Secondary pulmonary alveolar proteinosis after lung transplantation: a single-centre series

Abstract

Pulmonary alveolar proteinosis (PAP) is a rare disease characterized by accumulation of surfactant in alveolar space related to alveolar macrophage dysfunction. PAP occurs in three clinically distinct forms: autoimmune PAP (90% of cases), secondary PAP and genetic PAP [1]. Secondary PAP may be related to immunosuppressive disorders, with few cases associated with solid-organ transplant [1]. Indeed, to our knowledge, only five cases of symptomatic PAP secondary to lung transplantation have been reported [2][3][4].Here, we report a series of four new cases of PAP in lung transplantation recipients, with death associated with PAP-onset in all cases. One patient showed impaired granulocyte-macrophage colony-stimulating factor (GM-CSF) signalling in the absence of auto-antibodies, which argues for similar mechanisms as in autoimmune PAP. A specific enhanced risk associated with lung transplantation was also suggested by the lack of native lung involvement in single-lung transplantation recipients. Patient oneA 66-year-old man with idiopathic pulmonary fibrosis (IPF) underwent left single-lung transplantation from a 34-year-old male smoker. The immediate post-operative course was uneventful, with primary graft dysfunction determined to be grade 0. On post-operative day 72, acute rejection (grade A2B0) [5] was diagnosed without complement component 4d (C4d) staining. Donor-specific antibodies were detected by Luminex (human leukocyte antigen DQ7 (HLA-DQ7); mean fluorescent intensity (MFI)=4030) and steroid boluses were administered followed, on post-operative day 101, by anti-thymocyte globulins due to the persistence of histologically proven acute rejection (grade A2B0) [5]. Subsequent transbronchial biopsies ( post-operative day 134) showed complete resolution of the acute rejection episode (grade A0B0). Furthermore, bronchoalveolar lavage fluid (BALF) analysis did not show parasitic (Pneumocystis jirovecii), mycological, viral (using multiplex PCR assay), or bacterial infection (including Nocardia), and cardiac ultrasonography revealed normal left-ventricular function. Nevertheless, in parallel with histological resolution of the steroid-resistant acute rejection episode, repeat computed tomography (CT) scans showed progressively worsening lung opacities from post-operative day 129, with a "crazy-paving" pattern located exclusively in the graft (figure 1a). Re-examination of transbronchial biopsies from post-operative day 134 (figure 1b) and a new BALF analysis stained with periodic acid-Schiff (PAS) reagent (figure 1c) led to a diagnosis of PAP. Anti-(GM-CSF) antibodies were absent and the possibility of impaired GM-CSF signalling was investigated using a recently described test based on the ability of GM-CSF to rapidly increase cell-surface CD11b levels on neutrophils in flow cytometry (reflected by a CD11b stimulation index) [6]. The GM-CSF stimulation index in patient one was very low, with a value of seven as compared to values of 101, 55 and 102 in three stable lung-transplantation recipients used as positive ...

Pulmonary alveolar proteinosis after lung transplantation

“…Hence, reduction of immunosuppression is considered as an initial step in treatment. Successful treatment of two patients with post lung transplant secondary PAP after reducing baseline immunosuppression has been reported [3]; however; in four other patients this was not successful [4]. As in our patient, in the presence of recurrent acute rejections, minimizing immunosuppression treatment could be challenging [4].…”

“…WLL is the mainstay of treatment in persistent, progressive PAP [2]. WLL improves clinical, physiological, and radiological manifestations, but has mainly been used in primary PAP with only case reports in secondary PAP [4]. Here, we have demonstrated the successful use of WLL to treat PAP after lung transplantation.…”

“…CT chest will show patchy ground‐glass changes with interlobular septal thickening giving rise to a crazy‐paving pattern [2]. After lung transplantation, there are many common causes of pulmonary GGO, including infection and rejection making the PAP diagnosis challenging [4]. In the early course of his disease, most of his clinical and radiological manifestations were attributed to rejection and infection episodes.…”

“…Although post‐transplant infectious complications are common, the number and diversity of infectious complications experienced by our patient perhaps points to a defect of pulmonary innate immune function and PAP. PAP increases the risk of bacterial, viral, mycobacterial, and fungal pulmonary infections [2,4,5]. This is thought to be secondary to impaired macrophage chemotaxis, adhesion, phagocytosis, and microbicidal activity [2].…”

Secondary pulmonary alveolar proteinosis predominant in the transplanted lung in patients with idiopathic interstitial pneumonia: an autopsy case

“…Since 1983, more than 50,000 lung transplants have been performed worldwide (1). To date, few cases of secondary pulmonary alveolar proteinosis (PAP), as a rare complication following lung transplantation, have been reported (2)(3)(4)(5)(6) and the mechanism of pathogenesis is not fully clear.…”