Introduction

Bronchiolitis obliterans (BO) is a frequent late onset pulmonary complication occurring after allogeneic stem cell transplantation (SCT). Although the underlying pathogenic mechanisms leading to post-SCT-BO are poorly understood, this disorder is commonly attributed to chronic graft-versus-host disease (GVHD).¹ All studies report an increased mortality and an altered quality of life in SCT patients developing BO.^{1, 2, 3, 4, 5, 6, 7} The incidence of BO varies among series in part because of variable definitions and diagnostic criteria. Although pathological findings represent the gold standard criteria for the diagnosis of BO, lung biopsy is rarely performed in these patients and the diagnosis is usually based on the presence of irreversible airflow obstruction on pulmonary function tests (PFTs), in a compatible clinical setting.¹ The criteria used to define airflow obstruction differ among authors making it difficult to compare the different series.^{3, 4, 5, 7} For example, Chien et al.⁵ suggested that airflow obstruction in allogeneic SCT recipients was underestimated when using forced expiratory volume in 1 s (FEV₁)/forced vital capacity (FVC) ratio <70% as a diagnostic threshold and proposed to rather consider the annualized rate of FEV₁ decline to detect patients developing small-airways disease.⁵ Using this criteria, the incidence of airflow obstruction rose from 12 to 26% in that series. However, FEV₁ decline may occur only after numerous small airways are already narrowed. The earliest change associated with airflow obstruction in small airways is reflected by a proportionally greater reduction in mean expiratory flow between 25 and 75% of FVC (MEF25–75%) than in FEV₁, although MEF25–75% is a highly variable spirometric test that has to be analyzed with caution.⁸

More recently, high-resolution computed tomography (HRCT) of the lungs has been recognized as an useful tool for the exploration of small-airways diseases of different etiologies.⁹ Available lung HRCT in small series of patients with post-SCT BO showed air trapping at full expiration in all cases, strongly suggesting that lung HRCT should be considered for diagnosis of this disease.^{10, 11} Furthermore, lung HRCT may allow identification of patients at an earlier stage of BO, before the development of a significant airflow obstruction on pulmonary function tests.

Whatever the criteria used for the diagnosis of post-SCT BO, treatment of this disease is empiric, and consists of corticosteroids and increased immunosuppression, targeting chronic GVHD.¹ However, only few patients respond to treatment and show clinical improvement especially when the disease is severe; patients frequently develop progressive respiratory failure and/or severe infectious complications favored by immunosuppression.¹ Thus, alternative therapeutic strategies are strongly needed for these patients, especially at early stages of BO.

The combination of inhaled steroids (ICS) and long-acting bronchodilators (LABA) are known to improve respiratory symptoms and lung function in chronic obstructive pulmonary disease and asthma in which bronchiolar inflammation is a predominant feature.^{12, 13} Furthermore, this combination has been consistently superior to ICS monotherapy used at higher doses.^{14, 15} Thus, we hypothesized that this treatment may have beneficial effects in early stages of BO after SCT when bronchiolar inflammation has been shown to be present.^{16, 17}

We retrospectively evaluated the results obtained in our department with the use of a combination of ICS and LABA (Budesonide/Formoterol) in adults with clinical post-SCT BO and no extra-thoracic sign of GVHD requiring the increase of the immunosuppressive treatment. Because this treatment could be more effective in patients with mild disease, it was administered to patients with significant airflow obstruction as well as patients with no airflow obstruction on PFTs but with clinically suspected BO and extensive air-trapping at full expiration on lung HRCT.

Patients and methods

Patients

Between 1 January, 2003 and August 2005, 22 adult patients of the Bone Marrow Transplantation Unit were referred to our Pulmonary department for respiratory symptoms attributed to BO. Among them, 13 patients showed no extra-thoracic signs of chronic GVHD and therefore did not require the introduction or the increase of an immunosuppressive treatment. They received inhaled Budesonide/Formoterol without modification of their other medications.

Diagnosis of BO

The diagnosis of BO was based on results of lung function measurements and/or lung HRCT findings performed in all patients. PFTs were performed using a body plethysmograph in all cases (Jaeger Masterscreen Body; Jaeger, GmBH; Wurzburg, Germany). An obstructive ventilatory defect was defined by a reduced FEV₁/VC (vital capacity) ratio below the 5th percentile of the predicted value as recently recommended.⁸ Reversibility of airflow obstruction was systematically tested by measuring FEV₁ after administering inhaled short-acting -agonists. An increase of FEV₁12% and 200 ml was considered significant. Patients with a reversible bronchial obstruction were excluded. MEF25–75%, total lung capacity (TLC), residual volume (RV)/TLC ratio and VC values were also recorded.

Lung HRCT were performed on every patient using a dual-slice computed tomography (CT) Scanner (Mx Twin, Elscint, Haifa, Israel). Acquisitions were performed during both deep inspiration and expiration, with a patient lying in the supine position, by using 1.0 mm collimation, a 1-s scanning time, 120 kVp and 240 mAs. The images were reconstructed by using a high-spatial frequency algorithm. Two experienced pulmonary physicians (AB,AT), unaware of PFTs results, reviewed thin-section CT slices searching for the presence of bronchial dilatation, bronchial wall thickening, and heterogeneous hypo-attenuation areas. On expiratory scans, the extent of air trapping was estimated at three levels on axial images: upper, middle and lower for each lung, as described previously by de Jong et al.¹⁸ as following: 0, no air trapping; 1, <33% of the lung affected; 2, 33–67% affected; 3, >67% affected. For each lung, the maximum possible score was 9 (18 for both lungs). An air trapping score of five or more was considered as abnormal.¹⁸ No patient presented interstitial lung disease on lung HRCT.

The diagnosis of BO was retained when respiratory symptoms were associated with an irreversible obstructive lung disease on PFTs and/or a significant air trapping score on lung HRCT. In all cases, nasopharyngeal aspirate was performed for viral culture and, in patients with productive cough, sputum was analyzed for bacteria and fungi in order to exclude respiratory infections.

Budesonide/Formoterol treatment

Budesonide/Formoterol 400/12 g was administered twice a day using a turbuhaler device. Appropriate education for treatment with the inhaler was provided to every patient and both their clinical status and pulmonary function were evaluated on a regular schedule.

Statistical analysis

For continuous variables, meanstandard deviation (s.d.) is given. Mean increase of FEV₁ and MEF25–75% values were tested over time using mixed-effect model, accounting for intra-patient correlation of serial measures. All statistical tests were two-sided, with P-values of 0.05 or less denoting statistical significance.

Results

Demographic and clinical features of the 13 selected patients are displayed in Table 1. Mean age was 40.310.8 years at the beginning of treatment. Four patients were ex-smokers, two had a history of bacterial pneumonia and one had previously presented an interstitial pneumonia of unknown origin. No patients or donor had a history of allergy or asthma. Five patients had symptoms of gastro-esophageal reflux. All but two patients (4 and 5) underwent transplantation after a myeloablative conditioning regimen. The two remaining patients had reduced intensity conditioning and had received previous autologous SCT. GVHD prophylaxis regimen included the association of Methotrexate and Cyclosporin for all except two patients who received Cyclosporin alone or in association with Mycophenolate mofetil. Cytomegalovirus reactivation was previously noted for eight patients. Nine patients had previously presented acute GVHD. Twelve patients had mild to moderate chronic GVHD (six men, six women) diagnosed according to previously published criteria¹⁹ and one was free of signs of GVHD.

Table 1 - Patients and transplant characteristics.

Full table

All patients were referred for respiratory symptoms. Among the 13 patients, 10 complained of cough, 12 had dyspnea on exertion and seven had repeated 'bronchitis'. The intensity of dyspnea was assessed according to NYHA classification (class 1–4). Physical lung examination was normal for five patients, whereas squeaks and wheezing were present respectively in seven and five patients, respectively (Table 1).

The 13 patients were divided into two groups. Seven patients presented clinical respiratory symptoms associated with fixed airflow obstruction on PFTs as defined earlier.⁸ The six remaining patients were suspected to have BO because of respiratory symptoms and the presence of significant air trapping at full expiration on lung HRCT, but showed no airflow obstruction on PFTs. The median time from SCT to diagnosis of BO was 70 months (range 5–256).

For the seven patients with irreversible airflow obstruction, baseline PFTs, expressed as means.d., were as follows: FEV₁/VC ratio 62.29% (range 52–71%); FEV₁ 2506 ml1071 (7430.2% predicted); VC 3844 ml1367 (9329.5% predicted); TLC 6416 ml1312 (108.625.3% predicted); RV/TLC ratio 131.624.3% predicted. The mean variation in FEV₁ after short-acting agonists with 95% confidence interval was +92.7 ml (-9.8; +195.2 ml) in absolute values and +5% (-0.1%; +10.13%). Mean value of MEF25–75% at baseline was 1602861 ml/s (4425% of predicted values). Interestingly, previous PFTs performed before the diagnosis of BO were available for four patients: before SCT (patient 4), within the 2 months following SCT (patients 3 and 6), and 3 years post-SCT (patient 7). In all cases, FEV₁/VC ratio was above the 5th percentile of the predicted value. In these patients, the mean FEV₁/VC ratio decreased from 85.30.6 to 66.85.2% at the time of diagnosis of BO. Lung HRCT scan was abnormal for all patients, with hypo-attenuated areas and air trapping on expiration characteristic of bronchiolar lesions (Figure 1). Bronchiectasies were noted in 11 cases. HRCT scores of air trapping at full expiration are shown in Table 2 and were always of 5 or more. Importantly, the mean score of expiratory air trapping in the group of patients who presented respiratory symptoms of BO without airflow obstruction on lung function tests was similar to that of patients with airflow limitation (9.13.3 and 8.71.6, respectively, Table 2).

Figure 1.

HRCT of the lungs from a patient with clinically suspected BO and normal lung function, showing extensive air trapping at full expiration.

Full figure and legend (98K)

Table 2 - HRCT findings at the time of diagnosis.

Full table

Outcome of the patients under Budesonide/Formoterol treatment

The median length of follow-up from the date of initiation of treatment was 12.8 months (range: 5–29). Respiratory symptoms improved in all patients. The main positive effect concerned the intensity of dyspnea, which was improved in 11 patients at last follow-up (Table 3).

Table 3 - Evolution of dyspnea evaluated by NYHA Classification at last follow-up.

Full table

Among the two patients with no change in the class of NYHA over the time, one patient (patient 1) did not complain of dyspnea at diagnosis (Table 3). Moreover, the intensity of cough and the number of episodes of 'bronchitis' decreased in all patients concerned.

Both FEV₁ and MEF25–75% improved during the follow-up. Individual serial FEV₁ values and MEF25–75% for each patient are shown in Figure 2, beginning with the values at the time of initiation of treatment and follow-up measurements. The mean increase of FEV1 over time both in absolute values and in percentage was significant (P=0.018, 0.015, respectively) with an increase of FEV₁ of 534268 ml in absolute values and 3627% at last follow-up, compared to pretreatment measures. In all patients, the improvement of FEV₁ was greater than 10% of predicted values (16.97.2%) and/or 200 ml. Assuming a linear increase between treatment onset and FEV₁ measurements, we estimated at 2.3 months, the mean delay to reach an improvement of 200 ml of FEV₁ (range 0.2–7). The mean increase of MEF25–75% over time both in absolute values and in percentage was also significant (P=0.012 for both), with an increase of MEF25–75% of 891530 ml/s in absolute values and 7143% compared to pretreatment values. This response to treatment was sustained in all patients during follow-up except for patient 4 (Figure 2). For this patient, after a significant improvement at the beginning of treatment, the FEV₁ and MEF25–75% values decreased over time (Figure 2). Interestingly, this patient was the only one whose dyspnea did not improve under treatment. No patient died during the follow-up.

Figure 2.

Evolution of FEV₁ (a) and MEF25–75% (b) during follow-up in the seven patients with clinical BO and ventilatory obstructive defect before initiation of treatment. The improvement of FEV₁ and MEF25–75% over time was statistically significant (P=0.018, 0.012, respectively).

Full figure and legend (25K)

Discussion

In this series of patients with mild to moderately severe clinical BO following SCT, treatment with inhaled Budenoside/Formoterol combination resulted in a sustained improvement of respiratory symptoms in all cases and in a statistically significant increase of FEV₁ and MEF25–75% in those who initially presented airflow obstruction.

Although the gold standard criteria for post-SCT BO is lung histological findings,¹ because of the attendant risks of the surgical procedure, we did not perform open lung biopsy in our patients. Nevertheless, the diagnosis of post-SCT BO was based on the combination of several criteria: the presence of respiratory symptoms in the absence of other alternative cause, extensive air trapping on expiratory CT scans of the lungs, and airflow obstruction in a subgroup of patients. Lung HRCT was used as an important diagnostic criteria because it has been demonstrated to be very useful in identifying bronchiolar diseases.⁹ In particular, a strong correlation has been found between air trapping at full expiration and the diagnosis of BO after lung transplantation,^{18, 20, 21} whose presentation is similar to post-SCT BO.⁴ Moreover, although the accuracy of lung HRCT for the diagnosis of BO post SCT has not been precisely evaluated, air trapping was always present in these patients in two small series.^{10, 11}

Different radiological scores have been proposed for the quantification of air trapping on expiratory slices.^{18, 20, 21, 22} However, limitations to these scoring systems exist, mainly due to sensitivity and specificity for disease progression and inter-observer and intra-observer variability. With these limitations in mind, de Jong et al.¹⁸ evaluated very recently the accuracy of an air-trapping scoring system for the detection of post-lung transplantation-BO and found that an air-trapping score >5 could identify BO earlier than FEV₁, with a good inter-observer and intra-observer agreement. Using the same scoring system, values obtained in our patients were of five or more in all cases, and thus support the diagnosis of BO.

The presence of airflow obstruction was not considered as a necessary criteria for the diagnosis of post-SCT BO, because histologically proven BO with normal lung function has been previously reported.¹ Pulmonary function is reliable for identifying proximal bronchial obstruction but FEV₁/VC values are not altered until numerous small airways are narrowed.⁸ Thus, in the new classification of the BO syndrome following lung transplantation, an additional stage with minimal alterations of PFTs has been recently proposed to diagnose patients earlier in the course of the disease.²³ Nevertheless, 7/13 of our patients had an obstructive ventilatory defect on lung function testing as defined by recent ATS/ERS recommendations,⁸ and mean expiratory flow values were clearly decreased in this subgroup of patients. Furthermore, in four patients, the mean FEV₁/VC ratio was significantly decreased at the time of diagnosis of BO when compared to previous PFTs. Finally, no patients presented a history of pulmonary disease that could explain this airflow obstruction and no patients or donors had a history of allergy or asthma. Therefore, the diagnosis of post-SCT BO can be considered in the population of patients presented here.

Although this disease usually carries a poor prognosis, the significant improvement of both respiratory symptoms in all patients and of airflow parameters in those with initial obstructive ventilatory defect under treatment with inhaled Budesonide/Formoterol combination was not totally unexpected. Indeed, it has been suggested that combination of ICS and LABA act synergistically to reduce bronchial inflammation,^{14, 15} a finding observed in early stages of post-SCT BO.^{16, 17} Accordingly, our study population had mild to moderately severe post-SCT BO, at a stage where bronchial inflammation could still be present and potentially targeted by inhaled anti-inflammatory treatments.

These results are encouraging, as few treatments have been shown to be effective in patients with post-SCT BO. Recently, macrolides have been proposed in the treatment of both lung and allogeneic SCT patients with BO.^{24, 25} Interestingly, Khalid et al.²⁵ described eight patients with post-SCT BO, half of them did not have airflow obstruction on lung function testing, making their study population comparable to ours. However, little information was provided concerning clinical symptoms of their patients. Thus, although promising, these results need confirmation, especially with a longer follow-up.

The bearing of the results of our experience is, however, clearly limited by the absence of a control group and the small sample size, which can lead to overestimation of the therapeutic effect. Moreover, the selection of patients with mild to moderately severe post-SCT BO and without extensive extrathoracic GVHD certainly induced a bias in the results and probably the prognosis of the patients. Nevertheless, our experience suggests a potential role for combination of ICS and LABA in the treatment of BO in allogeneic SCT recipients. The confirmation of the action of this treatment requires further investigation with a larger randomized controlled clinical study.

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Acknowledgements

We thank M Mao for excellent technical assistance.