The initial evaluation of a child with anemia is a common task for general pediatricians or hospitalists. Defined as insufficient red blood cell (RBC) mass for the age of the patient, anemia can develop acutely or insidiously. In children, anemia that develops gradually over several weeks to months may be profound but with little clinical consequence other than obvious pallor. However, if anemia develops acutely, the patient has no time to compensate for decreased oxygen carrying capacity, and symptoms of anemia (ranging from fatigue to cardiovascular collapse) can develop rapidly. Because anemia can result from many disease processes, it is helpful to divide anemia into broad pathophysiologic categories: (1) decreased production of either hemoglobin or RBCs, (2) premature RBC destruction, or (3) blood loss.¹ Fortunately, distinguishing among these processes usually requires only basic, widely available laboratory tests. Once the pathophysiologic category is determined, the differential diagnosis narrows, and the evaluation is much less daunting. This chapter focuses primarily on children with newly recognized anemia for whom the evaluation is often initiated by pediatric hospitalists.

Anemia is often discovered incidentally during laboratory screening for other indications in a child who otherwise exhibits no symptoms of anemia.^2-4 Systematic evaluation of febrile hospitalized children demonstrated that a majority may exhibit mild anemia.^5,6 Alternatively, pallor and fatigue, the cardinal symptoms of anemia, may bring the patient to medical attention. Severe anemia, especially when there is a rapid onset, may present with weakness, obtundation, syncope, exertional dyspnea, congestive heart failure, or shock.

The probable causes of anemia can often be predicted by considering the age of the patient and taking a careful history. A directed history should thoroughly review the child’s diet, including the amount and type of milk, red meat, fruits, and vegetables consumed daily, as well as a history of pica. Growth and development, blood loss (i.e. melena, hematemesis, hemoptysis, hematuria), and recent illnesses are also important areas of inquiry. Acute and/or chronic inflammation often are underlying causes of anemia in hospitalized patients. Because many causes of anemia are inherited, the family history is critical and should include questions about transfusions, bleeding, splenectomy, cholelithiasis or cholecystectomy, and prior diagnoses of anemia.

The physical examination should focus on manifestations of anemia and diagnostic clues. Tachycardia, systolic murmur, and pallor suggest a moderate degree of anemia. Severe anemia can be accompanied by symptoms of congestive heart failure and tachypnea, despite children’s typically profound and effective cardiovascular compensatory mechanisms. Jaundice or dark urine suggests intravascular hemolysis and rapidly narrows the differential diagnosis. Similarly, hepatosplenomegaly, a physical sign of great importance in the diagnostic evaluation of an anemic patient, suggests extramedullary hematopoiesis (as in chronic hemolytic anemias) or other diagnoses (e.g. storage diseases, bone marrow infiltration, infections).

The initial laboratory evaluation typically includes a basic panel of hematologic studies, followed by selected studies as directed by the presentation and the history. A complete blood count (CBC) with differential white blood cell count, reticulocyte count, and direct and indirect antiglobulin (Coombs) tests are central for initial classification. RBC indices are usually included in the CBC and provide additional clues to the pathophysiology of the anemia (Table 88-1). Examination of the peripheral blood smear should be performed, with particular attention to RBC morphology and evidence of hemolysis (Table 88-2). Some examples of RBC abnormalities that may be seen on the peripheral smear are provided in Figure 88-1.

Evaluation for occult blood loss should include several stool guaiac tests for subclinical gastrointestinal bleeding. Although less common, trauma-related injuries should also be considered, such as femur fracture with major hematoma, hemothorax, or hemoperitoneum. Outside the special population of very premature infants, it is uncommon for intracranial hemorrhage to account for significant anemia, and unless neurologic symptoms or signs accompany the presentation, cranial imaging is not generally indicated.

Subclinical hematuria usually involves only small amounts of blood in the urine and generally does not result in significant anemia in the absence of some other causative factor. However, blood detected by urinalysis is an important finding and requires attention to both the urine dipstick and microscopic analysis. Blood detected by dipstick without a significant number of RBCs on the microscopic examination indicates the presence of either hemoglobin (suggesting intravascular RBC hemolysis) or myoglobin (due to rhabdomyolysis). Serum concentrations of muscle enzymes (e.g. creatine kinase) or free hemoglobin should help differentiate between myoglobinuria and hemoglobinuria.

Depending on the patient’s age and the history and physical examination findings, further evaluation can be tailored accordingly. Iron-deficiency anemia is a common cause of microcytic anemia, and further evaluation includes a serum iron level, total iron binding capacity, and ferritin. Microcytic anemia with risk factors for plumbism should prompt the measurement of serum lead levels. Clinical concerns for endocrine, renal, or hepatic disease justify the assessment of hepatic transaminases and thyroid and renal function. Hematologic consultation is often useful if initial efforts fail to yield a definitive diagnosis. Further laboratory studies such as hemoglobin electrophoresis (to investigate hemoglobinopathies) and osmotic fragility studies (to rule out spherocytosis) may be indicated. Bone marrow aspiration and biopsy may be useful in the diagnosis of anemias of unclear cause and to rule out diagnoses such as myelodysplastic syndrome, congenital dyserythropoietic anemias, aplastic anemia, and leukemia. Although occasionally presenting with isolated anemia, myelodysplastic syndrome and leukemia usually result in pancytopenia or the appearance of abnormal (e.g. dysplastic or immature) cells in the peripheral blood.

Comparing current RBC indices with those of previous blood examinations may provide important information, such as the rate and timing of onset of the anemia. In addition, whenever possible, specific laboratory studies should be obtained before blood product transfusion so that they reflect the patient’s condition rather than that of the blood donor.

Because anemia is associated with various pathophysiologic abnormalities, functional classification simplifies the initial evaluation. One approach divides anemias into those with microcytic, normocytic, or macrocytic erythrocytes based on the mean corpuscular volume (MCV); another considers whether the anemia results from diminished RBC production rather than increased RBC destruction. Table 88-3 unifies both classification schemes for the common anemias encountered by pediatric hospitalists. It is critical to interpret both the hemoglobin and the MCV based on the child’s age, because normal RBC parameters change with age.⁷ Multiple concurrent pathophysiologic processes often complicate even straightforward diagnoses. For example, it can be challenging to evaluate anemia in a patient with chronic renal failure and possible nutritional deficiencies who develops subclinical hemorrhage.

This class of disorders is characterized by anemia, generally in the absence of other cytopenias, together with reduced or inappropriately normal reticulocyte counts, and a negative Coombs test, also known as the direct antiglobulin test (DAT).

MICROCYTIC ANEMIA

Iron-Deficiency Anemia

Iron deficiency is the most common cause of anemia in the pediatric population, displaying a bimodal age of distribution affecting mainly toddlers and female adolescents.⁸ Although iron supplementation of infant formula has diminished its incidence, the absence of sufficient iron intake after the depletion of stores deposited in the third trimester commonly results in anemia in older infants and toddlers. Premature infants are also at high risk because of their inability to accumulate sufficient iron stores during the third trimester. Patients with iron-deficiency anemia may also exhibit microscopic stool blood loss from enterocolitis (e.g. cow’s milk protein allergy in toddlers). Although reduced intake is the most common cause of iron-deficiency anemia, malabsorption may also result in iron deficiency and should be suspected in patients with duodenal pathology, as the duodenum is the site of intestinal iron absorption. In toddlers, iron-deficiency anemia is sometimes accompanied by pica, the involuntary ingestion of inert compounds such as dirt, which can result in lead poisoning; this exacerbates iron-deficiency anemia because lead competes with iron for intestinal uptake. In young women, iron deficiency usually results from regular menstrual blood loss. Anemia in this context can be especially severe if associated with a low dietary iron intake.

A nutritional history suggestive of poor iron intake associated with microcytic anemia, a normal to slightly elevated reticulocyte count, an elevated RBC distribution width, and erythroid hypochromasia suggests iron deficiency. Reticulocyte hemoglobin content may be an early indicator of iron deficiency.^9,10 Typical laboratory findings in iron-deficiency anemia are summarized in Table 88-4. Bone marrow examination is rarely required to make this diagnosis. Concurrent causes of microcytic anemia such as α-thalassemia trait can be difficult to diagnose in the context of severe iron deficiency.

A therapeutic trial of oral iron is appropriate for likely iron-deficiency anemia before referral to a hematologist. Mild anemia can be treated with 3 mg elemental iron/kg per day, given once daily. Severe anemia may justify dosing up to 6 mg elemental iron/kg per day, given in divided doses. Although historically associated with the risk of significant side effects, iron may also be administered parenterally, particularly when there is concern for limited absorption or oral intake is insufficient to replenish iron stores. Several parenteral iron formulations, including iron sucrose, ferric gluconate, and ferumoxytol have supplanted high molecular weight iron dextran, which had been associated with anaphylactic reaction.^11-14 Given the gradual development of iron-deficiency anemia, pediatric patients rarely exhibit significant physiologic consequences necessitating RBC transfusion, despite presenting with profoundly low hemoglobin levels. However, diminishing physiologic compensation for severe anemia (e.g. symptoms of impending congestive heart failure) may justify RBC transfusion. In the absence of transfusion, severely anemic children should be observed, given the risk of decompensation in the event of cardiovascular challenge such as a febrile illness, and response to iron supplementation should be documented.