ANCA +ve vasculitis after autologous PBSC transplantation

Edward J. Kingdon1,, Rosalynd E. Johnston2, Rachel Pawson2, H. Grant Prentice2, Mike N. Potter2, Aine Burns1 and Stephen H. Powis1

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
 Top
 Introduction
 Case
 Discussion
 References
 
Acute renal failure (ARF) occurs frequently after bone marrow transplantation (BMT) and has ominous prognostic significance [1]. Sepsis, drug nephrotoxicity, veno-occlusive disease of the liver, haemolytic uraemic syndrome (HUS) and acute and chronic graft-versus-host-disease (GVHD) are important aetiological factors and post-transplant ARF is often multifactorial. HUS, which can occur independently of GVHD or cyclosporin use, should be considered when ARF occurs more than 6 months after transplantation and may present as an acute nephritic illness [1]. In patients presenting with chest signs or symptoms and ARF after BMT or peripheral blood stem cell transplant (PBSCT), sepsis dominates the differential diagnosis. We present the case of a recipient of an autologous PBSCT who presented with pulmonary and renal manifestations of a small vessel vasculitis more than 2 years after transplantation.



   Case
 Top
 Introduction
 Case
 Discussion
 References
 
A 47-year-old male presented in September 1988 with generalized lymphadenopathy. Lymph node biopsy revealed a low grade lymphoplasmacytoid non-Hodgkin's lymphoma (NHL) with IgM kappa immunoglobulin restriction. Further investigations demonstrated stage IIA disease with no associated paraprotein. A partial response was achieved with one cycle of COP (cyclophosphamide, vincristine and prednisolone) followed by six cycles of chlorambucil and prednisolone [2].

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 ({rho}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 0–10)). 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
 Top
 Introduction
 Case
 Discussion
 References
 
We have presented a case of an ANCA positive systemic vasculitis presenting with pulmonary and renal involvement 19 months after an autologous PBSCT. Prompt diagnosis allowed early introduction of appropriate therapy and although the patient required full supportive treatment in the face of life threatening pulmonary haemorrhage, immunosuppression eventually controlled disease activity.

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
 
Correspondence and offprint requests to: Dr E. J. Kingdon, Centre for Nephrology, Royal Free Campus, Royal Free and University College Medical School, University College London, Rowland Hill Street, London NW3 2PF, UK. Email: kingdon{at}rfc.ucl.ac.uk Back



   References
 Top
 Introduction
 Case
 Discussion
 References
 

  1. Zager RA. Acute renal failure in the setting of bone marrow transplantation. Kidney Int1994; 46: 1443–1458[ISI][Medline]
  2. Deane M, Amlot P, Pappas H, Norton JD. Independent clonal origin of T and B cell clones in a composite lymphoma. Leukemia Res1991; 15: 811–817[ISI][Medline]
  3. Harper L, Adu D. Glomerulonephritis and non-Hodgkin lymphoma. Nephrol Dial Transplant1997; 12: 1520–1525[Free Full Text]
  4. McCloy M, Morris TCM, McGuigan JA. Vasculitis post autologous transplant causing pulmonary shadows in a patient with Hodgkin's disease. Bone Marrow Transplant1996; 17: 869–870[ISI][Medline]
  5. Seiden MV, O'Donnell WJ, Weinblatt M, Licht J. Vasculitis with recurrent pulmonary haemorrhage in a long term survivor after autologous bone marrow transplantation. Bone Marrow Transplant1990; 6: 345–347[ISI][Medline]
  6. Jafri FM, Mendelow H, Shadduck RK, Sekas G. Jejunal vasculitis with protein losing enteropathy after bone marrow transplantation. Gastroenterology1990; 98: 1689–1692[ISI][Medline]
  7. Parkman R, Weinberg KI. Immunological reconstruction following bone marrow transplantation. Immunol Rev1997; 157: 73–78[ISI][Medline]
  8. Sanmarco M, Vialettes B, Maraninchi D, Bernard D. Autoantibody formation after bone marrow transplantation: a comparison between autologous and allogeneic grafts. Autoimmunity1991; 11: 7–12[ISI][Medline]
  9. Chan EYT, Lawton JWM, Lie AKW, Lau CS. Autoantibody formation after allogeneic bone marrow transplantation: Correlation with the reconstitution of CD 5 +ve B cells and occurrence of graft-versus-host disease. Pathology1997; 29: 184–188[ISI][Medline]
  10. Martin SJ, Audrain MAP, Oksman F, Ecoiffier M, Attal M, Milpied N, Esnault VL. Antineutrophil cytoplasmic antibodies (ANCA) in chronic graft-versus-host disease after allogeneic bone marrow transplantation. Bone Marrow Transplant1997; 20: 45–48[ISI][Medline]
Received for publication: 30. 4.01
Revision received 9.10.01.