Bronchodilator Response at Low Lung Volumes Predicts Bronchiolitis Obliterans in Lung Transplant Recipients

Bronchodilator Response at Low Lung Volumes Predicts Bronchiolitis Obliterans in Lung Transplant Recipients* Natarajan Rajagopalan, MD; Janet Maurer, MD; and Steven Kesten, MD, FCCP Background: Bronchiolitis obliterans syndrome (BOS) is the major obstacle to long-term lung allograft viability. The diagnosis often occurs after significant organ dysfunction is present, and BOS is often unresponsive to standard immunosuppressive agents. We have observed bronchodilator responses (BRs) at low lung volumes in many of our patients who have developed BOS. We therefore assessed whether BR could predict the development of BOS. Methods: We conducted a retrospective review of the clinical and pulmonary function laboratory records of 146 patients who underwent transplantation between March 1983 and November 1993. BR was defined as 25% or more increase in forced expiratory flow at 50% of vital capacity or 30% or more increase in forced expiratory flow at 75% of vital capacity. BOS was defined according to recently published FEV1 criteria. Bronchiolitis obliterans was defmed histologically according to criteria of the Lung Rejection Study Group. Results: Of the total population, 52 were excluded because of death or insufficient information. BRs of the small airways were seen in 31 patients (33%), 25 of whom developed BOS (83%). Approximately half of

those with BR who developed BOS had evidence of acute rejection in the month prior to the onset of BR. Two thirds (four of six) of patients with BR not developing BOS had acute rejection in the previous month. The sensitivity of BR in predicting BOS was 51% with a specificity of 87%. The positive predictive value was 81%. Conclusions: BR appears to be useful as an early marker of BOS. The development of BR in selected patients should lead to closer monitoring and possibly a trial of augmented immunosuppression to arrest the establishment of BOS. (CHEST 1996; 109:405-07)

Bronchiolitis obliterans (BO) is thought to be a chronic rejection process that occurs in approximately 50% of long-term smvivors of lung transplantation.1·2 Risk factors for the development of BO include recurrent episodes of acute rejection, inadequate or fluctuating maintenance of immunosuppression, and recurrent infection of any etiology.3·4 While no clear predictors of BO have been identified, donor-specific alloreactivity in cells from BAL has been shown in some cases to precede both acute rejection and B0.5 Transbronchial biopsy evidence of BO is relatively infrequent despite a compatible clinical scenerio. 6 Hence, a clinical definition for the bronchiolitis obliterans syndrome (BOS) has been developed.7 A noninvasive, easily measurable, and reproducible clinical parameter that could identifY potential patients at risk of developing BOS prior to significant declines in lung function might lead to early treatment

and an improved outcome. In searching for such a predictor, we observed that many transplant patients who eventually develop BOS have preceding small airway bronchodilator responses (BRs). We reviewed all our available data from prebronchodilator and postbronchodilator studies in an attempt to determine if BRs of small airways obstruction in lung transplant recipients predict BOS.

*From the Toronto Hospital, University of Toronto, Ontario, Canada. Manuscript received May 2, 1995; revision accepted September 19.

BO=bronchiolitis obliterans; BOS=bronchiolitis obliterans syndrome; BR=bronchodilator response; FEF50= forced expiratory flow at 50% of vital capacity; FEF 75= forced expiratory flow at 75% of vital capacity

Key words: bronchiolitis obliterans syndrome; bronchodi-

lators; diagnosis; lung transplant

MATERIALS AND METHODS

Study Design

We reviewed retrospectively the clinical and pulmonary function laboratory records of 146 patients who underwent 154 transplant procedures between March 1983 and November 1993. Thirty-two patients who died within 3 months of surgery and 20 patients without postbronchodilator spirometry were excluded. Spirometry

Laboratory-based spirometry was routinely performed prior to and after inhalation of 400 pg of albuterol at 1,3,6,9,12,18, and 24 months, and yearly thereafter. Laboratory-based spirometry was requested when a change in clinical status occurred (ie, respiratory symptoms, decline in home spirometry, radiologic abnormality). CHEST / 109 / 2 / FEBRUARY, 1996

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Forced expiratory flow-volume curves were done with a spirometer (Morgan). ABR was defined as 25%or more increase in forced expiratory flow at 50% of vital capacity (FEFso) or 30% or more increase in forced expiratory flow at 75%of vital capacity (FEF7s). Surveillance for Rejection and Infection

Although not part of a protocol for our initial experience with lung transplantation, most patients have undergone transplantation since the institution of surveillance bronchoscopies with BAL and transbronchial biopsies. Laboratory-based spirometry always has been performed whenever a surveillance bronchoscopy has been scheduled. The maintenance immunosuppressive regimen for all patients has included prednisone, cyclosporine, and azathioprine. Definition of BO

BO was defined histogically according to criteria of the Lung Rejection Study Group.8 BOS was defined according to recently published FEV 1 criteria.7 Data Analysis

Results are expressed as means±SDs. A x2 analysis was used to evaluatt> the presence ofBR aml tht> likt> lihood of developing )30S. Flow rates between groups were compared with the unpaired t test. Statistical significance was considered at p less than 0.05. Sensitivity, specificity, and positive predictive values of BR of small airways in predicting BOS were calculated. RESULTS Population Characteristics

The 94 patients in the study included 53 men and 41 women (mean age, 43±12 years; range, 15 to 64 years). There were 17 single lung transplant recipients and 77 double lung transplant recipients. Incidence of BR

Forty-nine patients developed BOS, 25 of whom showed preceding BR. Histologic evidence of BO by transbronchial biopsy was seen in 27 of 49 patients by transbronchial biopsy specimens. The underlying diagnoses of patients developing reversible obstruction preceding BO included the following: emphysema (six), cystic fibrosis (four),
Table 1-Prebronchodilator and Postbronchodilator Spirometric Results in the BR group (n=31) and the Group Without BR (n =63)

FEV1, L

FEFso, Umin

FEF7s, Umin

2.86±1.52 3.83±1.70*

1.20::':0.83 1.95±1.30*

3.67::':1.9I 3.90±1.70

1.59::':1.20 2.00±1.40

31.2±13.2 6.2::':7.1

35.1±34.0 7.8± 11.9

Prebronchodilator BR 2.59±0.94 no BR 2.04±0.9I Postbronchodilator BR 2.76±0.96 No BR 2.08±0.90 Percent increase BR 7::': 6 No BR 2.4±3.4 *p<0.05 compared with BR group.

lung recipients, 9 developed BOS. Seven of the nine showed BR before developing BOS. Only one of the single lung transplant recipients had evidence of BR without developing BOS during the study period. None of the single lung recipients had significant BRs prior to transplantation. Spirometry

The mean time interval between transplantation and BOS was 25±21 months. The mean interval spirometry indicating BR and BOS was 12.4± 17 months. In the group with BR, FEVI did not appear to exhibit significant bronchodilator responsiveness (Table 1). The mean time from transplantation to BR was 19.5±21.4 months in the double-lung transplant patients and 15.2±14.6 months in the single-lung transplant patients. In the group without BR, the mean increases in FEVI, FEF50, and FEF 75 following bronchodilator inhalation were all under 10%. Although a significant difference existed between the BR and no BR groups in both pre bronchodilator FEF50 and FEF 75 (p<0.05), no such difference could be detected in postbronchodilator values (Table 1). Analysis

There was a significant association between BRand BOS (p<0.0001). In the month preceding the development ofBOS, 13 of25 patients who showed BR had greater than grade 1 acute rejection and 1 had infection with cytomegalovirus at the time of surveillance bronchoscopy. Transbronchial biopsy specimens were inadequate for histologic diagnosis in three patients. In eight other patients, biopsies were not done at the time of demonstration of BR as the patients were asymptomatic, had no changes in FEVI that would lead to bronchoscopy, and were not scheduled for a surveillance bronchoscopy close to the time of demonstration of BR. These patients had postbronchodilator spirometry because of minor respiratory symptoms such as cough or chest tightness. Four of five patients with BR Clinical Investigations

in the non-BOS group had grade 1 rejection just prior to the demonstration of BR; there was no histologic evidence of rejection from the other biopsy procedures. The sensitivity of BR in predicting BOS was 51% with a specificity of 88%. The positive predictive value was 87%. The negative predictive value was 62%. DISCUSSION

The major obstacle facing long-term viability oflung allografts is chronic organ dysfunction from BO. Present therapeutic strategies are often ineffective in reversing BOS. However, it is possible that early identification of BOS may improve the likelihood of a satisfactory response to potential therapeutic agents. We have identified BRs at low lung volumes through FEF50 and FEF75 as potential early markers of BOS. In the present study of 94 patients, reversible obstruction of the small airways was seen in 31 patients (33% ), 25 of whom developed BOS (83%). Approximately half of those with BR who developed BOS had evidence of acute rejection beyond grade 1 in the month prior to the onset ofBR. Two thirds (four of six) of patients with BR not developing BOS had mild acute rejection (grade 1) in the previous month. Declines in FEF50 and FEF75 cannot be categorized as BOS by the present international classification. However, based on our data, we suspect that many of these patients will eventually develop BO. Our data might reflect subclinical rejection of the small airways and may enhance early detection and treatment. The small airways hyperreactivity was seen to precede BOS by an average of 1 year, although there was significant variability. H yperreactivity of the airways has been evaluated in the past by inhaling increasing concentrations of pharmacologic agents (ie, methacholine) and ultrasonically nebulized distilled water. A proportion of lung allograft recipients will develop hyperresponsiveness to methacholine, a phenomenon considered to represent denervation hypersensitivity. 9.1° Reactivity to methacholine has also been shown to be associated with acute rejection and infections. 11 However, to our knowledge, there are no reports demonstrating an association between hyperreactivity and BOS. Higenbottam et al 12 have shown an association between hyperreactivity to ultrasonically nebulized distilled water and the presence of perivascular infiltrates in transbronchial biopsy specimens. It has been hypothesized that this hyperreactivity is the result of the loss of a bronchodilator effect of nonadrenergic, noncholinergenic nerves in the airwaysP Burke et al 14 speculated that patients who show hyperreactivity to methacholine are at an increased risk of developing BO, but

no definite correlation was made. In summary, BR of small airways can be identified in approximately one half of patients developing BOS. Of patients with BR of small airways, 83% develop BOS, a finding that may precede BOS by many months. It is possible that the incidence may be higher with a longer period of follow-up. The positive predictive value of 0.8 of a bronchodilator responsive to albuterol makes it a very useful test in lung transplant recipients. Taken in conjunction with the decline in flows at lower volumes at the time of bronchodilator responsiveness, closer monitoring and a trial of augmented immunosuppression to arrest the establishment of BOS may be warranted. REFERENCES

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