Drug-Induced Hemolytic Anemia: A Fatal Complication Further Under-Recognized in Sickle Cell Disease

Drug-induced immune hemolytic anemia (DIIHA) is commonly attributed to cephalosporins. Ceftriaxone is the most frequently administered cephalosporin in patients with sickle cell disease. We present a pediatric patient with severe DIIHA (hemoglobin < 2 g/dl) who survived. Since DIIHA often goes undiagnosed until late in the course, vigilance of DIIHA minimizes unnecessary diagnostic tests and therapies. DIIHA likely remains under-recognized in all patient subpopulations due to its rarity and overlapping presentations with other conditions. Distinction between exacerbation of chronic hemolysis and new onset of acute hemolysis poses a unique challenge in patients with sickle cell disease. A thorough analysis is warranted to better identify factors within the pediatric sickle cell population that may increase the predisposition for DIIHA, particularly due to ceftriaxone.

Open Journal of Blood Diseases positive direct antiglobulin test with negative elution, thus making the direct antiglobulin test a cornerstone test in the diagnostic work-up of such acquired forms of DIIHA [4]. Although >100 drugs are implicated as causes of DIIHA today, ceftriaxone remains one of the most common culprits [5] [6]. This is particularly important as ceftriaxone is the most common empiric antibiotic administered in children with sickle cell disease (SCD) in the United States. This disproportionate incidence of high fatality rates from ceftriaxone-induced immune hemolytic anemia (CIIHA) is unique to children, as compared to adults [4], who have more comorbidities and poly-drug use [7]. Here, we present a child with SCD who experienced recurrent, severe intravascular hemolysis and actually survived. His course further highlights the rapidity of which ceftriaxone induces hemolysis in children (<1 hour) and underscores how diagnostic delay in the setting of chronic hemolysis leads to numerous diagnostic tests. This case presentation supports the need to increase provider awareness, particularly among those caring for the sickle cell population, and inspires discussion about future interventions to decrease fatalities.

Case Presentation
Our patient is an 8 year-old African-American male with sickle cell anemia (hemoglobin SS) followed at an outside facility. He had a baseline hemoglobin (Hb) of 7 -8 g/dl, normal annual transcranial Dopplers, and updated vaccinations. Past medical history was most notable for remote acute chest syndrome and suspected parvovirus-induced aplastic anemia. Prior to this admission, the estimated number of lifetime red blood cell (RBC) transfusions was 5 -6 times and lifetime doses of ceftriaxone, which were administered in the context of fever mostly in the emergency department (ED), was <10 times. He had not experienced any significant complications related to his underlying disease in the preceding 4 years.
Two weeks prior to transfer at our hospital, he complained of left elbow pain that was managed in the outpatient setting with ibuprofen and acetaminophen with codeine. Four days prior to transfer at our hospital, he developed intermittent fevers (101˚F) for which he received a single dose of ceftriaxone at 50 mg/kg and continued on clindamycin for cervical and submandibular lymphadenopathy. When fevers without a clear etiology became persistent (103˚F), family sought medical attention at the outside ED. There, he received a second dose of ceftriaxone and was admitted for further management.
On day of admission to this outside hospital, he was alert, oriented, and in no acute distress. Exam was also notable for mild hepatomegaly without jaundice.  Again, such a robust work-up represented the involvement of multiple subspecialty services.
Within 24 hours of discontinuation of ceftriaxone, Hb stabilized >10 g/dl without transfusions and our patient was extubated with baseline mental status.
Although creatinine normalized to baseline, hypertension persisted (>140/90 mmHg). This was attributed to acute renal injury and likely exacerbated by pulse steroids; there was no associated hypertension-related retinopathy. Blood pressures were controlled with lisinopril and labetalol while inpatient. Within a month in the outpatient setting, he was weaned off both anti-hypertensive agents by the nephrology service. Prior to discharge, send-out labs finally confirmed ceftriaxone-dependent red cell alloantibodies (Table 1). At discharge, the infec tious disease service recommended empiric coverage with levofloxacin for future fevers and reiterated avoidance of ceftriaxone.

Discussion
Vigilance of DIIHA in children remains challenging given its under-recognition and paucity of published data. The lack of a well-established incidence cannot be merely attributed to its rarity, as the incidence to other immune cytopenias has been documented [1]. There are varying proposals of mechanisms of actions accounting for DIIHA over the decades-the most recent is the unifying hypothesis-that underscores how the intricacies of DIIHA have yet to be fully elucidated. Further complicating our understanding is the rapidly changing drug landscape that leads to new culprits triggering DIIHA [6]. The first documented cases were in the 1950s and attributed to mephenytoin and stibophen [8] [9] [10]. During the 1970s, the most common pharmacological trigger was methyldopa, accounting for >60% of DIIHA cases, followed by penicillin [1] [11]. Since the 1990s, most DIIHA cases were due to the second-and third-generation cephalosporins, shortly after its commercial introduction into medicine [11]. Yet, perhaps the most impressive hindrance to documenting DIIHA may be from the intense and unique laboratory evaluations required for diagnosis. Definitive diagnosis requires demonstration of serum ceftriaxone antibodies in the presence of ceftriaxone. Since ceftriaxone does not bind as strongly to RBC membranes, it is difficult to create drug-coated RBCs for in vitro testing [6]. Access to such high sensitivity and specificity serological investigations is limited to several ref- SCD revealed the prevalence of anti-ceftriaxone antibody as 5.3% [12]. Statistics for the prevalence of SCD in the U.S. has yet to be updated, but was last estimated to be 100,000 individuals [13]. Incidence of SCD in the U.S. is ~1 in 2500, making it the most common condition identified on newborn screening [14].
Based on this data, >5000 individuals with SCD would be expected to be at risk for CIIHA in the United States! Yet, there is a marked lack of early recognition of the presenting signs and symptoms.
Specific contributors to the further under-recognition of CIIHA in SCD are: 1) the false reassurance among providers that a particular patient with SCD has tolerated multiple doses of ceftriaxone, and 2) misdiagnosis of hemolysis as a complication associated with SCD or an intervention. False reassurance among providers can be appreciated in the case report of a two-year-old male with Hb SS who developed severe hemolysis (Hb < 1 g/dl) <30 minutes after his 15 th lifetime dose of ceftriaxone. Post-mortem serologies confirmed antibodies to ceftriaxone and a retrospective chart review revealed that he experienced 5 prior transient episodes of hemoglobinuria immediately after ceftriaxone [15].
Perhaps the more important contributor is a misdiagnosis that leads to unne-