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Ann Thorac Surg 2000;69:1020-1024
© 2000 The Society of Thoracic Surgeons

ORIGINAL ARTICLES: GENERAL THORACIC

Segmental nonanastomotic bronchial stenosis after lung transplantation

Tsuyoshi Hasegawa, MDa, Aldo T. Iacono, MDb, Philip D. Orons, DOc, Samuel A. Yousem, MDa

a Department of Pathology, University of Pittsburgh Medical Center, Presbyterian University Hospital, Pittsburgh, Pennsylvania, USA
b Department of Pulmonary Medicine, University of Pittsburgh Medical Center, Presbyterian University Hospital, Pittsburgh, Pennsylvania, USA
c Department of Radiology, University of Pittsburgh Medical Center, Presbyterian University Hospital, Pittsburgh, Pennsylvania, USA

Address reprint requests to Dr Yousem, Department of Pathology, A 610, University of Pittsburgh Medical Center, Presbyterian University Hospital, 200 Lothrop St, Pittsburgh, PA 15213
e-mail: yousemsa{at}msx.upmc.edu


   Abstract
Top
 Abstract
Introduction
 Material and methods
 Results
 Comment
 References
 
Background. Nonanastomotic distal bronchial stenosis has been observed in some patients after lung transplantation. We investigated its relationship with acute cellular rejection (ACR), infection, and ischemia.

Methods. Between January 1994 and December 1997, 246 lung transplantations were performed at our hospital. These cases were retrospectively reviewed and evaluated to identify those patients with nonanastomotic bronchial stenosis.

Results. Six patients had bronchial stenosis within the grafted airway distal to the uninvolved anastomotic site. The average ACR before stenosis was 1.9 compared with 1.6 in a control group. ACR at the time of first recognition of the stenosis ranged from A2 to A3.5, with an average value of A2.9. All 6 patients demonstrated alloreactive airway inflammation before and at the time of stenosis. Four patients had evidence of ischemic damage in the perioperative period.

Conclusions. Segmental nonanastomotic large airway stenosis after lung transplantation should be assessed separately from anastomotic complications. Although the pathogenesis is unclear, certainly one should consider alloreactive injury, ischemic damage, and infection as individual and coercive causes.


   Introduction
Top
 Abstract
 Introduction
Material and methods
 Results
 Comment
 References
 
Lung transplantation is now an accepted therapeutic modality for respiratory failure due to end-stage lung disease [1, 2]. In the early days of clinical lung transplantation, a frequent source of mortality was airway complications [3]. Improvements in recipient and donor selection, lung allograft preservation, the surgical technique for bronchial anastomosis, perioperative and postoperative management, and immunosuppression regimen have all reduced the prevalence of airway complications, although such complications are still recognized as important limitations to successful lung transplantation.

Surgical complications involving the airways usually occur at the anastomotic site, but nonanastomotic bronchial stenosis may also occur. The pathophysiologic mechanism of these distal bronchial stenoses is unclear. Previous reports have not separated anastomotic complications and distal airway stenoses and therefore it has been difficult to determine if the causes for both complications are similar or distinct. We focused this study on nonanastomotic segmental stenoses in lung allografts that occurred in the distal large cartilaginous airways to investigate their clinical characteristics and relationship with acute cellular rejection (ACR), infection, and ischemia.


   Material and methods
Top
 Abstract
 Introduction
 Material and methods
Results
 Comment
 References
 
Between January 1994 and December 1997, 246 lung transplantations in 182 patients were performed at Presbyterian Hospital of University of Pittsburgh Medical Center. These cases were retrospectively reviewed and evaluated to identify those patients with nonanastomotic bronchial stenoses. The diagnosis of bronchial stenosis was defined as 75% narrowing of the diameter of the grafted airway based on bronchoscopic evaluation. Anastomotic complications such as exclusive anastomotic stenosis, bronchomalacia, infection, exophytic granulation tissue, and dehiscence without distal airway stenosis were excluded. Six cases satisfied these criteria.

All transplants were performed using previously described surgical techniques [4]. For the bronchial anastomosis, 3-0 nonabsorbable monofilament sutures were used to join the membranous portions of bronchi by continuous suture, and the modified dual mattress technique was used for the smaller airway to more closely hold the proximal rings to the mucosal surface of the larger airway. Wrapping the anastomosis with omentum was not done.

General principles of postoperative care provided to the patient population have been described [5, 6]. Cyclosporine (6 mg · kg-1 · day-1) or FK506 (0.2 mg/kg), azathioprine (2 mg/kg), and prednisone (0.3 mg/kg) were administered routinely. Cyclosporine and FK506 were adjusted to maintain serum trough levels of 800 to 1,000 µg/mL and 10 to 20 mg/mL, respectively. Perioperative antibiotics were administered routinely as infection prophylaxis.

ACR with coexistent airway inflammation, and bronchiolitis obliterans (OB) were diagnosed using the criteria of the Revised Working Formulation for the Classification of Pulmonary Allograft Rejection [7]. Average ACR was calculated as described previously [8, 9]. Infection was diagnosed on the basis of histologic evaluation. Ischemic damage was defined on the basis of gross bronchoscopic findings with histologic confirmation of coagulative necrosis.

Surveillance fiberoptic bronchoscopy was performed routinely within the first 10 days after transplantation and if indicated by clinical deterioration or suspicion of lung rejection. In later periods, bronchoscopy was done every 3 to 4 months within the first 2 posttransplantation years and twice yearly thereafter.

Bronchograms were performed when the patients underwent balloon dilatation or stent placement for the treatment of bronchial strictures. These films were reviewed to identify the location and extent of stenosis. All transbronchial biopsies and an autopsy examination were reviewed for correlation of histologic features with the stenosis.

Data analysis was accomplished using the Student’s t test analysis. For comparing average ACR, 20 transbronchial biopsy cases were selected at random from 1994 to 1997 and matched the study group in terms of the distribution of postoperation day. Statistical significance was determined at p less than 0.05, recognizing that the assessment of acute rejection is semiquantitative.


   Results
Top
 Abstract
 Introduction
 Material and methods
 Results
Comment
 References
 
Among 182 patients who underwent double and single lung and bilateral lobar lung transplantation (total of 246 lungs transplanted) at the Presbyterian University Hospital of University Pittsburgh Medical Center from January 1994 to December 1997, 6 patients had bronchial stenosis within the grafted airway distal to the unaffected anastomotic site (Table 1). Patient age ranged from 23 to 56 years (average, 38 years; median, 39 years). Two patients were men and 4 were women. Three patients received double lung transplantation, two had single lung transplantation, and 1 was a living-related double lobe lung transplantation. Indications for transplantation included 3 patients with cystic fibrosis, 2 with emphysema including one with alpha-1 antitrypsin deficiency, and 1 with secondary pulmonary hypertension due to congenital heart disease. The time to the first recognition of nonanastomotic bronchial stenosis ranged from 75 to 317 days (average, 138 days; median, 97 days). Mean ischemic time was 3.46 hours (range, 2.25 to 6.30 hours), and did not differ significantly from the remaining 240 cases (3.75 hours).


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  		Table 1. Patient Profiles in Nonanastomotic Bronchial Stenosis

 
The average ACR before stenosis was 1.9 compared with 1.6 (p = 0.388) in a control group of lung recipients without airway stenoses. Five of our 6 patients (83%) had one or more episodes of moderate to severe acute rejection before diagnosis. ACR at the time of first recognition of the stenosis ranged from A2 to A3.5, with an average value of A2.9 (p = 0.0068). All 6 patients demonstrated alloreactive airway inflammation as part of the ACR before and at the time of stenosis by bronchial biopsy. The average airway inflammation score (lymphocytic bronchitis/bronchiolitis) associated with ACR at the time of first recognition of the stenosis ranged from 1 to 3, with an average value of 2.0. Among the 6 patients, 4 developed OB but no patient had OB before identifying the stenosis. Four patients had evidence of ischemic damage in the perioperative period. No patient had a coexistent anastomotic infection at their stenosis. Two patients had bronchial infection before stenosis caused by invasive candidiasis.

Two patients had postoperative complications. One had pulmonary arterial anastomotic stenosis and underwent revision of the pulmonary artery anastomosis 1 week after transplantation. The second patient who had undergone double lung transplantation had a pulmonary arterial thromboembolism necessitating a right upper lobectomy 1 week after transplantation.

Bronchographic findings included long segmental stenoses at the site of bronchus intermedius (n = 4), main stem bronchus (n = 4), right lower lobe bronchus (n = 1), and orifice of upper lobe bronchus (n = 1) (Table 1). These stenoses were located distal to the anastomosis and ranged from 1 to 5 cm in length (Figs 1, 2). Among 3 patients with a double lung transplantation, 1 had stenosis in the left main stem to the orifice of left upper lobe, 1 in the right bronchus intermedius and left main stem, and 1 in both main stem bronchi. Both patients with right single lung transplantation developed stenosis in the bronchus intermedius. One patient with a left single procedure had stenosis in the orifice of left upper lobe.



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  		Fig 1. The stenotic segments showed a diffuse submucosal infiltrate of lymphocytes in most cases (top), with intraepithelial migration of lymphocytes with respiratory cell necrosis (bottom).

 


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  		Fig 2. (A) Right lung bronchogram demonstrated a concentric stricture (arrow) of the bronchus intermedius. The right upper lobe bronchus is filling through reflux. (B) Right lower and middle lobe bronchogram demonstrated a severe concentric stricture (black arrow) at the origin of the right lower lobe bronchus. Multiple air bubbles (open arrows) were seen as filling defects within the right middle and lower bronchus.

 
Pathologic review of autopsy specimens was performed in 1 patient who died due to respiratory failure secondary to severe rejection and pulmonary infection. Severe right bronchial stenosis with luminal narrowing to 0.4 cm and moderate left bronchial stenosis with the lumen narrowed to 1 cm diameter were confirmed. Histologic findings were diffuse congestion, patchy lymphocytic and plasmacytic infiltration in the subepithelial region, and extensive fibrosis of the bronchial submucosa (Fig 3).



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  		Fig 3. The region of bronchitis obliterans demonstrated squamous metaplasia and chronic inflammation (left). The submucosa was expanded and contained increased amounts of eosinophilic submucosal scar tissue admixed with chronic inflammatory cells (right).

 

   Comment
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
References
 
The first attempt at human single lung transplantation was performed in 1963 by Dr James D. Hardy [10]. The patient died due to renal failure on the 18th postoperative day and a necrotic defect in the membranous portion of the grafted bronchus was identified at autopsy. A collective review in 1970 contained data on 23 pulmonary transplantations with only 1 long-term survivor. Thirteen of the patients had respiratory insufficiency and died. No detailed description with regard to disruption of the airway was obtained but it probably accounted for one cause of death [11]. In another review in 1983, bronchial anastomotic complications included anastomotic disruption with air leakage, infection, bleeding, and stenosis or mucosal necrosis with aspiration pneumonia. In the 38 transplant recipients before 1981, these complications contributed directly to the death of most recipients who survived 10 days or more after the transplantation [3]. At the beginning of lung transplantation, these results suggested that poor bronchial healing was the Achilles’ heel of lung transplantation.

Bronchial complications have been attributed to ischemia of the donor bronchus. The bronchial arterial circulation is lost during the harvest of the donor lung, and limited rearterialization through recipient bronchial arteries requires 3 to 4 weeks after the operation [12]. The viability of the donor bronchus is also dependent upon the retrograde low-pressure poorly oxygenated blood supply from the pulmonary artery early after transplantation [13]. Currently, many improvements in operative techniques have led to reduced bronchial anastomotic complications. These include shortening the donor bronchial stump to two or less cartilaginous rings proximal to the upper lobe takeoff [14], reinforcing the anastomosis with a vascularized tissue pedicle such as the omentum [15] or intercostal muscle pedicle flap [16], and using the intussuscepting or telescoping bronchial anastomosis technique [17, 18]. Despite these advances, the continued occurrence of airway anastomotic complications, frequently manifesting weeks to months after transplantation, suggests that the pathogenesis of these complications is more complex than had been previously thought.

Airway complications after lung transplantation fall into various categories such as anastomotic stenosis, bronchomalacia, exophytic endobronchial granulation tissue, dehiscence, and anastomotic infection [19]. Appropriate definition and classification of airway complications after lung transplantation require separation of those affecting the anastomotic site and those affecting the distal cartilaginous airways. For example, Kshettry and colleagues [19] reported the anastomotic complications in 2 patients with right bronchus intermedius stenosis, and Date and coworkers [20] reported, as an anastomotic problem, complete obstruction of the bronchus intermedius. Such cases should be assessed separately from those involving the anastomotic sites when studying pathogenesis.

We focused on nonanastomotic distal bronchial stenoses developing after lung transplantation from the standpoint of associated comorbid conditions. Some reports have described no association between airway complications and rejection, but such evaluation is complicated because those study populations included patients with both anastomotic complications and distal airway stenoses [19, 20]. Our results showed the tendency of higher grades of ACR before and at the time of stenosis in patients who had distal bronchial stenosis than in patients who did not develop luminal compromise. This suggests distal bronchial stenosis or bronchitis obliterans is in part due to high-grade ACR. Additionally, airway inflammation appeared in all patients as part of the rejection phenomena. Airway inflammation is recognized as one component of the acute rejection process with alloreactive injury to the epithelium and mesenchyme induced by mononuclear cells [21–23]. Cytolytic airway damage is complicated by vasospasm resulting from endothelial injury by perivascular mononuclear cells that may cause decreased blood flow to the proximal airways, exacerbating the already reduced flow from the loss of the bronchial circulation. The large airway stenosis may be due in part to this dominant "airway rejection" process affecting the cartilaginous airways, and bronchitis obliterans represents one form of proximal airway rejection akin to the OB of the small airways.

The bronchial arterial circulation was not reestablished during the transplantation procedures, and rearterialization through recipient bronchial arteries does not occur until 3 to 4 weeks after transplantation [2]. Consequently, the viability of the donor bronchus is initially dependent upon retrograde low-pressure collaterals derived from the pulmonary artery as has been shown with laser-Doppler measurements of submucosal blood flow [24]. Interestingly, 3 of our 6 patients had histologic evidence of ischemic damage in the lung allograft resulting from pulmonary artery stenosis, thromboembolism of pulmonary artery, and prolonged mechanical ventilation. Thus a common risk factor in our patients also might be ischemic damage, although such ischemia would be expected to be greatest at the anastomosis—the patients in our study had no such complications.

In addition, anastomotic complications have been attributed to infection of donor bronchus. Lung transplantation is different from other solid organ transplantations in terms of the constant exposure to microbiologic agents. Loss of neural connection also leads to reduced microbial clearance ability of donor airway and predisposes to bronchitis and bronchopneumonia.

In summary, segmental nonanastomotic stenosis after lung transplantation should be assessed separately from anastomotic complications. Although their pathogenesis is unclear, certainly one should consider alloreactive injury, ischemic damage, and infection as individual and coercive causes.


   Acknowledgments
 
The authors gratefully thank Linda Shab for photographic aid, and the Pathology Education and Research Foundation for the financial support of this academic endeavor.


   References
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 References
 

  1. Griffith B.P., Hardesty R.L., Armitage J.M., et al. A decade of lung transplantation. Ann Surg 1993;218:310-318.[Medline]
  2. Cooper J.D., Patterson G.A., Trulock E.P., Washington University Lung Transplant Group. Results of 131 consecutive single lung and bilateral lung transplant recipients. J Thorac Cardiovasc Surg 1994;107:460-471.[Abstract/Free Full Text]
  3. Veith F.J., Kamholz S.L., Mollenkopf F.P., Montefusco C.M. Lung transplantation 1983. Transplantation 1983;35:271-278.[Medline]
  4. Griffith B.P., Magee M.J., Gonzalez I.F., et al. Anastomotic pitfalls in lung transplantation. J Thorac Cardiovasc Surg 1994;107:743-754.[Abstract/Free Full Text]
  5. Griffith B.P., Paradis I.L., Zeevi A., et al. Immunologically mediated disease of the airways after pulmonary transplantation. Ann Surg 1988;208:371-378.[Medline]
  6. Paradis I.L., Duncan S.R., Dauber J.H., Yousem S.A., Hardesty R., Griffith B.P. Distinguishing between infection, rejection and the adult respiratory distress syndrome after human lung transplantation. J Heart Lung Transplant 1992;11:S232-S236.[Medline]
  7. Yousem S.A., Berry G.J., Cagle P.T., et al. Revision of the 1990 Working Formulation for the Classification of Pulmonary Allograft Rejection. J Heart Lung Transplant 1996;15:1-15.[Medline]
  8. Bando K., Paradis I.L., Komatsu K., et al. Analysis of time-dependent risks for infection, rejection, and death after pulmonary transplantation. J Thorac Cardiovasc Surg 1995;109:49-59.[Abstract/Free Full Text]
  9. Bando K., Paradis I.L., Konishi H., et al. Obliterative bronchiolitis after lung and heart-lung transplantation. J Thorac Cardiovasc Surg 1995;110:4-10.[Abstract/Free Full Text]
  10. Hardy J.D., Webb W.R., Dalton M.L., Walker G.R. Lung homotransplantation in man. JAMA 1963;186:1065-1074.
  11. Wildevuur C.R.H., Benfield J.R. A review of 23 human lung transplantations by 20 surgeons. Ann Thorac Surg 1970;9:489-515.[Medline]
  12. Siegelman S.S., Hagstrom J.W.C., Koerner S.K., Veith F.J. Restoration of bronchial arterial circulation after canine lung allo-transplantation. J Thorac Cardiovasc Surg 1977;73:792-795.[Abstract]
  13. Barman S.A., Ardell J.L., Parker J.C., Perry M.L., Taylor A.E. Pulmonary and systemic blood flow contributions to upper airway in canine lung. Am J Physiol 1988;255:H1130-H1135.[Abstract/Free Full Text]
  14. Pinsker K.L., Koerner S.K., Kamholz S.L., Hagstrom J.W.C., Veith F.J. Effect of donor bronchial length on healing. J Thorac Cardiovasc Surg 1979;77:669-673.[Abstract]
  15. Morgan E., Lima O., Goldberg M., Ferdman A., Luk S.K., Cooper J.D. Successful revascularization of totally ischemic bronchial autograft with omental pedicle flaps in dogs. J Thorac Cardiovasc Surg 1982;84:204-210.[Abstract]
  16. Fell S.C., Mollenkopf F.P., Montefusco C.M., et al. Revascularization of ischemic bronchial anastomoses by an intercostal pedicle flap. J Thorac Cardiovasc Surg 1985;90:172-178.[Abstract]
  17. Calhoon J.H., Grover F.L., Gibbons W.J., et al. Single lung transplantation. Alternate indications and technique. J Thorac Cardiovasc Surg 1991;101:816-825.[Abstract]
  18. Veith F.J., Richards K. Improved technique for canine lung transplantation. Ann Surg 1970;171:553-558.[Medline]
  19. Kshettry V.R., Kroshus T.J., Hertz M.I., Hunter D.W., Shumway S.J., Morton Bolman R., III Early and late airway complications after lung transplantation. Ann Thorac Surg 1997;63:1576-1583.[Abstract/Free Full Text]
  20. Date H., Trulock E.P., Arcidi J.M., Sundaresan S., Cooper J.D., Patterson G.A. Improved airway healing after lung transplantation. J Thorac Cardiovasc Surg 1995;110:1424-1433.[Abstract/Free Full Text]
  21. Hruban R.H., Beschorner W.E., Baumgartner W.A., et al. Diagnosis of lung allograft rejection by bronchial intraepithelial Leu 7 positive T lymphocytes. J Thorac Cardiovasc Surg 1988;96:939-946.[Abstract]
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Accepted for publication October 13, 1999.




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