Immunological reaction against erythropoietin causing red-cell aplasia

Lucile Mercadal1,, Laurent Sutton2, Nicole Casadevall3, Corinne Bagnis1 and Claude Jacobs1

1 Department of Nephrology and Hematology 2 Pitié-Salpétrière Hospital Department of Hematology Hotel Dieu 3 Paris, France

Sir,

Anaemia is one of the most frequent medical problems in haemodialysis patients and its management was greatly improved with the use of human recombinant erythropoietin (rHuEpo). We present a case of uncommon anaemia in a uraemic patient.

Case. A 70-year-old woman was admitted to hospital in March 2000 because of rapid onset, severe anaemia. Her medical history was marked by diabetes mellitus with renal failure. She had received rHuEpo since September 1999 (4000 UI/week) with an initial favourable response (haemoglobin level between 11 and 12 g/dl, 11.3 g/dl in February 2000). At the time of admission, her haemoglobin level was 5.6 g/dl and serum creatinine was 267 µmol/l (Cockcroft and Gault clearance 15 ml/min). Her mean corpuscular level was 82.7 µm3 and reticulocyte count 2000 per mm3, with normal white-cell and platelet counts. Anaemia was well tolerated with no evidence of bleeding. Gastric endoscopy was normal. Serum vitamin B12, folate and ferritin levels were normal (706 pmol/l, 20 nmol/l and 472 µg/l, respectively).

The bone marrow showed pure red-cell aplasia with early termination of maturation (proerythroblasts 1%, basophilic erythroblasts 1%, polychromatophilic and acidophil erythroblasts 0%). There was no dysmyelopoiesis, no lymphoid proliferation and granulocytes and megakaryocytes were normal. Serologic tests for human B19 parvovirus and amplification of viral DNA with polymerase chain reaction in plasma and in bone marrow were negative. Serologic tests for human immunodeficiency virus and hepatitis C were negative. Serologic tests for cytomegalovirus, Epstein-Barr virus, HHV6 and hepatitis B were consistent with past infection. A thoracic computed tomographic scan did not reveal evidence of thymoma. Antinuclear antibodies were 1/160, with no anti-ds-DNA antibody, and a direct Coomb's test was negative with normal haemolytic markers. Our diagnosis was pure red-cell aplasia with no aetiological factor. The patient received up to 8000 IU/week (150 IU/kg/d) of rHuEpo. From March to December 2000, transfusion requirements were about 3 units of packed red cells per month. rHuEpo administration was stopped in August.

In October 2000, the presence of autoantibodies against rHuEpo was shown by immunoprecipitation of [125I]Epo. Determination using past serum revealed a negative result for September 1999 (0.09%). In November 2000, the level of autoantibodies had decreased slightly, with persistent anaemia but with an increase in reticulocyte count (81 000 per mm3) for a haemoglobin level of 6.2 g/dl before transfusion and 33% of erythroblasts in bone marrow. Because of persistent transfusion requirements, prednisone was introduced in December 2000 at 1 mg/kg/d; subsequently it was progressively tapered and stopped at 6 months. In May 2001, an autoantibody search against rHuEpo was negative. The haemoglobin level was around 9 g/dl.

Comment

Pure red-cell aplasia is typically associated with thymoma, viral infection (mainly parvovirus B19), immunological diseases such as systemic lupus erythematosus, and neoplasia such as chronic lymphocytic leukaemia.

The presence of autoantibodies against endogenous erythropoietin has been demonstrated in one report [1]. In uraemic patients, few reports have described a similar immunological reaction directed against rHuEpo [25]. rHuEpo may induce antibodies against itself, responsible for red-cell aplasia. The termination of rHuEpo in our patient permitted a decrease in autoantibody level concomitantly with an increase in reticulocyte count. After corticosteroid treatment, autoantibodies became undetectable and her haemoglobin level rose to a more acceptable range.

Antibodies against rHuEpo should be considered in chronic haemodialysis patients as a cause of absolute resistance to rHuEpo. The method of their detection has been validated adequately [6].

Notes

Email: lucile.mercadal{at}psl.ap\|[hyphen]\|hop\|[hyphen]\|paris.fr Back

References

  1. Casadevall N, Dupuy E, Molho-Sabatier P, Tobelem G, Varet B, Mayeux P. Autoantibodies against erythropoietin in a patient with pure red-cell aplasia. N Engl J Med1996; 334: 630–633[Free Full Text]
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