Bronchiolitis Obliterans Syndrome Complicating Lung or Heart-Lung Transplantation

John A. Belperio, MD; Kathleen Lake, PharmD; Henry Tazelaar, MD; Michael P. Keane, MD; Robert M. Strieter, MD; Joseph P. Lynch, III, MD

Disclosures

Semin Respir Crit Care Med. 2003;24(5)

Summary

Management of BOS complicating LT is difficult because no treatment strategies have been proven to influence survival or long-term outcome ( Table 6 ). For patients failing aggressive medical therapy, retransplantation is an option, but given the limited number of donor organs, the ethics and role of retransplantation in this context are controversial. Ultimately, a greater understanding of the pathogenesis of BOS may allow development of novel therapeutic strategies that may improve outcome.

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Funding information

This work was supported, in part, by grants from the NIH (HL04493 to JAB; HL03906 to MPK; P01HL67665 to MPK and RMS; and CA87879, P50CA90388, and HL66027 to RMS). JAB is a recipient of the ALA Research Grant Award, RG-019-B.

Reprint Address

John Belperio, M.D., Division of Pulmonary and Critical Care Medicine, University of California at Los Angeles, David Geffen School of Medicine, 900 Veteran Ave., 14-154 Warren Hall, Box 711922, Los Angeles, CA 90024-1922. E-mail: jbelperio@mednet.ucla.edu.

Table 1. Table 1. Histopathology of Lung Allograft Rejection
Acute (cellular) allograft rejection Perivascular lymphocytic infiltration (CD8+ predominant) May extend into alveolar interstitium and alveolar spaces Variable degrees of necrosis of epithelial cells Bronchiolitis obliterans Circumferential narrowing lumens of terminal and respiratory bronchioles Fibrosis, granulation tissue within or around airway lumens Bronchial epithelial cell necrosis Smooth muscle cells, myofibroblasts, mature collagen Obliterate airways Lymphocytic bronchitis/bronchiolitis Lymphocytic infiltration terminal and respiratory bronchioles May involve bronchial epithelium and mucosa Acute cellular rejection may be present concomitantly Bronchitis obliterans-organizing pneumonia Fibromyxomatous granulation tissue filling terminal and respiratory bronchioles Extends into alveolar ducts and alveolar spaces "Organizing pneumonia" distal to alveolar ducts Alveolar architecture is preserved

Table 2. Table 2. Clinical Features of Bronchiolitis Obliterans Syndrome
Shortness of breath, exercise limitation Airflow obstruction (reduced FEV₁, expiratory flow rates) Mosaic pattern of attenuation or air trapping on high-resolution computed tomographic scan Recurrent lower respiratory tract infections Isolation of Pseudomonas aeruginosa from respiratory cultures Increased neutrophils in bronchoalveolar lavage fluid

Table 3. Table 3. International Society of Heart and Lung Transplantation Staging System for Bronchiolitis Obliterans Syndrome
	1993 Grading System^[43]	2002 Revised Classification System^[11]
BOS 0	FEV₁ > 80% of baseline	FEV₁ > 90% and FEF_25-75 > 75% of baseline
BOS 0p	Not applicable	FEV₁ 81-90% and/or FEF_25-75 ≤ 75% of baseline
BOS 1	FEV₁ 66-80% of baseline	FEV₁ 66-80% of baseline
BOS 2	FEV₁ 51-65% of baseline	FEV₁ 51-65% of baseline
BOS 3	FEV₁ < 50% of baseline	FEV₁ < 50% of baseline

Reproduced with permission from Estenne, Hertz.^[5]

Table 4. Table 4. Bronchiolitis Obliterans Syndrome: High-Resolution Computed Tomographic Features
Bronchial wall dilatation Bronchial wall thickening Patchy regions of low attenuation (hyperlucency) Mosaic pattern (low and high areas of attenuation) Air trapping on expiratory computed tomographic scan

Table 5. Risk Factors for Obliterative Bronchiolitis
Reference	Patient Cohort	Risk Factors
^[75]University of Minnesota	121 LTRs surviving > 90 days	Multivariate analysis
		CMV pneumonitis (RR 3.2, p = 0.02)
		HLA mismatches at A locus (RR 2.4, p = 0.006)
		Late acute rejection (RR 1.3, p = 0.02)
^[77]University of Pittsburgh	162 LTRs surviving > 60 days	> 3 episodes of grade ≥ 2 AR (p = 0.00001); any grade ≥ 3 AR (p = 0.0001)
^[9]Papworth, Cambridge, UK	230 LTRs surviving > 90 days; OB in 109	Multivariate: early acute rejection (< 6 months); CMV serological status
^[27]Loyola University, Chicago	134 LTRs surviving > 90 days; OB in 66 (49%)	Cumulative AR score ≥ 180 days (p < 0.050; LBB at ≥ 180 days (< 0.01); late AR; decreased cyclosporine levels (p < 0.001)
^[25]Stanford	74 LTRs surviving > 90 days; OB in 48 (65%)	Univariate: sum of AR score (p = 0.0004); any AR (≥ grade 2, p = 0.014); lymphocytic bronchiolitis (p = 0.03)

AR, acute (cellular) rejection; CMV, cytomegalovirus; HLA, human leukocyte antigen; LBB, lymphocytic bronchitis/bronchiolitis; LTRs, lung transplant recipients; OB, obliterative bronchiolitis.

Table 6. Management of Bronchiolitis Obliterans Syndrome
Treat specific complications Treat/prevent episode of acute allograft rejection Supplemental oxygen (when hypoxemia documented) Bronchodilators (for symptomatic relief) Treatment of BOS of unproven value, but consider: Intensification of immunosuppressive therapy Intravenous pulse methylprednisolone (1 g daily × 3 days, oral taper) Substitution of mycophenolate mofetil for azathioprine Substitution of tacrolimus (or sirolimus) for cyclosporine Addition of methotrexate or cyclophosphamide Cytolytic therapy (antithymocyte globulin, antilymphocyte globulin, OKT3) Interleukin-2 receptor antagonists (e.g., daclizumab, basiliximab) Aerosolized cyclosporine Aerosolized corticosteroids Total lymph node irradiation Extracorporeal phototherapy Azithromycin Retransplantation for BOS failing medical therapy is controversial

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