Case Presentation: A 48-year-old female with spina bifida was admitted for sepsis secondary to sacral osteomyelitis. She improved with broad-spectrum antibiotics, and her antibiotic regimen was narrowed to Zosyn (piperacillin + tazobactam) to complete a 6-week course. On hospital day 12, discharge was delayed pending insurance approval of an air mattress for home. Three days later, a critical hemoglobin (Hgb) was reported to be 4.2. Clinically, the patient was stable, so a stat hemogram was repeated. An hour later, the patient became unresponsive, and a stroke code was called. Vitals remained stable, but it was noted that her urine was red. Head CT showed no acute abnormalities. Meanwhile, repeat hemogram showed a Hgb of 2.9. Massive transfusion protocol was initiated, and the patient was intubated and taken to the ICU. She responded to 4 units of packed red blood cells (pRBCs) with Hgb correction to 12 [table 1]. DIC was less likely given fibrinogen was elevated. LDH of 1940 suggested intravascular hemolysis. Initial work-up revealed direct antiglobulin test positive for IgG and complement. Further testing of her serum showed strong agglutination and antiglobulin test when soluble piperacillin was present, indicating the presence of drug associated RBC antibodies to piperacillin. She was started on steroids and immediately switched from Zosyn to ceftriaxone. 4 days after the stroke code was called, she was extubated, alert and oriented, and at her neurological baseline. She was ultimately discharged on IV ceftriaxone.
Discussion: Drug-induced immune hemolytic anemia (DIIHA) is a rare adverse effect that occurs in 1 in 1 million patients [1]. Drugs are theorized to bind to the RBC membrane, join with antibodies to form immune complexes that bind to the membrane (drug-dependent mechanisms), or induce autoantibodies without binding to the membrane (drug-independent mechanism) [2]. Piperacillin likely works through a drug-dependent mechanism, resulting in binding of IgG, complement activation, and intravascular hemolysis [2]. Time from drug administration to hemolysis ranges from hours to days. Once the drug is stopped, hemolysis diminishes rapidly. There is limited evidence for steroid use. 40% of reported cases of piperacillin-induced hemolysis occur in cystic fibrosis (CF) patients. The apparent increased incidence in CF patients more likely represents increased risk of a severe clinical course, which is thought to be related to decreased production of nitric oxide (NO) caused by the CFTR mutation [2-6]. The NO deficit is worsened in the setting of hemolysis because free Hgb scavenges NO [7]. Decreased availability of NO prevents small vessel dilation and decreases oxygen supply to tissues, exacerbating the oxygen deficit in hemolysis. Interestingly, mutations in NO synthase (NOS) genes have been implicated in spina bifida [8-9]. NOS is involved in neurulation through two mechanisms: NO production and homocysteine remethylation [9]. This is the first reported case of piperacillin-induced hemolysis in a spina bifida patient, but likely this patient population is also at an increased risk of severe hemolysis.
Conclusions: Though rare, hemolytic anemia is a life-threatening adverse effect of piperacillin among other drugs. Certain patient populations, including spina bifida and CF patients, might be at an increased risk of a severe clinical course because of decreased availability of NO in these patients. If recognized promptly, patients can recover rapidly with cessation of the offending drug.
