"Refractoriness" of airflow obstruction associated with isolated lymphocytic bronchiolitis/bronchitis in pulmonary allografts

Abstract

The clinical significance of an isolated "lymphocytic bronchiolitis/bronchitis" (grade B) as detected in transbronchoscopic biopsy specimens (TBB) is unclear. We therefore have reviewed the spirometric responses associated with isolated grade B diagnoses and contrasted them with episodes of "acute cellular rejection" (grade A); the latter are manifested by "perivascular lymphocytic infiltration." Because lymphocytic bronchiolitis/ bronchitis is considered a nonspecific histologic pattern that may be observed with either allograft rejection or respiratory infections, episodes were analyzed with respect to the presence (grade B [+] CMV) or absence (grade B [-] CMV) of cytomegalovirus infection. The maximum forced expiratory volume in 1 second (FEV1) during the preceding 3 months was used as a baseline for computing percent change in FEV1 coincident with transbronchoscopic biopsies (delta %FEV1 PRE) and maximum values obtained during the 3 months subsequent to specific therapies (delta %FEV1 POST). All episodes of acute cellular rejection (grades A1 to 4) and symptomatic lymphocytic bronchiolitis/bronchitis (grade B) were treated with "pulsed-dose" methylprednisolone, whereas intravenous ganciclovir was administered to patients at risk for recrudescence of cytomegalovirus. Between March 1, 1989, and September 1, 1995, 366 TBB procedures were performed for clinical indications in 57 lung transplant recipients. Histologic diagnoses with acceptable serial spirometric values included grade A1 (n = 9), grade A2 (n = 27), grade A3 (n = 2), grade B(-)CMV (n = 25) and grade B(+)CMV (n = 9). The delta %FEV1 PRE coincident with TBB were not statistically different for the different histologic groups. For grade A1, delta %FEV1 PRE was -14.6% +/- 5.2% (X +/- SEM); A2, -7.6% +/- 1.8%; B(-)CMV, -14.8% +/- 3.9%; and B(+)CMV, -14.8% +/- 2.3%. After treatment, the delta %FEV1 POST, relative to baseline values, were for grade A1, -8.8% +/- 7.1%, A2, +0.26% +/- 2.6%; B(-)CMV, -12.0% +/- 3.8%; and B(+)CMV, -6.2% +/- 2.8%. The delta %FEV1 POST values after pulsed methylprednisolone were significantly greater for histologic grade A2 than grade B(-)CMV (unpaired Student's t test, P < 0.01; 95% confidence interval for the difference of means: 3.34% to 21.2%). Grade A2 rejection was associated with spirometric improvement to within 10% of baseline values in 52% of episodes; whereas with grade B(-)CMV, this salutary response was observed in only 32% of episodes. Bronchiolitis obliterans syndrome stage 1b developed in 13 of 20 (65%) recipients, approximately 7.9 +/- 3.4 months after detection of histologic grade B and 21.2 +/- 9.5 months after transplantation. We conclude that the relative "refractoriness" of histologic grade B most likely reflects a continuum of bronchiolitis obliterans after lung transplantation and, hence, may warrant different immunosuppressive strategies. Furthermore, spirometric decrement associated with acute cellular rejection (grade A) may be ameliorated, but often not completely reversed, after pulsed methylprednisolone. We speculate that surveillance TBB may prove rewarding by enabling an earlier detection of these histologic diagnoses before the development of physiologic impairment.