Reappraisal of the Role of Anti-i in Haemolytic Anaemia in Infectious Mononucleosis

S ummary . Current literature implies that haemolytic anaemia in infectious mononucleosis is regularly caused by the temporary production of high thermal amplitude cold agglutinins of anti-i specificity. More recently, Capra et al (1969) suggested interaction between IgG anti-i and anti-IgG antibodies as the cause of haemolytic anaemia in infectious mononucleosis. A detailed serologic evaluation of three patients during moderate to severe haemolytic anaemia in infectious mononucleosis revealed high thermal amplitude anti-i in only one. This patient's direct antiglobulin test (DAT) was negative using anti-IgG but was 3 + using anti-C₃ and -C₄. The serum antibody titre against cord or adult Oi cells was 512 at 4°C and 4 at 31°C. The anti-i was inhibited by mercaptoethanol, and anti-IgG was not found in the patient's serum. Patient 2 had a negative DAT and patient 3 had a 2 + DAT using anti-C₃ and anti-C₄. Anti-i was present only in low titre at 4°C and was unreactive at 20°C. It was inhibited by mercaptoethanol. These patients' sera contained anti-IgG antibodies. In none of our patients were warm autoantibodies detected. This data demonstrates that haemolytic anaemia in infectious mononucleosis is not necessarily associated with high thermal amplitude anti-i. Further, since the anti-i antibodies in patients 2 and 3 were of low titre, were inhibited by mercaptoethanol, and did not react at physiologic temperatures, the mechanism of haemolysis in these patients does not seem related to the interaction of anti-IgG and IgG anti-i antibodies. Further work is necessary to clarify the mechanism of haemolytic anaemia in infectious mononucleosis.     

Auto-immune haemolytic anemia complicating infectious mononucleosis in a patient with hereditary elliptocytosis.

Auto-immune haemolytic anemia complicating infectious mononucleosis occurred in a patient with hereditary elliptocytosis. A cold antibody of IgM anti-i specificity with narrow thermal amplitude was identified in the serum and the erythrocytes were found to be coated with complement. Significantly excessive erythrophagocytosis was demonstrated in samples of the patient's blood which had been chilled and then incubated at 37 degrees C. The patient recovered spontaneously. The elliptocytosis does not appear to have contributed to the episode of haemolytic anaemia; the other elliptocytic member of the family (her father) had no history and no present evidence of haemolysis.     

Fatal cold anti-i autoimmune haemolytic anaemia complicating hairy cell leukaemia

Hairy cell leukaemia (HCL) is a rare lymphoproliferative disorder associated with pancytopenia, splenomegaly and the presence of typical hairy B lymphocytes in the bone marrow and/or peripheral blood. The most significant complication relates to opportunistic infections that arise as a consequence of neutropenia and monocytopenia. HCL is occasionally associated with systemic autoimmune disorders including polyarteritis nodosa and rheumatoid disease. Secondary autoimmune haemolytic anaemia (AIHA) appears to be rare. We report on two cases of HCL complicated by fatal cold anti-i AIHA. Fulminant haemolysis causing death is rare in cold AIHA and only a few individual cases have been reported, none having anti-i specificity.     

Severe hemolysis complicated by renal insufficiency in a patient with mitro-aortic bioprostheses and review of the literature

The authors report a very rare case of massive haemolytic anaemia complicated by renal failure in a patient with a double aortic and mitral bioprosthesis. The haemolysis was attributed to degeneration of the aortic bioprosthesis causing turbulent flow, aggravated by associated infectious endocarditis. The essential condition for haemolysis is a change in blood flow through the valve by degeneration or other associated pathology. The haemolytic anaemia completely regressed after aortic valve replacement as did the renal failure.     

Haemolytic anaemia in previously healthy adult patients with CMV infections: report of two cases and an evaluation of subclinical haemolysis in CMV mononucleosis

Whereas haemolytic anaemia is commonly encountered in infants and young children with cytomegalovirus (CMV) infections, it is an infrequent complication of CMV-induced infections in previously healthy adults. The data from 2 such patients are presented. One patient's Hb fell to a level of 36 g/l, and she required prednisone and blood transfusions. Her direct antihuman globulin test (DAT) was positive (IgG), and her red blood cell survival (51Cr) revealed a T 1/2 of 5 d. Both saline-agglutinating and low-molecular-weight cold agglutinins (CA) (4 degrees C) that reacted against both cord and adult cells were identified. In the second case, a moderate haemolytic anaemia (lowest Hb 87 g/l) was accompanied by negative DAT and CA studies. 20 other patients with CMV-mononucleosis were evaluated for evidence of subclinical haemolysis. Reticulocyte counts greater than 3.0% were noted in 9 of these patients. Haptoglobin values were below 0.5 g/l in 13 patients, and a positive DAT was recorded in 3/10 cases. This study documents haemolysis in many non-immunosuppressed adult patients with CMV infections. The mechanism responsible remains obscure.     

Cold agglutinins in infectious mononucleosis and heterophil-antibody-negative mononucleosis-like syndromes.

Cold agglutinins (CA) were evaluated prospectively in patients with various mononucleosis syndromes and in a large control group. Cold agglutinins with anti-i specificity were seen mainly in heterophil-positive or -negative Epstein-Barr virus (EBV)-induced infectious mononucleosis (31.8% of cases). Unclassified CA with equal reactivity against cord and adult erythrocytes were seen in 56 of 150 (37.3%) cases of heterophil-antibody-positive infectious mononucleosis (IM), in 1 of 7 (14.3%) cases of heterophil-negative EBV-induced IM, and in 12 of 31 (38.7%) cases of the heterophil-negative mononucleosis-like syndrome due to cytomegalovirus or other unspecified agents. One patient with heterophil-positive IM had a persistent, partially papain sensitive CA with anti-Pr-like activity. Anti-i CA were seen in less than 1.0% of healthy young adults (500) or patients without mononucleosis (500) submitted for heterophil studies. Unclassified CA were noted in 3.2% of the latter 1000 samples.     

Mixed-Type Auto-Immune Haemolytic Anaemia in a Patient with HIV Infection

A young HIV-infected patient presented with a severe auto-immune haemolytic anaemia with both warm and cold auto-antibodies, an infrequent category of anti-erythrocyte auto-immunity. Serological findings were compatible with the presence of a low-titre, high-thermal-amplitude anti-I cold-reacting antibody and a pan-reactive warm-reactive auto-antibody. Immunochemical characterisation of the warm antibody failed to identify any membrane protein acting as auto-antigen. This is, to our knowledge, the first reported case of mixed-type autoimmune haemolytic anaemia in a patient with HIV infection. Overt haemolysis is a very rare complication in HIV-infected patients, despite the high prevalence of a positive direct antiglobulin test reported in these patients. This suggests that HIV infection is a condition in which anti-erythrocyte auto-immunity is a serological finding without haemolytic effects in the large majority of cases.     

IgG-mediated haemolysis masquerading as cold agglutinin-induced anaemia complicating severe infection with Mycoplasma pneumoniae

Haemolytic anaemia complicating Mycoplasma infection has usually been attributed to IgM cold agglutinins. This report describes a patient with pneumonia due to Mycoplasma pneumoniae in whom severe haemolysis persisted despite declining thermal amplitude and titre of cold agglutinins as the infection resolved. Class-specific antiglobulin (Coombs) testing defined an IgG warm agglutinin coating the patient's erythrocytes that was distinct from the IgM cold agglutinin identified by Sephadex G-200 gel filtration and dithiothreitol inactivation. Monoclonal IgM(γ) and IgK (k) circulating proteins were identified and immuno-electrophoresis of the cold aggulutinin-containing cryoglobulin fraction identified the cold agglutinin as an IgM(γ). In this patient initially presumed to have cold agglutinin induced haemolysis secondary to Mycoplasma infection, an IgG warm agglutinin was identified as the aetiology for the patient's haemolysis, underscoring the clinical relevance of careful evaluation of the mechanism of haemolysis accompanying Mycoplasma pneumonia.     

An incomplete cold-reactive gamma G antibody with i specificity in infectious mononucleosis

Summary. A new cold reactive antibody directed against fetal (i) cells is described in 90% of patients with infectious mononucleosis. It appears to be the 7S counterpart of the previously described 19S anti-i antibody. The 7S anti-i antibody interacts with a 19S anti γ globulin and the combination is responsible for the majority of the cold agglutinin phenomena previously shown in this disorder. The highest titers were detected in patients with severe hemolytic anemia, leukopenia, thrombocytopenia or combinations thereof.     

Jaundice and intracardiac tumour

We report the case of a type B lymphoma originating from the mediastinum, characterized principally by massive metastatic invasion of the right cardiac cavities in the form of a projecting mass well visualized at echography responsible of the presenting features of the illness. This lymphoma was, moreover, associated with an auto-immune haemolytic anaemia due to cold agglutinins.     

Infectious mononucleosis complicated by haemolytic anaemia due to the Donath Landsteiner antibody and by severe neutropenia

Summary A young man developed infectious mononucleosis complicated by profound anaemia due to haemolysis. The Donath Landsteiner antibody was found in his serum. He was treated successfully by blood transfusion but subsequently developed severe neutropenia. Both complications have been reported previously but not in the same individcual. No underlying immune deficiency could be identified.     

The Complement System in Infectious Mononucleosis

The complement system in infectious mononucleosis. J. A. Charlesworth, B. A. Pussel, L P. Roy, S. Lawrence and M. R. Robertson, Aust. N.Z. J. Med., 1977, 7 , pp. 23–26. The complement system was investigated in 34 patients with infectious mononucleosis. Three had specific complications: one haemo-lytic anaemia, one severe arthralgia/myalgia and one proliferative glomerulonephritis. Complement changes consistent with classical pathway consumption were seen in ten of the uncomplicated group and the patients with haemolytic anaemia and arthralgia/myalgia. The patient with glomerulonephritis showed evidence of alternative pathway utilisation including C3 splitting activity and the deposition of properclin. on renal biopsy. The complement findings suggest that circulating immune complexes are common in such patients and are likely to play a role in the pathogenesis of the complications. It is proposed that both complement pathways may be required for the effective clearance of viral material from the circulation.     

Treatment of refractory fludarabine induced autoimmune haemolytic with the anti‐cd20 monoclonal antibody rituximab

A patient with cold‐type autoimmune haemolytic anaemia for 8 years developed progressive B cell chronic lymphocytic leukaemia (CLL). Despite the risk of fludarabine induced exacerbation of haemolysis, he was given aggressive anti‐CLL therapy with six courses of FCR (fludarabine 25 mg/m² D1–3, cyclophosphamide 250 mg/m² D2–4 and rituximab 375 mg/m² D1) every 4 weeks. This resulted in a marked acute increase in haemolysis shortly after completing each course of fludarabine. However, haemolysis had settled to its baseline level by the time of subsequent courses of FCR. FCR resulted in complete clinical remission of CLL but residual haemolysis persisted. The patient was then given four weekly infusions of single agent rituximab, resulting in ongoing remission of haemolysis. In this patient, rituximab appears to have controlled fludarabine induced exacerbation of autoimmune haemolysis. In addition, subsequent single agent rituximab therapy resulted in prolonged remission of cold‐type autioimmune haemolytic anaemia. It remains to be seen if the addition of rituximab will allow other patients with a positive direct Coomb's test and/or autoimmune haemolysis to receive fludarabine containing chemotherapy without undue risk of life‐threatening haemolytic anaemia.     

Cytomegalovirus-induced thrombocytopenia and haemolysis in an immunocompetent adult

We describe a patient with severe symptomatic thrombocytopenia and haemolytic anaemia caused by cytomegalovirus (CMV) infection. As far as we know, this is the second case in the literature. Treatment with ganciclovir seemed to be more effective for thrombocytopenia than treatment with corticosteroids. The hypothetical mechanisms leading to thrombocytopenia and haemolysis in CMV infection are briefly discussed. In cases of acute thrombocytopenia and clinical manifestations of an infectious disease, with or without haemolysis, testing for CMV may be useful in connection with therapeutic consequences.     

Cytomegalovirus-induced thrombocytopenia and haemolysis in an immunocompetent adult

We describe a patient with severe symptomatic thrombocytopenia and haemolytic anaemia caused by cytomegalovirus (CMV) infection. As far as we know, this is the second case in the literature. Treatment with ganciclovir seemed to be more effective for thrombocytopenia than treatment with corticosteroids. The hypothetical mechanisms leading to thrombocytopenia and haemolysis in CMV infection are briefly discussed. In cases of acute thrombocytopenia and clinical manifestations of an infectious disease, with or without haemolysis, testing for CMV may be useful in connection with therapeutic consequences.     

Haemolytic anaemia due to cold agglutinins caused by psittacosis

A 69-yr-old previously healthy woman, presenting with jaundice and the clinical symptoms of an atypical pneumonia, was hospitalized. Haemolytic anaemia due to cold agglutinins was diagnosed, and erythromycin therapy for a suspected Mycoplasma pneumoniae infection was instituted. Serological testing revealed, however, that the infection was attributable to Chlamydia psittaci. The literature on psittacosis and haematological complications is reviewed. Cold agglutinins are sometimes found in association with psittacosis, but a concomitant haemolytic anaemia is rare.     

ABO Haemolytic Anaemia in Transplanted Patients

A case of severe intravascular haemolysis, due to an 'auto-anti-B antibody', and a case of transient haemolytic anaemia, due to an 'auto-anti-A antibody', following allogeneic organ transplantation, are reported. Both patients were receiving immunosuppressive therapy with cyclosporin A and were non-secretors of A, B and H substances.     

Apropos of 2 cases of hemolytic anemia in mycoplasma pneumonia

The authors present 2 cases of mycoplasmal pneumonia associated with severe haemolysis. Haemolytic anaemia is a well-known and habitually mild complication of the disease. It is related to a peak of cold agglutinins, which are antibodies that agglutinate red blood cells usually at low temperatures but sometimes at 37 degrees C when they are present in high concentrations. The pathogenesis of cold agglutinins is thought to involve the secretion of peroxides by Mycoplasma pneumoniae with alteration of ed cell antigens which become immunogenic.     

Infectious mononucleosis in the case of two elderly (80 and 57 years old age) patients.

There are reported two cases of infectious mononucleosis in elderly. In the first case (80 years; probably the oldest in the geriatric literature) the infection provoked a very serious illness and the patient deceased three months after dimission, because of diminished resistance. In the second case the mononucleosis induced an autoimmune haemolytic anemia. The patient's daughter and granddaughter must be treated for complications of an infectious mononucleosis too.     

Haemolytic anaemia as initial manifestation of wilson's disease

Summary Common manifestations of Wilson's disease are disorders of the liver and brain. A rare complication of this inherited disease is acute intravascular haemolytic anaemia. We report the case of a 33-year old female patient who was admitted to the hospital with acute haemolysis as the initial symptom of Wilson's disease. The haemolysis preceded the definitive diagnosis by 20 months. It is concluded that in any case of unclear haemolytic anaemia, especially in adolescents or in young adults, Wilson's disease should be considered.