; SensorMedics) and with a multigas analyzer for single-breath diffusion capacity of the lung for carbon monoxide (DLCO) according to American Thoracic Society standards and expressed as percentage of predicted value.2425

CT Scan
CT examinations were performed on a CT scanner (Somatom Plus 4; Siemens; Erlangen, Germany) with 1-s rotation time. Eight to 12 scans with 1-mm collimation and 20-mm intervals were acquired at end-inspiration, in the sequential mode, with the patients in the supine position, from the apex to the base at standard (189 mA) current and 140 kilovolts of the radiograph tube.

Visual Analysis
Thin-section CT scans of the lungs were independently evaluated by two radiologists (M.B. and M.M.), who were blinded to the results of the other tests, on a remote workstation (Leonardo; Siemens) at fixed window width of 1,500 Hounsfield units (HU) and level (– 500 HU). Visual evaluation14 included a score of severity and a score of extent. The former is based on appreciation of five parenchymal abnormalities assumed to reflect increasing severity of lung involvement: ground-glass appearance (score = 1), irregular pleural margins (score = 2), septal and subpleural lines (score = 3), honeycombing (score = 4), and subpleural cysts (score = 5). The severity score thus ranged from 0 (no abnormality) to 15 (all abnormalities present). The extent score was obtained by counting the number of bronchopulmonary segments in which any of the previous abnormalities are observed: one to three segments involved implied a score of 1; four to nine segments implied a score of 2; more than nine segments implied a score of 3. The extent score thus ranged from 0 (no abnormality in any segment) to 15 (all five abnormalities in more than nine segments). Finally, severity and extent of disease scores were added to obtain a total score (range, 0 to 30).

To assess intraoperator reproducibility, one radiologist (M.B.) repeated the visual assessment in all 48 patients three times, separated by 1 week each. To assess interoperator reproducibility, the third visual reading was compared to that of another radiologist (M.M.). The third visual evaluation of the first radiologist (M.B.) was employed for regression analyses.

Densitometric Analysis
The computerized evaluation of the CT scans was independently performed by two radiologists (I.O. and C.B) who were blinded to the other results. The densitometric evaluation was performed using software26 (Pulmo CT; Siemens) on a remote workstation (Leonardo; Siemens). Manual interaction was generally needed for gross subpleural changes such as honeycombing and subpleural cysts, which the software tended to assimilate to the thoracic wall. Using custom-made software (available on request at diciotti{at}asp.det.unifi.it), MLA, kurtosis, and skewness of the lung density histogram were calculated for the entire data set of each patient.27 MLA represents the average global attenuation value of the lung. Kurtosis describes how sharply peaked a histogram is as compared to the histogram of a normal distribution. Consequently, while a normal distribution has a kurtosis of zero, a more peaked histogram has a positive kurtosis value. Skewness describes the degree of asymmetry of a histogram: a symmetric histogram has a skewness of zero, a long right tail lead to positive skewness, while a negative skewness is due to a long left tail.

To assess intraoperator reproducibility of the densitometric evaluation, one radiologist (I.O.) repeated the measurement three times, separated by 1 week each, in the first 29 patients enrolled in the study. To assess interoperator reproducibility, the measurements of the same radiologist in the 48 patients (including the first reading in the 29 patients) were compared to those of another radiologist (C.B.). The densitometric measurements of the first radiologist were employed for the linear regression analyses.

Statistical Analysis
Data are presented as mean ± SD. Differences for QLQ items, 6MWT data, and functional and radiologic variables between the patients with limited and diffuse disease were calculated using unpaired t tests.

The intraoperator and interoperator agreement was tested by means of weighted {kappa} statistic.28 Univariate linear regression analysis was used to investigate the relationship between CT measurements and all variables derived from QLQ, 6MWT, and PFT for a total of 28 variables. Multivariate regression analysis was also applied to the same data set considering in turn each CT measurement as the dependent variable. Furthermore, both disease severity and disease extent subscores of the visual score were entered separately in the multivariate model as dependent variable. A stepwise method was then applied to obtain the most powerful model with the least number of terms; the results were expressed as multivariate regression coefficient (R) and square regression coefficient corrected (R2c) for the number of variables entered in the analysis. This enables to weigh the predictivity of each multivariate model according to the number of variables entered in the model itself. Significance was set at p < 0.05. Statistical analysis was performed using a statistical package (SPSS/PC WIN 11.5.1; SPSS; Chicago, IL).

Results

This study was conducted according to the Strengthening the Reporting of Observational Studies in Epidemiology statement.29 All patients completed the study. Clinical, functional, and CT data are summarized in Table 1 . Figure 1 shows thin-section CT scans and lung density histograms in a patient with a visual score of 3 and in a patient with a visual score of 24, with decreased skewness and kurtosis and increased MLA in the latter.


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  		Table 1. Clinical Data, QLQs, 6MWT, Functional Parameters, Densitometric Data, and Visual Scores in SSc Patients

 

Figure 1
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  		Figure 1. Thin-section CT (top left, A) and lung density histogram (top right, B) in an SSc patient with a visual score of 3; and thin-section CT (bottom left, C) and lung density histogram (bottom right, D) in an SSc patient with a visual score of 24. The more compromised patient shows higher MLA (dotted line) and lower kurtosis and skewness.

 
Table 2 reports QLQ items, 6MWT, functional data, and CT findings in patients with limited and diffuse disease. Patients with diffuse disease had more severe impairment of BDI focal score, SpO2 at 6 min, visual score, MLA, and FVC. As could be expected, finger ulcers and pain prevailed in patients with limited disease.


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  		Table 2. Comparisons Among SHAQ and BDI Items, 6MWT, Functional Parameters, Densitometric Data, and Visual Score in SSc Patients With Limited Disease (n = 33) and Diffuse Disease (n = 15)*

 
Table 3 reports the results of intraobserver and interoperator agreement for visual and densitometric measurements. MLA, kurtosis, and skewness were consistently more reproducible than the visual score.


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  		Table 3. Intraoperator and Interoperator Agreement for Visual Score and Densitometric Measurements*

 
In univariate linear regression analysis considering in turn visual score and densitometric parameters as dependent variables, a significant relationship was found with PFT (Figs 2345 ), while only MLA, skewness, and kurtosis correlated with subscores of 6MWT and QLQ (Table 4 ). Multivariate regression showed a good correlation between both visual and computerized CT evaluation and all functional, exercise, and QLQ parameters. No difference was found in the predictivity of the different models of multivariate linear regression when global visual score, visual disease severity, and visual disease extent were considered in turn as dependent variable


Figure 2
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  		Figure 2. Figure 2. Univariate regression analysis of visual score (Visual sc) on PFT.

 

Figure 3
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  		Figure 3. Figure 3. Univariate regression analysis of MLA on PFT.

 

Figure 4
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  		Figure 4. Figure 4. Univariate regression analysis of skewness on PFT.

 

Figure 5
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  		Figure 5. Figure 5. Univariate regression analysis of kurtosis on PFT.

 

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  		Table 4. Univariate Linear Regression of Different Modalities of Lung CT Evaluation on Quality of Life and Exercise Performance and Lung Function Impairment in SSc Patients*

 
By multivariate stepwise method, only two functional parameters, percentage of predicted FRC and percentage of predicted FVC, predicted independently global visual score, extent, and severity scores (Table 5 ), and accounted for approximately 40% of their variance. On the contrary, the variance of the densitometric parameters was independently predicted, with a very high R2c, by volume and gas exchange functional parameters as well as by some exercise and QLQ data.


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  		Table 5. Multivariate Linear Regression Models for the Predictivity of Different Modalities of Lung CT Evaluation (Dependent Variables) on Quality of Life, Exercise Performance, and Lung Function Impairment in SSc Patients

 
Discussion

The results of this study indicate that lung density histogram parameters are more reproducible than visual assessment of thin-section CT and are more closely related to functional, exercise, and quality of life impairment in SSc. HRCT is the pivotal radiologic evaluation in interstitial lung disease because of its greater sensitivity as compared to chest radiography, especially for early changes.143031 A differential diagnosis among the various clinical conditions causing pulmonary fibrosis is allowed, to some extent, by the type and distribution of pulmonary involvement in thin-section CT.3233 Visual scales are commonly employed to assess the pattern and extent of interstitial lung changes in SSc.111314 In particular, a correlation between the ground-glass pattern and active inflammation as opposed to reticular pattern and irreversible fibrosis was initially noted,46 although it was later recognized that a ground-glass appearance could also reflect extensive fine fibrosis.13 However, several articles343536 have indicated that the extent of pulmonary changes, irrespective of the pattern and distribution, is correlated with functional impairment in SSc.

Densitometric assessment of interstitial lung diseases was initially criticized since in these conditions areas of increased density (ground-glass opacities) and decreased density (cystic spaces, honeycombing) usually coexist.13 MLA, yielding an average density, could then underestimate or obscure the regional differences in disease distribution and severity.

We demonstrate that analysis of lung densities with histograms is more reproducible than the visual assessment for quantitative evaluation of lung abnormalities. Furthermore, the quantitative CT analysis provides a synthetic description of the lung changes and an effective graphic representation of the density distribution by means of kurtosis and skewness, which are relatively independent of MLA and can overcome the above-mentioned limitations.

As a matter of fact, it has been shown that density histograms in IPF showed increased MLA and reduced values of skewness and kurtosis, which were correlated with extent and severity of lung changes as assessed by the visual scores.2737 Also in our SSc series, an increase of the visual score was accompanied by increased MLA, reduced peakedness (kurtosis), and decreased left-sided asymmetry (skewness).

Reproducibility is a key feature for improving standardization of the CT evaluation in diffuse lung disease. The intraoperator and interoperator reproducibility of the visual assessment in this series was good and comparable to that reported in another study36 employing the same scale we utilized. However, the visual assessment had a consistently lower reproducibility than densitometric assessment. In the latter, only the semiautomatic segmentation of lung parenchyma introduces some operator dependence, which could possibly explain the slightly lower values of the weighted {kappa} scores obtained for skewness and kurtosis with respect to MLA.

Furthermore, the good reproducibility of the densitometric measurements was combined in our patients with a closer relationship with other clinical and instrumental data as compared to that of visual score. Although the densitometric measurements could have been somewhat influenced by lack of spirometric control, the univariate and multivariate correlation found between densitometric data and some of the QLQ items and exercise parameters could indicate that progressive lung involvement causes quality of life deterioration and reduced exercise performance in SSc; in particular, it has been shown that the daily hygiene activity is able to increase oxygen demand in the same way as an exercise test, and therefore such an activity could be impaired in patients with respiratory diseases. However, the compromised abilities of reach and grip associated with quantitative CT measures in multivariate stepwise analysis to some extent could reflect the disease severity in SSc patients with lung involvement.

In patients with IPF, kurtosis has been shown to be the single density histogram parameter that reflects PFT and QLQ, and it has been proposed as the most predictive parameter in this condition.27 In our SSc series, the univariate analysis showed that MLA, kurtosis, and skewness were essentially equivalent in the prediction of PFT, QLQ, and 6MWT.

One can speculate whether lung CT densitometry represents a new tool for grading the extent and severity of lung involvement in SSc patients and monitoring its evolution, or it serves as a duplicate of the information that clinicians can derive (without the hazards of ionizing radiations) from clinical assessment, pulmonary function, exercise testing, and QLQs. The results of the multivariate stepwise regression analysis indicate that the combination of PFT, 6MWT, and QLQ explained the variance of lung densitometry, suggesting that the parameters derived from the CT density histograms may provide additional information not otherwise available. Furthermore, when the visual score is considered as the dependent variable in the stepwise method, only 40% of its variance can be explained by the model that entails only two volumetric parameters: percentage of predicted FRC and FVC. This might suggest that visual score is highly influenced by the reduction in lung volumes, while CT densitometry represents a more comprehensive and robust measure of lung involvement in SSc.

We recognized several limitations of our study. The number of patients we examined was relatively small. We did not use spirometric gating to control for lung volume during CT acquisition. Hence we cannot exclude the possibility that an inadequate inspiratory effort of the patient could lead to increase in lung attenuation potentially simulating the histogram metrics changes correlated to lung fibrosis. However, spirometric gating is of utmost importance especially in patients with airway obstruction and hyperinflation, and none of our patients had obstruction or hyperinflation. A further potential limitation of our study was the nonlinearity of the visual scale employed for CT evaluation. This could amplify the disease in patients with multiple patterns of disease abnormalities and minimize the disease in patients with few patterns. For the densitometric analysis, we used a homemade (not commercially available) software that has already been successfully employed for evaluation of IPF.37

Finally, mild PAH, which could affect visual and densitometric CT changes in SSc, was suspected in some of our patients on the basis of the DE results. Although an accurate diagnosis of presence and severity of PAH can be obtained only by pulmonary artery catheterization, we deemed such an invasive procedure unjustified in unselected patients with SSc. In conclusion, densitometric parameters could improve the standardization of lung CT evaluation and could represent a sensitive tool to investigate functional impairment due to lung involvement in SSc.

Acknowledgements

The authors thank Luca Ermini, Technician of Respiratory Medicine Laboratory, for his contribution in pulmonary function and exercise testing.

Footnotes

Abbreviations: BDI = baseline dyspnea index; DE = Doppler echocardiography; DI = disability index; DLCO = diffusion capacity of the lung for carbon monoxide; FRC = functional residual capacity; HRCT = high-resolution CT; HU = Hounsfield unit; IPF = idiopatic pulmonary fibrosis; MLA = mean lung attenuation; 6MWT = 6-min walking testing; PAH = pulmonary arterial hypertension; PFT = pulmonary function testing; QLQ = health-related quality of life questionnaire; R2c = square regression coefficient corrected; SHAQ = Systemic Sclerosis Health Assessment Questionnaire; SpO2 = pulse oxygen saturation; SSc = systemic sclerosis; VAS = visual analog scale

The authors have no conflicts of interest to disclose.

Received for publication June 3, 2006. Accepted for publication October 24, 2006.

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D. A. Lynch
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