Fulminant late onset cold
hemagglutinin disease after allogeneic bone marrow
transplantation
Wing Y. Au, Albert. K.W. Lie, Raymond Liang, Clarence C.K.
Lam, Yok-Lam Kwong
University Departments of Medicine and Pathology, Queen Mary
Hospital, Hong Kong
Correspondence: Dr. YL Kwong, University Department of Medicine,
Professorial Block, Queen Mary Hospital, Pokfulam Road, Hong Kong.
Tel: (852) 2855 4597. Fax: (852) 2816 2187
Autoimmune phenomena after allogeneic bone marrow
transplantation (BMT) may be related to graft versus host disease
(GVHD) or the abnormal immunological regeneration, particularly
with prolonged immuno-suppression.1-3 Cold
hemagglutinin disease (CHAD) is a rare autoimmune complication of
allogeneic BMT.4-6
A 22-year-old woman (blood group A+) with chronic myeloid leukemia
in second chronic phase underwent BMT from a matched unrelated
donor (blood group O+) (conditioning: busulphan 7 mg/kg,
cyclophosphamide 50 mg/kg and total body irradiation 12 Gy, GVHD
prophylaxis: cyclosporine and methotrexate). She engrafted on day
18 with grade III hepatic GVHD, controlled by anti-thymocyte
globulin and pulse steroids. Subsequent immunosuppression included
cyclopsorine, azathioprine, prednisolone and monthly intravenous
immunoglobulin. At eleven months post BMT, she developed an abrupt
painful acrocyanosis up to the thighs and elbows. With warming,
the pain improved but livedo reticularis remained. The peripheral
blood film showed extensive red cell agglutination. Tests for
intravascular hemolysis, the direct anti-globulin test (with anti-
immunoglobulin (Ig) and complement antibodies) and indirect
anti-globulin test at strict 37°C, and tests for
cryoglobulins were all negative. The test for cold agglutinin (CA)
was, however, strongly positive with a titer of 8192 at 4°C.
On elution, an IgM of broad specificity and thermal amplitude up
to 30°C was found. Reactivity against cord blood, papain and
neuraminidase treated red cells were not tested. Serum
immunoelectrophoresis showed a monoclonal IgM k band (1.7 g/L).
Serological tests for mycoplasma were negative. Bone marrow
biopsy, liver biopsy and computerised tomography of the abdomen
did not show evidence of lymphoproliferative disorder. A
polymerase chain reaction for Epstein-Barr virus (EBV) genome in
the peripheral blood and staining for EBV encoded small RNAs by in
situ hybridisation in the liver were negative. Her anemia and
hyperbilirubinemia persisted despite high dose prednisolone (2
mg/Kg/day), cyclophosphamide (4 mg/Kg), intravenous immunoglobulin
(0.5 gm/Kg/day), and cessation of cyclosporine. Plasmapheresis
failed because of extensive extra-corporeal agglutination, and
exchange transfusion did not reduced cold agglutinin titer. The
patient finally died of infection. CHAD can be due to a variety of
underlying disorders.7 Those with a monoclonal CA,
typically IgM k, may be idiopathic or secondary to a
lymphoproliferative disorder, while polyclonal CA are reactive to
viral or mycoplasma infection. The disease usually runs a benign
course, except in cases with a CA of high thermal amplitude that
may cause severe hemolysis.8. The high-titer CA with a
wide thermal amplitude and a fulminant clinical course
distinguished our case from idiopathic CHAD. A review of the
literature identified only four symptomatic CHAD cases following
allogeneic BMT (Table
1).4-6 The
common risk factors were chronic GVHD and prolonged
immunosuppression, leading to abnormal immunue
reconstitution.1 In none of these cases was a
lymphoproliferative disease demonstrable. A monoclonal paraprotein
is often found, reflecting B cell clonal dominance, probably due
to an impaired T cell regulation.3 Death occurred in
three of five cases
In conclusion, CHAD is a rare but serious complication of chronic
GVHD after BMT. Physician's awareness of this disease may lead to
early diagnosis and treatment, thus improving the
prognosis.
