Clinical characteristics of pulmonary hypertension in bronchiectasis

Abstract

Pulmonary hypertension (PH), as a complication of bronchiectasis, is associated with increased mortality. However, hemodynamic characteristics and the efficacy of pulmonary arterial hypertension (PAH) therapies in patients with bronchiectasis and PH remain unknown. Patients with bilateral bronchiectasis and concurrent PH were included in the study. Patient characteristics at baseline and during follow-up, as well as survival, were analyzed. This observational study was conducted in 36 patients with a mean age of 51.5 years (range, 17‒74 years). The 6 min walking distance was 300.8±93.3 m. The mean pulmonary arterial pressure (PAP) was 41.5±11.7 mmHg, cardiac output was 5.2±1.4 L/min, and pulmonary vascular resistance was 561.5±281.5 dyn·s·cm⁻⁵. The mean PAP was>35 mmHg in 75% of the cases. Mean PAP was inversely correlated with arterial oxygen saturation values (r = −0.45, P = 0.02). In 24 patients who received oral PAH therapy, systolic PAP was reduced from 82.4±27.0 mmHg to 65.5±20.9 mmHg (P = 0.025) on echocardiography after a median of 6 months of follow-up. The overall probability of survival was 97.1% at 1 year, 83.4% at 3 years, and 64.5% at 5 years. Given the results, we conclude that PH with severe hemodynamic impairment can occur in patients with bilateral bronchiectasis, and PAH therapy might improve hemodynamics in such patients. Prospective clinical trials focusing on this patient population are warranted.

Keywords

bronchiectasis / hemodynamics / pulmonary hypertension

Introduction

Bronchiectasis refers to the dilatation of bronchial walls resulting from chronic airway infection, which leads to the structural damage of lung tissue [ 1]. Bronchiectasis manifests as a repetitive productive cough and is occasionally associated with hemoptysis [ 2– 4].

Pulmonary hypertension (PH) is a severe complication of bronchiectasis [ 1, 5, 6]. The prevalence of PH, defined by a systolic pulmonary arterial pressure (PAP) of at least 36 mmHg on Doppler echocardiography, ranged from 33%–48% in recent bronchiectasis studies [ 1, 6]. Information regarding the hemodynamic profile of PH in bronchiectasis is limited. Data regarding the effect of pulmonary arterial hypertension (PAH) target therapies, such as phosphodiesterasetype-5 (PDE-5) inhibitors, endothelin receptor antagonists (ERAs), and prostacyclin derivatives, are also lacking.

This study aimed to (1) evaluate the hemodynamic characteristics of patients with bronchiectasis and PH not explained otherwise by right-sided heart catheterization (RHC), (2) examine whether PAH-specific therapy can result in significant clinical and/or hemodynamic improvement, and (3) determine the survival of PH patients with bronchiectasis.

Material and methods

This study was a retrospective analysis of patients with bilateral bronchiectasis and PH. The study was conducted in accordance with the amended Declaration of Helsinki, and the study protocol was approved by the Ethics Committee of Shanghai Pulmonary Hospital, Tongji University. Patients with bilateral bronchiectasis and PH, as confirmed by RHC evaluated between April 2009 and January 2015, were included.

Inclusion criteria

The following inclusion criteria were applied. (1) We enrolled patients with definite bilateral bronchiectasis diagnosed by clinical work up and confirmed by high-resolution computed tomography (HRCT) [ 7], including idiopathic bronchiectasis with bilateral involvement. By contrast, we excluded the patients with history of previous resectional lung surgery; bronchiectasis derived from other causes, such as tuberculosis, allergic bronchopulmonary aspergillosis (ABPA), or Kartagener syndrome; concurrent disease, including pulmonary embolism, cancer, or pneumothorax; or findings of localized disease on CT scan. Moreover, we did not include the patients who refused to undergo further study. Patients with (2) PH, defined as mean PAP>25 mmHg by RHC [ 8], and (3) bronchiectasis stable within the last 4 weeks with no evidence of acute infection were included.

The patients with PAH, either heritable, idiopathic, or associated with connective tissue diseases, congenital heart disease, PH due to left heart disease, or chronic thromboembolic PH not enrolled. The “severe PH group” was defined by a mean PAP≥35 mmHg.

Evaluation of patients

Transthoracic echocardiography was performed in all the patients with bilateral bronchiectasis as screening test for PH [ 9– 12]. We used continuous-wave Doppler sampling of peak tricuspid-valve regurgitant jet velocity (TRV) to calculate for the systolic PAP [ 1, 11, 13, 14]. RHC was performed in patients with systolic PAP>40 mmHg [ 11] as described elsewhere [ 15– 17].

Pulmonary function tests were performed in all patients on the basis of established guidelines [ 18– 20]. Lung volume was then measured by whole-body plethysmography (MasterScreen-PFT and MasterScreen plethysmography, Jaeger, Hoechberg, Germany), and data were calculated using accepted equations for Chinese adults [ 21]. A non-encouraged 6 min walk test was performed in accordance with recommendations [ 22].

HRCT of all the subjects (64-row computed tomography [CT] scanner, Siemens Definition AS+; Siemens Healthcare Sector, Forchheim, Germany) was obtained at baseline. Cylindrical bronchiectasis was diagnosed on the basis of dilatation and thickening of the bronchial wall with a broncho/arterial ratio>1 [ 23]. Cystic bronchiectasis was then diagnosed by the presence of thin-walled cystic spaces potentially containing fluid and observed in subsequent axial cuts either in conglomerate fashion or in branching order [ 24]. Mixed bronchiectasis included cylindrical and cystic patterns. The extent of bronchiectasis was determined by the number of segments involving bronchiectatic airways. A score of 1 indicated that bronchiectasis was confined to 1 bronchopulmonary segment (score range, 0–18).

The date of RHC was defined as the date of PH diagnosis, and all baseline data were obtained within 3 months of the RHC. Follow-up data were collected during the most recent follow-up after initiation of PAH-specific therapy. Treatment decisions, including the management of bronchiectasis and whether possible PAH-specific therapy was initiated after RHC, were left to the attending physician’s discretion. Survival was determined by chart review and telephone contact. Dates and causes of death were documented in those lost to death during follow-up.

Statistical analysis

The data were analyzed using Microsoft Excel 2007 and SPSS 13.0 (IBM Corp.). All values were expressed as mean±standard deviation (SD). Comparisons between two groups were performed using the student’s t test (two-tailed), and rates were compared using the c² test. Pearson’s coefficient was calculated to quantify the relationship between two variables. The proportion of patients that survived at each time point was estimated by the Kaplan–Meier method. For overall survival analysis, living patients were examined at the date of the last visit. Paired student’s t test was used to compare mean values for the initial and post-treatment cardiac functions, systolic PAP, arterial blood gases, and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels. P<0.05 was considered statistically significant.

Results

Patient population

Thirty-nine bilateral bronchiectasis patients with suspected PH during echocardiography subsequently underwent RHC. The estimated systolic PAP at echocardiography was significantly correlated with systolic PAP (r = 0.54, P = 0.001) and with mean PAP measured during RHC (r = 0.56, P<0.001). The mean difference between the systolic PAP estimated by echocardiography and that measured during RHC was -0.8 mmHg (95% confidence interval of -6.2 mmHg to 4.5 mmHg) (Fig. 1).

Three patients presented with a mean PAP<25 mmHg and were excluded from the subsequent analysis. Therefore, the final study population comprised 36 patients, with a mean age of 51.5±12.4 years. The baseline clinical data are shown in Table 1. Most of the patients required supplemental oxygen at low flow rates. Half of the patient population was maintained on long-acting inhaled bronchodilators, and five patients were treated with long-term macrolides.

Clinical and functional evaluations

Twenty-two bronchiectasis (61.1%) patients with PH were female. The mean time between first respiratory symptom and PH was 27.6±16.4 years (range, 1.0–60.0 years). Younger bronchiectasis patients with PH experienced more severe dyspnea and presented more frequently with right heart failure or finger clubbing (P<0.05).

CT showed cystic bronchiectasis in 15 (41.7%) patients, cylindrical bronchiectasis in 3 (8.3%) patients, and mixed bronchiectasis in the remaining 18 (50%) patients. The proportion of cystic and mixed bronchiectasis was higher in the patients with PH, but cylindrical bronchiectasis was more frequent in the patients without PH (P<0.001). The patients with combined bronchiectasis and PH revealed more segments involved than those without PH (P<0.01).

Most PH patients suffered from severely impaired lung functions. Mean values of FEV₁, DLco, and partial pressure of oxygen (PaO₂) in patients with PH were significantly lower than in those without PH. The partial pressure of carbon dioxide (PaCO₂) was significantly higher in PH patients (P<0.001). No significant difference was found in the mean forced vital capacity rate at 1 s and TLC between the groups.

Echocardiography showed dilated right ventricles in 24 of 36 (66.7%) patients. Mean systolic PAP, as estimated by echocardiography, was 70.6±21.4 mmHg. The mean right ventricular and atrial dimensions, systolic PAP, and TVR were significantly greater in the PH patients than those without PH (P<0.01). The tricuspid annular plane systolic excursion (TAPSE) was much lower in PH patients, along with higher NT-proBNP level and lower 6MWT (P<0.01).

Hemodynamics

Hemodynamic findings on RHC in the 36 PH patients are shown in Table 2. These patients achieved a high mean PAP (41.5±11.7 mmHg) and pulmonary vascular resistance (PVR) (561.5±281.5 dyn•s•cm^-5), but normal cardiac output (5.2±1.4 L/min) and pulmonary arterial wedge pressure (PAWP) (8.7±3.5 mmHg). Twenty-seven patients, almost 75% of the subjects, suffered from severe PH with mean PAP>35 mmHg. Most of the patients presented with pre-capillary PH, except for one patient who achieved a PAWP of 15 mmHg.

Mean PAP was inversely correlated with SaO₂ values (r = - 0.45, P = 0.02) (Fig. 2). No correlations were observed between hemodynamic parameters and other pulmonary function parameters, right heart dimension, or the extent of bronchiectasis.

Effects of PAH therapy

Thirty-two patients underwent PAH therapies after baseline evaluation. The initial PAH-specific therapy comprised PDE-5 inhibitors in 28 patients (sildenafil, n = 14; tadalafil, n = 8; and vardenafil, n = 6) and ERAs in 1 patient (bosentan, n = 1). Combination therapy of a PDE5 inhibitor plus ERA was used in 3 patients (sildenafil plus bosentan at n = 1 and vardenafil plus bosentan at n = 2) because of inadequate response to monotherapy. No patient was given prostacyclin derivatives.

After a median of 6 months of follow-up (range, 1.7–45.1 months), New York Heart Association (NYHA) class was improved by one level in 7 patients, two levels in 1 patient, and maintained in 18 patients (Fig. 3). No significant difference was observed in NYHA class (P = 0.14) between pre- and post-treatment. Among 24 patients with follow-up hemodynamic data assessed by echocardiography, systolic PAP was reduced from 82.4±27.0 mmHg to 65.5±20.9 mmHg (P = 0.025) and TRV was reduced from 4.2±0.8 m/s to 3.6±0.5 m/s (P = 0.012, Table 3) at post-treatment compared with pretreatment. NT-proBNP and arterial blood gases were unchanged (Table 3).

Survival analysis

During follow-up, 7 of 36 (19.4%) patients died because of severe cardiorespiratory failure. In the Kaplan–Meier curves, no difference was noted in survival time between bronchiectasis with and without PH (P = 0.23). The overall probability of survival was 97.1% at 1 year, 83.4% at 3 years, and 64.5% at 5 years (Fig. 4).

Discussion

Previous studies have only reported bronchiectasis–PH based on echocardiography [ 1, 6]. To the best of our knowledge, this is the first study that evaluated hemodynamics by RHC in patients with bilateral bronchiectasis. The present study is more comprehensive than others with complete hemodynamic results regarding PH in bronchiectasis.

Chronic lung diseases tend to result in relatively modest hemodynamic alterations at rest. Several studies in chronic obstructive pulmonary disease (COPD) patients under the previous GOLD (Global Initiative for Chronic Obstructive Lung Disease) stage IV showed that up to 90% of these patients presented with a mPAP of>20 mmHg, with most values ranging between 20 and 35 mmHg, whereas ~3% to 5% patients presented with mPAP>35 mmHg to 40 mmHg [ 25, 26]. Among idiopathic pulmonary fibrosis (IPF) patients, a small percentage may have presented with mPAP values>40 mmHg (~9%) [ 27]. In our study, hemodynamic impairment appeared more severely in bronchiectasis than in COPD and IPF. We found that the mPAP in three-fourths of bronchiectasis PH patients was>35 mmHg. The deterioration of gas exchange at rest, low DL_CO values, high Nt-proBNP levels, decreased exercise capacity, and gross right heart dilation/hypotrophy on echocardiography have been linked to the development of PH in bronchiectasis. The reasons for the severe hemodynamic impairment in bronchiectasis were manifold.

Impaired pulmonary function might be a reason for PH in bilateral bronchiectasis. Patients with PH achieved greater airflow obstruction than bronchiectasis patients without PH in the present study. Respiratory symptoms preceded PH diagnosis by almost three decades, indicating that PH often occurs in patients with more advanced pulmonary disease. Significant correlations were found between SaO₂ and hemodynamic parameters, with greater mean PAP in the patients with more decreased SaO₂.

We found that cylindrical bronchiectasis, as seen on HRCT, was less prevalent in patients with PH than in those without PH. These findings are consistent with the results of previous research. Alzeer et al. [ 1] found that 41.9% of patients with cystic disease developed PH compared with 15.6% that presented with cylindrical bronchiectasis. The absence of pulmonary arterial flow in the destroyed segment with retrograde filling of the pulmonary artery through the bronchial circulation is mainly observed in cystic bronchiectasis [ 28]. These hemodynamic alterations increase right-sided after-load because of the contribution of systemic pressure on pulmonary vascular resistance, which further increases PAP [ 1]. This phenomenon in part might explain why cystic and mixed disease types are more likely to develop PH than cylindrical bronchiectasis.

Little information is available regarding the treatment of bronchiectasis-associated PH. Almost all of the evidence on this condition has been obtained from case reports. Datta et al. observed a case of primary ciliary dyskinesia with bronchiectasis and severe PAH [ 29]. The patient responded to treatment with oxygen, intravenous broad-spectrum antibiotics, and oral sildenafil [ 29]. Daniil and coworkers described a case of severe PAH associated with bronchiectasis [ 30]. The patient’s condition greatly improved after inhaled iloprost was administered. Three months later, the PAH was almost reversed [ 30].

The use of drugs approved for PAH is usually not recommended for patients with PH because of lung disease [ 31]. Patients with more severe obstructive or restrictive lung disease or a combination thereof and severe PH as defined in previous text must be distinguished. These patients may be treated in accordance with the recommendations for PAH [ 31]. In our study, most of the bronchiectasis-associated PH cases were severe; we attempted to administer PAH-specific therapy in accordance with previous successful experience from the above-mentioned case reports. The present study with 32 patients treated off-label on an individual basis provided some interesting preliminary information on the efficacy and safety of PAH therapy in such condition. After PAH therapy, most of the patients showed favorable clinical responses. Besides NYHA class, echocardiography showed a significant improvement in systolic PAP. Notably, other treatments were considered besides PAH-specific therapy, such as long-acting inhaled bronchodilator, macrolide, and oxygen therapies. These therapies improved ventilatory function, as well as pulmonary systolic pressure. However, long-term randomized controlled trials that focus on patients with severe PH and bronchiectasis are needed. Only such an approach would provide reliable data for the use of PAH-approved drugs in these patients.

The prognosis of bronchiectasis-associated PH remains inconclusive [ 6]. In our patients, the 1-, 3-, and 5-year overall survival estimates were 97.1%, 83.4%, and 64.5%, respectively. A 5-year survival rate of only 36% was reported for COPD patients with mPAP values>25 mmHg, which is lower than that in our patients [ 32]. Similarly, Chaouat et al. [ 25] studied 11 patients with COPD and an out-of-proportion PH (i.e., mPAP>40 mmHg) and found that the 5-year survival rate was poor (<20%). Compared with severe PH associated with COPD, mortality in bronchiectasis PH appears to be better and at variance with severe hemodynamic impairment. This finding may be due to the small sample in studies, and the next large-sample study is required.

This study provides information on the utility of non-invasive methods for the screening for PH in bronchiectatic patients. The study was not designed to evaluate the diagnostic value of echocardiography, yet we suggest that bilateral bronchiectasis patients with estimated systolic PAP>40 mmHg on echocardiography undergo RHC. Echocardiography lacks specificity and accuracy in patients with advanced lung disease [ 13, 33– 37]. However, the correlation between PAP as estimated by echocardiography and as measured on RHC in our study is not completely dismissible. Such a discrepancy in the accuracy of echocardiography might be partially explained by the less severe hyperinflation associated with bronchiectasis compared with other lung diseases.

Several limitations are present in this study. Our study was a descriptive, retrospective study that reported the experience of as single center on bronchiectasis–PH. Decisions regarding the diagnosis and treatment of PH were accomplished by expert clinicians on an individual patient basis and not by any standardized clinical protocol or algorithm. The treatment was not blinded, and no control group was adopted. Therefore, our results were subject to selection and treatment biases. Finally, follow-up 6MWT values were missing from the majority of the patients studied. Therefore, we were unable to obtain changes in exercise tolerance after PAH therapy.

Conclusions

PH with severe hemodynamic impairment may occur in patients with bilateral bronchiectasis. Our study is the largest hemodynamic study to date in patients with bronchiectasis-associated PH. Despite the small number of patients, a hemodynamic benefit was demonstrated as assessed by changes in serial echocardiography results after therapy. Prospective, controlled studies of PAH agents are required to confirm this apparent benefit and to best define in which patients such therapy might be indicated.

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