BRONCHIOLITIS OBLITERANS 2
The pathologist must be aware that a slide displaying a well oriented cross section of a membranous or respiratory bronchiole is the exception rather than the rule in a TBBx. One needs to learn to recognize the interrupted fascicles of smooth muscle which define the respiratory bronchiole and to identify the amount of "normal" connective tissue surrounding the muscle and within the submucosa. This is essential because OB frequently is identified as bridging bands of scar tissue crisscrossing airway lumens and obliterating the conducting passage. Bands of blue collagen on trichrome connecting cords of red smooth muscle provide the key to early diagnosis. In our experience, the vast majority of histologic OB cases will have a clinical correlate in new onset pulmonary function abnormalities. In the absence of TBBx confirmation, a repeat TBBx will be performed which increases yield by 10 - 20%. If the diagnosis is still unconfirmed after two TBBx sessions, the patient is either given a clinical diagnosis of OB using the BOS criteria or taken to thoracoscopic wedge biopsy. It should be emphasized that scarring of the respiratory bronchioles or even alveolar ducts requires that one assumption be made about the donor lung - that it is normal when harvested. In fact, many donor lungs are from cigarette smokers and show evidence of smokers (respiratory) bronchiolitis with fibrosis of the alveolar ducts and airways. This needs to be factored when a diagnosis of OB is considered. Be certain to compare the current biopsy to previous ones, especially the first after transplant where OB is rarely seen. In the experience of the University of Pittsburgh approximately 30% of our patient population develops clinical and pathologic bronchiolitis obliterans usually late in the first year after transplant. The response of these patients to interventional therapy has been disheartening. Approximately two thirds of the patients experience a progressive unrelenting loss of pulmonary function which may continue for several years. The development of progressive obstruction is frequently accompanied by repetitive infectious episodes, primarily bacterial and fungal, which exacerbates this progressive decline. Ultimately patients expire of an infectious complication. Bronchiolitis obliterans develops on an average of 11 months post-transplant, however it has been noted to develop as early as two months after transplant and as late as several years after transplantation. New therapies are currently being developed to combat this chronic process, and at the University of Pittsburgh we have focused largely on the use of aerosolized cyclosporine. Graft Atherosclerosis:
Developing hand-in-hand with bronchiolitis obliterans is a progressive myointimal thickening of the pulmonary arteries and veins which corresponds to the graft atherosclerosis seen in the coronary arteries of heart allografts. In fact the development of pulmonary atherosclerosis in heart/lung recipients correlates strongly with the development of coronary artery changes in the cardiac allograft. The pulmonary vascular changes which develop seem to have little functional impact however and at this point in time are histologic curiosities. I have seen rare cases of marked vasculitis in acute rejection, which caused disproportionate vascular destruction and in these cases pulmonary hypertension was noted. We are unclear what isolated atherosclerosis in a TBBx means, in the absence of OB. It may occasionally be due to donor disease perhaps previous vascular damage from acute rejection, or a harbinger of OB. This finding needs to be further investigated. Philosophical Aside:
Although we classify acute rejection by the degree of perivascular infiltrates, it is important to recognize that the long term survival of the graft is tied to a progressive airway obliterative process. To many of us, this paradox highlights the need to grade the degree of airway inflammation in acute rejection reactions (B1-B4) and to study airway damage over time in lung allografts. With mononuclear cell damage to epithelium and mesenchyme, there comes a point in time where scarring develops and bronchiolitis obliterans is diagnosed. How this fibrosis develops is a question. Is bronchiolitis obliterans simply an uncontrolled acute rejection? Does bronchiolitis obliterans develop some time after transplantation when specific lymphocytes and mononuclear cells are stimulated and become alloreactive? Is there a low level of airway rejection in all transplant patients that smolders along until enough airways are damaged to cause obstructive function tests? Probably each hypothetical scenario accounts for some cases of chronic rejection. We also use fibrosis to differentiate bronchiolitis obliterans from the airway damage in acute rejection. In future grading schemes, it may be worthwhile to develop three scales of rejection grade: a perivascular inflammation grade, and airway inflammation grade, and a degree of fibrosis grade which, in the context of the number of vessels and bronchi/bronchioles affected, could generate a numerical score of rejection.
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