Cytolytic Therapy for the Bronchiolitis Obliterans Syndrome Complicating Lung Transplantation

doi:10.1378/chest.109.4.874

Chest

Volume 109, Issue 4, April 1996, Pages 874-878

https://doi.org/10.1378/chest.109.4.874 Get rights and content

The bronchiolitis obliterans syndrome (BOS) is the major cause of late morbidity and mortality after lung transplant (LTx). Previous studies suggest cytolytic therapy may be effective for the BOS but this therapy has not been proved effective or safe.

Method

A retrospective study of a predetermined treatment regimen to determine if the rate of fall in FEV₁ can be reduced by corticosteroids and cytolytic therapy. Since August 1992, 10 of 65 long-term survivors of LTx (5 men, 5 women; mean age 36 ±10 years) developed BOS. All had previously had lymphocyte immune globulin, antithymocyte globulin (equine) (ATGAM sterile solution; Upjohn Pty Ltd; Sydney, Australia) induction therapy and corticosteroid avoidance for the first 7 to 10 days post-LTx. Therapy for the BOS was initiated with pulse methylprednisolone and ATGAM (aiming for an absolute CD3 count of ≤100 cells per microliter for 5 days). ATGAM therapy was initiated at a mean 657±323 days post-LTx. Subsequent follow-up has been for 310±110 days (range, 163 to 530 days).

Results

Nine of ten patients had a response with tolerable side effects. Preintervention, there was a linear fall in FEV₁ of 0.22±0.15% predicted FEV₁ per day (mean±SD) (range, 0.06 to 0.56%) compared with a postintervention linear fall of 0.036±0.019% predicted per day (range, 0 to 0.13%) (paired t test; p<0.005). This effect is sustained over the follow-up period.

Conclusion

The fall off in FEV₁ that characterizes the BOS may be altered usefully by augmented immunotherapy. This effect can be rapid and sustained although it is neither completely arrested nor ever reversed. These data are preliminary but encourage a randomized control trial in the BOS.

Section snippets

Patient Population

Between March 1990 and March 1994, the Alfred Hospital Heart and Lung Transplant Service performed 82 heart-lung and lung transplants with an overall actuarial survival at 1 year of 77% and at 3 years of 62%. This includes 35 heart-lung, 24 single lung, and 23 double lung transplants. Since August 1992, 10 of 65 long-term survivors of lung transplantation (survived ≥30 days postoperatively) have developed the BOS and required treatment for this problem. Three other single lung transplant

Results

Ten patients have been treated for the BOS (Table 1). Nine patients had a response (Fig 1 and 2; Table 2) as judged by a reduced rate of fall of FEV₁ post-AT-GAM. One patient (patient 8) did not respond and ultimately died 9 months after the ATGAM as a result of chronic airflow limitation. The mean gradient (±1 SD) of the fall in percentage predicted FEV₁ per day preintervention was 0.22±0.15 and postintervention was 0.036±0.019 (p<0.005, paired t test). Pulse steroids were given 45±23 days

Discussion

These results suggest the decline in lung function associated with the BOS is able to be attenuated with augmented immunotherapy with acceptable side effects.

The time course of the change in slope of the FEV₁ with therapy suggests the ATGAM, rather than the corticosteroid, is probably the main contributor to a response. There is only limited support for use of corticosteroids alone in the literature. Paradis et al2, 17 and Allen et al¹¹ report a response to corticosteroids alone in the BOS, but

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Cited by (100)

Antithymocyte Globulin Treatment for Chronic Lung Allograft Dysfunction in Lung Transplant Recipients: Experience From a National Reference Transplant Center
2021, Transplantation Proceedings
Citation Excerpt :
In our experience, the cytolytic treatment with ATG is an alternative to consider in those patients with CLAD who do not respond to conventional therapies such as azithromycin or increasing immunosuppressant levels and in whom gastroesophageal reflux have been ruled out as the main etiology of CLAD. The results of our study are consistent with previous studies [18-20]. We have achieved and improvement or stabilization of lung function in 50% of the patients, figures that are superimposable to the works of Kesten et al [19] and Date et al [20], which obtained a success rate, understood as improvement or stabilization of FEV1, of 46% and 60%, respectively.
Chronic lung allograft dysfunction (CLAD) is the leading cause of mortality after the first year of transplantation and treatments can have little impact on CLAD progression in some cases. The objective of this study was to evaluate the effectiveness and safety of antithymocyte globulin (ATG) in lung transplant recipients with CLAD.
We reviewed all patients from our center that had undergone a lung transplant between 2008 and 2019 and selected those with CLAD who were treated with ATG. The closest lung function (forced expiratory volume in the first second) to the ATG administration was recorded, as well as the values 3, 6, and 12 months before and after treatment. We followed and recorded survival during the 12 months after treatment.
A total of 13 patients with CLAD received ATG treatment. A favorable positive response to treatment (improvement or stabilization on lung function) was achieved in half of the patients. Most patients (71%) who responded well to ATG were in CLAD stage 1 to 2. The fall slope of forced expiratory volume in the first second is better after treatment. The median survival was 27 months, and we found a trend toward better survival in early CLAD stages 1 to 2. There were also differences in survival between rapid decliners and nonrapid decliners.
ATG treatment could play a role in patient with CLAD who do not respond to conventional therapies. The effect of cytolytic therapy with ATG is clearly better in those patients in early stages, with little effect in those in CLAD stage 3.
Chronic Lung Allograft Dysfunction
2021, Encyclopedia of Respiratory Medicine, Second Edition
Lung transplantation is an effective short-term intervention for select patients with end-stage lung disease; however, long-term outcomes remain limited with a median posttransplant survival of only 5–6 years. Chronic lung allograft dysfunction (CLAD) is the leading cause of late death among lung transplant recipients. CLAD is characterized by an irreversible decline in lung function and correlates histologically with allograft fibrosis. This article summarizes the key diagnostic features of CLAD and its clinical phenotypes. We also discuss the pathobiology and risk factors for CLAD, consider therapeutic strategies, and comment on future avenues to improve long-term lung recipient outcomes.
Efficacy of Extracorporeal Photopheresis in Patients With Bronchiolitis Obliterans Syndrome After Lung Transplantation
2017, Transplantation Proceedings
Lung transplantation (LT) is only therapeutic option for patients affected by chronic respiratory failure. Chronic rejection, also known as bronchiolitis obliterans syndrome (BOS), is still the main cause of death and the most important factor that influences post-transplantation quality of life. Currently available therapies have not been proven to result in significant benefit in the prevention or treatment of BOS. Extracorporeal photopheresis (ECP) seems to reduce the rate of lung function decline in transplant recipients with progressive BOS.
From 1991 until now, 239 LTs were performed at our center. Fifty-four patients (22.5%) developed BOS; 15 of these (27.7%) were treated with ECP. At the beginning of the treatment, all patients showed a mean decline of forced expiratory volume in 1 second (FEV₁) from baseline values of 45.8% ± 17.2%; 2 patients were in long-term oxygen therapy.
Mean follow-up from November 2013 to June 2016 was 11.6 ± 7 months. Twelve patients (80%) showed lung function stabilization with an FEV₁ range after treatment between −6% to +8% from the pre-treatment values. We did not report any adverse effects or increase of infections incidence.
ECP seems to be an effective and well-tolerated therapeutic option for LT patients with BOS in terms of stabilization of lung function and increased survival.
Effectiveness of Rabbit Antithymocyte Globulin in Chronic Lung Allograft Dysfunction
2016, Transplantation Proceedings
Citation Excerpt :
We are aware of only three other reports in the medical literature that studied the effect of rATG on chronic lung allograft rejection. Snell et al. [12] found a significant decrease in the linear rate of decline in FEV1 after treatment with ATG in 10 patients. The effect seen was a slowing the decline rate of FEV1 rather than complete stabilization or improvement.
Rabbit antithymocyte globulin (rATG) therapy has been shown to be beneficial in lung transplant recipients as induction therapy for treating acute lung rejection; however, its role in chronic lung rejection has been reported only rarely. We evaluated the effectiveness of rATG therapy in slowing the progression of chronic lung allograft dysfunction (CLAD) syndrome.
We conducted a retrospective review of 25 lung transplant patients with CLAD who received rATG therapy in the Pulmonary Institute of Rabin Medical Center, Israel, between May 2005 and February 2016. Response to treatment was divided into 2 categories: stabilization, defined as a halting of the decline of forced expiratory volume in 1 second (FEV₁) for ≥6 months after rATG therapy, and deterioration, defined as showing a continued decline in FEV₁.
Of 25 subjects, 8 (32%) were categorized as part of the stabilization group and 17 (68%) were categorized as showing continued deterioration. The stabilization group was older (61 ± 8 vs 44 ± 19 years) and showed longer survival rate after rATG therapy (930 ± 385 vs 414 ± 277 days). The stabilization group also demonstrated a lower mean white blood cell count (7.9 ± 1.8 vs 8.5 ± 2.9 × 10⁹ cells/L) and lymphocyte count (0.37 ± 0.1 vs 0.55 ± 0.3 × 10⁹ cells/L) during rATG treatment. The stabilization group also demonstrated a higher FEV₁ after lung transplantation (91% ± 21% vs 75% ± 15.4%), at the beginning of rATG therapy (51% ± 11% vs 39% ± 9.6%) and at 6 months after rATG therapy follow-up (51% ± 9.1% vs 28% ± 7.6%).
rATG was effective in stabilizing rejection progression in approximately one-third of our patients with CLAD. rATG therapy should be considered early in the course of CLAD. Randomized, controlled studies should be considered to confirm these findings.
Suppression of bronchiolitis obliterans in allogeneic rat lung transplantation-Effectiveness of everolimus
2013, Experimental and Toxicologic Pathology
Chronic rejection (CR) after lung transplantation (LTX) manifests pathologically by fibrotic airway remodelling and bronchiolitis obliterans (BO). The role of the mammalian target of rapamycin inhibitor everolimus in preventing this process is poorly understood.
A rat model of left lung allo-transplantation (Fisher 344 to Wistar Kyoto) was used to analyze the effect of everolimus (2.5 mg/kg/day) on the development of CR. Drug therapy began on postoperative day (POD) 0, 7 and 14 characterizing different grade of acute rejection (AR) of the allograft before drug treatment.
Non-treated recipients developed severe acute rejection (AR) and first signs of CR on POD 20 and a pronounced CR on POD 60. On POD 20, only application of everolimus from POD 0 to 60 significantly reduced acute inflammatory infiltration (p < 0.001). Independent of treatment scheme, everolimus suppressed the development of early signs of chronic alterations (POD 20). However, neither early (POD 7–60) nor late (POD 14–60) application of everolimus affected the progression of CR (POD 60). Only its initial treatment (POD 0–60) inhibited the development of BO and vasculopathy (p < 0.001). An additional finding was a decrease in body weight after drug application.
The effectiveness of everolimus after rat LTX depended on the grade of inflammation of the allograft before initiation of drug treatment. Only allografts with no or low grade AR benefit from long-term treatment with everolilmus in the prevention of BO after LTX. It could be speculated that conversion to an everolimus-based immunosuppression after LTX might only be successful in patients free of BO.
Esophageal motor dysfunction and gastroesophageal reflux are prevalent in lung transplant candidates
2010, Annals of Thoracic Surgery
Gastroesophageal reflux and aspiration contribute to the development of bronchiolitis obliterans and accelerate graft deterioration after lung transplantation (LTx). We evaluated LTx candidates for esophageal motor abnormalities and gastroesophageal reflux.
Consecutive patients evaluated for LTx underwent 24-hour pH monitoring using a dual-channel pH probe and high-resolution esophageal manometry. High-resolution manometry was also performed in healthy control subjects. The prevalence of abnormal acid exposure was noted in the LTx candidates.
Thirty LTx candidates and 10 control subjects were evaluated. Lung transplantation candidates had higher residual upper and lower esophageal sphincter pressures. The mean proportion of peristaltic swallows was 21% lower in LTx candidates. Both hypotensive and aperistaltic swallows were sixfold more prevalent in LTx candidates than in control subjects. All control subjects had normal high-resolution manometry whereas 23 LTx candidates (76.7%) had esophageal peristaltic dysfunction. Abnormal acid exposure time was seen in the proximal and distal esophagus in 25% and 36% of LTx candidates, respectively. Lung transplantation candidates with idiopathic pulmonary fibrosis had more aperistaltic contractions, more negative minimum intrathoracic pressure, and a higher frequency of abnormal distal esophagus acid exposure. The majority of patients with complications after LTx demonstrated motor, anatomic, or pH abnormalities.
Disordered esophageal motor function and gastroesophageal reflux are common in LTx candidates. We believe high-resolution esophageal manometry is a valid tool to use and the abnormalities we identified may be representative of this unique patient population. The role of this study in predicting a worse outcome should be further studied in patients after LTx.

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Chest

Clinical Investigations: Lung TransplantationCytolytic Therapy for the Bronchiolitis Obliterans Syndrome Complicating Lung Transplantation

Method

Results

Conclusion

Section snippets

Patient Population

Results

Discussion

J Thorac Cardiovasc Surg

Clin Chest Med

Chest

J Thorac Cardiovasc Surg

Chest

Hum Pathol

A working formulation for the standardization of nomenclature and for clinical staging of chronic dysfunction in lung allografts

J Heart Lung Transplant

Immunologically mediated disease of the airways after lung transplantation

Ann Surg

Sequelae of cytomegalovirus pulmonary infections in lung allograft recipients

Am Rev Respir Dis

Clinical Investigations: Lung Transplantation
Cytolytic Therapy for the Bronchiolitis Obliterans Syndrome Complicating Lung Transplantation