Chest
ReviewBronchiolitis Obliterans After Lung Transplantation: A Review
Section snippets
Incidence and Prevalence
At Stanford University, the prevalence of clinically or histologically diagnosed BO in lung transplant recipients surviving longer than 3 months was 68%.10 The incidence within the first year after transplantation was 28% and the actuarial freedom from BO was 67, 47, 42, and 15% at 1, 2, 3, and 5 years after lung transplantation. Long-term data indicate that the cumulative risk of BO may reach 60 to 80% after 5 to 10 years after transplantation.11,12 Some reports indicate that the prevalence
Histology
The histopathologic features of posttransplant BO have been described in various reports.17, 18, 19, 20 The hallmark is an organizing inflammatory response centered on the respiratory and terminal bronchioles, and mature collagen is a key requirement for the pathologic diagnosis of BO. The collagen may totally or subtotally fill the lumen of the bronchiole or may lie in a subepithelial location. The mature collagen may be accompanied by the chronic inflammatory infiltrate and by proliferating
Pathogenesis
Graft rejection has been traditionally classified by its histopathologic pattern as acute or chronic. Acute rejection is orchestrated primarily by helper T-lymphocytes, which recognize donor major histocompatibility complex epitopes and secrete cytokines stimulating proliferation of cytotoxic T lymphocytes. These cells in turn cause injury to the graft. During acute rejection, donor-specific alloreactive lymphocytes have been found in BAL fluid and transbronchial biopsies.29, 30, 31, 32 In
Animal Models of BO
Animal transplant models have added substantially to the understanding of chronic allograft rejection. As outlined above, acute rejection is believed to be one of the most important precursors for later chronic rejection. To investigate this particular aspect of BO, an animal model, as a stable system with fewer confounding factors than are present in the setting of human transplantation, would be of great value. In a mouse model of skin and cardiac allografts, blocking T-cell-dependent immune
Risk Factors for Nontransplant BO
RO can be caused by many different factors in a variety of nontransplant settings. The development of BO has been described after inhalational injury with thionyl chloride,73 zinc chloride,74 and smoke;75 after infections with respiratory syncytial virus, parainfluenza virus, influenza virus, adenovirus,76 measles virus,77 and Mycoplasma pneumoniae;78,79 after drug treatment with d-penicillamine80 and tiopronine;81 after aspiration of charcoal;82 after irradiation;83 after working in the animal
Clinical Symptoms and Signs
The original descriptions of BO in heart-lung transplant recipients reported shortness of breath and chronic productive cough as major symptoms.2 Such early reports may have reflected findings of advanced disease with complicating bacterial infection or bronchiectasis. Today, BO is often diagnosed earlier due to close monitoring with pulmonary function studies and a high level of awareness.
Symptoms and signs of early BO are nonspecific. A decrease in FEV1 may occur before any clinical symptoms
Pulmonary Function Tests
After surgery, bilateral lung transplant recipients and heart-lung transplant recipients demonstrate normally shaped flow-volume curves. In contrast, single lung transplant recipients continue to show a pathologic flow-volume loop pattern depending on the underlying disease in the remaining native lung.124,125 A sustained decline in FEV1 of at least 20% compared to baseline (calculated as [(current FEV1 – baseline FEV1)/(baseline FEV1)]×100 in the absence of acute rejection or infection is a
Clinical Course of Bo
Three distinct patterns of presentation and progression in the clinical course of BO have been described.154 The first pattern is characterized by a rapid onset followed by a relentlessly progressive course, usually leading to death due to respiratory failure within 1 year of diagnosis. The second pattern is characterized by a similar rapid onset and initial rapid decline, but stabilization of lung function follows. The third pattern is characterized by an insidious onset and chronic
Treatment
In general, the range of available treatment options for established BO is narrow and disappointing. Complete return of lung function in cases of established BO has been described only anecdotally. To date, the best possible result is often a stabilization of lung function. As previously stated, the natural course of BO varies among affected patients. The variability of course and the frequency of concomitant airway infections further complicate evaluation of the success of different therapies.
Conclusion
BO occurs in more than half of lung transplant recipients who survive for more than 5 years and is the leading cause of death in the late posttransplant period. Our understanding of BO has been enhanced by studying quite reliable and reproducible animal models of obliterative airways disease that are likely to be reasonable surrogates of BO. Prevention of BO is the most useful direction for therapeutic interventions, particularly as it relates to the early diagnosis and treatment of acute
ACKNOWLEDGMENTS
The contributions of P. Vogt, MD, Department of Pathology, who provided us with FIGURE 1, FIGURE 2, FIGURE 3, FIGURE 4, and M. Hauser, MD, Department of Radiology, University Hospital, Zurich, Switzerland, who provided us with Figure 5, are gratefully acknowledged.
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Supported by a grant from the Swiss National Scientific Foundation and a grant from the Swiss Respiratory Society (Dr. Boehler).