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.     

Serologic characteristics of ceftriaxone antibodies in 25 patients with drug-induced immune hemolytic anemia

BACKGROUND: Ceftriaxone, a third‐generation cephalosporin, is commonly used to prevent and treat infections. Since 1987, it has been the second most common cause of drug‐induced immune hemolytic anemia (DIIHA) investigated in our laboratory. STUDY DESIGN AND METHODS: Samples from 79 patients (1987‐2010), suspected of having DIIHA caused by ceftriaxone, were studied for the presence of ceftriaxone antibodies. Direct antiglobulin tests (DATs) and tests with ceftriaxone‐treated red blood cells (RBCs) or untreated and enzyme‐treated RBCs in the presence of ceftriaxone were performed. RESULTS: Twenty‐five (32%) of the 79 patients had antibodies to ceftriaxone detected. Seventeen (68%) of the 25 patients were children; reactions in children were usually dramatic and severe. Nine (36%) of the 25 patients had fatal DIIHA. Nineteen of the 25 samples had DATs performed by our laboratory; 100% of samples were reactive with anti‐C3 and 47% were reactive with anti‐IgG. All 25 sera had ceftriaxone antibodies detected when testing untreated or ficin‐treated RBCs in the presence of ceftriaxone (resulting in agglutination, hemolysis or sensitization of test RBCs). These antibodies were primarily IgM and reactivity was enhanced by testing ficin‐treated RBCs. Sixteen (64%) of the 25 sera reacted with test RBCs when no ceftriaxone was added in vitro; this was most likely due to the transient presence of drug or drug‐immune complexes in the patient's circulation at the time that the blood samples were drawn. CONCLUSION: Ceftriaxone antibodies can cause severe intravascular hemolysis. Complement can usually be detected on the patient's RBCs and IgM antibodies are usually detected in the patient's serum.     

Autoimmune hemolytic anemia

Diagnosis of autoimmune hemolytic anemia (AIHA) requires both serologic evidence of an autoantibody and hemolysis. Based on the characteristic temperature reactivity of the autoantibody to red cell membranes, AIHA is classified into warm AIHA or cold AIHA (cold agglutinin disease and paroxysmal cold hemoglobinuria). Sensitized RBCs are destructed by intravascular and/or extravascular hemolysis. On the basis of etiology, AIHA are classified as idiopathic or secondary. The common cause of secondary AIHA is lymphoproliferative disorders, autoimmune diseases, and infections. The first line therapy of patients with warm AIHA is glucocorticoids and primary treatment for cold AIHA is avoiding cold exposure. The other standard treatments include splenectomy and immunosuppressive drugs. Recently, rituximab, a monoclonal anti-CD20 antibody, has been used in refractory AIHA with excellent responses.     

Congenital hemolytic anemia

Gene analysis in Japanese patients with congenital hemolytic anemia due to red cell membrane disorders, thalassemias, unstable hemoglobinopathies and red cell enzymopathies were summarized. In hereditary spherocytosis, twenty-four mutations of band 3, five mutations of protein 4.2 and twenty mutations of ankyrin have been identified. In beta thalassemia, fourty-seven mutations of beta globin have been found, and ten mutations among them comprise 80% of beta thalassemia patients in Japan. Most common alpha0 and alpha+ thalassemia are--SEA and--alpha3.7, respectively. Fourty glucose-6-phosphate dehydrogenase mutations and twenty-three pyruvate kinase mutations have been identified, allowing a better understanding of the structure-function relationships of these enzymes.     

Procainamide-induced hemolytic anemia

The paper reports a case of hemolytic anemia induced by procainamide hydrochloride treatment. Decreases in hemoglobin concentration are correlated with 11 months of procainamide treatment along with a marked increase in hemoglobin following cessation of the drug. The patient exhibited no symptoms suggestive of drug-induced Lupus Erythematosus that has been frequently reported as a sequela of procainamide therapy. Direct antiglobulin tests were consistently positive throughout the clinical course, and an ether-eluate prepared from the patient's red blood cells showed panagglutinability. The antibody in the eluate reacted with Rhnull, D−−, LW negative, and U negative red blood cells without addition of procainamide or pretreatment of red blood cells with the drug. It is noted that this antibody reacts similarly to the antibody produced as a consequence of alpha-methyl-dopa therapy.     

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.     

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.