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Evaluation of pallor in children

Evaluation of pallor in children
Literature review current through: Jan 2024.
This topic last updated: Feb 20, 2023.

INTRODUCTION — This topic will review the differential diagnosis and approach to children with pallor.

The approach to the child with anemia is discussed separately. (See "Approach to the child with anemia".)

BACKGROUND — The development of pallor can be acute and associated with a life-threatening illness, or it can be chronic and subtle, occasionally first noted by someone who sees the child less often than the parents or caregivers. The onset of pallor can provoke anxiety for caregivers who are familiar with the descriptions of the presentation of leukemia in childhood. In some instances, only reassurance may be needed, as in the case of a light complexioned or fair-skinned, non-anemic child. In other instances, pallor may occur in patients with nonhematologic conditions such as shock, anaphylaxis, respiratory failure, or hypoglycemia. Even if there is a hematologic cause for the pallor, it often is a temporary condition readily amenable to therapy. However, pallor can portend a serious disease, and when onset is acute, it can herald a true pediatric emergency for which rapid diagnosis and treatment are needed.

CAUSES — Any condition that decreases the concentration of hemoglobin or alters the distribution of blood away from the body's surface may present as pallor (table 1). Clinically, pallor caused by anemia usually can be appreciated when the hemoglobin concentration is below 8 to 9 g/dL (4.96 to 5.56 mmol/L), although the complexion of the child and the rapidity of onset may influence this value.

The concentration of hemoglobin in the blood can be lowered by three basic mechanisms:

Decreased erythrocyte production

Increased erythrocyte destruction

Blood loss

Anemias may also be classified by the size of the red blood cell: microcytic, normocytic, or macrocytic. The most common causes of anemia seen in the emergency department (ED) are iron deficiency, infection, and blood loss, but several less common diseases remain important considerations.

Nonhematologic causes of pallor include complexion ("fair skin"), hypoperfusion from shock, respiratory distress, hypoglycemia, skin edema, and pheochromocytoma.

Life-threatening causes — The conditions that are life-threatening and cause pallor can be divided into nonhematologic and hematologic causes (table 1).

Nonhematologic — Pallor may be associated with respiratory failure, poor tissue perfusion (shock), and hypoglycemia. Etiologies for shock include sepsis, hypovolemia, traumatic brain or spinal cord injury, heart failure, arrhythmia, or anaphylaxis. These conditions require recognition and intervention prior to knowing the results of hematologic studies (algorithm 1).

Severe blood loss — Massive hemorrhage (eg, severe trauma) is accompanied by signs of hypovolemic shock and is considered an emergency. Rapid fluid resuscitation is required to reverse the hemodynamic abnormalities. The initial hemoglobin and indices are typically normal due to lack of equilibration. (See "Hypovolemic shock in children in resource-abundant settings: Initial evaluation and management".)

Autoimmune hemolytic anemia — Pallor caused by autoimmune hemolytic anemia (AIHA) is usually acute in onset and may be associated with severe anemia. On physical examination, the child with AIHA often will be pale and jaundiced. Tachycardia is typically present, as is a systolic flow murmur, reflecting a high-output anemic state. However, cardiovascular compromise (eg, congestive failure) is uncommon unless the hemoglobin concentration is <5 g/dL (3.10 mmol/L). The liver and spleen may be palpable, but the presence of massive organomegaly or lymph node enlargement should suggest another disorder such as malignancy (eg, leukemia, lymphoma) or infection (eg, HIV, malaria, tuberculosis).

The presence of only a moderate anemia (6 to 8 g/dL [3.72 to 4.96 mmol/L]) at diagnosis should not detract from consideration of this disease as a hematologic emergency because brisk hemolysis may result in a sudden, additional fall in the hemoglobin level that could be life-threatening. It is usually characterized by a positive direct anti-globulin test (DAT or direct Coomb test) and an increased reticulocyte count. Spherocytes are commonly seen in the peripheral smear (picture 1). (See "Autoimmune hemolytic anemia (AIHA) in children: Classification, clinical features, and diagnosis", section on 'Clinical presentation'.)

The etiology and treatment of AIHA in children is discussed separately. (See "Overview of hemolytic anemias in children" and "Autoimmune hemolytic anemia (AIHA) in children: Treatment and outcome".)

Sickle cell disease with splenic sequestration — The sequestration episodes of sickle cell disease (SCD) and related hemoglobin disorders (SC disease, S-beta (0) thalassemia, S-beta (+) thalassemia) result from acute pooling of red cells and plasma in the spleen.

The sudden and severe anemia and the hypovolemia associated with this complication constitute a true hematologic emergency and, if untreated, may rapidly lead to death. The presence of increased pallor and acute enlargement of the spleen in a patient with SCD should prompt immediate investigation of a possible sequestration crisis.

Although this complication rarely occurs in children with homozygous sickle cell disease (SS) or S-beta (0) thalassemia after the age of five years, sequestration crises may occur much later in children with milder forms of SCD such as SC or S-beta (+) thalassemia, in which early splenic infarction is uncommon. Additionally, patients with SS or S-beta (0) thalassemia started on disease modifying therapy at a young age (ie, hydroxyurea or chronic red cell transfusions) could have persistence of splenic tissue and remain at risk for splenic sequestration after the age of five years. (See "Overview of the clinical manifestations of sickle cell disease", section on 'Splenic sequestration crisis'.)

Hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP) — The red blood cell destruction in both of these processes is secondary to fibrin deposition resulting in microangiopathic hemolysis with schistocytes, helmet cells, and RBC fragments on the peripheral blood smear (picture 2 and picture 3). Thrombocytopenia and uremia may lower the hemoglobin concentration even further by causing bleeding, impaired red cell production, shortened red cell survival, and increased plasma volume. In some instances, the anemia may be moderately severe when the uremia is only mild and thrombocytopenia is absent, leaving doubt about the correct diagnosis. In more typical cases, however, the diagnosis is readily apparent from the findings of oliguria, central nervous system (CNS) abnormalities, increased blood urea nitrogen (BUN), and thrombocytopenia. (See "Clinical manifestations and diagnosis of Shiga toxin-producing Escherichia coli (STEC) hemolytic uremic syndrome in children", section on 'Typical course' and "Diagnosis of immune TTP".)

Disseminated intravascular coagulation (DIC) — In DIC, abnormal fibrin deposition within small blood vessels results in mechanical injury to the erythrocytes. Thrombocytopenia and clotting abnormalities, which often herald the onset of DIC, also may contribute to the anemia by causing diffuse bleeding. The main diagnostic findings are red cell fragments in the peripheral blood smear (picture 2 and picture 3), platelet and clotting abnormalities typical of a consumptive coagulopathy, and the clinical features of a disease such as septic shock, which is associated with DIC. (See "Disseminated intravascular coagulation in infants and children", section on 'Clinical manifestations' and "Disseminated intravascular coagulation in infants and children", section on 'Laboratory findings'.)

Malignancy — Hypoplastic anemia can be the presenting symptom of childhood malignancies. The pallor can be severe, and although all three cell lines of the bone marrow usually are affected, anemia may be the only notable hematologic abnormality. The diagnosis can be suspected from the presence of other symptoms or findings such as lymphadenopathy, bruising, limb pain, gum bleeding, or an abdominal mass. Malignancies that can present with anemia include leukemias, lymphomas, and other solid tumors that infiltrate the bone marrow (eg, neuroblastoma). (See "Overview of the clinical presentation and diagnosis of acute lymphoblastic leukemia/lymphoma in children" and "Clinical presentation, diagnosis, and staging evaluation of neuroblastoma", section on 'Presenting symptoms'.)

Common hematologic conditions — The common hematologic conditions that result in pallor can be divided into decreased RBC production, increased RBC destruction, and blood loss (table 1).

Decreased RBC production

Iron deficiency anemia – Anemia from iron deficiency is usually seen in the first two years of life, at which time the dietary iron content is often insufficient to meet the demands of the rapidly increasing red cell mass. It is the most common hematologic disorder in childhood, affecting approximately 5 to 10 percent of young children. The typical presentation of iron deficiency anemia (IDA) is an otherwise asymptomatic, well-nourished infant or child who has a mild to moderate microcytic, hypochromic anemia (picture 4). Much less frequent are infants with severe anemia, who present with lethargy, pallor, irritability, cardiomegaly, poor feeding, and tachypnea. (See "Iron deficiency in infants and children <12 years: Screening, prevention, clinical manifestations, and diagnosis", section on 'Clinical manifestations of iron deficiency anemia'.)

For infants presenting with a mild microcytic anemia and a presumptive diagnosis of IDA, a therapeutic trial of iron is the most cost-effective strategy. In children older than two years of age, dietary causes of iron deficiency are less likely, and other causes of anemia (eg, chronic blood loss, chronic disease, celiac disease) need to be considered. (See "Iron deficiency in infants and children <12 years: Screening, prevention, clinical manifestations, and diagnosis", section on 'Evaluation for suspected iron deficiency anemia'.)

Aplastic episodes in patients with a hemolytic anemia – Patients with inherited hemolytic anemias such as spherocytosis or SCD may develop red cell aplasia, usually in association with parvovirus B19 infection. Decreased red cell production in the face of ongoing hemolysis causes an exacerbation of the anemia. The usually elevated reticulocyte count falls to inappropriately low levels, often less than 1 percent. Although the platelets and white cells are generally unaffected, they may be mildly decreased. Red cell transfusions are appropriate if the anemia is associated with cardiovascular signs or symptoms or if continuing reticulocytopenia indicates that the anemia is likely to become severe before the usual spontaneous recovery after three to seven days. (See "Clinical manifestations and diagnosis of parvovirus B19 infection", section on 'Transient aplastic crisis'.)

Transient aplastic episodes in patients with immunocompromise and parvovirus infection – Patients with an immunodeficiency from either a congenital immune disorder or acquired immune dysfunction in the setting of chemotherapy for malignancy, immunosuppression post-transplant or HIV infection can experience a parvovirus B19 related aplastic episode from an inability to clear the parvovirus infection with resultant persistent reticulocytopenia. (See "Clinical manifestations and diagnosis of parvovirus B19 infection", section on 'Transient aplastic crisis'.)

Lead poisoning – Lead poisoning reduces heme synthesis, but significant anemia is unusual unless blood lead levels are markedly elevated. Iron deficiency is common in children with increased lead levels and usually accounts for the microcytic anemia found in these patients. If a concomitant hematologic disorder cannot be found in the anemic patient with plumbism, particular care should be given to the possibility of severe lead intoxication. (See "Childhood lead poisoning: Clinical manifestations and diagnosis", section on 'Hematologic'.)

Anemia of inflammation – Occasionally, pallor is the only presenting finding of a serious systemic inflammatory disorder. Chronic inflammatory diseases are often accompanied by a normocytic or microcytic anemia that is multifactorial related to abnormal iron homeostasis, impaired erythropoiesis, and a blunted erythropoietin response (see "Anemia of chronic disease/anemia of inflammation", section on 'Differential diagnosis').

Inflammation increases hepcidin production, which is a negative regulator of iron, decreasing iron absorption in the gastrointestinal (GI) tract; as well as sequestration of macrophage iron, which results in iron restricted erythropoiesis. Laboratory results in anemia of inflammation demonstrate a reduced serum iron and low total iron-binding capacity with a normal to high ferritin. (See "Anemia of chronic disease/anemia of inflammation", section on 'Iron studies'.)

Increased RBC destruction

Sickle cell syndromes – Patients with sickle cell disease have a baseline hemolytic anemia and pallor. Acute accentuation of the pallor can result from an aplastic crisis, increased hemolysis, or acute pooling of red cells in the spleen. (See 'Sickle cell disease with splenic sequestration' above and 'Decreased RBC production' above.)

Hereditary spherocytosis – Patients with hereditary spherocytosis, the most common of the red cell membrane disorders, typically present with anemia, jaundice, and splenomegaly. Hemolysis can be worsened in the setting of an acute febrile illness. However, the degree of anemia is extremely variable and may be absent, mild, moderate, or severe to the point of threatening life.

Because hereditary spherocytosis often is inherited in an autosomal dominant fashion, a family history of anemia, splenomegaly, splenectomy, or cholecystectomy may be helpful. However, a particularly severe form of spherocytosis occurs as an autosomal recessive disorder, and some children with more typical disease lack an informative family history. Consequently, the diagnosis should not be dismissed in the absence of other affected family members, in that only 75 percent will have a family history. The red cell morphology often permits the diagnosis of spherocytosis to be made from the peripheral smear (picture 1). (See "Hereditary spherocytosis", section on 'Clinical presentation'.)

Chronic blood loss — Although sudden, massive hemorrhage usually is accompanied by signs of hypovolemic shock, the repeated loss of smaller amounts of blood may be associated with few findings other than pallor. The finding of iron deficiency anemia despite normal dietary iron intake or iron supplementation may be a clue to the presence of chronic blood loss from the GI tract (eg, Meckel diverticulum, peptic ulcer, variceal bleeding), heavy menstrual bleeding in females, or within the lungs (eg, pulmonary hemosiderosis).

Other conditions that cause pallor

Decreased red blood cell production

Acquired aplastic anemia – The clinical presentation of aplastic anemia (AA) is variable and includes symptoms and signs related to cytopenia in each of the three cell lineages including fatigue, pallor, and cardiovascular complaints caused by progressive anemia; hemorrhagic manifestations secondary to thrombocytopenia; and/or fever, mucosal ulcerations, and bacterial infections resulting from neutropenia. A diagnosis of AA is suggested by the presence of pancytopenia with absolute reticulocytopenia, suggestive of bone marrow failure. The condition is often idiopathic but has been associated with exposure to certain drugs and chemicals (chloramphenicol, benzene, pesticides), radiation, and viral infections (especially hepatitis). (See "Treatment of acquired aplastic anemia in children and adolescents".)

Transient erythroblastopenia of childhood (TEC) – TEC is a condition often associated with a recent viral illness, and it is characterized by moderate to severe anemia caused by diminished red cell production. The mean corpuscular volume (MCV) usually is normal at the time of diagnosis. The white cell count is normal or moderately decreased; the platelet count is normal. The reticulocyte count is decreased, and the direct antiglobulin test (direct Coomb test) is negative. Bone marrow examination shows reduction or absence of erythrocyte precursors initially, followed by erythroid hyperplasia during recovery. TEC that occurs in the first six months of life may be difficult to distinguish from Diamond-Blackfan anemia. Spontaneous recovery ultimately confirms the diagnosis of TEC. (See "Overview of causes of anemia in children due to decreased red blood cell production", section on 'Transient erythroblastopenia of childhood'.)

Folic acid and vitamin B12 deficiency or other associated abnormalities – These nutritional anemias are uncommon in children in the United States and rarely develop in the absence of a grossly altered diet, extended hyperalimentation, intestinal resection, celiac disease, or chronic diarrhea. Unusual alterations of B12 and folic acid absorption and metabolism may cause symptoms similar to those of the nutritional megaloblastic anemias. Megaloblastic anemia is rarely severe enough to be life-threatening. (See "Treatment of vitamin B12 and folate deficiencies".)

The condition is characterized by normochromic, macrocytic red blood cells, elevated red cell distribution width (RDW), hypersegmented neutrophils, and an elevated serum level of lactate dehydrogenase (LDH). Leukopenia and thrombocytopenia may be present, but a bone marrow aspirate demonstrates hypercellularity with megaloblastic changes. The diagnosis of folate deficiency is confirmed by the finding of low folate level and an elevated homocysteine. B12 deficiency is confirmed by a low serum vitamin B12 and/or an elevated serum homocysteine and methylmalonic acid. In addition, the diagnosis is confirmed with a response to vitamin B12 or folate replacement. (See "Treatment of vitamin B12 and folate deficiencies".)

Diamond-Blackfan syndrome – Diamond-Blackfan syndrome is congenital hypoplastic anemia commonly detected in the first few months of life. The anemia can be severe at the time of diagnosis. The red blood cells are normocytic or macrocytic. The reticulocyte count is low. The white blood cell count is low in 10 percent of affected patients, but thrombocytopenia only occurs rarely. The diagnosis is made by examination of a bone marrow aspirate that shows markedly reduced or absent erythrocyte precursors. (See "Overview of causes of anemia in children due to decreased red blood cell production", section on 'Diamond-Blackfan anemia'.)

Dyskeratosis congenita Dyskeratosis congenita is an inherited bone marrow failure syndrome secondary to accelerated telomere shortening. It is characterized by oral leukoplakia, hyper and hypopigmentation, and dystrophic nails. Patients are at risk for developing aplastic anemia, myelodysplastic syndrome or leukemia. (See "Dyskeratosis congenita and other telomere biology disorders".)

Fanconi anemia – Fanconi anemia is characterized by pancytopenia and associated abnormalities, including hyperpigmentation and hypopigmentation, microcephaly, strabismus, small stature, intellectual disability, and abnormalities of the thumbs and radii. Unlike Diamond-Blackfan, all three cell lines of the bone marrow are affected, and the hematologic abnormalities rarely develop before three to four years of age. The anemia is normochromic and macrocytic. (See "Clinical manifestations and diagnosis of Fanconi anemia".)

Sideroblastic anemia – Sideroblastic anemia is a disorder of hemoglobin synthesis resulting in hypoproductive state. This disorder is characterized by a microcytic, hypochromic anemia. Sideroblastic anemia may be inherited (sex-linked) or acquired. Iron use within the developing red cell is abnormal, accounting for the presence of diagnostic ringed sideroblasts in the bone marrow. The serum iron and ferritin levels usually are markedly elevated. (See "Sideroblastic anemias: Diagnosis and management".)

Thalassemia – The production of the globin portion of the hemoglobin molecule is reduced or absent resulting in a compensating increase of other globin chains and reduced or absent production of adult hemoglobin A. Beta-Thalassemia major (Cooley's anemia) presents with severe pallor usually between 6 and 12 months of age, as the fetal hemoglobin level declines but the normal rise in the adult hemoglobin (HbA) production fails to occur because of reduced or absent beta-globin production. Although beta-thalassemia is often associated with Mediterranean ancestry, this disease and related disorders (eg, E-beta thalassemia, HgH disease) also are seen commonly in Southeast Asian populations and children of Indian, Pakistani, and Chinese ancestry. The presence of hepatosplenomegaly and characteristic red cell morphology, including marked variation in red cell shape, makes this diagnosis readily apparent. (See "Diagnosis of thalassemia (adults and children)".)

Increased red blood cell destruction

Erythrocyte membrane defects – Elliptocytosis, stomatocytosis, and pyknocytosis describe other erythrocyte membrane defects that are less common than hereditary spherocytosis. Moderate or severe anemia is less common in these disorders. Elliptocytosis and stomatocytosis have characteristic findings on peripheral blood smear (picture 5 and picture 6). Infantile pyknocytosis is a hemolytic anemia seen during the first few months of life and is characterized by distorted and contracted erythrocytes and burr cells. The disorder may be associated with pallor and hyperbilirubinemia. Spontaneous recovery usually occurs by six months of age. (See "Hereditary elliptocytosis and related disorders".)

Erythrocyte enzyme defects – Erythrocyte enzyme defects such as pyruvate kinase deficiency and certain variants of glucose-6-phosphate dehydrogenase (G6PD), may be associated with pallor from increased red blood cell destruction. In G6PD deficiency, pallor may be accentuated by acute hemolytic crises after exposure to oxidant stress (eg, naphthalene-containing mothballs, drugs, acidosis). Although alterations in red cell morphology sometimes are found in these enzyme disorders, assays of specific enzymes or substrates are required for definitive diagnosis. (See "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency" and "Pyruvate kinase deficiency".)

Kasabach Merritt syndrome – The abnormal proliferation of blood vessels within vascular tumors (most commonly tufted angioma or hemangioendothelioma) may trap red cells or may initiate a localized consumptive coagulopathy, causing erythrocyte destruction. Anemia is rarely severe unless the thrombocytopenia, which is more typical of the disorder, causes blood loss. (See "Tufted angioma, kaposiform hemangioendothelioma (KHE), and Kasabach-Merritt phenomenon (KMP)".)

Chronic blood loss – Blood loss can occur in conjunction with autoimmune disorders including inflammatory bowel disease and anti-glomerular basement membrane disease (Goodpasture syndrome). Idiopathic pulmonary hemosiderosis results from slow but intractable hemorrhage into the bronchioles and alveoli resulting in iron deficiency anemia. (See "Idiopathic pulmonary hemosiderosis".)

EVALUATION

Stabilization — Initial assessment of a child with pallor should include an immediate determination of the degree of illness. The acute onset of pallor consistent with life-threatening hemorrhage or hemolysis requires emergency evaluation and treatment as described separately. (See "Hypovolemic shock in children in resource-abundant settings: Initial evaluation and management", section on 'Management' and "Autoimmune hemolytic anemia (AIHA) in children: Treatment and outcome", section on 'Severe or life-threatening anemia'.)

If the child with pallor is not acutely ill, a deliberate search for the cause of pallor should be undertaken.

History — Initial assessment of a child with pallor should include an immediate determination of the degree of illness. If the child with pallor is not acutely ill, a deliberate search for the cause of pallor should be undertaken. A thorough yet relevant history should be obtained with particular attention to the type of onset of pallor. The slow development of pallor, which may be noticed by a family member or friend who sees the child only occasionally, suggests diminished red cell production, as is found in iron deficiency or bone marrow aplasia.

However, the acute onset of pallor is consistent with the brisk hemolysis found in autoimmune hemolytic anemia and often is accompanied by jaundice, dark urine, and cardiovascular changes.

After establishing the type of onset of anemia, the history can be directed toward more narrow categories of anemia or specific diseases (table 2). A detailed dietary history, with particular attention to milk intake, is important in young children with suspected iron deficiency. Vitamin B12 deficiency may accompany strict vegetarian diets from which meat and egg products are excluded for many years and may occur in breast fed infants of vegetarian mothers or mothers with pernicious anemia. Sources of internal or external blood loss should be carefully sought. Chronic gastrointestinal (GI) bleeding may escape detection until iron deficiency anemia develops.

Similarly, small pulmonary hemorrhages associated with idiopathic pulmonary hemosiderosis are often mistaken for other pulmonic processes until several recurrences of iron deficiency anemia suggest a hidden site of blood loss. If increased bruising or bleeding accompanies pallor, multiple blood elements are probably affected. The circulation time for platelets is short in comparison with that of red cells. Clinical findings of thrombocytopenia often are present by the time pallor develops in patients with acquired aplastic anemia, Fanconi anemia, and acute leukemia.

The family history helps in the diagnosis of hemoglobinopathies and inherited disorders of red cell membranes and enzymes. Because results of previous hemoglobin testing may have been explained inadequately or recalled inaccurately, a negative family history or newborn screening for hemoglobinopathies should not preclude evaluation of the patient's hemoglobin phenotype if a sickling disorder is suspected. A history of splenomegaly, splenectomy, or early cholecystectomy in family members may help identify a hemolytic disorder such as hereditary spherocytosis or pyruvate kinase deficiency. Finally, a well-directed review of systems is essential in looking for systemic disorders such as chronic renal disease, hypothyroidism, or rheumatologic disorders.

Physical examination — In the examination of the severely anemic patient, pallor of the skin and mucous membranes usually is readily apparent. When anemia is less severe or when the skin color is dark, pallor may be appreciated only in the nailbeds and palpebral conjunctivae.

Vital signs – Blood pressure and pulse should be measured to be sure that hypovolemic shock and high output cardiac failure are neither present nor imminent. If anemia or volume loss is mild to moderate, tachycardia may be present, but normal blood pressure is preserved.

Eyes – Scleral icterus suggests shortened red cell survival with hemolysis. Conjunctival pallor, although insensitive, is often noted when the hemoglobin falls below 10 grams/dL (6.21 mmol/L).

Cardiac – A systolic flow murmur is often heard when the hemoglobin level falls below 8 to 9 grams/dL (4.96 to 5.56 mmol/L).

Lymph nodes and abdomen – Lymphadenopathy and splenomegaly may suggest a malignancy or an infectious disease such as mononucleosis. When splenomegaly occurs without lymphadenopathy, however, attention is drawn to hemolytic disorders such as hereditary spherocytosis and autoimmune hemolytic anemia or hemoglobinopathies.

Careful auscultation of the abdomen may detect hemangiomas of the viscera. The finding of an unusually large and firm spleen in the absence of increasing scleral icterus suggests that red cells are being sequestered.

Skin – Lack of red color in the palmar creases is associated with a hemoglobin that is less than 7 grams/dL (4.34 mmol/L). The presence of large hemangiomas suggests microangiopathic anemia.

Musculoskeletal – Bony abnormalities associated with red cell disorders include frontal bossing from compensatory expansion of the bone marrow in hemolytic disease and radial and thumb anomalies found in some patients with Fanconi anemia.

Laboratory studies — A complete blood cell count (CBC) with differential and a reticulocyte count is the first step in determining if pallor is due to a hematologic abnormality and, in the anemic patient, the likely cause. The use of hemoglobin, hematocrit, mean corpuscular volume, and reticulocyte count in the evaluation of pallor in a child is presented here. Additional discussion of other indices (eg, red cell distribution width [RDW], mean corpuscular hemoglobin concentration, and peripheral smear) is presented separately. (See "Approach to the child with anemia", section on 'Laboratory evaluation'.)

Hemoglobin and hematocrit — Anemia may be defined as a reduction in red blood cell mass or blood hemoglobin concentration below the standard for age (table 3). In practice, anemia most commonly is defined by reductions in one or both of the following (see "Approach to the child with anemia", section on 'Definition of anemia'):

Hemoglobin – This is a measure of the concentration of the red blood cell (RBC) pigment hemoglobin in whole blood, expressed as grams per 100 mL (dL) of whole blood (or mmol/L). The normal value for HGB in a child aged 6 to 12 years is approximately 13.5 g/dL (8.38 mmol/L).

Hematocrit – The hematocrit is the fractional volume of a whole blood sample occupied by red blood cells; it is expressed as a percentage. As an example, the normal HCT in a child aged 6 to 12 years is approximately 40 percent (0.4 fraction).

Mean corpuscular volume — The mean corpuscular volume (MCV) is measured directly by automated blood cell counters and represents the mean value (in femtoliters, fL) of the volume of individual RBCs in the blood sample. Values may be low (microcytic), normal (normocytic), or large (macrocytic).

The MCV provides a quick, accurate, and readily available method of distinguishing the microcytic anemias (iron deficiency, thalassemia syndromes) from the normocytic (membrane disorders, enzyme deficiencies, autoimmune hemolytic anemia, most hemoglobinopathies) or macrocytic (bone marrow/stem cell failure, disorders of B12 and folic acid absorption or metabolism) anemias.

As with hemoglobin and hematocrit, the MCV varies with age, necessitating the use of age-adjusted normal values (table 3). In addition, the measured MCV represents an average value. If microcytic and macrocytic red cells are present in the peripheral blood as, for example, in a patient with combined iron deficiency and B12 deficiency, the MCV may remain normal. Thus, the peripheral smear should be examined carefully to determine whether the MCV reflects a single population of red cells of uniform size or two or more populations of distinctly different size. The red cell distribution width (RDW) is elevated in the presence of increased variation in red cell size. (See "Approach to the child with anemia", section on 'Red blood cell indices'.)

Reticulocyte count — Reticulocytes are the youngest red cells in the circulation, and are identified via the presence of residual RNA, which gives them a blue tint on standard Wright-Giemsa stains (picture 7). They are quantitated via staining with vital dyes, such as new methylene blue or thiazole orange, and are reported as a percentage. The reticulocyte count can be performed rapidly and helps to distinguish the various causes of impaired red cell production on the basis of decreased reticulocyte count versus increased reticulocyte count.

Correction — Because the reticulocyte count is expressed as a percent of total red cells, it must be corrected for the degree of the anemia. The easiest way to make this correction is to multiply the reticulocyte count by the reported hemoglobin or hematocrit (HCT) divided by a normal hemoglobin or hematocrit:

Reticulocyte count x HCT(pt)/HCT(nL)

As an example, a reticulocyte count of 5 percent in a child with severe iron deficiency anemia and a hematocrit of 6 percent is not elevated when corrected for the degree of anemia (5 percent x 6 percent/33 percent = 0.9 percent).

Interpretation — Once anemia is identified, the reticulocyte count and MCV help in the initial classification of anemia but leave the clinician with broad categories of disease, rather than specific diagnoses. In many instances, the history and physical examination, when coupled with these laboratory measurements, permit identification of a particular disorder (table 4 and algorithm 2).

In addition, the reticulocyte count should be interpreted with caution. Disorders of shortened red cell survival are not always characterized by an increased reticulocyte count. As an example, reticulocytopenia may occur in an autoimmune hemolytic anemia despite active hemolysis and increased erythropoiesis in the bone marrow. Chronic hemolytic disorders, such as sickle cell anemia or hereditary spherocytosis, may first be detected during an aplastic crisis when the reticulocyte count is low. Unless the underlying disorder is recognized, the clinician may be misled by this finding.

APPROACH — The initial approach to a patient with pallor includes determining if the patient is seriously ill and requires immediate supportive measures (algorithm 3). Afterward, the history should be taken to determine if the pallor was acute or insidious in onset. A complete blood count with differential, mean corpuscular volume (MCV), and reticulocyte count will help further delineate the cause of the anemia:

Increased reticulocytes and low MCV — The thalassemia syndromes associated with moderate or severe anemia can be recognized by distinctive abnormalities of red cell morphology. In beta-thalassemia major, the red cells generally are small but vary markedly in size and shape. Many cells appear to contain little or no hemoglobin; the central pallor extends to the cell membrane. Nucleated red cells, basophilic stippling, and polychromasia reflect active erythropoiesis. The parents of an affected child usually have a low MCV characteristic of thalassemia trait. (See "Diagnosis of thalassemia (adults and children)".)

Children with HbS-beta-thalassemia have microcytic red cells, although the alterations of red cell morphology are not as dramatic as in beta-thalassemia major. Sickled forms are often but not always present. Target cells are common. Hemoglobin electrophoresis reveals HbS and reduced (less than 50 percent) or absent HbA.

Increased reticulocytes and normal MCV — Most membrane disorders can be readily identified by the characteristic changes in the red cell shape that lend their names to the diseases (eg, spherocytosis, elliptocytosis, and stomatocytosis). When the diagnosis of a membrane disorder is uncertain, examination of the biologic parents' peripheral smears may be helpful because, in many cases, the inheritance pattern is autosomal dominant. (See "Hereditary spherocytosis", section on 'Clinical presentation' and "Hereditary elliptocytosis and related disorders".)

Abnormalities of red cell morphology are less striking in erythrocyte enzymatic defects. Blister cells (cells with asymmetric distribution of hemoglobin) may be found during episodes of active hemolysis in G6PD deficiency. If transfusion is necessary, a pretransfusion sample should be saved for assay of specific enzymes. (See "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency".)

The reticulocyte count usually is markedly elevated in autoimmune hemolytic anemia, but it may be normal or only slightly elevated during the first days of the disease. In rare instances, reticulocytopenia persists. Spherocytes usually are present on the peripheral smear. Clumping of red cells from agglutination may be seen. This agglutination causes a falsely elevated MCV because the electronic counter measures the volume of the red cell couplets or triplets. The direct Coombs test is positive in 90 percent of cases. Patients with a negative Coombs test present a challenging diagnostic problem because the initial findings may be similar to those in hereditary spherocytosis. (See "Autoimmune hemolytic anemia (AIHA) in children: Classification, clinical features, and diagnosis", section on 'Clinical presentation'.)

Homozygous sickle cell disease (SCD) usually is recognized by the finding of sickled red cells on the peripheral smear. Rarely, however, such cells are absent, even during an acute illness. Target cells are commonly found in SCD but are more prominent in HbSC. Hemoglobin electrophoresis reveals the presence of the abnormal hemoglobin(s) and the absence of HgA. The broad application of newborn screening allows for identification of most affected children prior to the onset of clinical signs and symptoms or RBC morphological abnormalities. (See "Diagnosis of sickle cell disorders".)

Red cell fragments are found in those diseases characterized by microangiopathic hemolytic anemia. In HUS or TTP, thrombocytopenia is present, renal or neurologic function is usually impaired, and thrombotic complications may be present. The platelet count also is low in DIC, and clotting studies are abnormal. If intravascular hemolysis is severe, as in anemia associated with certain artificial cardiac valves, hemosiderin may be detected in the urinary sediment. (See "Clinical manifestations and diagnosis of Shiga toxin-producing Escherichia coli (STEC) hemolytic uremic syndrome in children", section on 'Typical course' and "Diagnosis of immune TTP" and "Disseminated intravascular coagulation in infants and children", section on 'Clinical manifestations' and "Disseminated intravascular coagulation in infants and children", section on 'Laboratory findings'.)

Low, normal, or slightly increased reticulocytes and low MCV — In severe iron deficiency anemia, red cells are markedly microcytic and show substantial variation in size and shape. Elongated red cells (pencil forms) are common. Platelets are often increased. (See "Iron deficiency in infants and children <12 years: Screening, prevention, clinical manifestations, and diagnosis", section on 'Clinical manifestations of iron deficiency anemia'.)

Anemia is uncommon in lead poisoning but, when present, resembles the anemia of iron deficiency in its red cell morphology. Basophilic stippling is found in a small percentage of cases. (See "Childhood lead poisoning: Clinical manifestations and diagnosis", section on 'Hematologic'.)

Low, normal, or slightly increased reticulocytes and normal or elevated MCV — With the exception of mild macrocytosis, red cell morphology usually is normal in childhood disorders of bone marrow or stem cell failure. Thrombocytopenia and neutropenia are present in aplastic anemia and Fanconi anemia. Although the platelet and white count are occasionally low in patients with Diamond-Blackfan syndrome, the red cells are most severely affected. Erythropoiesis is most severely affected in TEC and acquired red cell aplasia, although neutropenia may accompany the former disorder. (See "Overview of causes of anemia in children due to decreased red blood cell production" and "Aplastic anemia: Pathogenesis, clinical manifestations, and diagnosis".)

The clinical features at the onset of acute leukemia may closely resemble those of aplastic anemia. Examination of a bone marrow aspirate is required to distinguish these disorders. This procedure is rarely performed in the emergency department. Therapy, such as corticosteroids, which might interfere in the interpretation of the bone marrow aspirate, should be withheld until a definitive diagnosis has been made. (See "Overview of the clinical presentation and diagnosis of acute lymphoblastic leukemia/lymphoma in children".)

The MCV is usually increased in megaloblastic anemias unless other nutritional disorders are present. Hypersegmentation of the polymorphonuclear leukocytes is characteristic. In severe or long-standing megaloblastic anemia, neutropenia and thrombocytopenia also may be found. In such cases, the findings in the peripheral blood may be similar to those of aplastic anemia or even acute leukemia; examination of the bone marrow and measurement of specific nutrients (B12, folic acid) are necessary to distinguish these disorders. (See "Treatment of vitamin B12 and folate deficiencies".)

SUMMARY AND RECOMMENDATIONS

Causes and clinical recognition – Any condition that decreases the concentration of hemoglobin or alters the distribution of blood away from the body's surface may present as pallor (table 1). Clinically, pallor caused by anemia usually can be appreciated when the hemoglobin concentration is below 8 to 9 g/dL (4.96 to 5.56 mmol/L). (See 'Causes' above and 'Physical examination' above.)

Stabilization – The first priority in evaluating children with pallor is to determine if the patient is seriously ill (eg, life-threatening blood loss or hemolytic anemia) and requires immediate supportive measures (algorithm 3). (See "Hypovolemic shock in children in resource-abundant settings: Initial evaluation and management", section on 'Management' and "Autoimmune hemolytic anemia (AIHA) in children: Treatment and outcome", section on 'Severe or life-threatening anemia'.)

Diagnostic approach – In stable children, a thorough history, physical exam, and simple laboratory studies (complete blood count with peripheral smear, mean corpuscular volume, reticulocyte count, peripheral blood smear) usually identifies the underlying etiology (algorithm 3 and table 1 and algorithm 2). (See 'History' above and 'Physical examination' above and 'Laboratory studies' above.)

Topic 6447 Version 22.0

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