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A four-year-old male presents to the emergency department with a history of six days of fever and acute onset of red colored urine. Birth history and past medical history are unremarkable. Family history is non-contributory. He has a two-year-old sister who is healthy. There has been no recent travel. He was seen by his PCP approximately five days ago for evaluation of cough and rhinorrhea and was prescribed Augmentin for an ear infection. ROS is negative for dysuria, bloody stools, hemoptysis, or epistaxis. He has no increased bruising, no petechiae, and no extremity pain. He has been having intermittent fevers for three days.

Vitals: Temperature 104.6degrees Fahrenheit, HR 100, RR 22, Oxygen saturations 98% on room air.
Physical Exam: (+) scleral icterus, (+) jaundice, (+) soft flow murmur on cardiac exam. Physical exam is otherwise normal.

Labs: Initial hemoglobin 10.4 g/dL--> decreased to 6.3 g/dL 12 hours later, Platelets 153,000 cells/UL, Reticulocyte count 0.4%, White blood cells 11.1 x10³ cells/UL (48% bands, 16% lymphocytes), Absolute neutrophil count 7.90 x 10³ cells/UL. Coagulation studies normal. Liver function test are normal. LDH is 5056 Units/ml, haptoglobin 12 mg/dL (low). Unconjugated bilirubin is 3.7 mg/dL, Conjugated bilirubin is 1.2 mg/dL. Electrolytes are all within normal limits. Viral panel is pending.

DAT: IgG, C3 (+).

Urinalysis: dark, red-brown urine, 3+ blood, 3+ protein, 0-4 RBCs/hpf, 0-4 WBCs/hpf, urobilinogen >8mg/dL.

Case study submitted by Robyn Dennis, MD, Texas Children’s Cancer Center, Houston, TX.

1. What would be the next best test to help determine this patient’s diagnosis?

1. Mycoplasma titers
2. Abdominal ultrasound to detect splenomegaly
3. Donath-Landsteiner assay
4. Peripheral smear

2. What is the best initial therapy for this patient?

1. Emergent plasmapheresis
2. Warmed intravenous fluids, packed red blood cell transfusion, observation
3. Rituximab
4. Splenectomy

Answers: (1) C; (2) B.

Explanation

This patient's clinical presentation and laboratory results suggest that he has a form of autoimmune hemolytic anemia (AIHA). More specifically, this child has a type of paroxysmal cold hemoglobinuria also known as Donath-Landsteiner hemolytic anemia (DLHA). DHLA is relatively rare (3/100,000) representing 30 percent to 40 percent of autoimmune hemolytic anemia in children. DLHA is caused by Donath-Landsteiner (D-L) auto antibody activation against the P-antigen on the red blood cell (RBC), which causes activation of complement, resulting in RBC membrane perforation and intravascular hemolysis (hence, the red urine and elevated urobilinogen in the urine). D-L auto-antibodies appear approximately one week following an acute illness, usually a virus, causing sudden onset of hemoglobinuria, jaundice, and anemia. Direct antibody test (DAT) is typically positive. C3, IgG, and P-antigen are positive. This is in contrast to cold agglutinin disease (CAD) which is typically IgM positive. Anemia and reticulocytopenia may be seen. The next best test to confirm his diagnosis is the Donath-Landsteiner assay which exposes the patient’s plasma to normal plasma at varying temperatures to determine the temperature at which RBCs are lysed by D-L autoantibody-associated complement fixation. RBC hemolysis due to D-L autoantibody activation typically occurs at cold temperatures (28-31 degrees Fahrenheit). Although evaluation of viral titers such as mycoplasma may help determine the etiology it will not confirm the diagnosis, however a treatable etiology should always be investigated. Hepatosplenomegaly may be observed in 25 percent of cases but is not specific to DLHA. A peripheral smear is always essential for diagnosis of hemolytic anemia and may reveal shistocytes, spherocytes, and/or rouleaux formation (more suggestive of warm autoimmune hemolysis). The best initial therapy for this patient is to keep him warm (gloves, hat, warming blanket, etc.). Warmed intravenous fluids and red blood cells are essential. If an underlying etiology is determined (i.e., mycoplasma infection) it should be treated. The most likely etiologies for this patient’s AIHA are the history of a preceding viral illness +/- initiation of Augmentin (several commonly prescribed medications have been associated with this form of AIHA). Splenectomy is typically reserved for refractory cases. Plasmapheresis should only be used in severe cases that are refractory to initial therapy. The role of steroids in D-L AIHA is controversial. Generally, this disease is self-limited in children and young adults, although antibodies may persist for up to three months. Recurrence may occur but is rare in children.