1 Centre for Nephrology, 2 Department of Haematology, Royal Free and University College Medical School, University College London, UK
Keywords: anti-neutrophil cytoplasmic antibody; haemoptysis; non-Hodgkin's lymphoma; peripheral blood stem cell transplantation; vasculitis
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() |
---|
![]() |
Case |
---|
![]() ![]() ![]() ![]() ![]() |
---|
In March 1990 the patient represented with large submandibular, cervical, inguinal and axillary lymphadenopathy. A T-cell lymphoma with histological features of both Lennert's lymphoma and angioimmunoblastic lymphoma was found at lymph node biopsy [2]. T-cell receptor (TCR ß) gene rearrangement studies and immunoglobulin heavy chain gene fingerprinting were performed on stored lymph node biopsy material from 1988 and verified the original diagnosis of B-cell NHL [2]. The same techniques confirmed the coexistence of both T and B cell lymphomas at the time of representation in 1990 [2].
The patient remained well until October 1994 when he developed stridor and dysphagia. Investigation at this time revealed extensive lymphadenopathy, biopsy of which demonstrated an intermediate grade T-cell lymphoma. Preparation for autologous PBSCT began following further progression of the lymphadenopathy, despite combination chemotherapy. Further combination chemotherapy (mitozantrone, cytosine-arabinoside and etoposide) was administered and followed by granulocyte colony stimulating factor (G-CSF) to allow PBSC harvesting on count recovery. The patient was left with residual chronic renal impairment (creatinine 145 µmol/l) after an episode of acute renal failure attributed to a combination of sepsis and nephrotoxic drugs in May 1995. Finally, following conditioning by total body irradiation (TBI 750 cGy single fraction, dose rate 15 cGy/min) and cyclophosphamide (120 mg/kg total dose) the first stem cell transplant was undertaken in June 1995. Post-transplant consolidation radiotherapy (3500 cGy) was delivered to the mediastinum. A second infusion of stem cells was required in January 1996 because of a poorly functioning graft. Further radiotherapy was required to control a localized peripancreatic recurrence between January and March 1996 (5000 cGy).
In October 1997 the patient represented with a dry cough, progressive exertional dyspnoea, malaise, epistaxis and haemoptysis. There were no palpable lymph nodes or stigmata of vasculitis or infective endocarditis but urinalysis was strongly positive for blood and protein. Diffuse fluffy opacities on chest X-ray were associated with significant hypoxia (O2 9.6 kPa with FiO2 60%) and an acute fall in haemoglobin (Hb 6.9 g/dl, 12.1 g/dl one month earlier). The patient had acute on chronic renal failure (creatinine 322 µmol/l, 185 µmol/l one month earlier) and phase contrast microscopy of the urine demonstrated an active urinary sediment. A renal biopsy showed a pauci-immune focal necrotizing glomerulonephritis with extensive chronic interstitial damage. An elevated carbon monoxide transfer factor (KCO 2.4) corrected for the low haemoglobin, suggested pulmonary haemorrhage which was confirmed at bronchoscopy. A perinuclear ANCA was demonstrated by indirect immunofluorescence and shown to have specificity for myeloperoxidase (MPO-ANCA 102 EU (normal 010)). Extensive imaging did not reveal evidence of recurrent lymphoma.
Treatment was commenced with high dose corticosteroids (i.v. methyl prednisolone 0.5 g x3 followed by oral prednisolone/i.v. methyl prednisolone 60 mg/day), oral cyclophosphamide (100 mg/day), intravenous immunoglobulin and plasma exchange. Thirty six hours after presentation the patient rapidly deteriorated and required ventilation with an FiO2 of 100%. Culture of bronchoalveolar lavage for bacteria, fungi and viruses, repeated blood cultures and serology for atypical infection were all negative. Gas exchange began to improve 48 h after commencing ventilation and weaning from the ventilator was completed within 10 days. The patient remained dialysis-independent during his ITU admission and was discharged with stable renal function (creatinine 240 µmol/l). The patient made a good recovery and returned to work part-time following his discharge from hospital.
In July 1998 an abdominal CT scan demonstrated a mass of lymph nodes posterior to the head of the pancreas which was highly suggestive of further lymphoma. Attempts to obtain a tissue diagnosis were unsuccessful. However, the lesion disappeared after a course of local radiotherapy.
During a further 21 months of follow-up there were no vasculitic relapses. Cyclophosphamide was poorly tolerated by the patient because of pancytopaenia and ANCA titres remained high on maintenance immunosuppression with corticosteroids and intravenous immunoglobulin. The patient died of overwhelming staphylococcal sepsis in April 2000.
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() |
---|
Necrotizing or pauci-immune renal vasculitis may be associated with NHL [3] but the literature contains only three reports of small vessel vasculitis (SVV) following BMT or PBSCT [46]. McCloy et al. [4] describe a 35-year-old man presenting with pulmonary haemorrhage 25 months after autologous BMT for recurrent NHL in whom an open lung biopsy revealed a pauci-immune pulmonary vasculitis. ANCA were detectable by immunofluorescence, but no antigen specificity was documented. Treatment with prednisolone and cyclophosphamide achieved a remission and the patient remained well after 2 years follow-up. Thorascopic lung biopsy was used to diagnose a pulmonary vasculitis in a patient found to have pulmonary nodules after autologous BMT and PBSCT for relapse of Hodgkin's disease [5]. There was no evidence of recurrent lymphoma and the vasculitis remained in remission 24 months after treatment with oral prednisolone. In the single reported case of vasculitis after allogeneic BMT Jafri et al. [6] describe a 37-year-old male patient who developed a jejunal vasculitis 2 months after successful BMT for chronic myeloid leukaemia.
In our case the precipitant of the small vessel vasculitis was unclear at presentation. The subsequent relapse of the patient's lymphoma leads us to speculate that an earlier, clinically silent lymphoma recurrence may have precipitated the vasculitis. It is possible that previous cases of post-transplant vasculitis may also have been associated with sub-clinical disease recurrence but that additional immunosuppression used to control vasculitis prevented recurrent lymphoma from becoming clinically apparent.
Other factors may have predisposed this patient to develop small vessel vasculitis. Pre-graft conditioning, immunological reconstitution following BMT and post-graft bacterial and viral infections may all contribute to immune dysregulation and the development of autoreactivity [7]. The development of autoantibodies including ANCA is reported following both allogeneic and autologous BMT [8].
ANCA detectable at immunofluorescence may not be recognized by antigen-specific ELISAs for antibodies against the neutrophil antigens myeloperoxidase and proteinase 3 [9]. ANCA directed against lactoferrin have been found in allogeneic bone marrow transplant recipients with chronic GVHD [10]. However, this is the first case report of anti-myeloperoxidase specific antibodies occurring following BMT or PBSCT in association with clinically significant vasculitis.
This is also the first report of SVV associated with relapsed lymphoma after PBSCT and we suggest that a small vessel vasculitis should prompt a vigorous search for recurrent lymphoma in this context.
![]() |
Notes |
---|
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() |
---|