Clinician’s Corner

CASE 2 PRESENTATION: A PALE, JAUNDICED CHILD WITH DARK URINE

A three-and-a-half-year-old previously healthy East Indian girl was admitted to hospital because of anemia and hemoglobinuria. Three weeks before admission, she had a self-resolving upper respiratory tract infection. She was then well until three days before admission when she presented to her primary care physician with a fever and abdominal pain. A urine dipstick on a midstream urine sample tested positive for blood, and she was started on trimethoprim-sulfamethoxazole for a presumed urinary tract infection. One day before admission, the family noted the onset of pallor, jaundice and cola-coloured urine, and the girl was taken to hospital. Past medical history was noncontributory. She had not taken any medications, except for three doses of trimethoprim-sulfamethoxazole. Family history was negative for anemia, episodes of jaundice, gallstones, splenectomy or hematuria.

On physical examination, pallor and scleral icterus were evident, and the girl was in no apparent distress. She was tachycardic with a heart rate of 130 beats/min. There was no lymphadenopathy or hepatosplenomegaly. Cardiovascular examination revealed bounding peripheral pulses and a 2/6 systolic ejection murmur with no signs of cardiac failure.

Laboratory investigations showed a hemoglobin concentration of 54 g/L, white blood cell count 7.2·10⁹/L and platelet count 320·10⁹/L. The initial reticulocyte count was 54·10⁹/L (normal, 10 to 100·10⁹/L). The blood smear showed normocytic red blood cells (RBCs) with polychromasia and spherocytes; there were no atypical lymphocytes. A urine dipstick tested strongly positive for blood, positive for urobilinogen, and negative for bilirubin and protein. Urine microscopy showed no RBCs. Unconjugated bilirubin was elevated at 46 ·mol/L, with normal transaminases, serum electrolytes and renal function tests.

The gamma (Direct Coombs Test) DAT was negative. Glucose-6-phosphate dehydrogenase deficiency, osmotic fragility and pyruvate kinase assays were normal. Hemoglobin electrophoresis was normal. A further diagnostic test revealed the cause of this child’s anemia.

CASE 2 DIAGNOSIS: AUTOIMMUNE HEMOLYTIC ANEMIA

Discussion

The nongamma DAT was subsequently reported to be positive, with an immunoglobulin (Ig) M Donath-Landsteiner antibody detected. The child was hemodynamically stable and did not require transfusion. Her urine gradually cleared with no hemoglobin detected by dipstick by the fifth day in hospital, and her unconjugated bilirubin returned to normal.

Investigations for an infectious etiology including serology for Epstein-Barr virus, cytomegalovirus, hepatitis A and B, and parvovirus; a nasopharyngeal swab for viruses; and a throat swab for mycoplasma polymerase chain reaction were negative. Her reticulocyte count was 366·10⁹/L, and her hemoglobin was 64 g/L at discharge on the seventh hospital day.

This case, describing a girl with an acute autoimmune hemolytic anemia (AIHA), contains several important lessons for the clinician. A urine sample that tests positive for blood by dipstick should be examined microscopically to confirm the presence of intact RBCs. While the finding of a positive urine dipstick for blood is most often related to RBCs in the urine, myoglobinuria in the setting of rhabdomyolysis and hemoglobinuria in the presence of intravascular hemolysis will cause the same colour changes on a urine dipstick.

The differential diagnosis of a child with hemolytic anemia includes either immune-mediated causes of RBC destruction or nonimmune-mediated causes that can be divided into membrane defects (spherocytosis, elliptocytosis), enzyme defects (glucose-6-phosphate dehydrogenase deficiency, pyruvate kinase deficiency) and hemoglobinopathies (sickle cell disease, thalassemia). AIHA is caused by the production of antibodies (IgG or IgM) against one’s own erythrocyte membrane antigens. IgG-mediated AIHA generally involves a warm antibody directed against an Rh antigen on the surface of the RBCs, which are then destroyed by macrophages predominantly in the spleen. IgM antibodies are usually cold agglutinins directed against the I/i antigen and involves complement-mediated destruction that may occur intravascularly. The Donath-Landsteiner antibody sensitizes RBCs at cold temperatures and causes hemolysis as the temperature is raised, often causing a paroxysmal cold hemoglobinuria. Donath-Landsteiner AIHA is more common in children than in adults and may be responsible for over 30% of childhood AIHA. It has been associated with many common infections, including mycoplasma, parvovirus, Epstein-Barr virus and varicella.

Children with acute AIHA typically present with pallor, jaundice, lethargy, abdominal pain, low-grade fever and 1 signs of a hyperdynamic circulation, often after an unremarkable viral illness. Laboratory investigations usually show a normocytic, normochromic anemia with reticulocytosis and polychromasia, and spherocytes on a blood smear. The DAT test is positive. It is important to recognize that the gamma DAT test is only positive if the RBC has IgG on the surface. In IgM-mediated AIHA, as in this case, only the nongamma DAT test is positive.

Acute onset AIHA is usually self-limited and resolves without therapy within six months. Transfusion is only needed in cases of cardiovascular compromise. Steroids and intravenous immune globulin are effective in 80%, and splenectomy is helpful in 20% to 60% of cases of IgG-mediated illness, but are much less effective in IgM-mediated disease.

Clinical pearls

• A positive urine dipstick for blood may be caused by hemoglobinuria or myoglobinuria in addition to hematuria.

• Hemolytic anemia may be caused by immune (IgG or IgM antibody-mediated destruction) or nonimmune causes (RBC membrane defects, enzymopathies and hemoglobinopathies).