CASE REPORT

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A 50-year-old white man was referred to our center in 1988 for LT. The patient was suffering from pulmonary emphysema related to α-1 AT deficiency (Pi [protease inhibitor] ZZ phenotype) and to superimposed smoking (30 pack-years). He was dyspneic at rest and was oxygen dependent. Blood gas analysis on room air showed Pa_O2 and Pa_CO2 values at 47 and 63 mm Hg, respectively. Pulmonary function test results are given in Table 1

The donor was an 18-year-old man who had sustained a stroke. The early postoperative course was simple (extubation at Day 6, acute rejection at Day 9). A computed tomography scan of the thorax at Day 12 did not disclose any parenchymal abnormality of the grafted lung. At 6 months after transplant (M6), the patient was able to climb three flights of stairs without dyspnea. FEV₁ was 2,200 ml (63% predicted) (Table 1). Pa_O2 and Pa_CO2 values on room air were 80 and 43 mm Hg, respectively. From July 1990 to July 1991, the patient experienced eight episodes of acute rejection with, at each time, return to baseline after pulse steroid therapy.

Up to March 2000 (M124), dyspnea, pulmonary function test results (Table 1), and blood gas values remained stable as compared with the postoperative status at M6. Despite counseling, the patient resumed light smoking from December 1997 (10 cigarettes per week). In January 1999 (M110), a computed tomography scan of the thorax disclosed multiple abnormal low attenuation areas on the transplant (right side). These areas of low attenuation surrounded by normal parenchyma were lacking distinct walls and were thus highly suggestive of emphysema (Figures 1A and 1B)

Figure 1. Computed tomography scan of the thorax obtained in January 1999 (M110). Two sections at different levels (A and B) disclose multiple abnormal low attenuation areas on the lower lobe of the transplanted lung (right side). These areas of low attenuation surrounded by normal parenchyma are lacking distinct walls and thus are highly suggestive of emphysema.

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From March 2000 (M124) to March 2002 (M148), a progressive deterioration of lung function was observed (Table 1), but the patient remained clinically stable without breathlessness for moderate exercise. Smoking was stopped in May 2001, and thereafter, the patient remained abstinent. He underwent in September 2001 (M142) a fiberoptic endoscopy with bronchoalveolar lavage (BAL) on the grafted side, which did not disclose any infection. The computed tomography scan of the thorax confirmed the presence of emphysematous lesions characterized by large low attenuation areas on the grafted lung predominating on the lower lobe (Figure 2)

Figure 2. Computed tomography scan of the thorax obtained in October 2001 (M143). A frontal section discloses a pattern of abnormal low attenuation areas on the lower lobe of the transplanted lung (right side).

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In March 2002 (M148), the FEV₁ value was 36% predicted (Table 1), and the patient was dyspneic for moderate exercise. An acute rejection was suspected, and the patient received pulse IV methylprednisolone for 3 days, which led to a marked improvement of lung function (Table 1) and to a relief of breathlessness. In May 2002 (M150), fiberoptic endoscopy with BAL on the grafted side did not disclose any opportunistic infection.

Assessment of elastolytic activity was performed in BAL fluids and sera obtained in September 2001 and in May 2002. We used specific synthetic substrate N-methoxysuccinyl-ala-pro-val-para-nitroanilide (Sigma, L'Isle d'Abeau Chesne, France), as previously described (13). Assays were performed in triplicate in three separates sets of experiments and included the patient samples (serum and BAL fluid). The patient sample was compared with a normal subject serum (40-year-old healthy volunteer, without a history of either respiratory pathology, emphysema, or tobacco use), with commercially available human serum (AbCys, Paris, France), and with purified human elastase (Worthington, Serlabo, France). A standard curve was built with increasing concentrations of purified elastase, and results obtained from each sample were plotted against the standard curve to calculate the concentration of elastase in each sample. Significant elastolytic activity was found in BAL fluids and sera of the patient, whereas no activity was found in either normal subject or commercially available human sera. This activity was entirely inhibited by 4-(2-Aminoethyl)benzenesulnonyl fluoride hydrochloride (Sigma) but not by ethylenediaminetetraacetic acid (inhibitor of metalloprotease), demonstrating that it was due to the neutrophil serine–elastase. The level of elastase activity found in BAL fluids corresponded to 10⁻⁸ M of elastase and to 5.10⁻⁹ M in the serum.

At last follow-up (M172), the patient was dyspneic for climbing two flights of stairs, and FEV₁ was 52% predicted (Table 1).

DISCUSSION

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We present the case of a patient with α-1 AT deficiency in whom a recurrence of pulmonary emphysema was detected on the graft 10 years after LT. To our knowledge, such a recurrence has never been published previously.

Within the last 2 decades, LT (single or double) has become a valid option for selected patients with end-stage chronic obstructive pulmonary disease. Functional results have been excellent, and medium-term survival has been good. The results are similar in terms of lung function and outcome in the subgroup of patients in whom emphysema is caused by α-1 AT deficiency. These latter patients who represent less than 1% of chronic obstructive pulmonary disease patients are characterized by the premature development of panlobular emphysema and an accelerated loss of lung function especially in cigarette smokers. At this time, chronic obstructive pulmonary disease, including α-1 AT deficiency, is the most common indication of LT.

The recurrence of the primary disease is a well known problem after solid organ transplantation. Such a recurrence was thus expected as clinical LT came of age in the 1990s. Up to now, recurrence of sarcoidosis (1, 2), lymphangioleiomyomatosis (6, 7), desquamative interstitial pneumonia (11), Langerhans' cell histiocytosis (3–5), bronchioloalveolar carcinoma (8), giant cell pneumonitis (10), alveolar proteinosis (12), and diffuse bronchiolitis (9) have been described. In an abstract presented at the American Thoracic Society meeting in 2002, Glanville and coworkers reported the case of two α-1 AT–deficient patients in whom emphysema (not suspected while these patients were alive) was pathologically demonstrated at postmortem examination of their lung allografts (14). In the series of 28 α-1 AT–deficient patients who had a lung transplant for emphysema at our center, no other cases of recurrence of the disease have been detected.

In case of α-1 AT deficiency, given what is known about the natural history of the development of emphysema, a recurrence of the initial disease might be expected theoretically within several decades after a LT (i.e., more than the usual life of a graft), provided that the patient abstained from smoking. On the other hand, the frequent exposition of the lung allograft to inflammatory aggressions such as infection and/or rejection might increase the proteinase–antiproteinase imbalance and might accelerate the development of pulmonary emphysema.

Two studies previously assessed the question of elastase activity in BAL in lung transplant recipients with α-1 AT deficiency (15, 16). Compared with lung transplant control patients, King and coworkers demonstrated that free elastase activity was present during periods of respiratory tract inflammation (acute lung injury, rejection, pulmonary infection) but not when healthy (15). Similar results were found by Meyer and colleagues (16). In the case of our patient, the significant amount of unopposed neutrophil elastase found in BAL and serum is thought to have played a role in the recurrence of emphysema. The neutrophil elastase activity in BAL and serum detected in our patient could be explained by the potential development of bronchiolitis obliterans because his lung function was declining. However, the decline in lung function may also simply be ascribed to the recurrence of emphysema on the graft or to the worsening of emphysematous lesions on the native lung. The numerous acute lung rejection episodes that he experienced within the first 2 years after transplant may also have played a role in the presence of unopposed neutrophil elastase activity in BAL and serum. Besides the speculative role of rejection, the resumption of smoking has probably played a central role in the recurrence of emphysema, and this case report suggests that smoking is strongly contraindicated after a LT for emphysema related to α-1 AT deficiency.

The obvious underlying and yet unresolved question is whether α-1 AT–deficient lung transplant recipients require an intravenous replacement of α-1 AT after surgery. The previously mentioned studies (15, 16) suggest that supplementation of α-1 AT could be considered in patients experiencing an elastase-mediated injury to the transplanted lung (infection, rejection, reperfusion injury). This approach is not recommended yet, but supplementation might be rational for α-1 AT–deficient recipients who develop chronic rejection (17, 18). In that case, α-1 AT supplementation might be indicated to inhibit the increased elastase-mediated injury related to the increased burden of neutrophils within the lung parenchyma.

In summary, we describe a case of recurrence of pulmonary emphysema in a patient with α-1 AT deficiency. The long survival of the patient after transplantation has permitted observation of this recurrence, which might have been accelerated by the resumption of smoking. A significant amount of unopposed elastase activity was detected on two occasions in BAL and serum, suggesting an implication in the recurrence of emphysema.