BRANDON C. KU
HISTORY OF PRESENT ILLNESS
A 5-month-old African-American boy presented with pallor, difficulty breathing, and lethargy. He was in his usual state of good health until 4 days prior to admission when he developed a fever to 102-103°F with rhinorrhea. There was no coughing, vomiting, or diarrhea. The patient otherwise seemed well at the time. During the next few days, he developed increased work of breathing with decreased appetite. One day prior to admission, the mother noted that he seemed lethargic and irritable. Oral intake was significantly decreased; the infant was taking in only 8 ounces rather than his typical 48 ounces over the day. The patient was brought to the emergency department. In retrospect, the father noted that his abdomen seemed to be increasing in size and firmness over the last month with some tenderness.
The infant was born at term after an uncomplicated pregnancy. He was taken home on the second day of life. He had no known allergies. He did not receive any medications. Immunizations appropriate for age had been promptly administered, including two doses of the pneumococcal conjugate vaccine. The family history was notable for sickle cell disease in a paternal cousin and reactive airway disease, cervical cancer, and ovarian cancer in several maternal relatives. A great uncle died of “jaundice” at 3 years of age and a cousin at 10 years of age.
T 38.4°C; HR 160 bpm; RR 58/min; BP 83/38 mmHg; Weight 5.7 kg
In general, the child was lethargic and responsive only to painful stimuli. He also had severe respiratory distress. The anterior fontanel was sunken. The pupils were equal, round, and reactive to light. The conjunctivae and oral mucosa were pale. The lips were dry and cracked. There were white patches on the buccal mucosa that were easily removed with scraping. There was shotty anterior and posterior cervical adenopathy. The lungs were clear to auscultation but the child had mild grunting and flaring. There was a 2/6 systolic ejection murmur at the left lower sternal border. The abdomen was firm with a liver edge palpable 5 cm below the right costal margin. The spleen was palpable at the level of the umbilicus. Bowel sounds were present. The extremities were cool with delayed capillary refill (5 seconds). On neurologic examination, the child localized pain but had decreased tone and diminished spontaneous activity.
In the emergency department, the patient had an oxygen saturation of 94% in room air. He received several normal saline boluses as well as sodium bicarbonate and intravenous dextrose. Blood and urine cultures were obtained. The patient received intravenous cefotaxime for presumed sepsis.
White blood 14 300 cells/mm3 (2% band forms; 52% segmented neutrophils, 42% lymphocytes, 2% eosinophils, 2% atypical lymphocytes). Hemoglobin, 2.6 g/dL; platelets, 184 000/mm3; MCV, 88 fL; red sell distribution width, 17.4; total bilirubin, 4.6 mg/dL with an unconjugated level of 3.8 mg/dL; hepatic transaminases were normal; lactate dehydrogenase level was 2984 IU/L (normal range, 934-2150). Chest radiograph was normal. There was no cardiomegaly, infiltrates, or mediastinal masses.
COURSE OF ILLNESS
The peripheral blood smear (Figure 10-2), in conjunction with other laboratory findings, suggested the diagnosis.
FIGURE 10-2. Peripheral blood smear.
DISCUSSION CASE 10-3
This child came to the hospital with significant severe pallor of acute onset. The child has had no medications or unusual exposures. It was clear that the child was critically ill. Despite the severe illness, white blood cell and platelet counts were normal. The most significant finding was the severe anemia. The increased unconjugated bili-rubin and lactate dehydrogenase levels suggested a hemolytic process. Other causes of hemolytic anemia were considered in this case, including drug associated hemolytic anemia, disorders of red cell membrane and cytostructure (e.g., hereditary spherocytosis), abnormalities of red blood cell metabolism (e.g., glucose-6-phosphate-dehydrogenase deficiency), as well as sepsis with disseminated intravascular coagulation. The patient was given antibiotics to cover this later possibility. Parvovirus B19 infection may cause severe anemia but usually due to bone marrow suppression rather than hemolysis.
Patients with a microangiopathic hemolytic anemia such as hemolytic uremic syndrome and thrombotic thrombocytopenic purpura usually have schistocytes rather than spehrocytes on peripheral blood smear. Both of these conditions usually present with severe thrombocytopenia. A child of this age should be closely examined for physical abnormalities seen with Diamond-Blackfan syndrome and Fanconi anemia. Laboratory studies allowed differentiation of the diagnostic possibilities.
The peripheral blood smear revealed a nucleated red cell (erythroid progenitor cell) prematurely released from the bone marrow into the peripheral circulation (Figure 10-2). There were also many small spherocytes. Polychromasia was also noted because the bone marrow releases large numbers of reticulocytes and nucleated red blood cells to compensate for accelerated red cell destruction. A direct antiglobulin test (DAT or Coombs) was positive, confirming the presence of antibodies to circulating red blood cells. Specifically, this test was positive for IgG and negative for C3, consistent with the diagnosis of warm agglutinin autoimmune hemolytic anemia. The patient had autoimmune hemolytic anemia of the warm agglutinin type.
INCIDENCE AND EPIDEMIOLOGY OF AUTOIMMUNE HEMOLYTIC ANEMIA (AHA)
Autoimmune hemolytic anemia (AHA) occurs as a result of antibody, antibody and complement complex, or complement binding to the red blood cell. The resulting immunologic reaction destroys red cells and causes anemia. Infectious agents, drugs, and other agents may stimulate the process. Some autoimmune disease such as systemic lupus erythematosus may also generate anti-red cell antibodies and red cell destruction. The true incidence of AHA is unknown but is estimated at 1-3 cases per 100 000 population per year. Acute AHA usually presents in the first 4 years of life.
CLINICAL MANIFESTATION OF AUTOIMMUNE HEMOLYTIC ANEMIA
Children usually present with signs and symptoms of severe anemia. In younger children, parents or other family members may note pallor or weakness. Older children may complain of exercise intolerance or dizziness. Jaundice and scleral icterus result from the recycling of unconjugated bilirubin released from hemolyzed red blood cells. Dark urine suggests hemoglobinuria. On examination there is usually mild or moderate splenic enlargement. Some patients present with congestive heart failure related to the rapid development of anemia.
Complete blood count. The anemia of acute onset AHA is usually significant. Most children have a hemoglobin level of 4-7 g/dL. The MCV may be relatively normal, reflecting the weighted average of small microspherocytes and large reticulocytes. Erythrocyte agglutination within the sample tube may artifactually raise the MCV on an automated counter. An elevated red cell distribution width may be a clue that several different red cell populations are present such as microspherocytes forming after partial splenic ingestion and large reticulocytes. There is an increase in reticulocytes once the bone marrow has a chance to respond. The white blood cell and platelet counts are typically normal. Concurrent thrombocytopenia indicates Evan syndrome, aplastic anemia, hemolytic uremic syndrome, or other conditions rather than isolated autoimmune hemolytic anemia.
Direct antiglobulin (Coombs) test. A positive Coombs test confirms the suspected diagnosis. To establish a diagnosis there must be antibody and evidence of hemolysis. The red cell antibodies that react at 37°C (warm antibodies) are usually IgG and do not cause spontaneous agglutination of cells unless Coombs antiserum is added. Cold antibodies are usually IgM and react at 4°C. These are considered complete antibodies because no antiserum needs to be added to cause the red blood cell destructive process. There are also cases of mixed-type autoimmune responses.
Other studies. Other tests can provide evidence of an underlying hemolytic process: elevated unconjugated bilirubin, elevated lactate dehydrogenase, decreased serum haptoglobin, and urinalysis revealing blood on dipstick but no red blood cells on microscopy (hemoglobinuria). Hepatic transaminases should be normal.
The mainstay of treatment is corticosteroids administered 2-10 mg/kg/day. In severely ill patients, like our index case, the steroids should be administered intravenously. Otherwise, the care is supportive and includes replacement therapy. However, a compatible cross match may not be possible. But if the patient is in extremis blood type group O, RH-negative blood should be used in aliquots that are given slowly and in amounts sufficient to stabilize the cardiovascular system. The patient should be adequately hydrated to avoid renal involvement. At times, splenectomy may be necessary for those who fail steroid therapy.
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