Ceftizoxime-induced hemolysis due to immune complexes: case report and determination of the epitope responsible for immune complex-mediated hemolysis

BACKGROUND: Several occurrences of immune complex-mediated, cephalosporin-induced intravascular hemolysis have been reported. This report describes the first case of hemolytic anemia caused by an immune-complex mechanism associated with ceftizoxime and delineates the epitope responsible for hemolysis. CASE REPORT: The patient's serum was tested for antibody that reacted with five penicillins and 30 cephems (all types of cephalosporins) by using protocols to detect drug-adsorption and immune-complex mechanisms. The patient's antibody that formed immune complexes with ceftizoxime reacted with 10 of 30 cephems. These 10 drugs were classified as oxime-type cephalosporins, which have a common structural formula consisting of [(Z)-2-(2-amino-4-thiazolyl)-2-methoxyiminoacetoamido] at the C7 position on 7-aminocephalosporinic acid with or without substitution at the C3 position. CONCLUSION: The patient's antibody recognized a common structure in 10 oxime-type cephalosporins, and immune complexes formed by the antibody specifically or nonspecifically bound to red cell membranes. Therefore, when intermittent antibiotic therapy is required, as in this case, care should be taken in antibiotic selection to avoid drug-induced hemolytic anemia. In addition, when this type of hemolysis is observed, tests for antibody that reacts by adsorption and immune-complex mechanisms should be performed against penicillins and cephems to select antibiotics not showing a cross-reaction.     

Sulindac-induced immune hemolytic anemia

BACKGROUND: Sulindac, a nonsteroidal, anti-inflammatory, indene-derived drug, caused life-threatening immune hemolytic anemia in an individual with back pain. CASE REPORT: A patient was admitted to the hospital with immune hemolytic anemia and kidney and liver failure after several days ingestion of sulindac. The direct antiglobulin test was positive with polyspecific and monospecific anti-IgG but not with anti-C3. The eluate did not react in routine tests but reacted strongly after the addition of sulindac. The serum contained a sulindac-dependent antibody reacting to a titer of 32. The sulindac-dependent antibody was of both IgG and IgM classes and had no apparent blood group specificity. The antibody agglutinated red cells from humans and chimpanzees but not from chickens, rabbits, or sheep, which implied that a specific component on human and chimpanzee red cells was needed for reactivity. The antibody reacted with red cells treated with trypsin, papain, pronase, dithiothreitol, and sialidase. With aggressive medical care, the patient's condition improved. CONCLUSION: These findings appear compatible with the so-called immune complex mechanism for drug-induced immune hemolytic anemia. Physicians are alerted to the severe nature of this syndrome.     

Immune hemolytic anemia caused by sensitivity to a metabolite of etodolac, a nonsteroidal anti-inflammatory drug

BACKGROUND: Immune hemolytic anemia can be caused by sensitivity to many different drugs. In some instances, the sensitizing compound can be identified by in vitro testing, but results are often negative. One reason for this is that a drug metabolite formed in vivo can be the sensitizing agent, but the responsible metabolites have rarely been identified at a chemical level. This report describes a patient who developed severe, Coombs-positive hemolytic anemia on two occasions after taking the nonsteroidal anti-inflammatory drug etodolac. Studies were performed to characterize etodolac metabolites to which this patient was sensitive. CASE REPORT: Serum was tested for antibody in the presence and absence of drug using conventional methods and urine from individuals taking etodolac as a source of drug metabolites. Urinary metabolites of etodolac were identified by high-pressure liquid chromatography analysis. Glucuronide conjugates of etodolac and the 6-OH metabolite of etodolac were synthesized in a rat liver microsomal system to obtain reference standards. RESULTS: The patient's serum gave only trace (+/-) reactions with normal RBCs in the presence of etodolac but reacted strongly (4+) in the presence of urine from an individual taking this drug. The active urinary metabolites were identified as etodolac glucuronide and 6-OH etodolac glucuronide. CONCLUSION: This patient appears to have experienced acute, severe immune hemolytic anemia on two occasions because of sensitivity to the glucuronides of etodolac and 6-OH etodolac. In patients suspected of having drug-induced immune hemolytic anemia, RBC-reactive antibodies can sometimes be detected by using urine from an individual taking the implicated medication as the source of drug metabolites in in vitro reactions. For patients who present with acute immune hemolysis, a careful history of drug exposure should be taken, and, where indicated, confirmatory testing should be performed to identify the sensitizing drug and prevent inadvertent reinduction of hemolysis at a later time.     

Fatal immune hemolytic anemia due to cefotetan

In the first death associated with immune hemolytic anemia due to cefotetan, the patient developed hemolytic anemia and renal failure, dying 12 days after the beginning of 1 week's cefotetan therapy. The patient's serum contained strong antibodies reacting with cefotetan-treated red cells (RBCs) and with uncoated RBCs in the presence of cefotetan; a much weaker, drug-independent antibody was also detected. Three-days before the patient's death, the antibody reacting with cefotetan-coated RBCs rose to a titer of 262,144; the titer of the antibody to uncoated RBCs, in the presence of cefotetan, rose to 2048; the titer of the drug-independent antibody remained at 4.     

Immune hemolytic anemia associated with tolmetin and suprofen

This article reports the first case of immune hemolytic anemia possibly associated with the ingestion of suprofen. The patient suffered from massive hemoglobinuria and acute renal failure. Serologic studies of the patient's serum revealed suprofen-dependent red cell antibodies. However, tolmetin-dependent antibodies were also found in the serum, showing the same properties as the suprofen antibodies and an even higher titer. The patient not only had drug-dependent antibodies in the serum, but also had developed autoantibodies, a phenomenon that has been described for several other drugs. The working mechanism by which suprofen and tolmetin caused immune hemolysis had properties of both the immune complex model and the induction of autoimmunity. Although it was unclear whether the immune hemolytic anemia was the result of suprofen, tolmetin, or cross-reacting antibodies, we feel that suprofen should be added to the list of nonsteroidal anti-inflammatory drugs associated with a positive direct antiglobulin test.     

The first example of a patient with etoricoxib‐induced immune hemolytic anemia

BACKGROUND: Etoricoxib, a selective inhibitor of cyclooxygenase 2, is increasingly used in pain relief. Here, we report the first case of etoricoxib‐induced immune hemolytic anemia. STUDY DESIGN AND METHODS: An 84‐year‐old male patient developed anemia 1 week after treatment with etoricoxib. There was no evidence of hemoglobinemia or hemoglobinuria. Administration of the drug was halted, and the patient recovered without further complications. RESULTS: The patient's red blood cells (RBCs) were found to be strongly coated with immunoglobulin G and C3d. Eluted antibodies and dialyzed serum from the patient were not reactive with untreated RBCs, but with etoricoxib‐treated RBCs, RBCs in the presence of etoricoxib, urine containing drug metabolites (ex vivo antigen), and two of four additional COX inhibitor drugs analyzed. DISCUSSION: Although the causative antibodies were drug dependent usually leading to abrupt and intravascular hemolysis, the patient only gradually developed anemia. These findings together with a positive direct and indirect antiglobulin test may lead to confusion with autoimmune hemolytic anemia of warm type. A nonreactive eluate was the key serologic finding in identifying drug‐induced immune hemolytic anemia in this case. CONCLUSION: Etoricoxib should be considered as a risk in the development of immune hemolytic anemia, with the causative antibodies potentially reacting with other COX inhibitors.     

Plasma exchange in the treatment of immune disease

Plasma exchange was investigated as an alternative to the use of toxic drugs to remove unwanted antibody. Studies in rabbits immunized with bovine serum albumin demonstrate that exchange transfusion after a primary immunization results in a rebound of antibody to above preexchange levels. However, exchange transfusion seven, 11, or 18 days after secondary immunization results in permanent lowering of antibody levels. Plasma exchange with the continuous flow centrifuge was used in four patients with hematologic diseases. White cell isoantibodies were removed in a septic leukopenic patient, permitting white cell transfusions. Two patients with immune thrombocytopenia were exchanges; one showed prompt and permanent elevation of platelet count, while the other did not improve. A patient with immune hemolytic anemia had stabilization of hemoglobin levels and decreased Coombs reactivity following plasma exchange.     

Cefotetan disodium-induced hemolytic anemia.

OBJECTIVE: To report a case of cefotetan disodium-induced hemolytic anemia. DATA SOURCES: Original research articles and case reports. DATA SYNTHESIS: A 46-year-old woman developed fulminant hemolytic anemia following a second exposure to intravenous cefotetan disodium for postoperative prophylaxis. She developed respiratory failure requiring intubation and acute renal failure requiring hemodialysis. The hemolysis was successfully treated with plasmapheresis, but the patient died on the 25th postoperative day. Positive Coomb's tests have been reported in less than three percent of patients receiving cefotetan. To our knowledge, this is the first case of fulminant hemolytic anemia associated with intravenous cefotetan disodium therapy. CONCLUSIONS: Cefotetan should be added to the list of drugs known to cause hemolytic anemia. Monitoring for hemolysis should be considered for patients who receive multiple courses of therapy.     

Immune hemolytic anemia associated with teicoplanin

BACKGROUND: Several drugs can cause immune hemolytic anemia. Here a patient who developed hemolytic anemia after treatment with teicoplanin is described. CASE REPORT: Owing to a two-vessel disease, a 68-year-old white man underwent coronary artery bypass grafting. He was readmitted for superficial sternal wound infection and sternal instability. Rewiring was required and worsening anemia characterized the course after the reoperation. Drugs used in the second admission were gentamycin, teicoplanin, paracetamol, and codeine. They were considered as a possible cause of drug-induced hemolytic anemia. RESULTS: The DAT was positive for complement and IgG. Autoanti-e was identified in the patient's undiluted serum sample. The eluate was reactive with all RBCs tested only after adding teicoplanin; when diluted 1:4, anti-e specificity was observed in the presence of teicoplanin. CONCLUSION: To our knowledge, this is the first report of immune hemolytic anemia owing to teicoplanin.     

Immune hemolytic anemia induced by 6-mercaptopurine

BACKGROUND: Myelosuppression is the main hematotoxic effect of 6-mercaptopurine (6-MP), which is an antimetabolite chemotherapy drug. Immune hemolytic anemia associated with this drug has not been previously reported. CASE REPORT: A 67-year-old man with chronic myelomonocytic leukemia presented with anemia 2 weeks after 6-MP therapy had been initiated. Additional tests provided laboratory evidence of hemolysis. When treatment was stopped, the patient's condition and laboratory results showed a progressive improvement. RESULTS: The direct antiglobulin test was positive for IgG. The eluate and the serum were not reactive with panel red cells but reacted with 6-MP-treated red cells, while the normal serum pool was unreactive. The direct antiglobulin test was no longer positive by 20 days after the cessation of 6-MP therapy. CONCLUSION: This drug, 6-MP, should be added to the list of drugs that have been reported to cause immune hemolytic anemia by means of the so-called hapten mechanism.     

A fatal case of ceftriaxone (Rocephin)-induced hemolytic anemia associated with intravascular immune hemolysis

Fatal hemolytic anemia developed in a 52-year-old woman who was treated with a cephalosporin, ceftriaxone. The patient's red cells (RBCs) were coated with C3, but no RBC-bound IgG, IgA, or IgM was detected. Her serum contained an antibody that did not react with cephalosporin- coated RBCs but reacted strongly with RBCs in vitro when her serum was added to drug and RBCs. This is the first case of immune hemolytic anemia associated with ceftriaxone, the first case of fatal cephalosporin-induced hemolytic anemia, and the second case in which a cephalosporin antibody showed in vitro and in vivo characteristics usually thought to be associated with the so-called immune complex mechanism.     

Pulmonary aspergillosis and central nervous system hemorrhage as complications of autoimmune hemolytic anemia treated with corticosteroids

Warm, active antibody adult autoimmune hemolytic anemia is the most common form of hemolytic anemia not related to drug therapy. Mortality in adult autoimmune hemolytic anemia is related to the inability to successfully treat patients' underlying disease, or the infectious complications of splenectomy and prolonged steroid therapy. Predisposing factors for invasive aspergillosis are neutropenia and steroid therapy. We present a fatal case of aspergillosis complicating a nonneutropenic case of warm active antibody adult autoimmune hemolytic anemia treated with prolonged steroid therapy.     

Autoimmune hemolytic anemia associated with IgG auto anti-N

A second case of autoimmune hemolytic anemia mediated by an IgG auto Anti-N is described. The patient's red blood cells were sensitized with both IgG and complement. The serum antibody was not inactivated by 2- mercaptoethanol treatment, and reacted by indirect antiglobulin test at 37 C with monospecific anti-IgG. The IgG antibody eluted from the red blood cells and in the serum showed anti-N specificity. The patient was thought to have systemic lupus erythematosus. Following steroid therapy, the hemolytic anemia resolved with disappearance of the anti-N.     

Thrombotic thrombocytopenic purpura in a patient with rheumatoid arthritis treated by plasmapheresis.

Thrombotic thrombocytopenic purpura (TTP) is a multisystem disorder characterized by consumptive thrombocytopenia, microangiopathic hemolytic anemia, and neurologic symptoms. TTP is associated with many diseases and several therapeutic drugs. We report the rare case of a patient with rheumatoid arthritis who developed TTP that was not associated with drug therapy, 18 months after the onset of rheumatoid arthritis. She recovered from the TTP following daily sessions of therapeutic plasma exchange (TPE) with fresh frozen plasma replacement and glucocorticoid therapy. Recent pathogenic mechanisms are reviewed as they relate to von Willebrand factor. In this report of the rare association of TTP with rheumatoid arthritis, an immediate relationship is likely because both are of an immune nature. Awareness of the possible development of TTP in rheumatoid arthritis is important for early diagnosis and treatment.     

Coombs'-negative spherocytic hemolytic anemia and severe necrotizing renal vasculitis

Vasculitis may be complicated by either hypoproliferative or hemolytic anemias. We have described a patient with a Coombs'-negative spherocytic hemolytic anemia and severe necrotizing renal vasculitis, two disorders not having been previously linked. The disorders were temporally related and both responded to immunosuppressive therapy. The precise cause of the hemolytic anemia remains unknown.     

Drug-induced hemolytic anemias: increasing complications to therapeutic interventions.

There are recent reports of severe drug-induced immune hemolysis caused by several different classes of drugs. Second and third generation cephalosporins, diclofenac, fludarabine, carboplatin, and beta-lactamase inhibitors are among the drugs associated with severe or fatal hemolysis. Studies on patients who exhibit hemolysis after ingesting these drugs indicate that the four classical mechanisms of drug-induced hemolytic anemia may overlap. These studies appear to support the unified theory for induction of drug-induced immune hemolytic anemia.     

Levofloxacin-induced autoimmune hemolytic anemia

OBJECTIVE: To report a case of autoimmune hemolytic anemia (AIHA) secondary to levofloxacin. CASE SUMMARY: An 82-year-old white man was treated with levofloxacin 500 mg/d for cellulitis. Three days following completion of levofloxacin therapy, the patient presented to the emergency department with severe jaundice, dizziness, and loss of vision. He received packed red blood cells (PRBCs) and was discharged home. Two days later at the follow-up visit, he was diagnosed with AIHA secondary to levofloxacin. The patient was hospitalized and treated with a tapering dose of prednisone and additional PRBC infusion. He was discharged from the hospital in stable condition after 3 days. Repeated hematologic laboratory studies following discharge demonstrated that the hemolytic anemia had resolved. DISCUSSION: Hemolytic anemia due to levofloxacin is an extremely rare, but potentially fatal, adverse drug event. An objective causality assessment revealed that the adverse reaction was probable. To our knowledge, this is the first published case of levofloxacin-induced AIHA. However, there are published case reports of hemolytic anemia with other fluoroquinolones including ciprofloxacin (n = 12) and temafloxacin (n = 95). Temafloxacin was withdrawn from the market in 1992 due to this adverse effect. The mechanism by which levofloxacin triggers hemolytic anemia is unknown. We believe that an immune-mediated reaction is most likely. CONCLUSIONS: Levofloxacin-induced AIHA is a rare but serious complication of therapy. Immediate discontinuation of the offending medication and treatment of the hemolytic anemia are essential. Until more information is available, levofloxacin should not be prescribed for patients with previous reactions to any fluoroquinolone.     

The first case of drug-induced immune hemolytic anemia due to hydrocortisone

BACKGROUND: Drug‐induced immune hemolytic anemia (DIIHA) is a well‐known complication of drug treatment. Sensitization can occur, due to interaction of the drug and/or its metabolites with cells of the immune system, after the first drug administration, while the hemolytic crisis generally occurs after repeated administration of a drug. This event occurred in the case described here of acute hemolysis due to the administration of corticosteroids. STUDY DESIGN AND METHODS: To define the etiopathogenesis of the hemolytic crisis, immunohematologic screening and specific tests were performed to identify antibodies against a possible drug–red cell (RBC) complex and circulating drug–anti‐drug antibody immune complexes. Six drugs administered to the patient were tested and results were confirmed by test repetition using other types of corticosteroids. RESULTS: Indirect antiglobulin test performed with the patient's serum sample on 22 RBC samples from commercial panels was strongly positive, while it was negative on RBCs from ABO‐compatible donors. The same test repeated on commercial RBCs after washing was negative. Specific tests were negative for five of the six tested drugs, while RBCs incubated with hydrocortisone strongly reacted with the patient's serum. The same tests performed using other types of corticosteroids confirmed a reaction with the same positivity score on all tested molecules. CONCLUSION: The positive reaction observed each time the patient's serum sample was incubated with RBCs in the presence of corticosteroids suggested that the triggering cause of hemolysis was an immune‐mediated mechanism and the drug responsible for DIIHA was hydrocortisone.     

Immune hemolytic anemia due to cimetidine: the first example of a cimetidine antibody

BACKGROUND: Although there have been a few reports of immune hemolytic anemia (IHA) thought to be due to cimetidine, none of them provided proof (e.g., serologic detection of anti‐cimetidine and/or repeat of IHA upon drug rechallenge). One report used cimetidine as an example of how temporal associations of drug administration and hemolytic anemia are not proof of a cause‐effect relationship. STUDY DESIGN AND METHODS: A 63‐year‐old cancer patient developed IHA on two occasions after receiving cimetidine (with and without chemotherapy). Serologic methods included testing cimetidine‐treated red blood cells (RBCs) as well as testing untreated RBCs in the presence of cimetidine. RESULTS: The patient's direct antiglobulin test was positive (C3 only) and a serum antibody to cimetidine was detected by both testing methods. An eluate from the patient's RBCs was nonreactive. Cimetidine‐treated RBCs were optimally prepared at room temperature and needed to be tested on the day of preparation. CONCLUSIONS: This is the first reported case of IHA due to a cimetidine antibody where a drug‐dependent antibody was demonstrated. The patient had IHA after receiving cimetidine on two separate occasions.     

Agranulocytosis and hemolytic anemia in patients with renal cell cancer treated with interleukin-12

Interleukin-12 (IL-12) is a cytokine with effects on immune function and hematopoiesis. In this article, the authors describe two patients with renal cell cancer in whom grade 4 neutropenia and grade 3 hemolytic anemia developed, respectively, during treatment with twice-weekly intravenous recombinant human interleukin-12 (rhIL-12) during a phase 1 trial. The severe neutropenia was associated with bone marrow agranulocytosis and a preponderance of large granular lymphocytes in the peripheral blood, whereas the hemolytic anemia was negative for the Coombs test and associated with splenomegaly. The agranulocytosis and hemolytic anemia persisted after the rhIL-12 was stopped, but both subsequently responded to treatment with cyclophosphamide. steroids, or both. These findings indicate that rhIL-12 can induce unique hematologic toxic effects that can be reversed with immunosuppressive drugs.