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* From the Departments of Cardiothoracic Surgery (Drs. Deb and Thurber) and Pulmonary and Critical Care Medicine (Drs. Yun and Omron), National Naval Medical Center, Bethesda, MD; and Inova Heart and Vascular Institute (Drs. Burton and Nathan), Falls Church, VA.
Correspondence to: Steven D. Nathan, MD, FCCP, Heart and Lung Transplant Center, Inova Heart and Vascular Institute, 3300 Gallows Rd, Falls Church, VA 22042; e-mail: steven.nathan{at}inova.com
Abstract
Prior to the advent of effective medical therapies, the only treatment option for patients with idiopathic pulmonary arterial hypertension (IPAH) was lung transplantation. We present the case of a woman who underwent single-lung transplantation for the treatment of IPAH > 10 years ago in whom chronic rejection developed. Despite complete obliteration of the allograft, it was noted that her PA pressure levels had almost normalized. Therefore, an allograft pneumonectomy was performed. To our knowledge, this is the first reported case of the regression of pulmonary vascular disease following lung transplantation with subsequent successful removal of the allograft.
Key Words: graft rejection • hypertension • lung transplantation • pneumonectomy • pulmonary
Idiopathic pulmonary arterial hypertension (IPAH) is an idiopathic disorder with an estimated incidence of 1 to 2 cases per million people. IPAH is defined by a mean PA pressure of > 25 mm Hg at rest or > 30 mm Hg with exercise, with a wedge pressure of < 15 mm Hg without any associated cause.1 Prior to the advent of effective medical therapies, the reported median survival time for patients with this condition was 2.8 years.2 The only recourse for such patients was lung transplantation.
We present the case of a woman who underwent single-lung transplantation for the treatment of IPAH > 10 years ago in whom chronic rejection of the allograft with sustained near normalization of her PA pressure levels subsequently developed. This allowed for the successful performance of an allograft pneumonectomy. To our knowledge, this is the first reported case of the reversal of pulmonary vascular disease following lung transplantation that enabled the allograft and its incumbent immunosuppressive medications to be successfully removed.
Case Report
The patient presented in 1992 at age 28 years with syncope, palpitations, and worsening dyspnea on exertion. Her chest radiograph revealed cardiomegaly, and echocardiography ruled out an intracardiac shunt but revealed right heart enlargement. A workup was initiated that included ruling out an underlying connective tissue disorder with standard serology tests, a left and right heart catheterization to rule out congenital heart disease and left heart valvular disease, normal pulmonary function tests, a ventilation-perfusion (
/
) scan to rule out thromboembolic disease, and a CT scan of the chest, which demonstrated normal lung parenchyma. The patient’s right heart catheterization revealed a pulmonary artery (PA) pressure of 82/44 mm Hg with a mean of 57 mm Hg, a right atrial pressure of 11 mm Hg, and a cardiac index of 2.65 L/min/m2. Primary pulmonary hypertension was diagnosed based on these results and the exclusion of other etiologies. A second cardiac catheterization was performed 5 months later and revealed slightly higher pressures with a PA pressure of 100/40 mm Hg (mean, 64 mm Hg) with a pulmonary capillary wedge pressure of 5 mm Hg. Her pulmonary vascular resistance was measured at 14.4 Wood units, and her cardiac index was 2.5 L/min/m2. She was treated with oral calcium channel blockers; however, her dyspnea worsened to the point of New York Heart Association class 3 symptomatology, and she was therefore referred for lung transplantation.
In March 1994, at age 30 years, the patient underwent a left single-lung transplant without complications. Pathologic examination of the explanted lung showed changes that are considered to be typical for primary pulmonary hypertension, including thickened hyperplastic pulmonary arterial intima with narrowed lumina. There was no pathologic evidence of vasculitis or any type of parenchymal lung disease. The patient underwent a quantitative / scan, which revealed 97% perfusion to the allograft, early in the postoperative period. Following transplantation, the right ventricular dimensions and function returned to normal levels. The patient’s posttransplant history was significant for several episodes of acute rejection and recurrent allograft infections. Over time, these recurrent allograft problems resulted in progressive fibrotic changes and bronchiectasis in the allograft. Chronic renal insufficiency due to long standing hypertension and chronic calcineurin therapy also developed.
In August 2004, Pseudomonas pneumonia and left mainstem bronchostenosis just distal to the airway anastomosis were diagnosed. An expandable metallic stent was deployed in the left mainstem bronchus. However, the stent migrated into the trachea and required removal 2 months later. The patient continued to experience dyspnea on exertion, a productive cough, as well as left shoulder and chest pain. Chest radiography revealed severe volume loss and air bronchograms of the left hemithorax (Fig 1
). A CT scan revealed a totally atelectatic left lung with bronchiectasis and fibrosis (Fig 2
). Echocardiography showed normal cardiac dimensions, and an ejection fraction of 65% with mild diastolic dysfunction. Cardiac catheterization revealed a mean PA pressure of 32 mm Hg at rest. The pulmonary vascular resistance was measured at 3.3 Wood units. / scanning showed almost no ventilation or perfusion to the allograft.
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At 6 months of follow-up, the patient is doing very well. She has occasional dyspnea with exertion. She is not receiving oxygen therapy, and her left shoulder and chest pain have receded. Her postpneumonectomy chest radiograph is shown in Figure 3 . Follow-up transthoracic echocardiography shows normal right ventricular dimensions and a left ventricular ejection fraction of 70%. Repeat cardiac catheterization 6 months following surgery revealed the following hemodynamic profile: mean right atrial pressure, 8 mm Hg; pulmonary capillary wedge pressure, 12 mm Hg; PA systolic pressure, 47 mm Hg; PA diastolic pressure, 29 mm Hg; mean PA pressure, 35 mm Hg; and cardiac output as measured by thermodilution, 4.7 L/min. Despite stability in her symptoms, the patient has been started on oral therapy with bosentan (Actelion; Allschwil, Switzerland) for treatment of her IPAH. The patient consented to having her case submitted as a report.
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We have reported the case of a patient who underwent successful single-lung transplantation for the treatment of IPAH in 1994 and > 10 years later underwent a successful allograft pneumonectomy. This was predicated by the total destruction of the allograft and apparent reversal of the IPAH in the patient’s residual native lung.
In 1990, approximately 10% of all lung transplants were performed for the treatment of IPAH, whereas in 2002 only about 3% of transplants were performed for treatment of this condition.3 This is an attestation to the efficacy of the medical therapies that have been made available for this otherwise lethal condition. There are now five such agents that are approved by the Food and Drug Administration for the treatment of IPAH, and therefore the need for lung transplantation continues to diminish. Of the currently available therapies, IV epoprostenol was the first to be approved, but was only made available subsequent to our patient undergoing lung transplantation.4 Since our patient was not one of the small group of patients who respond to therapy with calcium channel blockers, the only recourse available at the time was lung transplantation.5 It is controversial as to which form of transplantation is best for the treatment of IPAH. Initially, heart/lung transplants were performed for these patients, until the realization of the remarkable recuperative properties of the right ventricle.678 Since then, it has remained controversial as to whether a single or bilateral lung transplant should be performed. Most programs prefer the bilateral procedure due to issues of / mismatching with single lungs.9 Despite this, patients who undergo single-lung transplants can do quite well, with reports of survival statistics similar to those seen in patients undergoing the bilateral procedure.3101112 An advantage of single-lung transplantation is that it lends to greater allograft availability and a simpler operative procedure.
Our report underscores another potential advantage of the single-lung procedure. Unexpectedly, there was sufficient regression of the disease in the remaining native lung that, despite the development of severe bronchiolitis obliterans syndrome resulting in the total destruction of the allograft, the patient had sufficient native lung recovery to sustain her. Ultimately, a transplant pneumonectomy could successfully be accomplished nearly 11 years later. In a sense, the transplant functioned as a "bridge to recovery." The allograft pneumonectomy has also allowed the discontinuation of her immunosuppressive medications and the amelioration of the inherent side effects associated with these. Although inflammation and some of the cytokines invoked in the pathogenesis of IPAH might have been affected by the patient’s immunosuppression, it is unlikely that they had any role in the regression of the patients’ primary disease.
Prior to 1994, there were not many lung transplants performed, and a small minority were for the treatment of IPAH. The 10-year survival rate post-lung transplant is also quite low at < 25%; and therefore it is likely that there are not many patients with IPAH who received single-lung transplants who could have survived for > 10 years.3 Therefore, it is impossible to predict what proportion of such patients might experience regression of their disease. There is one other case report13 of a patient with IPAH who received a single-lung transplant but ultimately died from bronchiolitis obliterans syndrome. At autopsy, the apparent resolution of the IPAH was noted.13 Regression of pulmonary arterial hypertension (PAH) has been described in some patients receiving long-term epoprostenol therapy, with successful discontinuation of therapy. This only occurs in a very small percentage of such patients and has generally been attributed to "remodeling" of the pulmonary vasculature.14 Whether this is a direct action of the drug or is perhaps a flow-mediated phenomenon is uncertain. Our case lends credence to the latter concept, in that the likely cause of regression of the disease was related to the low flow and reduced shear stress to the native lung.13 Supportive of this is the early postoperative quantitative perfusion scan, which showed only 3% of the flow to the native lung. This is a common accompaniment of single-lung transplants in patients with high native lung pulmonary vascular resistance.8 This might represent the reverse phenomenon that results in the genesis of PAH in patients with Eisenmenger physiology. This same phenomenon of "resting" a diseased organ has been shown to result in regression of the disease in certain patients with cardiomyopathies.1516
It is commonly held that IPAH occurs in individuals who are so predisposed, with precipitating factors perhaps fueling or precipitating the process. Our report lends support to the role of the mechanical effects of flow as part of this process in some of these patients. While it is encouraging that our patient has experienced a sustained regression of her PAH, the same predisposition for the subsequent progression of PAH likely exists. Therefore, with the high flow to her residual lung, it is likely that her IPAH will progress in the future; indeed, there is early evidence of such with her recently recorded pressures. Although she remains classified in World Health Organization class II, her mild PAH and propensity for progression has factored into the decision to start her on bosentan therapy. One of the limitations of our case report is that we only have 6 months of follow-up. It is possible that future progression of her disease might necessitate more aggressive therapies or even require consideration of the patient for retransplantation.
In summary, we have described the case of a patient with regression of PAH in a patient with IPAH who previously had undergone single-lung transplantation. This allowed a successful allograft pneumonectomy to be performed with discontinuation of immunosuppressive therapy. Our case has possible implications with regard to the pathogenesis of IPAH, the potential for regression, and the optimal transplant procedure for those patients whose disease progresses despite medical therapy.
Footnotes
Abbreviations: IPAH = idiopathic pulmonary arterial hypertension; PA = pulmonary artery; PAH = pulmonary arterial hypertension; / = ventilation-perfusion
None of the authors have a conflict of interest to declare.
Received for publication November 30, 2005. Accepted for publication January 18, 2006.
References
This article has been cited by other articles:
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  D. C. Grinnan, P. Fairman, J. Pinson, and S. D. Nathan Recurrence of Severe Pulmonary Hypertension Following the Removal of a Lung Allograft Chest, December 1, 2007; 132(6): 2057 - 2058. [Full Text] [PDF]
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