Are we near to an effective drug treatment for bronchiolitis obliterans?

Abstract

Lung transplantation remains the only effective therapeutic option for well-selected patients with end-stage (cardio) pulmonary diseases such as emphysema, cystic fibrosis, lung fibrosis and pulmonary arterial hypertension. Although the results have improved lately, the long-term survival is still far behind other organ transplantations. This is mainly due to the development of chronic lung allograft dysfunction (CLAD), with bronchiolitis obliterans (BO) being the most frequent manifestation and restrictive CLAD or restrictive allograft syndrome (RAS) being a rather novel distinct entity, with a worse survival. Although the pathology of BO has been well described, this is not an obvious diagnosis after lung transplantation, because of the low sensitivity of transbronchial biopsies to detect BO. As a consequence, BO syndrome (BOS), the clinical correlate of BO, characterized by a progressive and obstructive decline in FEV₁, has been introduced and is used worldwide to describe patients affected by this condition. BOS is the major long-term problem after lung transplantation, occurring in some 50% of patients within 5 years after the transplant procedure and causing up to 30% of late mortality between 3 and 5 years after transplantation. Its treatment remains very difficult, although recent advances have certainly improved the survival after diagnosis of BOS. We will here review the current therapeutic options to try to prevent BOS on the one hand and to treat BOS on the other hand.

Keywords::

• bronchiolitis obliterans syndrome
• bronchiolitis obliterans
• lung transplantation
• treatment

1. Prevention of bronchiolitis obliterans syndrome

Since acute rejection episodes are a major risk factor for the later development of bronchiolitis obliterans syndrome (BOS), every effort should be undertaken to prevent acute rejection. Several immunosuppressive regimens, with or without induction treatment, are currently used, nevertheless this did not result in an important improvement in the prevalence of BOS. Although the combination of tacrolimus and mycophenolate seems to cause the least episodes of acute rejection in all age groups, compared to other regimes, this does not always translate into a lower prevalence of BOS [1,2]. In a recent Cochrane review, however, tacrolimus seemed to be significantly superior to cyclosporine regarding the incidence of BOS (RR 0.46, 95% CI 0.29 – 0.74), although this did not affect mortality (RR 1.06, 95% CI 0.75 – 1.49), nor incidence of acute rejection (RR 0.89, 95% CI 0.77 – 1.03) [3]. Whether or not to give induction treatment at the moment of transplantation remains controversial. Although the ISHLT registry report suggests a reduction in AR episodes and in the incidence of BOS and also a survival benefit in patients with induction treatment [2], there is very limited convincing evidence from controlled studies [4].

Gastro-esophageal reflux is a known risk factor for the development of BOS; hence, fundoplication has been advocated to prevent BOS. In a recent study, however, a significant improvement in the best postoperative FEV₁ and in the FEV₁ at 1 year was observed in patients who underwent fundoplication after transplantation, but the prevalence of BOS itself was not studied [5] and it remains unclear whether this procedure is able to really prevent BOS.

In a double-blind, placebo-controlled, randomized study in de novo lung transplant patients, addition of azithromycin, a macrolide antibiotic with immunomodulatory effects, to the current immunosuppressive drug regimen, was demonstrated to significantly prevent the development of BOS 2 years after transplantation [6].

In a single-center, randomized, double-blind, placebo-controlled trial, aerosolized cyclosporine, initiated within 6 weeks after lung transplant along with routine systemic immunosuppression did not improve the rate of acute rejection but improved survival and extended periods of chronic rejection-free survival [7]. Confirmation of this data in larger multicenter studies is still lacking.

Addition of inhaled corticosteroids (fluticasone propionate 750 mg BID) failed to prevent the development of BOS in a 2-year placebo-controlled study [8].

2. Treatment of established BOS

Once BOS has developed, survival is restricted to about 50% 2 years after diagnosis, but this is influenced by several factors such as early (< 2 years) or late BOS development and the initial BOS grade at diagnosis [9]. Giving this dismal prognosis, every effort is needed to try to stabilize the pulmonary function decline. Several treatment options are available, but none of them proved very effective.

2.1 Immunosuppressive agents

Changing basic immunosuppression has been investigated in several small and mostly retrospective studies. Conversion of cyclosporine to tacrolimus may arrest the decline in FEV₁ and the same has been demonstrated when switching from azathioprine to mycophenolate [10]. Whether mTOR inhibitors (rapamycin and everolimus) exert the same effect, is still a matter of debate [10].

Different other immunosuppressive agents such as cyclophosphamide, methotrexate and cytolytic therapy have been shown to exert identical effects; however, most studies are retrospective with small numbers of patients, which does not allow to draw firm conclusions [11].

Long-term treatment with high-dose corticosteroids (≥ 30 mg/day prednisone or an equivalent) has not been shown to improve BOS, while it is associated with numerous and frequent severe side effects. As such, this is not recommended.

2.2 Nonimmunosuppressive agents

Beneficial effects of the addition of azithromycin have been reported for approximately 35 – 40% of lung transplant recipients, affected with BOS. Complete reversal of FEV₁ decline may occur in some patients and those with BAL neutrophilia appear to represent a subset of patients that are particularly likely to respond to azithromycin therapy [12]. It remains, however, to be acknowledged that about 30% of patients, who initially responded to azithromycin, will later on redevelop BOS [13].

At present, a trial with azithromycin in all lung transplant recipients who develop BOS is therefore strongly recommended [1]. It is advised to check the QT interval before starting treatment with azithromycin, as sudden death due to prolonged QT interval is a potential risk, although this was so far not reported in lung transplant patients [12].

In a retrospective study, addition of montelukast (10 mg/day; 11 patients) to the immunosuppressive regimen, significantly decreased the FEV₁ decline from 112 ± 26 ml/month before BOS diagnosis to 13 ± 13 ml/month after 6 months of treatment. In the control group (n = 11), there was no significant change in the rate of FEV₁ decline (from 103 ± 20 ml/month before BOS diagnosis to 114 ± 27 ml/month). Although it was concluded from this study that adding montelukast may be a promising treatment option in patients with low neutrophilic (< 15%) BOS and already or concurrently being treated with azithromycin, this data certainly need confirmation in a prospective placebo-controlled trial [14].

In a small case series of BOS patients who are azithromycin-unresponsive, it was recently demonstrated that anti-TNF treatment may also be effective to arrest/improve the FEV₁ decline [15].

2.3 Extracorporeal photopheresis and total lymphoid irradiation

In several retrospective studies, extracorporeal photopheresis (ECP) treatment was demonstrated to reduce the rate of decline in lung function associated with progressive BOS, with some 25% of patients experiencing an FEV₁ improvement. Thirty-one of 51 ECP-treated patients responded to therapy and showed sustained stabilization of lung function over 6 months. Responders to ECP showed significantly improved survival and less need for retransplantation than nonresponders. Factors associated with an inferior treatment response were cystic fibrosis as underlying lung disease and a longer time between transplantation and development of BOS. Compared with BOS patients not treated with ECP, the ECP responders showed an improved graft survival [16]. In another study, ECP seemed to be particularly effective in BOS patients with increased bronchoalveolar lavage neutrophilia, who further deteriorate under azithromycin treatment [17]. No serious side effects were observed using ECP. Total lymphoid irradiation (TLI) treatment also resulted in an arrest in the decline in FEV₁ in lung transplant patients with progressive BOS. In 27 recipients who completed > 8/10 TLI fractions, FEV₁ decline was 122.7 ml/month pre-TLI compared to 25.1 ml/month post-TLI, p = 0.0004. TLI was well tolerated and associated with few serious side effects [18].

2.4 Retransplantation

Retransplantation for well-selected patients with progressive BOS may be the ultimate treatment option. Survival after retransplantation for BOS is reported to be largely comparable to survival after initial transplantation and much better than for primary graft dysfunction or persistent acute rejection [19]. Risk factors for survival after re-LTx are largely unknown, but earlier retransplantation and retransplantation in patients needing assistance were associated with worse outcome.

3. Conclusion

BOS after lung transplantation remains a very challenging condition, confronting the patient and the clinician with a lot of problems and an insecure future. Several treatment options have been investigated, of which none, except perhaps azithromycin, seems to really restore the pulmonary function to normal (at least temporarily). Conversion of basic immunosuppression is usually proposed as a first step, resulting in a treatment regimen with tacrolimus, mycophenolate and low-dose steroids. A trial with azithromycin is always advocated as this may improve the pulmonary function and the patient’s survival without serious side effects and with low cost. In case of further progression despite these adaptations, ECP seems to be the most promising and accepted treatment. Retransplantation can only be offered to a low percentage of patients with progressive BOS.

4. Expert opinion

Since the pathophysiology of BOS and bronchiolitis obliterans (BO) in general remains speculative, it will be difficult to reverse the declining FEV₁ with current available treatments. Although it is accepted that BO/BOS starts with (neutrophilic) inflammation, resulting in fibrotic obliteration and scarring of the airways, this is not evident in every patient. Indeed some patients do not show any inflammation in their BAL fluid, nevertheless, they may rapidly progress to end-stage BOS. In fact, this concept led to further phenotyping of BOS, which has become essential in treating these patients. The introduction of azithromycin changed the field and allowed to differentiate BOS in a neutrophilic phenotype, which may be responsive to azithromycin treatment, and a non-neutrophilic phenotype that is very difficult to treat and usually does not respond to azithromycin. This last phenotype is indeed characterized by fibrotic plugging of the preterminal bronchioles, but in addition shows limited areas of complete collapse of airways, without any overt intraluminal fibrosis nor inflammation being present [20]. As a consequence, it seems acceptable that treatment of inflammation does not improve the pulmonary function in all patients. In this respect, one might suggest that antifibrotic agents such as pirfenidone, which was recently shown to improve survival of patients with idiopathic pulmonary fibrosis, might be of interest. Such studies are eagerly awaited and might indeed open new perspectives for the treatment of BOS. Whether other routes of drug delivery such as for instance inhaled treatment will have an effect on the development or progression of BOS remains debatable, as for instance inhaled cyclosporine proved to be not very effective with a lot of side effects and addition of inhaled steroids was ineffective. In this respect, the potential role of anti-TNF treatment should certainly be further explored.

The major problem with the current available literature regarding the treatment of BOS is the retrospective and mostly single-centered nature of the studies, without proper control patients. Multicenter, placebo-controlled trials in carefully selected BOS patients (who are progressive while under azithromycin treatment) are definitely needed if we really want to improve our therapeutic strategies and hence the outcome of our patients with this devastating condition.

In addition to BOS, phenotyping of chronic lung allograft dysfunction (CLAD) also identified a progressive and irreversible restrictive pulmonary function defect, called restrictive CLAD or restrictive allograft syndrome (RAS), with comparable risk factors, but certainly a different outcome, with RAS having a worse prognosis [1]. Specific treatment options for this form of CLAD are not available at present, indeed azithromycin seems ineffective and the different treatment options discussed in the BOS section, have so far not specifically been addressed in RAS. As already stated, multicenter and concerted efforts will be necessary to design appropriate studies to tackle this specific issue as well.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.