Lung Transplantation for α1-Antitrypsin Deficiency Emphysema

doi:10.1378/chest.110.6_Supplement.284S

Chest

Volume 110, Issue 6, Supplement, December 1996, Pages 284S-294S

https://doi.org/10.1378/chest.110.6_Supplement.284S Get rights and content

Lung transplantation is an option for appropriately selected patients with end-stage emphysema caused by α₁-antitrypsin deficiency. The functional results have been excellent after single or bilateral lung transplantation, and the medium-term survival results have been good. However, the role of α₁-antitrypsin replacement therapy after lung transplantation remains uncertain, and further investigation is needed.

Section snippets

CURRENT ACTIVITY

Two international registries have accumulated data on lung transplantation, the Registry of the International Society for Heart and Lung Transplantation and the St. Louis International Lung Transplant Registry.14, 15 Both of these registries have shown an exponential rise in activity since the late 1980s (Fig 1), and COPD and α₁-AT deficiency emphysema have been among the most common indications (Table 1).

The trend in transplant activity for COPD and α₁-AT deficiency is illustrated in Figure 2.

RECIPIENT SELECTION

α₁-AT deficiency is associated with the premature development of pan lobular emphysema and an accelerated loss of lung function, especially in cigarette smokers.16, 17 Furthermore, estimates of survival probability in patients with α₁-AT deficiency emphysema have indicated a shortened lifespan compared with the normal population.¹⁷ Thus, although α₁-AT deficiency emphysema is the cause of only a small portion of all COPD, it is a common indication for lung transplantation. Because most patients

TIMING OF TRANSPLANTATION

When should transplantation be undertaken? This question cannot be answered precisely. Recent clinical events, trends in physiologic parameters, overall functional status, and quality of life must be integrated into the analysis. An enhanced quality of life is an important motivation for many patients who are referred for transplantation; however, the patient's prognosis should be the main determinant in timing the procedure.

Actuarial survival after transplantation is shown in Figure 4. These

CHOICE OF PROCEDURE

Both single and bilateral lung transplantation have been performed for COPD and α₁-AT deficiency emphysema.10, 12, 13,26, 27, 28 Standard pulmonary function test results have, not surprisingly, been better after bilateral lung transplantation, but the difference in exercise capacity has been less impressive.27, 29, 30 Although there was no significant difference in actuarial survival at 1,2, or 3 years after transplantation between single-and bilateral-lung recipients with COPD, including α₁-AT

RESULTS

The outcome of lung transplantation can be gauged in several ways, but the most common measures are actuarial survival, lung function and exercise performance, and quality of life. Quality of life has not been extensively studied, and this section will focus on survival statistics and physiologic results.

Actuarial survival has been better for recipients with COPD or α₁-AT deficiency emphysema than for recipients with other diagnoses (Fig 4). The differences in survival appear relatively early

α₁-AT REPLACEMENT THERAPY AFTER TRANSPLANTATION

The safety and biochemical efficacy of α₁-AT replacement therapy have been demonstrated.33, 34 Even though the impact of replacement therapy on the subsequent clinical or physiologic course remains uncertain, guidelines for selecting and treating patients with α₁-AT deficiency emphysema have been promulgated.³⁵ Although a modest number of patients with α₁-AT deficiency have undergone transplantation, to our knowledge, there is no widely accepted policy or practice regarding replacement therapy

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Cited by (28)

Surgery for patients with Alpha 1 Antitrypsin Deficiency: A review
2019, American Journal of Surgery
Citation Excerpt :
A minority of AATD patients (around 7%) undergo lung transplantation.28 A 1994 report by the St. Louis International Lung Transplant Registry recorded as many as 13% of lung transplants to be as a result of AATD.29 Since the implementation of the lung allocation score (LAS), this number has declined in recent years, with the proportion recently assessed as under 5% (Fig. 2) ‒ nonetheless, AATD remains the fourth most common indication for lung transplantation worldwide.30
Alpha 1 Antitrypsin Deficiency (AATD) is a genetic cause of emphysema/chronic obstructive pulmonary disease (COPD) and liver disease, making AATD patients a high-risk surgical group. Additionally, patients may eventually require lung and/or liver transplantation or lung volume reduction surgery (LVRS). This narrative review discusses perioperative considerations for elective procedures in AATD patients, and reviews patient outcomes in AATD-related transplantation and LVRS.
PubMed search terms included: “pre-/peri-/post-operative management”; “COPD”; “AATD”; “lung/liver transplant”; “lung volume reduction.”
Lung and liver transplantation in AATD patients are associated with very good long-term survival rates that are comparable to, and sometimes superior to, other transplant indications. Although not currently recommended in AATD, LVRS may have a role in a minority of patients. The value of Alpha 1 Antitrypsin (AAT) augmentation therapy following lung transplantation requires further study. Wherever possible, AAT therapy should be continued in the period around elective surgeries.
Survival benefit of lung transplantation for chronic obstructive pulmonary disease in Sweden
2014, Annals of Thoracic Surgery
Citation Excerpt :
To our knowledge, this is the first study showing that AATD recipients have an approximately doubled survival time after LTx compared with recipients who have usual COPD. Previous studies have shown only either slightly better survival or relatively similar outcome [3, 8, 9]. The difference in mortality risk between AATD recipients and non-AATD recipients is difficult to explain.
Lung transplantation (LTx) is a therapeutic option for patients with life-threatening chronic obstructive pulmonary disease (COPD) that is refractory to conventional therapies. The survival benefit of LTx for COPD is difficult to assess. The aim of this study was to evaluate the Swedish series of LTx performed to treat COPD and to identify differences in outcome between COPD related to severe alpha-1-antitrypsin deficiency (AATD) and COPD with normal alpha-1-antitrypsin (AAT) levels.
We retrospectively reviewed the data of 342 patients (128 AATD and 214 non-AATD) receiving lung transplants for end stage COPD from 1990 through 2012.
The majority (71%) of patients received a single lung transplant. The median survival time after LTx for all COPD patients was 9 years (95% confidence interval [CI]: 8 to 10). Non-AATD recipients had a shorter survival time than AATD recipients, 6 years (95% CI: 5.0 to 8.8) versus 12 years (95% CI: 9.6 to 13.5, p = 0.000). Mortality was higher among non-AATD recipients after adjusting for age, pack-years of smoking, body mass index, oxygen therapy use, exercise capacity, donor age, cytomegalovirus mismatch, and transplant type (hazard ratio 1.70, 95% CI: 1.02 to 2.82). The 5-year and 10-year survival rates for the AATD recipients were 75% and 59%, respectively, compared with 60% and 31% for the non-AATD recipients. Early deaths were mainly due to cardio/cerebrovascular accidents and sepsis, and late deaths to bronchiolitis obliterans syndrome and pulmonary infections.
Survival after LTx is significantly better for patients with severe AATD and end stage COPD than for the patients with COPD related to cigarette smoking.
Lung Volume Reduction Surgery for Patients with Alpha-1 Antitrypsin Deficiency Emphysema
2009, Thoracic Surgery Clinics
Citation Excerpt :
The increased incidence of septic complications in patients who had A1AD may be related to deficiencies in antiprotease activity causing a blunted response to reperfusion injury and infection.26 Whether or not a benefit exists in providing augmentation therapy post transplantation, particularly during periods of respiratory infection, is not known.27 By removing the most diseased portions of the emphysematous lung, LVRS aims to improve the elastic recoil and provide more space for the otherwise compressed and comparatively less diseased remaining lung.
Alpha-1 antitrypsin deficiency (A1AD) is a rare genetic disorder characterized by early-onset emphysema and, rarely, liver disease and vasculitis. In the lungs, unopposed and enhanced elastase activity results in accelerated parenchymal destruction leading to emphysematous changes predominantly in the lower lung fields. Medical treatment includes standard therapies for emphysema and so-called “augmentation therapy” using purified pooled plasma alpha-1 antitrypsin. Surgical options include lung transplantation and lung volume reduction surgery. The option of lung volume reduction surgery potentially provides palliation of dyspnea and a bridge to lung transplantation.
Thirteen-year experience in lung transplantation for emphysema
2002, Annals of Thoracic Surgery
Emphysema is the most common indication for lung transplantation. Recipients include younger patients with genetically determined alpha-1 antitrypsin deficiency (AAD) and, more commonly, patients with chronic obstructive pulmonary disease (COPD). We analyzed the results of our single-institution series of lung transplants for emphysema to identify outcome differences and factors predicting mortality and morbidity in these two groups.
A retrospective analysis was undertaken of the 306 consecutive lung transplants for emphysema performed at our institution between 1988 and 2000 (220 COPD, 86 AAD). Follow-up was complete and averaged 3.7 years.
The mean age of AAD recipients (49 ± 6 years) was less than those with COPD (55 ± 6 years; p < 0.001). Hospital mortality was 6.2%, with no difference between COPD and AAD, or between single-lung transplants and bilateral-lung transplants. Hospital mortality during the most recent 6 years was significantly lower (3.9% vs 9.5%, p = 0.044). Five-year survival was 58.6% ± 3.5%, with no difference between COPD (56.8% ± 4.4%) and AAD (60.5% ± 5.8%). Five-year survival was better with bilateral-lung transplants (66.7% ± 4.0%) than with single-lung transplants (44.9% ± 6.0%, p < 0.005). Independent predictors of mortality by Cox analysis were single lung transplantation (relative hazard = 1.98, p < 0.001), and need for cardiopulmonary bypass during the transplant (relative hazard = 1.84, p = 0.038).
AAD recipients, despite a younger age, do not achieve significantly superior survival results than those with COPD. Bilateral lung transplantation for emphysema results in better long-term survival. Accumulated experience and modifications in perioperative care over our 13-year series may explain recently improved early and long-term survival.
Genetics of obstructive airways disease cystic fibrosis, α-1 antitrypsin deficiency, and Hermansky-Pudlak syndrome
2002, Immunology and Allergy Clinics of North America
Liver injury in alpha<inf>1</inf>-antitrypsin deficiency
2000, Clinics in Liver Disease
Citation Excerpt :
Actuarial survival for patients in this category who underwent transplantation between 1987 and 1994 is approximately 50% for 5 years. Lung function and exercise tolerance is significantly improved.96 Replacement of α1AT by somatic gene therapy has also been discussed in the literature.19
Alpha₁-antitrypsin (α₁AT) deficiency is a relatively common autosomal recessive disorder, affecting 1 in 1600 to 1 in 2000 live births.⁹² Although only a subset of α₁AT–deficient children develop liver disease, it is the most common genetic cause of liver disease in children and the most frequent genetic diagnosis for which children undergo liver transplantation.⁶⁶ This deficiency has also been associated with chronic liver disease and hepatocellular carcinoma in adults.²⁵
It has been suspected for some time that liver injury is caused by the toxic effect of the mutant molecule α₁ATZ retained within the endoplasmic reticulum (ER) rather than secreted into the blood and body fluids. It now appears that most α₁AT-deficient patients are protected from liver disease because the mutant α₁ATZ molecule is recognized as abnormal by the quality control apparatus of the ER and degraded. Susceptible hosts are α₁AT-deficient individuals in which unlinked genetic traits or environmental factors result in an alteration in the functional activity of the ER quality control system and, in turn, in greater or more prolonged retention of the presumably hepatoxic mutant protein.¹⁰⁷ Recent basic cell biologic studies have shown that the ER quality control system is extremely sophisticated.⁴⁵ It includes a series of molecular chaperones that reside in the ER and facilitate folding and assembly of wild-type proteins and degradation of misfolded proteins. It also includes pathways by which misfolded proteins are transported out of the ER into the cytoplasm and multiple pathways by which the misfolded proteins are then degraded in the cytoplasm. The quality control system is also characterized by an ancient, evolutionarily conserved response, the unfolded protein response, by which the cell can make new ER chaperones and new ER membrane so that it can expand and accommodate an increased load of misfolded proteins.63, 87 It is not surprising, then, that there are several different genetic and biochemical mechanisms by which the quality control system can be altered and an α₁AT-deficient host be rendered susceptible to liver injury. This article, reviews the current knowledge about the quality control system in α₁AT deficiency, how this information is being used to prevent liver disease, and how it is helping researchers understand more about the fundamental cellular machinery of stress responses.

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Chest

Lung Transplantation for α1-Antitrypsin Deficiency Emphysema

Section snippets

CURRENT ACTIVITY

RECIPIENT SELECTION

TIMING OF TRANSPLANTATION

CHOICE OF PROCEDURE

RESULTS

α1-AT REPLACEMENT THERAPY AFTER TRANSPLANTATION

Ann Thorac Surg

Ann Thorac Surg

Ann Thorac Surg

Chest

J Thorac Cardiovasc Surg

Chest

Chest

Ann Thorac Surg

J Thorac Cardiovasc Surg

Clin Chest Med

J Thorac Cardiovasc Surg

Chest

Problems in the management of human lung transplant patients

Vasc Surg

Regional ventilation and perfusion after lung transplantation in patients with emphysema

N Engl J Med

The other lung

N Engl J Med

Single lung transplantation in experimental and human emphysema

Ann Surg

Unilateral lung transplantation for pulmonary fibrosis

N Engl J Med

Experience with single-lung transplantation for pulmonary fibrosis

JAMA

Lung Transplantation for α₁-Antitrypsin Deficiency Emphysema

α₁-AT REPLACEMENT THERAPY AFTER TRANSPLANTATION