Acute Antibody-mediated Rejection 1 Week After Lung Transplantation Successfully Treated With Eculizumab, Intravenous Immunoglobulins, and Rituximab

Mounting evidence exists on the risk of antibody-mediated rejection (AMR) after lung transplantation.1,2 In 2016, the International Society for Heart and Lung Transplantation established for the first time a consensus report, which defines and stages clinical and subclinical AMR (acute or subacute) based on the presence of donor specific-antibodies (DSA), specific histopathologic features, including neutrophil margination and neutrophil capillaritis and arteritis, capillary C4d deposition, and exclusion of other differential diagnoses.3 The optimal management of acute AMR remains poorly defined and is mostly based on previous experience derived from kidney transplantation with plasmapheresis (+/− eculizumab), high-dose IVIG, and rituximab administration.4,5 CASE PRESENTATION A 48-year-old woman received bilateral lung transplantation because of lymphangioleiomyomatosis with severe obstructive syndrome. Before transplantation, she had only 1 detectable (>500 mean fluorescence intensity [MFI]) preformed class II DSA (HLA DR17: MFI 1783) by Luminex (Austin, TX), but with a negative flow cytometry crossmatch. Standard immunosuppressive induction therapy (two 20-mg doses of basiliximab at days 0 and 4, intravenous methylprednisolone, tacrolimus and mycophenolate mofetil) was administered. After an uneventful early posttransplant course, she developed at day 7 rapidly progressive dyspnea with hypoxemia (Figures 1A-B) without the need for mechanical ventilation or ECMO support. The chest X-ray showed new bilateral interstitial pulmonary infiltrates. Repeat Luminex assay on postoperative days (PODs) 7, 9, and 13 revealed an increase of class-I (anti-HLA A24 and B8) and class II (anti-HLA DR17 and DQ2) DSA with positive flow cytometry T and B crossmatches (Figures 1C-D). She was treated on POD 8 with a single 600-mg dose of eculizumab preceded with 250 mg intravenous methylprednisolone, followed by 3 weekly high-dose IVIG (2 g/kg), and on POD 28 with 1 dose of rituximab (375 mg/m2). Terminal complement blockade (>97% inhibition) within 48 hours after eculizumab administration was demonstrated by functional analysis of the complement cascade (classical pathway, alternative pathway, and lectin pathway of complement activation). The transbronchial lung biopsy confirmed the presence of diffuse linear C4d endothelial deposits with few pericapillary mononuclear infiltrates and neutrophils (Figures 1E-H). C5b-C9 staining was negative. Oxygen requirements rapidly decreased within 24 hours after eculizumab administration, and she was off oxygen therapy by day 14 posttransplantation (Figure 1A). Circulating DSA progressively decreased below 2000 MFI by POD 41 and remained under 2000 MFI thereafter (Figure 1C). Control transbronchial biopsy at 18 months posttransplantation did not reveal any residual active immunohistological signs for AMR (C4d negative). The patient is currently doing well with a 3-year follow-up, without any evidence for chronic lung allograft dysfunction and peripheral B cells are still depleted (<10 B cells/μL).FIGURE 1: A, Oxygen maximal flow rate over time. Treatment with eculizumab (600 mg) on POD 8, 3 weekly high-dose intravenous immunoglobulins (2 g/kg) and rituximab (375 mg/m2) on POD 28. B, Chest X-ray at PODs 4 and 9. C, Donor-specific class I and class II antibodies over time. D, Flow cytometry crossmatches gated on viable (propidium iodide negative) donor CD3 or CD19 cells on PODs 0, 7, and 9. NC are third-party serum controlled for anti-HLA antibodies co-cultured with donor cells. Lung biopsy performed on POD 13 showing CD3 staining (E, magnification, ×20), hematoxylin-eosin coloration (F, magnification, ×40), C4d immunofluorescence on frozen section (G, magnification, ×40), C4d immunohistochemistry on paraffin section (H, magnification, ×40). Arrows show C4d deposits on the pulmonary capillaries. ICU, Intensive care unit.DISCUSSION We report that acute AMR developed 1 week after lung transplantation in a sensitized recipient who had low-level preformed DSA before transplantation. Acute AMR was successfully treated with eculizumab, IVIG, and rituximab. Of note, it had been previously reported that eculizumab can be safely used in the setting of “hyperacute rejection” associated with immediate posttransplant lung dysfunction due to preformed high-level antibodies. In this hyperacute setting, the patient received high-dose eculizumab, together with plasma exchange, IVIG, bortezomid, and rituximab.6 Both cases, although different in the timing and characteristics of AMR, highlight the risks associated with transplantation of sensitized recipients and the importance to closely monitor DSA and crossmatches in such patients posttransplantation. Interestingly, recent data indicate that de novo DSA appearing within the first 30 days after lung transplantation are associated with significantly worse long-term clinical outcomes.7 Moreover, C1q binding and detection of intragraft DSA may be additional useful tools for the diagnosis of AMR, as recently suggested by a retrospective analysis of 51 lung transplant recipients.8 Also, the clinical potential of tissue-based study of gene transcripts in allograft biopsies (gene expression profiling) may become a key diagnostic tool to identify AMR, as recently demonstrated in heart transplant recipients.9 In our patient, eculizumab administration rapidly reversed the acute AMR episode after lung transplantation, without the need for T cell–depleting agents (eg, thymoglobulin) or plasmapheresis, which can be cumbersome in that setting. Histopathologic findings from the lung biopsy suggested that blockade of the terminal complement pathway by eculizumab could neutralize the consequences of pathogenic DSA (ie, C5b-C9 deposits were not detected), but as expected, C5 blockade did not inhibit complement classical pathway activation as shown by the presence of diffuse capillary C4d deposits on lung's biopsy, similar to the report by Stegall et al10 in kidney transplantation. It is also known that, in kidney transplantation, the histological findings can be normal (except for the presence of C4d) if the biopsy is performed very early on in an acute AMR episode.11 The decision to administer eculizumab in our patient was taken based on the acute lung dysfunction, increasing levels of DSA with the demonstration of a newly positive crossmatch, in the absence of evidence for lung infection or of other causes. It should be mentioned that eculizumab alone is unlikely to be sufficient for the long-term treatment of AMR as suggested by the negative results of a recent randomized trial on eculizumab for chronic active AMR after kidney transplantation.12 Indeed, eculizumab does not target B cells neither DSA production. Until recently, the treatment of severe acute AMR, mostly in kidney transplantation, has been based on the immediate removal of DSA by plasmapheresis or immunoadsorption and on B-cell immunomodulation by IVIG, rituximab, or bortozemib therapy.4,13 Thus, administration of high-dose IVIG and rituximab, in addition to eculizumab and the baseline maintenance immunosuppression (tacrolimus/mycophenolate mofetil/steroids), was likely critical in the successful short-term and long-term management of the AMR episode. Rituximab was administered after IVIG and the initial decrease in DSA titers as “consolidating therapy” of AMR to prevent future development of chronic lesions. This was suggested by our own experience with rituximab after kidney transplantation14 and previous reports showing that rituximab can prevent chronic rejection in highly sensitized recipients and in ABO-incompatible transplants.15,16 Interestingly, anti–T-cell therapy was not necessary, probably because the rejection process was predominantly humoral and not cellular in its effector mechanisms. Finally, it should be mentioned that analysis of the cost-effectiveness of eculizumab, as compared with conventional plasmapheresis or immunoadsorption,6,11,17 will require well-designed prospective multicenter studies due to the low incidence of reported acute AMR in lung transplant recipients. ACKNOWLEDGMENTS The authors would like to thank all the medical doctors, nurses, pharmacists and laboratory technicians who were involved in the management of the patient, particularly Dr Carine Berutto.