Endobronchial valve deployment in severe α-1 antitrypsin deficiency emphysema: a case series

Authors

  • Mary Majella Tuohy,

    1. Advanced Lung Disease and Lung Transplant Programme, Mater Misericordiae University Hospital, University College Dublin, Dublin, Ireland
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  • Kasper Friedrich Remund,

    1. Advanced Lung Disease and Lung Transplant Programme, Mater Misericordiae University Hospital, University College Dublin, Dublin, Ireland
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  • Roger Hilfiker,

    1. Advanced Lung Disease and Lung Transplant Programme, Mater Misericordiae University Hospital, University College Dublin, Dublin, Ireland
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  • Dara Thomas Murphy,

    1. Department of Radiology, Mater Misericordiae University Hospital Dublin, Dublin, Ireland
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  • John Gerard Murray,

    1. Department of Radiology, Mater Misericordiae University Hospital Dublin, Dublin, Ireland
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  • Jim John Egan

    Corresponding author
    1. Advanced Lung Disease and Lung Transplant Programme, Mater Misericordiae University Hospital, University College Dublin, Dublin, Ireland
      Jim John Egan, MD, Advanced Lung Disease and Lung Transplant Programme Medicine, Mater Misericordiae University Hospital, University College Dublin, Eccles Street, Dublin 7, Ireland. Tel: +353 1 8034296, Fax: +353 1 8034773, email: jegan@mater.ie
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  • Authorship and contributorship

  • JJ Egan designed the study/protocol; Kasper Remund and JJ Egan performed study; MM Tuohy and Kasper Remund collected data; R. Hilfiker, Dara T Murphy and John E Murray analysed data; MM Tuohy and Kasper Remund wrote paper.

  • Ethics

  • The protocol has been approved by the Audit and Research Ethics Committee of the Mater Misericordiae University Hospital and was performed with the ethical standards laid down in the 2000 Declaration of Helsinki. All persons gave their informed consent prior to inclusion in the study.

  • Conflict of interest

  • The authors have stated explicitly that there are no conflicts of interest in connection with this article.

Jim John Egan, MD, Advanced Lung Disease and Lung Transplant Programme Medicine, Mater Misericordiae University Hospital, University College Dublin, Eccles Street, Dublin 7, Ireland. Tel: +353 1 8034296, Fax: +353 1 8034773, email: jegan@mater.ie

Abstract

Introduction:  Patients with end-stage emphysema because of α-1 antitrypsin (AAT) deficiency represent a challenging clinical management problem, and studies of volume reduction therapy to date have largely excluded these patients. We report the outcome of bronchoscopic volume reduction with the insertion of Emphasys endobronchial valves (Emphasys Medical, Redwood City, CA, USA) in six patients with end-stage emphysema because of AAT deficiency.

Case Series:  Of 51 patients with end stage emphysema referred for transplantation, we studied six patients with AAT deficiency and utilized the BODE index and lung allocation score for survival estimation.

Measurements and Main Results:  The forced expiratory volume in 1 s improved from a median of 0.575 L to 0.905 L (P = 0.028). There was a median reduction in total lung capacity (TLC) of 0.61 L. The residual volume /TLC fell from 74.0% to 58.4%. Before treatment, four patients had a BODE index of greater than eight units, which correlates with a 4-year survival of 18%. After treatment, two patients improved their BODE index to below seven units, which correlates with an estimated 4-year survival of over 50%.

Conclusions:  The data from this case series suggest that this intervention may provide bridging therapy to subsequent transplantation for younger AAT patients with end-stage emphysema.

Please cite this paper as: Tuohy MM, Remund KF, Hilfiker R, Murphy DT, Murray JG and Egan JJ. Endobronchial valve deployment in severe α-1 antitrypsin deficiency emphysema: a case series. Clin Respir J 2013; 7: 45–52.

Introduction

α-1 antitrypsin (AAT) deficiency is a hereditary disorder that is associated with early onset of emphysema. The incidence in the United States is one in 5000 newborns. Patients with AAT deficiency usually become symptomatic in third and fourth decades of life, and there is associated reduced life expectancy (1, 2). Despite smoking cessation and intensive pulmonary rehabilitation, many of these patients have significant limitations in their daily routine because of shortness of breath. Lung transplantation is an accepted treatment option for end-stage disease but may not confer an improved survival advantage. Recently, the lung allocation score (LAS) has been derived to optimize the utilization of lung transplantation. The LAS allows the prioritization of patients for lung transplant based on survival estimates and the potential benefit of a transplant (3). This has resulted in fewer numbers of patients with emphysema and a larger number of idiopathic pulmonary fibrosis patients undergoing lung transplant (4). Surgical lung volume reduction (SLVR) in patients with AAT deficiency is associated with poor outcomes and a higher mortality when compared with other patients (5, 6).

Bronchoscopic lung volume reduction is an emerging, minimally invasive endobronchial approach in patients with end-stage emphysema who are not suitable for lung volume reduction surgery. A retrospective multicentre report of 98 patients treated with Emphasys endobronchial valves (EBVs) has shown a positive trend for improving lung function and 6-min walking distance (6MWD), while the mortality (1%) and complication rates were low (7). Published results from the endobronchial Valve for Emphysema palliatioNTrial (VENT), a randomized multicentre study investigating bronchoscopic volume reduction with EBV placement, have shown an improvement in lung function, 6MWD and quality of life (8, 9). However, AAT deficient patients were excluded from this prospective study. We report the outcome in a challenging group of patients with end-stage emphysema because of AAT deficiency who were referred for transplantation and were previously excluded from an industry-based study.

Materials and methods

Patients

We offered EBV therapy to patients with end-stage heterogeneous emphysema with significant hyperinflation because of AAT deficiency. All patients had been referred for lung transplant assessment. Inclusion criteria included: total lung capacity (TLC) of greater than 120% predicted, residual volume (RV) greater than 180% predicted and RV/TLC ratio greater than 60%. Exclusion criteria included frequent infective exacerbations of chronic obstructive pulmonary disease (COPD), and/or evidence of bronchiectasis on high-resolution computed tomography and the presence of pulmonary arterial hypertension. The protocol was approved by the Research Ethics Committee of the Mater Misericordiae University Hospital, and informed consent was obtained.

Baseline measurements

AAT phenotyping was performed with the HYDRAGEL® AAT Isofocusing kit (Sebia, Inc., Norcross, GA, USA), and the protein serum content was analysed with the Dade Behring BN® II Nephelometer (Dade Behring/Siemens Healthcare, Maarburg, Germany).

All patients underwent pulmonary rehabilitation prior to baseline measurements (10).

Lung function tests included spirometry and body-box measurements. Six-min walk test (6MWT) were performed according to American Thoracic Society and European Respiratory Society (ATS/ERS) statement guidelines (11–13). Arterial blood gases were analysed at rest with no additional oxygen supply. The pulmonary arterial systolic pressure and right ventricular function were estimated by echocardiography or measured using right-heart catheterization. Quality of life was assessed by St George's Respiratory Questionnaire (StGQ), and for evaluating patients' dyspnoea, the Modified Medical Research Council (MMRC) scale was used (14, 15).

Spiral computed tomography (CT) was performed at maximal inspiration with a multi-slice scanner on all patients both before and after valve insertion (Somatom Sensation 16; Siemens Medical Systems, Erlangen, Germany). Imaging was reviewed in axial, coronal and sagittal planes using DICOM imaging software (Osirix, Geneva, Switzerland). Lung and target lobar volumes were calculated independently by two different investigators (DM, KR) by performing 2D and 3D growing region using a threshold (interval) algorithm. The interval value was set at 500. Polygonal regions of interest were created for each slice in the data set, and a subsequent volume was calculated. Volumes were calculated in the axial plane where possible or in the coronal plane when the fissure was difficult to isolate because of being ‘in plane’.

Two different multidimensional indices, BODE index and LAS were calculated for survival estimation. The BODE includes the composition of body mass index, airflow obstruction, dyspnoea and exercise capacity (16). The BODE index has been shown to predict survival of patients with emphysema at baseline and during longitudinal follow-up after therapeutical intervention (17). The LAS is defined as the potential transplant benefit minus the waiting list urgency measure. The calculation is derived by a multivariate modelling including different clinical factors for estimated pre-transplant mortality and post-transplant survival and is normalized to a 0–100 scale (3). The LAS was calculated from the UNOS web page (http://www.unos.org).

Run-in and follow-up

The patients were followed for 6 months prior to treatment, and infection rates were determined. Following EBV, the patients underwent lung function tests, 6MWD, MMRC, BODE index and LAS at 1–2 months, 4 months, 6 months and 1 year following valve insertion. CT was repeated after 6 months and 1 year.

Endobronchial valve insertion

The second-generation endobronchial one-way valve (EBV) (Zephir®) of Emphasys, Redwood City, CA, USA was deployed, as described in detail in the review of Venuta et al. The valves were loaded on a delivery catheter and inserted into the target bronchi via flexible bronchoscope (18). The procedure was performed in the setting of a routine bronchoscopy with minimal sedation with intravenous midazolam. The procedure time ranged between 20 min and 1 h. Microbiological analysis of central airway aspirates was performed at the time. Bronchoscopy was performed under general anaesthesia in one patient because the accessibility of the segmental bronchi of his left lower lobe was judged to be difficult.

Target lobes

Target lobes were determined by the team (JE, KR, JM). Lobes that demonstrated marked lung destruction with an intact fissure were targeted. Two patients had upper lobe predominant emphysema, and four patients had lower lobe predominant emphysema. The target lobes included the left lower lobe for patients 1 and 6, the middle lobe for patients 2 and 3, the right upper lobe for patient 4 and the left upper lobe for patient 5.

Statistical analysis

We calculated the median, interquartile range (IQR) for the baseline values and the follow-up values. Data were analysed with a Wilcoxon test (SPSS, v17.0.0; SPSS inc. Chicago, IL, USA). All tests were two-tailed. We considered 0.05 as the significance level (α).

For graphical presentation, we plotted box plots for the values at baseline and at the latest available follow-up. Individual patient lung function data at baseline and at follow-up time points are presented.

Results

Patient characteristics

Of 51 patients with end-stage emphysema referred for lung transplantation, eight patients had AAT deficiency, and six were considered eligible for EBV treatment. Five patients were males, and one was female. The mean age was 48 years (range 30–58). The AAT phenotype was ZZ in all patients with a median protein serum level of 0.28 g/L (range 0.21 g/L–0.75 g/L). The mean follow-up was 8 months. The last available post-treatment data were used for comparison with baseline measurements. Four of the six patients were unable to complete Carbon Monoxide Diffusion Capacity (DLCO) measurement because of inability to hold their breath. The patients were subjected to observation for 6 months prior to procedure and underwent a 12-week rehabilitation programme. During this period, the patients had a mean of two hospital admissions (range 0–5) during the 6 months prior to the EBV.

Observed changes after valve insertion

Lung function

The forced expiratory volume in 1 s (FEV1) improved from a baseline median of 0.575 L (IQR: 0.15 L–0.5 L) to 0.905 L (IQR: 0.8 L–1.07 L) (P = 0.028). (Table 1) Percent predicted FEV1 improved from a median of 18.3% to 26.2% (P = 0.028). All patients improved their forced vital capacity (FVC), with a median improvement of 1.33 L (P = 0.028). Percent predicted FVC median values improved from 41.5% to 84.9% (P = 0.028). Patient 6 had no improvement in FEV1 (Fig. 1). There was a median reduction in TLC of 0.61 L. Predicted RV values fell from 335.9% to 256.8%. The RV/TLC fell from 74.0% to 58.4%. At follow-up, the optimal achieved lung function was observed (patients 2–5) at 2 months after valve insertion and the patients then maintained their improvements (Fig. 1 Panel A). Patient 1 achieved optimal lung function at 6 months after the procedure.

Table 1. Group data change from baseline
 BaselineLast available post-procedure dataDifference (post-procedure – baseline) P value
Median (p25–p75)Median (p25–p75)Median (p25–p75)
  1. P values for the differences between baseline measurements and last available data of patients were calculated with the Wilcoxon test. The mean follow-up was 8 months.

  2. HRCT, high-resolution computed tomography.

Lung functionForced vital capacity (FVC) (L)1.75 (1.42; 3.29)3.63 (3.31; 3.63)1.33 (0.62; 1.96)0.028
FVC predicted (%)41.45 (32.70; 76.60)84.9 (77.9; 91.6)34.3 (17; 45.2)0.028
Forced expiratory volume in 1 s (FEV1) (L)0.575 (0.56; 0.74)0.905 (0.8; 1.07)0.265 (0.15; 0.5)0.028
FEV1 predicted (%)18.3 (14.6; 21.4)26.15 (24; 30.9)7.5 (4.4; 16)0.028
FEV1/FVC (%)30.69 (22.54; 33.82)27.775 (22.69; 32.6)−0.535 (−7.56; 1.73)0.600
Total lung capacity (TLC) (L)9.19 (8.85; 9.59)8.46 (8.05; 8.79)−0.61 (−1.34; 0.23)0.116
TLC predicted (%)141.1 (131.4; 152.5)133.4 (119.3; 135.2)−9.1 (−20.8; 3.8)0.116
Residual volume (RV) (L)6.62 (6.19; 7.26)4.83 (4.72; 5.87)−2.06 (−2.54; −0.32)0.046
RV predicted (%)336.3 (286; 365.5)256.8 (210, 297)−110 (−113; −21)0.046
RV/TLC (%)76.13 (65.02; 80.72)58.4 (56.04; 59.76)−17.5 (−22.7; −4.78)0.046
6-min walking distance (m)157.5 (105, 365)320 (180, 517)71 (0, 155)0.138
Body mass index (kg/m2)23.61 (21.71; 23.8)24.31 (22.95; 24.31)1.13 (1.00; 2.46)0.028
Modified Medical Research Council dyspnoea scale4 (3, 4)2.5 (2, 3)−1 (−1.00; −1.00)0.034
BODE index8 (5, 9)5.5 (3, 7)−1.5 (−3.00; 0.00)0.068
Lung allocation score31.204 (30.5–32.7)30.453 (30.3–30.6)−1.050 (−2.2; −0.2)0.028
St. George's QuestionnaireSymptom45.7 (38; 81.5)24.5 (17.9; 31.9)−24.7 (−63.1; −4.2)0.138
Activity80 (79.7; 92.5)79.1 (41.3; 92.5)−7.5 (−51.2; 0)0.273
Impact28.5 (26.6; 61.8)15.2 (13.48; 21.8)−14.9 (−15.5; −11.4)0.043
Total52.9 (45.4; 67.9)37.9 (34.01; 41.9)−10.9 (−15; −8.69)0.043
HRCTComputed tomography (CT) total lung volume (L)8.390 (8.020; 8.557)7.375 (6.791; 7.821)−0.769 (−1.580; −0.380)0.068
CT target lobe volume (L)2.870.0 (0.765; 0.3878)0.545 (0.326; 1.522)−0.724 (−3.551; 0.100)0.043
Figure 1.

Panel A: individual patient data is plotted against time pre (baseline measurements), 2 months, 6 months and 12 months following Emphasys endobronchial valves (Emphasys, Redwood City, CA, USA) treatment. Panel B: box plot group data for 6-min walking distance (6MWD), St George's Respiratory Questionnaire (StGQ), BODE index and lung allocation system (LAS). The baseline measurements (pre) are compared with the last available measurements (post). FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; TLC, total lung capacity; RV, residual volume; MMRC, Modified Medical Research Council.

6MWD, StGQ, MMRC

The 6MWD improved, but this did not reach statistical significance. (Table 1) Four out of the six patients improved their 6MWD by greater than 60 m. Four patients showed a significant improvement in StGQ. (Fig. 1, Panel B). Patient 6 failed to complete the StGQ. The MMRC improved in all patients except in patient 6, with a median improvement of one unit (P = 0.034)

CT

The analysis of volumetry by CT scans mirrored the lung function trends. Patients 1 and 3 showed atelectasis of the treated target lobe. Patients 2 and 4 had a reduced lung volume of 200 mL. Patient 5 had no CT follow-up performed. Patient 6 had an increase of 100 mL in lung volume.

BODE index and LAS

Four out of the six patients improved their BODE index. Before treatment, four patients had a BODE index of greater than eight units, which correlates with a 4-year survival of 18%. After treatment, two patients (patients 1 and 3) improved their BODE index to below seven units, which correlates with an estimated 4-year survival of over 50% (16, 17). The calculated LAS improved following valve insertion and was statistically significant (P = 0.028). (Table 1)

Microbiological data

The microbiological culture analysis of central airway aspirates and of sputum revealed Stenotrophomonas maltophilia in one patient, a growth of Moraxella catharralis in two patients, Streptococcus pneumonia in one patient, Staphylococcus aureus in one patient, Acinetobacter species in one patient. All bacterial growths were treated according to the sensitivity testing.

Complications

Patient 1 had a small pneumothorax post-procedure that resolved spontaneously. Patient 2 required hospital admission for the treatment of an infective exacerbation at 3 months following valve insertion. During this episode, the patient coughed up his valve. Patient 5 had a new-onset pulmonary consolidation in the contralateral untreated right lung 1 month after valve insertion. A diagnostic bronchioalveolar lavage revealed the growth of Mycobacterium avium intracellulare. The patient received appropriate treatment, and the consolidation improved. Two months later, a pneumothorax of the treated left lung occurred, and this required surgical therapy.

Patient 6 had to be admitted four times during a follow-up of 12 months with infective exacerbations and other medical conditions. The remaining three patients had no hospitalizations. There was an average of 0.83 admissions in the range 0–3 during the first 6 months after the valve treatment. This compares with two admissions for the 6 months prior to EBV treatment.

Discussion

We have studied the impact of EBV therapy outside the confines of an industry-sponsored study in a challenging group of patients with end-stage emphysema specifically referred for lung transplantation. The profile of these patients matched those individuals in the National Emphysema Treatment Trial (NETT Study) who are recognized as being high risk and not benefiting from LVRS (19). Consequently, they present a challenging clinical problem to referral centres.

Four of the six patients in our study with end-stage disease improved their dynamic and static lung volumes, walking distance and quality of life. This is consistent with the findings of the VENT where there was an increase of 4.3% in the FEV1 in the EBV group (increase of 1.0 percentage point in percent of predictive value) as compared with a decrease of 2.5% in the control group with a mean between group difference of 6.8%. Similar between group differences were observed for 6MWT (9). In contrast to the VENT, this study looked at patients with AAT who were excluded from entry to VENT. Also, endobronchial valves were placed in the right middle lobe in patients 2 and 3 with good effect, whereas the middle lobe was excluded from evaluation for valve placement in the VENT study. Patient 2 showed atelectasis of the targeted right middle lobe but experienced an infective exacerbation at month 3 when the valve was expectorated. Patient 3 showed a reduction in volume of 200 mL and improved his/her BODE index to below seven units.

Significantly, both the LAS and BODE index improved for four of the six patients. The LAS and BODE indices are accepted surrogate markers of prospective survival and disease severity (3, 4, 16, 17). A recent American Thoracic Society and European Respiratory Society Task Force on outcomes of COPD has indicated that a 150 mL change in FEV1 is clinically important (13). This benchmark is further supported by Herpel et al. who, after analysing the variability in intersession spirometry measurements, determined that a change of 0.225 L for FEV1 and 0.4 L for FVC are clinically relevant (20). Our data for group difference showed a change in FEV1 of 265 ml in patients with a mean FEV1 of 0.57 L. In patients who received pharmacotherapy, the prevention of decline of 16 mls per year was observed in the Towards a Revolution in COPD Health (TORCH) study (21). This comparison is very encouraging when calculating the impact of EBV therapy especially given the characteristics of the AAT patients described.

Nevertheless, a key question in this patient group relates to whether a group change in FEV 1 constitutes a clinically relevant improvement for individual patients. To further address this issue, we employed both the composite BODE index and the LAS as surrogate markers of disease severity and prognosis. Both these indices improved.

We have presented our data in the format of group data (Table 1) but also in the format of individual single-point data. The individual response is clearly most relevant to the individual patient, and this is most pertinent to patients with end-stage emphysema whose FEV1 is low because of lung destruction. It is potentially naive to expect a major change in FEV1 in patients who, by definition, have extensive lung destruction. The modest change we have observed is important and corroborated by surrogate makers such as the BODE and LAS.

In patients with end-stage emphysema because of AAT deficiency, lung transplantation is the only therapeutic option recommended by the ATS/ERS Task Force in 2003. SLVR was not recommended because of substantial morbidity and mortality (5, 6). However, the shortage of organs and waiting times for transplantation emphasize the need for a bridging therapy in this patient group. Prior to the development of new bronchoscopic techniques, our intention would have been to offer palliative treatment with the goal of improving the quality of life. However, in these difficult cases with end-stage emphysema, we exceeded our expectations. Three patients improved their lung function and 6MWD to a degree that they did not closely fulfil the criteria for active transplant listing, indicating that this therapy may be considered as a bridging option to lung transplantation in the future.

Post hoc analysis shows that two patients experienced no benefit; one patient as a consequence of coughing out the valve and the other (patient 6) because of frequent infective exacerbations. This highlights challenges for the future. First, as the NETT and VENT studies, there is a need to further define those patients who are most likely to benefit from EBV in the context of achieving volume reduction. This would involve identifying those patients with evidence of collateral ventilation that may confound efforts at volume reduction. It would also involve identifying patients with high heterogeneity as improvements in FEV1 and 6MWT were demonstrated as being significant with increasing magnitudes of heterogeneity in the VENT study within any quartile from the lower quartile to the upper quartile of baseline values and overall was greater with increasing magnitudes of heterogeneity (9). Second, patients may experience infective exacerbations following the procedure. We observed comparable rates of adverse events compared with reports in patients without AAT deficiency. Episodes of pneumonia in valved segments or lobes of the lung were not observed (7, 8). Nevertheless, infective complications may occur. In the VENT study, the rate of the composite of six major complications (death, emphysema, massive haemoptysis, pneumonia distal to an implanted valve, prolonged air leak lasting greater than 7 days or respiratory failure with ventilator support >24 h) at 6 months was 6.1% in the EBV group and 1.2% in the control group (9). At 90 days in the VENT EBV group, as compared with the control group, there were increased rates of infective exacerbations requiring hospitalization and haemoptysis (9). The rate of pneumonia in the target lobe in the VENT EBV group was 4.2% at 12 months (9). Out of 220 patients in the EBV group in the VENT study, three patients expectorated the valves (9).

Our findings from this case series justify the further study of this technological advancement with a goal of providing a bridge to transplantation for younger AAT patients with end-stage emphysema.

Ancillary