Pulmonary Hypertension in Patients With Bronchiectasis: Prognostic Significance of CT Signs

Cardiopulmonary Imaging Original Research Devaraj et al. CT of Pulmonary Hypertension Cardiopulmonary Imaging Original Research Anand Devaraj 1,2 Athol U. Wells 3 Mark G. Meister 1 Michael R. Loebinger 4 Robert Wilson 4 David M. Hansell 1 Devaraj A, Wells AU, Meister MG, Loebinger MR, Wilson R, Hansell DM Keywords: bronchiectasis, CT, prognosis, pulmonary hypertension DOI:10.2214/AJR.10.5221 Received June 24, 2010; accepted after revision November 26, 2010. 1 Department of Radiology, Royal Brompton Hospital, Sydney St, London, SW3 6NP, UK. Address correspondence to D. M. Hansell. 2 Department of Radiology, St. George s Hospital, London, United Kingdom. 3 Interstitial Lung Disease Department, Royal Brompton Hospital, London, United Kingdom. 4 Host Defence Unit, Royal Brompton Hospital, London, United Kingdom. AJR 2011; 196:1300 1304 0361 803X/11/1966 1300 American Roentgen Ray Society Pulmonary Hypertension in Patients With Bronchiectasis: Prognostic Significance of CT Signs OBJECTIVE. The purpose of this study was to evaluate the association between pulmonary hypertension estimated with CT and outcome among patients with bronchiectasis. MATERIALS AND METHODS. The cases of 91 patients with bronchiectasis were studied. CT signs of pulmonary hypertension examined were main pulmonary artery diameter, right and left main pulmonary artery diameters, and the ratio between the diameters of the main pulmonary artery and the ascending aorta. CT scans were scored for extent of bronchiectasis and presence of bronchial dilatation, bronchial wall thickening, mucous plugging, mosaicism, and emphysema. Univariate, bivariate, and multivariate Cox proportional hazards models were used to test the influence of CT signs on mortality. RESULTS. Average right and left main pulmonary artery diameter was the best predictor of mortality (hazard ratio, 1.24; 95% CI, 1.13 1.35; p < 0.0001) and was associated with outcome independent of CT signs of bronchiectasis. CONCLUSION. Pulmonary hypertension, reflected by pulmonary arterial enlargement on CT scans, is a highly significant prognostic indicator in the evaluation of patients with bronchiectasis. B ronchiectasis is characterized by progressive permanent dilation of the airways. High-resolution CT is the imaging test of choice for the diagnosis of this condition [1]. Bronchiectasis is generally regarded as being associated with considerable morbidity but low mortality [2]. However, detailed knowledge of mortality in bronchiectasis is lacking because few studies of long-term outcome among patients with bronchiectasis have been performed. One study showed a mortality of 25% at 9 years [3] and another a mortality of 42% at 4 years [4]. In the latter study, Onen et al. [4] found that age, hypoxia, and extent of bronchiectasis were the main risk factors for death. In a more recent study, we found [5] that a reduced carbon monoxide transfer coefficient is a key prognostic indicator for mortality among patients with bronchiectasis and that the CT features most closely associated with mortality are the extent of bronchiectasis and the presence of bronchial dilatation, bronchial wall thickening, and emphysema. Carbon monoxide transfer coefficient reflects gas exchange. In addition to the presence of emphysema, a reduction in carbon monoxide transfer coefficient in patients with bronchiectasis can be explained by the presence of pulmonary hypertension (PH) [5, 6]. Because of hypoxic pulmonary vasoconstriction or destruction of the vascular bed, increased pulmonary artery (PA) pressure might be expected in patients with long-standing and severe bronchiectasis. However, the prevalence of PH among patients with bronchiectasis has not been systematically investigated. One study of 94 patients [7] showed that nearly one third of the subjects had elevated PA pressure estimated with echocardiography. The lack of reports of results of right-heart catheterization and echocardiography reflects the low rate at which these tests are performed for patients with bronchiectasis. Consequently, the effect of PH on outcome among patients with bronchiectasis has not been explored, to our knowledge. In this study we used CT to investigate the effect of PH on mortality among patients with bronchiectasis. We evaluated the prognostic strength of CT signs of PH in determining mortality and compared it with the prognostic significance of CT signs of bronchiectasis. Materials and Methods Patients This retrospective study had institutional review board approval, and patient consent was obtained in all cases. The cases of 91 patients (38 men, 53 1300 AJR:196, June 2011

CT of Pulmonary Hypertension women; mean age, 51.7 [SD, 12.1] years) at our institution whose condition was diagnosed as bronchiectasis on the basis of clinical and high-resolution CT criteria [8] were studied. These patients were originally recruited over a 4-month period in 1994 as part of a study of the St. George s respiratory questionnaire [9] and were included in the study that identified carbon monoxide transfer coefficient as a highly significant prognostic marker in patients with bronchiectasis [5]. Fifty-one of the 91 patients (56.0%) had idiopathic bronchiectasis. The other causes of bronchiectasis were infection in 20 patients (22%), allergic bronchopulmonary aspergillosis in eight patients (9%), primary ciliary dyskinesia in five patients (5%), Young syndrome in four patients (4%), and hypogammaglobulinemia in three patients (3%). Patient outcome was recorded as of March 2007. Information about patient survival as of March 2007 or the date of death was obtained by review of patient notes, from the patients family physicians, or from the Office for National Statistics, United Kingdom. CT Acquisition and Image Interpretation All patients underwent imaging with an electron-beam CT scanner (Imatron, GE Healthcare). Thin sections (1.5 mm) were acquired at 10-mm intervals during maximum inspiration with the patient supine. At a workstation running AquariusNet software (TeraRecon), observers blinded to the clinical details reviewed the CT scans initially obtained after patient recruitment. Measurements of the PA were made with electronic calipers on CT scans. The following dimensions, which have been found to accurately reflect right-heart catheter-derived mean PA pressure [10 13], were measured: diameter of the main PA at the level of the bifurcation [10 13], diameter of the main PA at the level of the right main PA [12], axial diameters of the right and left main PAs [10], and ratio between PA diameter and ascending aortic diameter [12]. These measurements were made by a single experienced observer because of reproducibility of CT caliper measurements of the PAs and aorta [12, 14]. Mediastinal window settings were used (level, 40 HU; width, 400 HU). Two observers (5 and 6 years of radiologic experience) scored the CT images for signs of bronchiectasis at lung window settings (level, 500 HU; width, 1500 HU). CT scores were based on previously described systems [15, 16], as follows. For bronchial dilatation, 1 indicated mild (1 2 diameter of corresponding PA) and 2 severe (> 2 diameter of artery) (Fig. 1) (score range, 0 12). For bronchial wall thickness, 1 indicated 0.5 diameter of adjacent PA; 2, 0.5 1 diameter of adjacent PA; and 3, > 1 diameter of adjacent PA (score range, 0 18). For mucous plugging, 1 indicated minimal and 2 extensive Fig. 1 45-year-old man with bronchiectasis. CT scan shows severe bronchial dilatation in left lower lobe (score, 2) and low attenuation of lung as part of mosaic pattern in left lower lobe, signifying small airways disease. (score range, 0 12). A subjective estimation was made to the nearest 5% of the low-attenuation component within an area of mosaic attenuation and of emphysema extent (score range, 0 100). The extent of bronchiectasis was judged by the number of segments containing bronchiectatic airways. A score of 1 indicated bronchiectasis confined to one bronchopulmonary segment; 2, > 1 segment; and 3, generalized cystic bronchiectasis (score range, 0 18). Scores were obtained for each lobe (lingula considered a separate lobe), and a total value was calculated. Scores were expressed as a percentage of the maximum possible score. A consensus score was reached between the two observers in cases in which there was more than a 1-point discrepancy in semiquantitative scores and more than 15% discrepancy for mosaicism and emphysema. The other scores were averaged. Pulmonary Function Testing Spirometric volumes were measured with standard equipment and expressed as percentage predicted value normalized for age, sex, and body surface area [17]. Samples for blood gas analysis were obtained via the earlobe with the patient at rest breathing room air. Statistical Methods Descriptive data were presented as mean with SD for normally distributed data, median with range for nonnormally distributed data, and number with percentage for frequency data. Group comparisons were made by Student t test for normally distributed numeric data, the Mann-Whitney U test for nonnormally distributed data, and chisquare test for categoric data. All variables tested against survival were analyzed with univariate, bivariate, or multivariate Cox proportional hazards models. Hazard ratio (HR) for all-cause mortality was given with CI for significant (p < 0.05) TABLE 1: Characteristics, CT Bronchiectasis Scores, and CT Measurements in Patients With Bronchiectasis (n = 91) Characteristic Value Sex Men 38 (42) Women 53 (58) Age (y) 51.7 (12.1) Forced expiratory volume in 1 s (%) 65.8 (28.1) Forced vital capacity (%) 88.7 (23.6) CT score Extent of bronchiectasis 27.8 (5.6 100) Bronchial dilation 33.3 (8.3 100) Bronchial wall thickening 22.2 (0 58.3) Large airways mucous plugging 8.3 (0 54.1) Mosaicism 4.2 (0 45.8) Emphysema 0 (0 45.8) Pulmonary artery diameter (mm) 25.26 (3.5) Ratio of pulmonary artery to aortic diameter 0.83 (0.13) Average diameter of right and left main pulmonary arteries (mm) 18.14 (3.61) Note Data are mean with SD, median with range, or number with frequency (percentage) in parentheses. CT scores are expressed as percentage of maximum score or percentage of lung involved (mosaicism and emphysema). Patient characteristics are at the time of entry into the study. AJR:196, June 2011 1301

Devaraj et al. TABLE 2: Characteristics and CT Parameters Among Survivors and Nonsurvivors (n = 91) Characteristic Survivors (n = 64) Nonsurvivors (n = 27) p Sex Men 23 15 0.08 Women 41 12 0.08 Age (y) 49.3 (11.3) 57.3 (12.4) < 0.005 Forced expiratory volume in 1 s (%) 72.9 (23.6) 48.7 (30.1) 0.0001 CT score Extent of bronchiectasis 25.0 (5.6 75.0) 50.0 (8.3 100) < 0.005 Bronchial dilatation 33.3 (8.3 95.8) 55.0 (8.3 100) < 0.005 Bronchial wall thickening 16.7 (0 50.0) 30.6 (5.6 58.3) 0.0001 Large airways mucous plugging 8.3 (0 50.0) 16.7 (0 54.1) 0.02 Mosaicism 1.8 (0 45.8) 8.8 (0 36.7) < 0.005 Emphysema 0 (0 16.7) 2.1 (0 45.8) 0.1 Average diameter of the right and left main pulmonary arteries (mm) 16.99 (2.71) 20.59 (4.08) < 0.0001 Note Data are mean with SD, median with range, or number with frequency in parentheses. CT scores are expressed as percentage of maximum score or as a percentage of lung involved for mosaicism and emphysema. Patient characteristics are at the time of entry into the study. trends. A stepwise approach was used for multivariate analyses. Statistically significant variables were examined together, but at p > 0.10, variables were removed in turn, starting with the weakest. The CT signs of PH most strongly predictive of mortality were identified. Bivariate analyses were then performed to compare CT signs of PH and CT signs of bronchiectasis as determinants of outcome. This assessment was followed by multivariate analysis to identify whether CT signs of PH were predictive of mortality independently of CT signs of bronchiectasis and bronchiectasis severity. Post hoc univariate analyses (Spearman correlation) were performed to examine the relations between CT signs of PH and CT signs of bronchiectasis, bronchiectasis severity, and Pao 2. Further post hoc analysis was performed to identify a cutoff value for the CT sign that was the best predictor of mortality. All statistical analyses were performed with software (Stata version 4, Statacorp). Results CT Scores and Patient Follow-Up Patient characteristics and CT scores are summarized in Table 1. Patients participated in follow-up for a median interval of 11.9 years after CT (range, 7 months 12.4 years). During the follow-up period, 27 of 91 patients (30%) died. The deaths of 19 of the 27 patients (70%) were attributed to bronchiectasis and its complications. The other causes of death were renal failure in two cases; colon cancer in two cases; and heart failure, cerebrovascular accident, liver metastasis, and pulmonary embolism in one case each. Patient characteristics and CT parameters among survivors and nonsurvivors are summarized in Table 2. Predictors of Mortality CT signs of pulmonary hypertension CT dimensions of the PA tree that were predictors of mortality in univariate analysis are shown in Table 3. Increasing diameter of the right and left main PAs (Fig. 2) had the strongest relation to outcome. For the right main PA, the HR was 1.18 (95% CI, 1.09 1.29; p < 0.0001) and for the left main PA, the HR was 1.25 (95% CI, 1.14 1.37; p < 0.0001). There was a weak association between death and main PA diameter measured at the level of the right main PA but no association between death and main PA diameter measured at the bifurcation. Dividing dimensions of the main PA by ascending aortic diameter did not result in significant HRs. Because the diameters of both the right and left main PAs were strongly related to outcome and these structures represent the same generation of the PA tree, a mean value of right and left main PA was tested against survival. This result also had a significant relation to mortality (HR 1.24; 95% CI, 1.13 1.35; p < 0.0001). CT signs of pulmonary hypertension in comparison with CT signs of bronchiectasis The strongest CT sign of PH (average diameter of the right and left main PAs) was tested as a predictor of mortality in bivariate analyses with CT signs of bronchiectasis. In each bivariate analysis, the average right and left main PA diameter remained an independent and significant predictor of outcome and had a closer relation to mortality than did large airways mucous plugging, mosaicism, and emphysema (Table 4). CT signs of pulmonary hypertension and CT signs of bronchiectasis adjusted for severity of bronchiectasis A multivariate analysis was performed that included average dimension of the right and left main PAs (established in this study as the strongest CT sign of PH that was predictive of mortality), extent of bronchiectasis, and presence of bronchial dilatation and bronchial wall thickening (the strongest CT signs of bronchiectasis that were predictive of mortality). Forced expiratory volume in one second (FEV 1 ) was separately input as a marker of disease severity [18]. Variables independently related to survival with control for FEV 1 were the mean diameter of the right and left main PAs (HR, 1.29; 95% CI, 1.15 1.45; p < 0.0001) and, less significantly, the TABLE 3: Significant Hazard Ratios for CT Markers of Pulmonary Hypertension in Univariate Analysis (n = 91) Parameter Hazard Ratio 95% CI p Main PA diameter at level of right main PA 1.11 1.00 1.23 0.04 Diameter of right main PA 1.18 1.09 1.29 < 0.0001 Diameter of left main PA 1.25 1.14 1.37 < 0.0001 Average diameter of right and left main PAs 1.24 1.13 1.35 < 0.0001 Note PA = pulmonary artery. 1302 AJR:196, June 2011

CT of Pulmonary Hypertension Fig. 2 76-year-old man with bronchiectasis who died after 4 years of follow-up. A, CT scan shows left main pulmonary artery (31.25 mm) is visibly larger than main pulmonary artery. B, CT scan at lung window settings shows bronchiectasis (scored 1 for bronchial dilatation) and low-attenuation mosaic lung in right middle lobe. CT extent of bronchiectasis (HR, 1.04; 95% CI, 1.02 1.06; p = 0.001) (Table 5). These variables remained predictive of mortality when adjusted for age and sex. Because CT signs of PH were predictive of mortality independently of CT signs of bronchiectasis and FEV 1, a post hoc univariate analysis was performed to test whether CT signs of increased PA pressure were related to CT signs of bronchiectasis or FEV 1. We found no link between the average diameter of the right and left main PAs and bronchial dilatation, extent of bronchiectasis, bronchial wall thickness, large airways plugging, mosaicism, or emphysema. There was, however, an inverse relation between average right and left main PA diameter and FEV 1 (r = 0.32; p < 0.01). We hypothesized that because FEV 1 was related to CT signs of PH, increased PA pressure in patients with bronchiectasis might be related to hypoxia. Among the 57 patients who had blood gas analysis results, only a weak relation (r = 0.28; p = 0.04) was found between Pao 2 and average right and left main PA diameter. Identifying a cutoff for CT signs of pulmonary hypertension predictive of mortality Having established average right and left A main PA diameter as the strongest independent predictor of mortality, we sought to identify a cutoff value of this parameter that was the best predictor of outcome. We obtained this value by examining HRs for 1-mm increments in right and left main PA diameter between 16 and 20 mm (which represented the range between approximately the 25th and 75th percentiles). The strongest HR was achieved for an average right and left main PA diameter greater than 18 mm (HR, 8.3; 95% CI, 3.08 22.4; p < 0.0001) (Fig. 3). B Discussion The prevalence and importance of PH in bronchiectasis are not well studied, partly because conventional tests for evaluating PA pressure are not routinely performed on bronchiectasis patients. Right-heart catheterization is an invasive test, and echocardiography can be unreliable in the evaluation of patients with lung disease [19]. By using CT, which is commonly performed in the investigation of bronchiectasis, we found that PH is an independent predictor of mortality among patients with bronchiectasis. Previous evidence [4, 5] shows that survival is linked to the severity of bronchiectasis visualized on CT scans. The findings from the current study, however, suggest that the most important prognostic CT features are signs of PH. Our observations strongly support the hypothesis that the development of PH is an important event in some patients with bronchiectasis [7] and is a significant contributor to mortality among these patients. Because the prevalence of PH in bronchiectasis patients is unknown, there is little understanding of the mechanisms underlying its development. Although one study showed a weak association between PA pressure and global CT bronchiectasis scores [20], we found no link between CT signs of PH and CT signs of bronchiectasis and only a weak link with hypoxia. Further studies are needed to establish the precise prevalence of PH and its mechanisms in bronchiectasis patients, including, for example, an evaluation of overnight oxygen saturation. The presence of an average right and left main PA diameter greater than 18 mm was found to be associated with a significant and substantial increase in mortality (eightfold) among patients with bronchiectasis. This finding must be validated in a separate patient sample. It has potential, however, for use in clinical practice in stratification of patients at risk of dying of PH who need further tests such as echocardiography and right-heart catheterization. Identifying PH in bronchiectasis may also be important because of the development of anti-ph agents that have been used successfully in the care of patients with other causes of increased PA pressure [21]. It should be noted that it was the diameter of the right and left main PAs that linked most strongly to outcome in our study (rather than the main PA diameter or ratio of the diameter TABLE 4: Significant Hazard Ratios for CT Features of Bronchiectasis and Pulmonary Hypertension in Bivariate Analysis (n = 91) CT Bronchiectasis Scores Average Right and Left Main Pulmonary Artery Diameter Parameter Hazard Ratio 95% CI p Hazard Ratio 95% CI p Bronchiectasis extent 1.05 1.03 1.07 < 0.0001 1.33 1.20 1.49 < 0.0001 Bronchial dilation 1.04 1.03 1.06 < 0.0001 1.36 1.21 1.52 < 0.0001 Bronchial wall thickness 1.08 1.04 1.11 < 0.0001 1.24 1.12 1.36 < 0.0001 Large airways plugging 1.04 1.02 1.07 < 0.005 1.23 1.12 1.35 < 0.0001 Mosaicism 1.04 1.00 1.07 0.03 1.23 1.13 1.35 < 0.0001 Emphysema 1.05 1.01 1.09 0.01 1.23 1.12 1.35 < 0.0001 AJR:196, June 2011 1303

Devaraj et al. TABLE 5: Significant Hazard Ratios for Independent CT Signs of Bronchiectasis and Pulmonary Hypertension (n = 91) Parameter Hazard Ratio 95% CI p Average diameter of the right and left main pulmonary arteries 1.29 1.15 1.45 < 0.0001 Extent of bronchiectasis 1.04 1.02 1.06 0.001 Forced expiratory volume in 1 s (%) 0.97 0.95 1.00 0.02 Note Forced expiratory volume in 1 s was used to adjust for severity of disease. Survival Probability (%) 100 90 80 70 60 50 40 30 20 10 0 0 2 4 6 8 10 12 14 Time (y) Fig. 3 Kaplan-Meier plot shows survival over time of patients with bronchiectasis and average diameter of right and left main pulmonary arteries of either greater than (dashed line) or less than (solid line) 18 mm. of the PA to that of the ascending aorta). The causes of this finding are not clear. Whereas most previous studies have shown size of the main PA to be the most reliable marker of mean PA pressure [10 13], studies only of patients with bronchiectasis are lacking. It may be that the size and shape of the main PA in patients with bronchiectasis are related to factors other than mean PA pressure, such as thoracic shape and intrathoracic pressure. It can be speculated that the left and right main PAs, by contrast, may be less liable to be influenced by these confounding factors. There were limitations to this study. It was retrospective, and the sample consisted of patients from a tertiary referral center. The results therefore may not be applicable to all patients with bronchiectasis. We did not consider the influence of treatment on survival. We did, however, find significant results across a spectrum of patients regardless of therapy. In addition, some patients died of conditions other than bronchiectasis. It is not possible to know with certainty what contribution bronchiectasis would have made to mortality among patients who did not die of this condition. Similarly, it is not possible to quantify the effect on survival of comorbid conditions among patients who died of bronchiectasis. We also acknowledge that we did not have right-heart catheterization data for confirmation of the CT signs of PH. However, studies of noninvasive markers of PH that rely on right-heart catheterization are liable to selection bias because right-heart catheterization is performed only in cases in which there is a high index of suspicion of increased PA pressure. CT, in contrast, is routine in the care of patients with bronchiectasis. Conclusion By examining CT signs of PH, we found that increased PA pressure is a significant complication in the care of some patients with bronchiectasis and that evidence of PH is the most important prognostic CT feature. References 1. Dodd JD, Souza CA, Muller NL. Conventional high-resolution CT versus helical high-resolution MDCT in the detection of bronchiectasis. AJR 2006; 187:414 420 2. Kolbe J, Wells AU. 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