Symptom-Based Diagnosis in Pediatrics (CHOP Morning Report) 1st Ed.

CASE 8-2

Twenty-Month-Old Boy

NATHAN TIMM

HISTORY OF PRESENT ILLNESS

The patient was a 20-month-old African-American male who arrived by flight squad from another emergency department. The mother was on her way to the hospital and was not available; however, the squad relayed the history from the previous emergency department. The mother reported that her son had a week-long upper respiratory infection and developed a fever yesterday. Today he had four episodes of emesis and was more tired than usual. Several children in his day care have had bronchiolitis. There was a pet hamster at home.

MEDICAL HISTORY

There was no personal or family history of sickle cell disease. The child is otherwise healthy.

PHYSICAL EXAMINATION

T 37.5°C; RR 28/min; HR 140 bpm; BP 80/60 mmHg; SpO2 85% in room air

Height 50th percentile; Weight 50th percentile

Initial examination revealed a pale appearing, lethargic child who was responsive to painful stimulation. Head and neck examination was significant for pale conjunctivae and scleral icterus. Mucous membranes were moist, and there was no meningismus or lymphadenopathy. Mild subcostal retractions were present but the lungs were clear to auscultation. The cardiac examination revealed tachycardia and a III/VI systolic ejection murmur at the left upper sternal border. There were no gallops or rubs. Capillary refill was 2 seconds and he had strong peripheral pulses. The abdomen was nondistended and soft. There was no hepatomegaly; however, a mildly tender spleen tip was palpable. The rectal examination was normal. There were no rashes, bruises, or petechiae noted on skin examination.

DIAGNOSTIC STUDIES

Laboratory analysis revealed 30 800 WBCs/mm3 with 77% segmented neutrophils, 14% lymphocytes, 7% monocytes, and 8% nucleated RBCs. The hemoglobin was 3.1 g/dL and there were 608 000 platelets/mm3. The mean corpuscular volume was 90 fL and the reticulocyte distribution width was 21. The reticulocyte count was 10.5%. The blood type was O+ with a negative direct Coombs test. Electrolytes were significant for a blood urea nitrogen of 22 mg/dL. The remainder of the electrolytes was normal. The child’s glucose was 117 mg/dL and liver function tests were significant for a lactic dehydrogenase of 1250 U/L and total bilirubin of 5.2 mg/dL (direct fraction, 0.4 mg/dL). A chest radiograph showed no cardiomegaly. The urine was tea colored and urinalysis tested positive for hemoglobin. Blood and urine cultures were subsequently negative.

COURSE OF ILLNESS

The child was placed on 100% nonrebreather face mask and intravenous access was obtained. The child received 10 cc/kg normal saline. With these interventions the child’s comfort level and vital signs improved with a pulse oximeter reading of 96%, heart rate of 110 bpm, and respiratory rate of 22 breaths per minutes. The results of the peripheral blood smear suggested the cause of his severe anemia (Figure 8-2). The mother arrived and provided an additional piece of information that confirmed the suspected diagnosis.

Image

FIGURE 8-2. Peripheral blood smear.

DISCUSSION CASE 8-2

DIFFERENTIAL DIAGNOSIS

The physical examination (pallor, scleral icterus, spenomegaly) and laboratory tests (anemia, elevated unconjugated bilirubin, elevated reticulocyte count) point toward the diagnosis of a hemolytic anemia. Hemolytic anemias can be classified into red blood cell intrinsic abnormalities or extrinsic forces acting on the red blood cell. Membrane (spherocytosis) and metabolic (glucose 6-phosphatase deficiency, pyruvate kinase deficiency) deficiencies in addition to the hemoglobinopathies (sickle cell and thalassemias) make up the intrinsic abnormalities of red blood cells that lead to hemolysis. The extrinsic causes are autoimmune hemolytic anemia, physical trauma on the red blood cell (prosthetic valve), infection (malaria) and drug/toxin (G6PD deficiency).

DIAGNOSIS

The mother provided additional information when she arrived. The child had been seen at an emergency department 4 days earlier when she found a mothball in his mouth. His hemoglobin at that time was 10 g/dL. The present blood smear showed schistocytes, blister cells, bite cells, 3+ anisocytosis, and 4+ poikilocytosis, consistent with red blood cell hemolysis (Figure 8-2). The diagnosis of napthalene ingestion in a child with glucose-6-phosphatase dehydrogenase deficiency was confirmed.

INCIDENCE AND EPIDEMIOLOGY

Glucose-6-phosphatase dehydrogenase (G6PD) deficiency is an X-linked enzyme disorder that affects nearly 200 million people worldwide. Kurdish Jews (60%), Saudi Arabian descent (13%), and African-Americans (11%) are most affected. The female heterozygote carrier state provides a survival advantage against malaria.

The enzyme G6PD is present in all cells in the body; however, red blood cells are most severely affected by its absence. G6PD aids in the biochemical pathway that replenishes glutathione, the chemical responsible for breaking down oxygen free radicals and peroxide. Therefore, the enzyme deficient patient is at particular risk when confronted with stressors leading to an “oxidative challenge.” Fava beans, infection, and drugs such as antimalarials, sulfonamides, nitrofurantion, and naphthalene (mothballs) are the most notorious culprits leading to red blood cell damage in patients with G6PD deficiency.

CLINICAL PRESENTATION

Acute hemolytic anemia results in a child with G6PD deficiency after napthalene ingestion. Hemolytic anemia can develop as early as 1 day after naphthalene exposure. The oxidative metabolite, alpha-naphthol, causes a depletion of glutathione. The G6PD deficient red blood cell is unable to replenish the glutathione leading to hemoglobin and protein oxidation. Hemoglobin and proteins are denatured into Heinz bodies, and the red blood cell membrane is lysed. The spleen removes the Heinz body containing RBCs leading to splenomegaly and “bite cells” in peripheral smear. The destruction of the red blood cells leads to a normocytic anemia, increase in unconjugated bilirubin, increased reticulocyte production, and hemoglobinuria. The clinical features include nausea, emesis, dark urine, icterus, abdominal pain, pallor, and lethargy.

DIAGNOSTIC APPROACH

History and physical examination findings are the mainstay of the diagnosis. Additional laboratory test to help differentiate the hemolytic anemias include the following:

Complete blood count and peripheral smear. Peripheral blood smear reveals anisocytosis, poikilocytosis, schistocytes, bite cells, and occasional Heinz bodies.

Reticulocyte count. The reticulocyte count is usually elevated after hemolysis to compensate for increased red blood cell destruction.

Coombs test. Direct and indirect Coombs tests are negative in G6PD but should be performed to exclude autoimmune hemolytic anemia.

Serum haptoglobin. Binds to free hemoglobin and is decreased with hemolysis.

Hepatic function panel. Plasma indirect bilirubin, aspartate aminotransferase, and lactate dehydrogenase are elevated due to the release of intracellular enzymes during hemolysis.

Urinalysis. Increased urine bilirubin is noted. Hemoglobinuria occurs once hemoglobin binding sites in the plasma, such as haptoglobin and hemopexin, are saturated.

G6PD assay. A G6PD assay measures production of NADPH using a spectrophotometer. G6PD assay may be normal immediately after a hemolytic episode, despite G6PD deficiency, since younger red blood cells (reticulocytes) with normal levels of G6PD will have replaced the older, more deficient population. This screening test should be performed at least 2 weeks after a hemolytic episode. Additional screening tests are also available that utilize dye decolorization techniques that quantify G6PD levels as normal or deficient (<30% normal activity). The limitations of these screening tests are that they do not detect heterozygotes and are only helpful for steady-state levels; therefore, they are unreliable during or after active hemolysis.

TREATMENT

Supportive care is the mainstay of treatment. Activated charcoal and cathartics are helpful in acute napthalene ingestions. In addition, patients should avoid milk or fatty meals which would aid the absorption of the lipophilic napthalene. The hemolytic anemia may require blood product transfusion if there is hemodynamic instability. Otherwise, hemoglobin levels will return to normal in 3-6 weeks without intervention. Hemoglobinuria rarely leads to the development of renal failure in children.

SUGGESTED READINGS

1. Cohen AR. Hematologic emergencies. In: Fleisher GR, Luwdig S, eds. Textbook of Pediatric Emergency Medicine. 4th ed. Philadelphia: Lippincott Williams & Wilkins; 2000:859-863.

2. Desforges, J. Glucose 6 phosphate dehydrogenase deficiency. N Engl J Med. 1991;324:169-194.

3. Luzzato L. Hemolytic anemias. In: Nathan D, Orkin S, eds. Hematology of Infancy and Childhood. 5th ed. Philadelphia: WB Saunders; 1988:704-722.

4. Wason S, Siegel E. Mothball toxicity. Pediatr Clin N Am. 1986;33:369-374.