Hereditary Spherocytosis Mimicking β-Lactam-Induced Hemolytic Anemia

Sir—Hereditary spherocytosis, a hematologic disorder characterized by anemia, jaundice, and splenomegaly, usually presents in infancy or childhood but may present in young adulthood. Activation of the reticuloendothelial system during infection is thought to bring about hemolytic crises [1, 2]. We describe a case of hereditary spherocytosis that mimicked b-lactam–induced hemolytic anemia. A 24-year-old, previously healthy woman experienced traumatic left knee disarticulation and proximal femur fracture in a motor vehicle accident while on military service in Iraq. In the course of emergent external fixation and debridement, she experienced a maculopapular rash during cefazolin infusion. After air evacuation to Walter Reed Army Hospital (Washington, D.C.), she underwent amputation above the knee followed by 7 surgical debridements (some performed with vancomycin/tobramycin beads) before final closure of the surgical site 30 days after the initial injury. Culture of tissue from the amputation site grew an extended-spectrum b-lactamase (ESBL)–producing strain of Escherichia coli that was susceptible to amikacin, cefotetan, imipenem, and piperacillin/tazobactam. Imipenem therapy was started on hospital day 14, and within 3 days, the patient developed severe anemia, fever, and dark-colored urine. The hemoglobin level dropped to 6.0 g/dL, and the hematocrit fell to 18.7%. Evaluation for hemolytic anemia was done: the result of a direct antiglobulin test was negative, the reticulocyte percentage was 19.9%, the mean corpuscular hemoglobin concentration was elevated, the haptoglobin level was ! 10 mg/dL, the fibrinogen level was 702 mg/dL, the lactate dehydrogenase level was 5358 U/L, and iron stores were normal. Abdominal CT revealed splenomegaly. An investigation for causes of hemolytic anemia and splenomegaly was done: blood smears were negative for malaria parasites, serological studies were negative for HIV and parvovirus, and Leishmania studies (bone marrow culture, ELISA for recombinant K-39 antigen, and PCR) yielded negative results. Bone marrow specimens were hypercellular and were negative for Brucella organisms, fungi, and bacteria by culture and staining. Antibiotic therapy was changed to meropenem, then to amikacin, then to empiric therapy with prednisone, and this eliminated the fever but had no effect on the hemolysis. Results of serological tests for antidrug antibodies (to vancomycin, imipenem, and meropenem) were negative. A peripheral-blood smear showed numerous spherocytes, and an RBC osmotic fragility test yielded a positive result. Throughout this process, the amputation stump healed nicely, and there was no dehiscence, erythema, or pain. The patient began using a prosthesis with no problems. MRI of the amputation site was done to evaluate whether there was infection-induced hemolysis secondary to hereditary spherocytosis, and T2-weighted images demonstrated a rim-enhancing fluid collection 1.4 cm in diameter at the distal femur. Ultrasonography-guided aspiration of the fluid was performed, and a fluid sample was positive for the same ESBL–producing strain of E. coli isolated previously. After aspiration, the hemoglobin level rose to 8.6 g/dL, and an MRI revealed near-resolution of the fluid collection. Therapy with pipercillin/tazobactam was started, and the patient was discharged with a hematocrit of 34. The fever and hemolysis that occurred after treatment with carbapenem agents led us to suspect b-lactam-induced hemolysis. Hemolytic anemia occurs infrequently in patients receiving b-lactam agents and has mostly been associated with penicillin G and secondand thirdgeneration cephalosporins, particularly ceftriaxone [3, 4]. Carbapenems appear to be among the b-lactam agents that do not cause hemolysis as an adverse effect. A review of 3470 patients treated with imipenem/cilastatin revealed 1 patient with a positive direct Coombs test result but 0 patients with hemolysis [5]. To our knowledge, this is the first description of a case of osteomyelitis-induced hemolytic anemia in a patient with hereditary spherocytosis. Hereditary spherocytosis should be considered as part of the differential diagnosis for splenomegaly, fever, and anemia. An aggressive search for and treatment of occult infection in patients with hereditary spherocytosis should be performed to prevent severe hemolysis.