Pirfenidone: A Potential New Therapy for Restrictive Allograft Syndrome?



This case report describes the evolution of pulmonary function findings (FVC, FEV1 and TLC) and CT features with pirfenidone treatment for restrictive allograft syndrome following lung transplantation. Furthermore, we herein report hypermetabolic activity on 18F-FDG PET imaging in this setting, which could indicate active fibroproliferation and pleuroparenchymal remodeling. These findings may warrant further investigation.


18F-fluorodeoxyglucose positron emission tomography


bronchiolitis obliterans syndrome


chronic lung allograft dysfunction


computed tomography


donor specific antigen


forced expiratory volume in the first second


forced vital capacity


human leukocyte antigen


idiopathic pulmonary fibrosis


lung transplantation


obliterative bronchiolitis


pleuroparenchymal fibroelastosis


restrictive allograft syndrome


rabbit antithymocyte globulin


transforming growth factor-beta


total lung capacity


tumor necrosis factor-alpha


video-assisted thoracoscopic surgery

Restrictive allograft syndrome (RAS) has been recently defined as a novel phenotype of chronic lung allograft dysfunction (CLAD) after lung transplantation (LTx). RAS occurs in approximately 30% of CLAD patients and is characterized by a restrictive pulmonary function, persistent infiltrates on computed tomography (CT) scan and worse survival compared to strictly obstructive CLAD patients, so-called (fibroproliferative) bronchiolitis obliterans syndrome (BOS) [1, 2]. CT features in RAS typically include ground-glass opacities, interstitial reticular shadows, consolidation, traction bronchiectasis, architectural distortion and (sub)pleural thickening [3]. Histologically, diffuse alveolar damage, focal fibroblastic foci, pleuroparenchymal fibroelastosis (PPFE) and concurrent obliterative bronchiolitis (OB) are seen [4]. Risk factors for RAS, as for CLAD, comprise frequent episodes of acute cellular rejection, lymphocytic bronchiolitis, pulmonary infection and colonization with Pseudomonas aeruginosa [5]. The pathophysiological mechanisms in RAS are thought to be similar to those in idiopathic pulmonary fibrosis (IPF), as both conditions are characterized by progressive interstitial fibrosis leading to a decrease in lung volume, progressive respiratory insufficiency and often death [6]. The devastating prognosis of RAS and the lack of adequate therapeutic options provide a strong rationale for a novel therapeutic approach of this disease.

One of these potential new treatment options may be pirfenidone, a small synthetic nonpeptide molecule (5-methyl-1-phenyl-2-[1H]-pyridone) that has recently been approved for the treatment of IPF in Europe, Canada, Japan and South Korea. Both in vitro and in vivo studies have demonstrated a potent antifibrotic effect of pirfenidone, which inhibits the synthesis of transforming growth factor-beta (TGF-β) and tumor necrosis factor-alpha (TNF-α), important mediators of fibrosis and inflammation [6]. Subsequently, pirfenidone reduces fibroblast proliferation and collagen synthesis, resulting in a smaller decline in lung function in animal models of fibrosis and a reduction of the decline in forced vital capacity (FVC) in IPF patients [6, 7]. Interestingly, inhibitory effects of pirfenidone on dendritic cells and on lung allograft rejection in an orthotopic murine lung transplant model have recently also been described [8]. There has been a single published case describing the use of pirfenidone in (obstructive) BOS after LTx until now, demonstrating stabilization of forced expiratory volume in the first second (FEV1) during the subsequent 6 months [9].

We report on a 64-year-old male with a history of combined pulmonary fibrosis and emphysema, who underwent a double-sided LTx (cytomegalovirus donor+/recipient− status). Induction therapy consisted of rabbit antithymocyte globulin (rATG), and maintenance immunosuppressive therapy comprised steroids, tacrolimus and mycophenolate. Routine infection prophylaxis included nebulized amphotericin B until discharge, valganciclovir until day 90 and life-long trimethoprim–sulfamethoxazole. The initial post-LTx course was uneventful, except for P. aeruginosa infection, which was treated with meropenem.

During the first year thereafter, he developed recurrent P. aeruginosa infections despite azithromycin (250 mg, 3 times/week), treated by intravenous antibiotics guided according to bacterial sensibility (i.e. combination of ceftazidim–gentamycin, ceftazidim–obracin, tazocin–colimycin) for 10–14 days; and isolation of Aspergillus fumigatus, treated by oral voriconazole for 3 months. FEV1 reached BOS stage 1 at 237 days post-LTx (Figure 1). However, following a late severe acute cellular rejection (A3B0) episode at day 365 and subsequent A1B0 rejection at day 458, equally treated with IV pulse steroids (Solumedrol 500 mg/day, 3 days) followed by steroid tapering over the next 3 weeks, both FEV1 (BOS Stage 3) and FVC (restrictive, with stable body mass index) rapidly declined despite administration of montelukast (10 mg/day), at which moment long-term oxygen therapy (2.5 L/min) was initiated. High-resolution CT scan demonstrated the appearance of persistent and progressive subpleural ground-glass opacities and pleural thickening, which demonstrated hypermetabolic activity on 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) scan (maximum pulmonary 18F-FDG uptake (SUVmax) 6.17 in right- and 6.47 in left-sided lesions; Figures 2 and 3). Concurrent infection (negative broncho-alveolar lavage for bacteria, cytomegalovirus and other viruses or fungi), cellular (A0B0) or humoral rejection (absence of anti-human leukocyte antigen or donor specific antigen antibodies) was excluded, after which a diagnostic video-assisted thoracoscopic surgery biopsy of the inferior left lobe was performed, demonstrating a diffuse fibrous thickened visceral pleura upon inspection. Histology demonstrated a combination of diffuse PPFE, alveolar fibrosis and OB (Figure 4), confirming our diagnosis of RAS. Treatment options were limited: redo-transplantation was not considered a realistic option because of the patient's age and foreseen waiting time. Furthermore, total lymphoid irradiation (TLI) was not initiated since the waiting time for starting TLI in our center currently is about 3–4 weeks and TLI takes 5 more weeks before completion, in which time we suspected further respiratory deterioration, possibly making TLI not feasible at all anymore. Alemtuzumab, a humanized rat monoclonal antibody directed against CD52 whose use was recently reported in four patients with interstitial lung injury after LTx [10], is only available either for the treatment of acute steroid- refractory organ rejection (when ATG is not appropriate) or as an induction therapy through a compassionate use program for solid organ transplantations in Belgium; thus, this was no option for our patient. Therefore, pirfenidone (3 × 267 mg t.i.d. or 2403 mg/day, InterMune® Benelux; InterMune Benelux B.V., Nieuwegein, the Netherlands) was administered in compassionate use after patient informed consent and approval from the local Ethics Committee (ML9190; start day 494). Because of nausea, pirfenidone dose was reduced after 40 days (2 × 267 mg t.i.d. or 1602 mg/day) and continued for a total of 83 days, during which period no other side effects were noted and hepatorenal function remained stable. Tacrolimus daily dose had to be increased 2.5-fold to maintain stable trough levels (around 8 µg/L). Spirometry after pirfenidone initiation demonstrated a less pronounced decline of both FVC (decrease 470 mL/month before vs. 110 mL/month after pirfenidone, p = 0.029) and FEV1 (decrease 210 mL/month before vs. 110 mL/month after pirfenidone, p = 0.029); whereas total lung capacity (TLC) even mildly increased (total increase of 410 mL or 180 mL/month after pirfenidone vs. total decrease of 1570 mL or 370 mL/month before pirfenidone, p < 0.0001). High-resolution CT scan mainly demonstrated a decrease in (subpleural) consolidations and ground-glass opacities in some areas (Figure 3, Table 1). On auscultation, course crackles decreased with pirfenidone. However, because of persistent debilitating dyspnea and subjective poor quality of life (persistently oxygen dependent; 2.5–3 L/min) the patient finally opted for admission on a palliative ward, at which moment pirfenidone was stopped (day 577) and after which he died at 579 days post-LTx.

Figure 1.

Evolution of pulmonary function [FVC (L), FEV1 (L), Tiffeneau-index and TLC (L)] over time after lung transplantation (LTx) and with pirfenidone. Acute rejection episodes (histologic A and B score) and pulmonary infections (pathogen) are indicated with arrows, CT#1 and CT#2 indicate time points of high-resolution CTs depicted in Figure 3; cross indicates patient death at 579 days post-LTx. A. fumig, Aspergillus fumigatus; AZI, azithromycin; BOS, bronchiolitis obliterans syndrome; CT, computed tomography scan; FEV1, forced expiratory volume in the first second; FVC, forced vital capacity; LTOT, long-term oxygen therapy; LTx, lung transplantation; MLK, montelukast; OLB, open lung biopsy; P. aerug, Pseudomonas aeruginosa; PET, positron emission tomography; PFD, pirfenidone; Tiff, Tiffeneau-index (FEV1/FVC); TLC, total lung capacity. Note: The A1B0 rejection episode at CT#1 was treated with IV pulse steroids because of suspected underestimation of the grade A-score at that moment, given the clinical evolution/condition of the patient.

Figure 2.

(A) Anterior, sagittal and posterior view of 18F-FDG PET imaging demonstrating hypermetabolic activity [maximum pulmonary 18F-FDG uptake (SUVmax) 6.17 in right- and 6.47 in left-side lesions] in zones of subpleural consolidations and ground-glass opacities in RAS after lung transplantation (performed on postoperative day 458, together with CT#1 in Figure 3; black full arrows). (B) Additional axial PET-CT fusion images at upper (left panel) and lower lobes (right panel) highlighting the hypermetabolic activity (black full arrows). The supraclavicular intense capitation is due to tracer stasis in the patient's port. 18F-FDG PET, 18F-fluorodeoxyglucose positron emission tomography; CT, computed tomography; RAS, restrictive allograft syndrome.

Figure 3.

Evolution of high-resolution computed tomography (CT) scan features during pirfenidone treatment in restrictive allograft syndrome (RAS), demonstrating a decrease in subpleural consolidations and ground-glass opacities in some areas (black arrows).

Figure 4.

H&E staining of open lung biopsy [left inferior lobe, (A) 12×, (B) 50×] demonstrating a combination of diffuse pleuroparenchymal fibroelastosis (PPFE; black full arrows), alveolar duct fibrosis (circle) and concurrent obliterative bronchiolitis (OB; black unfilled arrow).

Table 1. Evolution of CT features in RAS
 Before pirfenidone (CT#1)During pirfenidone (CT#2)p-Value
  1. CT data sets were evaluated using a semi-quantitative scoring system based on previous descriptions and was performed by one board-certified chest radiologist (PADJ) with over 10 years of experience in reading chest CT scans, for whom the reproducibility has also previously been described [11]. Inspiratory and expiratory CT scanning protocol was previously described [11], and examinations were scored blinded to the time point of RAS. Both coronal and axial images were used for scoring. In general, abnormalities were defined according to the Fleischner Society nomenclature [12]. Lung periphery was defined as the outer one-third of the lung. Each abnormality was scored in five lung lobes (RUL, RML, RLL, LUL, LLL), and per lobe the extent involved with the abnormality was estimated as absent (score 0), less than one-third/mild (score 1), between one-third and two-thirds/moderate (score 2); and more than two-thirds of the lobar volume/severe (score 3). Absolute values (percentage) of extent involved of all five lung lobes before and during pirfenidone are summarized in the table. p-Values (paired t-test) are calculated using CT scores of each lobe before and during pirfenidone. p < 0.05 was considered significant (bold). CT, computed tomography; RAS, restrictive allograft syndrome; RUL, right upper lobe; RML, right middle lobe; RLL, right lower lobe; LUL, left upper lobe; LLL, left lower lobe.
Mucus plugging00NA
Centrilobular nodules2 (13%)00.18
Airway wall thickening10 (67%)10 (67%)NA
Consolidation central6 (40%)3 (20%)0.071
Consolidation peripheral13 (87%)11 (73%)0.18
Ground-glass central5 (33%)1 (7%)0.016
Ground-glass peripheral11 (73%)1 (7%)0.0032
Architectural deformation00NA
Volume loss00NA
Hilus retraction00NA
Septal and nonseptal lines1 (7%)00.37
(Sub)Pleural thickening6 (40%)6 (40%)NA
Apicobasal gradient00NA

Although no subjective improvement was seen, the evolution of pulmonary function findings and attenuation of specific CT features with pirfenidone may warrant future investigation of pirfenidone treatment in (early) RAS. However, we acknowledge some possible shortcomings of the current report, such as the relative short duration of pirfenidone therapy (less than 3 months) and the drug intolerance necessitating dose reduction. Furthermore, the fact of a less rapid decline in FVC and FEV1 with pirfenidone may reflect the natural history of disease in RAS. Also, the statistically significant increase in TLC in the context of a declining FVC may perhaps not reflect a relevant physiologic improvement. Nevertheless, the hypermetabolic activity seen on 18F-FDG PET imaging in this case of documented RAS could indicate active fibroproliferation and pleuroparenchymal remodeling. Of note, since this case report, we observed similar hypermetabolic activity (SUVmax 5.39 in right- and 6.01 in left-sided lesions) in another patient diagnosed with RAS. As this maximum pulmonary 18F-FDG uptake in RAS seems even higher than reported in IPF [12], this finding may also need further investigation.


G.M.V. is holder of the Glaxo Smith Kline (Belgium) chair in respiratory pharmacology at the KULeuven and is supported by the Research Foundation Flanders (FWO; G.0723.10, G.0679.12 and G.0679.12), Vlaams Agentschap voor Innovatie door Wetenschap en Technologie (IWT; TBM.100756) and Onderzoeksfonds KULeuven (OT/10/050). B.M.V., L.J.D. and D.E.V.R. are senior research fellows of the FWO.


The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.