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Pulmonary Embolism in Idiopathic Pulmonary Fibrosis Transplant Recipients* FREE TO VIEW

Steven D. Nathan; Scott D. Barnett; Bruce A. Urban; Cynthia Nowalk; Brian R. Moran; Nelson Burton
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*From the Inova Transplant Center (Drs. Nathan and Burton, Ms. Nowalk, and Mr. Moran), the Inova Heart Institute (Dr. Barnett), and the Department of Radiology (Dr. Urban), Inova Fairfax Hospital, Falls Church, VA.

Correspondence to: Steven D. Nathan, MD, FCCP, Inova Transplant Center, 3300 Gallows Rd, Falls Church, VA 22042; e-mail: steven.nathan@inova.com



Chest. 2003;123(5):1758-1763. doi:10.1378/chest.123.5.1758
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The objectives of the study were the assessment of the incidence of pulmonary embolism (PE) in lung transplant recipients. We performed a retrospective review of the medical records in a tertiary center lung transplant program. A total of 72 lung transplants were performed. There were seven symptomatic PE events diagnosed among six patients (group 1). All PE events were in the subgroup of patients with idiopathic pulmonary fibrosis (IPF) [6 of 23 patients (27%) vs 0 among all other patients (0%); p < 0.001]. All patients were out of the hospital, not receiving oxygen therapy, and were ambulatory at the time of the event. The median time to occurrence of the PE was 175 days posttransplant (range, 26 to 541 days). All patients who developed PEs were men. The group of IPF patients with no PEs was evenly split between genders (group 2; p < 0.009). PE patients required a longer posttransplant hospitalization (mean [± SD], 18.5 ± 3.9 vs 13.5 ± 4 days, respectively; p < 0.018). Aside from this, there was no apparent difference in patient functional status between the two groups. PEs appear to be relatively common in IPF lung transplant recipients. This should be considered in the differential diagnosis of any such patient who presents with dyspnea or hypoxia posttransplant. Patients do not appear to have been predisposed to their embolic events through lack of activity or prolonged hospital stays.

Figures in this Article

There are many causes of allograft dysfunction in the lung transplant recipient. Most of these are of parenchymal or airway origin. The most common complications seen are related to infection, ischemia/reperfusion, or immunologic injury. Posttransplant pulmonary vascular complications are rare, although complications from vascular anastomotic problems can occur.12 Pulmonary embolisms (PEs) have been reported to occur after transplant, but there have been no reports of a predilection for any particular patient group.3

Some patients with idiopathic pulmonary fibrosis (IPF) will succumb to PEs as the terminating event of their disease.4 This has been attributed mostly to inactivity in the later stages of the disease. However, to our knowledge, there have been no reports of a predisposition among IPF patients for the development of thromboembolic complications. We report a high incidence of PEs in IPF patients who received single-lung transplants.

We reviewed the records of all patients who had undergone transplantion at our facility between September 1996 and January 2002. The breakdown of primary disease for which the patients received transplants is shown in Table 1 . Patients who developed PEs were compared and contrasted to those with similar primary diseases who did not. Specifically in this regard, we compared the pretransplant pulmonary function test (PFT) results from IPF patients who had developed PEs (group 1) to IPF patients who did not develop PEs (group 2). Comparisons also were made between the length of the posttransplant hospital stays and the results of the posttransplant PFTs between the two groups. Our program did not obtain routine perfusion scans posttransplant, and therefore there were no baseline scans for comparison in the group of patients with PEs. The time to presentation and the clinical manifestations of the PEs also were assessed. Continuous and categoric data were assessed via t tests and χ2 tests, where appropriate. Tests were two-tailed, and a p value of ≤ 0.05 was considered to be statistically significant. All statistical analyses were conducted using statistical software (SAS, version 8.01; SAS Institute; Cary, NC).

There were a total of 72 patients who received lung transplants during the time period. All except two patients were successfully discharged from the hospital posttransplant, and only one patient died within the first month for a 1-month survival rate of 98.6%. There were seven episodes of PEs among six patients. All episodes occurred in the subpopulation of IPF transplant recipients (6 of 23 patients) for an incidence of 27%. None of the recipients with other primary diseases (0 of 49 patients; 0%) developed clinical evidence or were diagnosed with PEs (p < 0.001). Of the six patients, all (left-sided lung transplant [LSLTx], three patients; right-sided lung transplant [RSLTx], three patients) developed PEs in their transplanted lungs, while the one patient who had two embolic episodes had his first to the left native lung. Of note, this patient was not receiving coumadin therapy at the time of his second event. In terms of diagnostic procedures, one of the patients had undergone a ventilation-perfusion scan, three of the patients had undergone pulmonary angiograms, and five of the patients had undergone spiral CT scans (Fig 1, 2 ). The clinical characteristics of those IPF patients who developed PEs posttransplant (group 1) and those who did not (group 2) are contrasted in Table 2 . There were no differences in their pretransplant or first posttransplant spirometric indexes. Similarly, there was no difference in the maximal values that the groups attained posttransplant. Based on the FEV1 value obtained in closest proximity to the subsequent PE event (mean, 15 days prior), there was no patient who qualified as having bronchiolitis obliterans syndrome at the time of the PE. Only three of the patients underwent PFTs within 3 days of their embolic event. In one of these patients, there was a 9% decrement in the FVC and FEV1 on the day of the PE. Spirometry was stable in the second patient, and in the third patient the set of PFTs that he underwent on the day prior to the PE represented his best posttransplant spirometry effort. The clinical presentations of the six patients are shown in Table 3 .

The major causes of death in the early post-lung transplant period include primary graft failure, infection, and, rarely, acute rejection. Although there has been one prior report3 of thromboembolic complications post-lung transplant and after heart-lung transplant, there is generally a paucity of data on this potentially lethal complication in lung transplant recipients. Kroshus et al3 reported a 12.1% incidence of PE. However, there was no mention of any predilection for one patient group. In our series, we have shown a strong propensity for PEs in the IPF subpopulation of transplant recipients. Although the difference in the occurrence rate between our COPD and IPF patients appears to be quite striking, with the small numbers in our study we cannot exclude the possibility that we have erroneously concluded that the occurrence rates in COPD and IPF patients differ (ie, type I error). Similarly, the incidence of this complication exclusively in male recipients is noteworthy but could also represent a type 1 error. With patients having complicated conditions such as lung transplant recipients, we also cannot exclude the possibility that other patients may have had PEs that went undiagnosed. However, it is noteworthy that in four of the episodes, these were not subtle events, with three of the patients presenting with oxygen saturations in the 60% range (one of whom had a respiratory arrest) and one patient presenting with hemodynamic compromise and right heart failure.

Why patients with IPF might be more predisposed to thromboembolism is uncertain and raises a number of issues. First, are these patients sicker and hence less mobile prior to undergoing transplantation? This appears to be unlikely since, compared to patients in the COPD population, IPF patients generally have been sick for less time when listed for transplantation. Also, a prerequisite for acceptance into our transplant program is that patients have to be actively engaged in pulmonary rehabilitation. The median time to occurrence of the embolic events was 175 days, which would suggest that patients’ pretransplant functional status had a minimal impact on their predisposition for the embolic events.

There appeared to be a slightly longer hospital length of stay posttransplant, which might imply that these patients had a slower recovery. However, a median in-hospital stay of 19 days is unremarkable for patients with transplanted lungs. Indeed, most of the embolic events were far removed from the patient’s initial hospitalization, with more than half of the events occurring > 4 months after transplantation.

The functional status of the patient at the time of the event also does not appear to have played a significant predisposing role. All patients were oxygen-independent, ambulatory without limitation, and outpatients at the time of the events. As a further objective measure of their functional status, we found no difference between their posttransplant PFT results compared to the IPF patients who had no thromboembolic complications. The PFT results that were available prior to the PE events also attest to the patients’ otherwise stable pulmonary status at the time of their thromboembolic complication, with none of the patients qualifying as having bronchiolitis obliterans syndrome.

It is interesting to speculate that there may be something inherent in the disease itself that predisposes patients to thromboembolism. Indeed, approximately 3% of patients with IPF will succumb to a thromboembolic event.4 This possibly represents an underestimation as some patients with IPF who decompensate may incorrectly have this attributed to progression of their underlying disease. Although there has been at least one case report5 of an association with antiphospholipid syndrome, to our knowledge, there has been no systematic research into whether IPF patients have a thromboembolic predisposition.

Until the advent and popularity of spiral CT scanning, the only definitive way to diagnose PEs in this patient population was via pulmonary angiography, since ventilation-perfusion scanning is known to be inaccurate in the IPF patient.6 Contrast-enhanced spiral CT scanning has been used increasingly to diagnose PE, and, although there are data to attest to its accuracy, the sensitivity and specificity have not as yet been fully determined.7 For the five patients in our cohort in whom PE was diagnosed by this modality, the detected PEs were large in size and central in location, and as such were diagnosed with certainty. Spiral CT scanning also helped to quantify the clot burden, which supported the clinical decision to use thrombolytic therapy in two of the patients.

The clinical presentation of PE in this group of patients is well worth noting. In most the cases, the initial index of suspicion for PE was high, based on their clinical presentation. Consequently, only one patient underwent PFTs on presentation as part of his workup. Although this patient’s PFT results were reduced, there is no apparent reason to believe that PE should be added to the list of causes of reduced spirometry in lung transplant recipients. Indeed, when there is hypoxemia that is out of proportion to any spirometric or radiographic changes, then the index of suspicion for PE should be raised. It is not surprising that 86% of the embolic events (six of seven events) were on the side of the transplant, since it is well-recognized that the majority of the blood flow goes to the allograft posttransplant. All of the patients presented with shortness of breath, and none of them had associated chest pain. This is interesting from the standpoint that the patients still had their native parietal pleura. In terms of the clinical consequences of their PEs, the lack of a bronchial circulation theoretically placed them at higher risk for lung infarction. Chest imaging, including CT scans, in four of the patients at the time of their presentation did not show any evidence of this. One of the patients had a respiratory arrest requiring intubation but was stable hemodynamically throughout the event. One of the six patients presented with associated right heart failure and was the only patient to succumb to the event. The other patients appeared to tolerate their embolic events quite well from a hemodynamic standpoint, despite evidence of large clot burden in five of the remaining six episodes. This raises the notion of their right ventricles being “preconditioned” by virtue of their underlying IPF and associated pretransplant pulmonary hypertension.

In summary, thromboembolic events appear to be relatively common in lung transplant recipients with IPF. This should be considered in the differential diagnosis of any such patient who presents with shortness of breath and/or hypoxia posttransplant. With their abnormal lung parenchyma, spiral CT scans can be very useful diagnostic tools. The question of whether IPF patients in general have a predilection for thromboembolic events may warrant further study.

Abbreviations: IPF = idiopathic pulmonary fibrosis; LSLTx = left single-lung transplant; PE = pulmonary embolus; PFT = pulmonary function test; RSLTx = right single-lung transplant

Table Graphic Jump Location
Table 1. Summary of Transplant Recipients by Primary Disease
Figure Jump LinkFigure 1. Spiral CT scan of a 56-year-old man with PE. The soft-tissue window reveals large, discrete, filling defects in the main right pulmonary artery of the transplanted lung.Grahic Jump Location
Figure Jump LinkFigure 2. Spiral CT scan of a 58-year-old man with PE. The soft-tissue window reveals large, discrete, filling defects in the left lower lobe pulmonary artery of the transplanted lung.Grahic Jump Location
Table Graphic Jump Location
Table 2. Clinical Features of the Two Groups of IPF Patients*
* 

Values given as mean ± SD, unless otherwise indicated. NA = not applicable; LOS = length of stay.

 

First posttransplant FVC and FEV1 data are from first set of PFT results obtained posttransplant.

 

Max posttransplant FVC and FEV1 data are taken from posttransplant PFT results with highest FEV1.

§ 

Includes both PE episodes in patient 4.

Table Graphic Jump Location
Table 3. Clinical Presentation of PEs in IPF Patients*
* 

L = left; R = right; SOB = shortness of breath; V̇/Q̇ = ventilation-perfusion; Y = yes; N = no; IVC = inferior vena cava; TPA = tissue plasminogen activator; p = pulse.

Griffith, BP, Magee, MJ, Gonzalez, IF, et al (1994) Anastomotic pitfalls in lung transplantation.J Thorac Cardiovasc Surg107,743-754. [PubMed]
 
Leibowitz, DW, Smith, CR, Michler, RE, et al Incidence of pulmonary vein complications after lung transplantation: a prospective transesophageal echocardiographic study.J Am Coll Cardiol1994;24,671-675. [PubMed] [CrossRef]
 
Kroshus, TJ, Kshettry, VR, Hertz, MI, et al Deep venous thrombosis and pulmonary embolus after lung transplantation.J Thorac Cardiovasc Surg1995;110,540-544. [PubMed]
 
Panos, RJ, Mortenson, RL, Niccoli, SA, et al Clinical deterioration in patients with idiopathic pulmonary fibrosis: causes and assessment.Am J Med1990;88,396-404. [PubMed]
 
Kelion, AD, Cockcroft, JR, Ritter, JM Antiphospholipid syndrome in a patient with rapidly progressive fibrosing alveolitis.Postgrad Med J1995;71,233-235. [PubMed]
 
Pochis, WT, Krasnow, AZ, Collier, BD, et al Idiopathic pulmonary fibrosis: a rare cause of scintigraphic ventilation-perfusion mismatch.Clin Nucl Med1990;15,321-323. [PubMed]
 
Blachere, H, Latrabe, V, Montaudon, M, et al PEssm revealed on helical CT angiography: comparison with ventilation-perfusion radionuclide lung scanning.AJR Am J Roentgenol2000;174,1041-1047. [PubMed]
 

Figures

Figure Jump LinkFigure 1. Spiral CT scan of a 56-year-old man with PE. The soft-tissue window reveals large, discrete, filling defects in the main right pulmonary artery of the transplanted lung.Grahic Jump Location
Figure Jump LinkFigure 2. Spiral CT scan of a 58-year-old man with PE. The soft-tissue window reveals large, discrete, filling defects in the left lower lobe pulmonary artery of the transplanted lung.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1. Summary of Transplant Recipients by Primary Disease
Table Graphic Jump Location
Table 2. Clinical Features of the Two Groups of IPF Patients*
* 

Values given as mean ± SD, unless otherwise indicated. NA = not applicable; LOS = length of stay.

 

First posttransplant FVC and FEV1 data are from first set of PFT results obtained posttransplant.

 

Max posttransplant FVC and FEV1 data are taken from posttransplant PFT results with highest FEV1.

§ 

Includes both PE episodes in patient 4.

Table Graphic Jump Location
Table 3. Clinical Presentation of PEs in IPF Patients*
* 

L = left; R = right; SOB = shortness of breath; V̇/Q̇ = ventilation-perfusion; Y = yes; N = no; IVC = inferior vena cava; TPA = tissue plasminogen activator; p = pulse.

References

Griffith, BP, Magee, MJ, Gonzalez, IF, et al (1994) Anastomotic pitfalls in lung transplantation.J Thorac Cardiovasc Surg107,743-754. [PubMed]
 
Leibowitz, DW, Smith, CR, Michler, RE, et al Incidence of pulmonary vein complications after lung transplantation: a prospective transesophageal echocardiographic study.J Am Coll Cardiol1994;24,671-675. [PubMed] [CrossRef]
 
Kroshus, TJ, Kshettry, VR, Hertz, MI, et al Deep venous thrombosis and pulmonary embolus after lung transplantation.J Thorac Cardiovasc Surg1995;110,540-544. [PubMed]
 
Panos, RJ, Mortenson, RL, Niccoli, SA, et al Clinical deterioration in patients with idiopathic pulmonary fibrosis: causes and assessment.Am J Med1990;88,396-404. [PubMed]
 
Kelion, AD, Cockcroft, JR, Ritter, JM Antiphospholipid syndrome in a patient with rapidly progressive fibrosing alveolitis.Postgrad Med J1995;71,233-235. [PubMed]
 
Pochis, WT, Krasnow, AZ, Collier, BD, et al Idiopathic pulmonary fibrosis: a rare cause of scintigraphic ventilation-perfusion mismatch.Clin Nucl Med1990;15,321-323. [PubMed]
 
Blachere, H, Latrabe, V, Montaudon, M, et al PEssm revealed on helical CT angiography: comparison with ventilation-perfusion radionuclide lung scanning.AJR Am J Roentgenol2000;174,1041-1047. [PubMed]
 
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